US20170065653A1 - Phosphodiesterase Inhibiting Phytochemical Compositions

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Abstract

Description

Claims

US20170065653A1

Publication number: US20170065653A1
Application number: US15/122,391
Authority: US
Inventors: Matthew L. Tripp; Clinton J. Dahlberg; John G. Babish
Original assignee: Natures Sunshine Products Inc
Current assignee: Natures Sunshine Products Inc
Priority date: 2014-02-28
Filing date: 2015-02-26
Publication date: 2017-03-09
Also published as: CA2941096C; CA2941096A1; WO2015130995A1; US10179155B2; US20170065652A1; WO2015130994A1; CA2941099A1

Phosphodiesterase (PDE) such as phosphodiesterase type V (PDE5) inhibiting compositions comprising a Sceletium extract are disclosed and described. Methods and systems for inhibiting PDE, as well as, dosage forms comprising a Sceletium extract are also disclosed. Additionally disclosed are methods for enhancing the potency or PDE inhibitory activity of a Sceletium extract by addition of an activity enhancer.

PRIORITY DATA

This application claims priority benefit to U.S. Provisional Patent Application Ser. No. 61/966,704 filed on Feb. 28, 2014 which is incorporated herein by reference. This application also incorporates by reference Patent Cooperation Treaty application serial no. PCT/US2015/017857 filed on Feb. 26, 2015 under Thorpe North & Western attorney docket no. 3901-002.PCT.

BACKGROUND

Phosphodiesterase type 5 (PDE5) is an enzyme that degrades the phosphodiester bond in the second messenger molecules of cellular cyclic guanosine monophosphate (cGMP), thereby regulating the localization, duration, and amplitude of cGMP signaling. cGMP is a regulator of ion channel conductance, glycogenolysis, and cellular apoptosis and relaxes smooth muscle tissues. cGMP functions in several biochemical processes. The specific effect of cGMP depends on the protein kinase acted upon and the cell type. Sustaining cellular cGMP levels can inhibit numerous diseases and conditions. PDE5 inhibitors block the PDE5 induced degradation of cGMP thereby sustaining cellular cGMP levels and prolonging the effects of cGMP mediated physiological processes. Accordingly, PDE5 inhibitors can be valuable agents in treating or managing a number of diseases or conditions.
Consumers continue to demand pharmaceuticals and nutraceuticals that include naturally derived active ingredients. Accordingly, the present inventors recognize a need for naturally derived PDE5 inhibitors which attain a desired level of PDE5 inhibition with little to no adverse side effects.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a schematic diagram of endothelial molecular pathways that control NO activity, smooth muscle relaxation, and site of action of PDE5 inhibitors in erectile dysfunction;

FIG. 2 shows a cGMP-mediated cell signalling;

FIG. 3 shows roles of brain insulin deficiency and brain insulin resistance in Tau pathology;

FIG. 4 shows a schematic of the role of GSK3 activation by brain insulin resistance and its role in the development of Tau pathology;

FIG. 5 shows GH/IGF-1 Axis and targets;

FIG. 6 shows IGF-1 receptor pathway.

DETAILED DESCRIPTION

Reference will now be made to exemplary invention embodiments and specific language will be used herein to describe the same. It will nevertheless be understood that no limitation in scope is thereby intended. Alterations and further modifications of inventive features described herein, and additional applications of inventive principles which would occur to one skilled in the relevant art having possession of this disclosure, are to be considered as inventive subject matter. Further, before particular embodiments are disclosed and described, it is to be understood that this disclosure is not limited to the particular process and materials disclosed herein as such may vary to some degree. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.
It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an extract” includes one or more of such extracts.
As used herein, the term “about” refers to a degree of deviation based on experimental error typical for the particular property identified. The latitude provided the term “about” will depend on the specific context and particular property and can be readily discerned by those skilled in the art. When used in connection with a numerical value, the term “about” is used to provide flexibility and allow the given value to be “a little above” or “a little below” the specific number stated. Further, unless otherwise stated, the term “about” shall expressly include “exactly,” consistent with the discussion below regarding ranges and numerical data.
As used herein, a “subject” refers to an organism that produces PDE5 in the course of its cellular function. In one aspect, a subject can be a mammal. In another aspect, a subject can be a human. In another aspect, the subject can be of either male or female gender.
As used herein, “activity enhancer” refers to any agent or combination of agents that increases PDE inhibition when combined with Sceletium, or a sceletium extract as compared to the Sceletium or sceletium extract alone. In some embodiments, the amount of increase can exceed the additive effect that would be achieved by the Sceletium or sceletium extract and the activity enhancer individually. This synergistic (i.e. more than additive) effect can occur when both the Sceletium or sceletium extract and the activity enhancer have PDE5 inhibitory activity, or when only the Sceletium or sceletium extract has PDE5 inhibitory activity. For example if F1 produces response X, F2 produces response Y, then the combination of F+F2>X+Y. In some situations F2 produces no response and the value for Y is equal to zero.
As used herein, “compounds” may be identified either by their chemical structure, chemical name, or common name. When the chemical structure, chemical name, or common name conflict, the chemical structure is determinative of the identity of the compound. The compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures encompass all possible tautomeric forms of the illustrated or identified compounds. The compounds described also encompass isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. Also contemplated are congeners, analogs, hydrolysis products, metabolites and precursor or prodrugs of the compound. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure.
In this disclosure, “comprises,” “comprising,” “comprised,” “containing” and “having” and the like can have the meaning ascribed to them in U.S. Patent law and can mean “includes,” “including,” and the like, and are generally interpreted to be open ended terms. The term “consisting of” is a closed term, and includes only the methods, compositions, components, systems, steps, or the like specifically listed, and that which is in accordance with U.S. Patent law. “Consisting essentially of” or “consists essentially” or the like, when applied to devices, methods, compositions, components, structures, steps, or the like encompassed by the present disclosure, refer to elements like those disclosed herein, but which may contain additional structural groups, composition components, method steps, etc. Such additional devices, methods, compositions, components, structures, steps, or the like, etc., however, do not materially affect the basic and novel characteristic(s) of the devices, compositions, methods, etc., compared to those of the corresponding devices, compositions, methods, etc., disclosed herein. In further detail, “consisting essentially of” or “consists essentially” or the like, when applied to the methods, compositions, components, systems, steps, or the like encompassed by the present disclosure have the meaning ascribed in U.S. Patent law and is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments. In this specification when using an open ended term, like “comprising” or “including,” it is understood that direct support should be afforded also to “consisting essentially of” language as well as “consisting of” language as if stated explicitly and vice versa. Each term provides support for the others as if expressly stated.
As used herein, “formulation” and “composition” can be used interchangeably and refer to an active agent or ingredient in a form suitable for administered to a subject. In some embodiments, one or more additional active agents or inactive ingredients (i.e. which do not exert an appreciable physiologic effect on a subject) may be added and be part of the formulations.
As used herein, “active agent” refers to a molecule, compound, mixture, or ingredient that has a measurable physiologic effect on a subject when administered thereto in an appreciable amount, such as an effective, or therapeutically effective amount. Like terms such as “active fraction,” “active component,” and “active constituent” can be used interchangeable therewith.
Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “about 0.01 mg to 2.0 mg” should be interpreted to include not only the explicitly recited values of about 0.01 mg to about 2.0 mg, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 0.5 mg, 0.7 mg, and 1.5 mg, and sub-ranges such as from 0.5 mg to 1.7 mg, from 0.7 mg to 1.5 mg, and from 1.0 mg to 1.5 mg, etc. This same principle applies to ranges reciting only one numerical value. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.
As used herein, a “derivative” is a compound obtained from a source compound an analog, homolog tautomeric form, stereoisomer, polymorph, hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, by a simple chemical process converting one or more functional groups, by means of oxidation, hydrogenation, alkylation, esterification, halogenation and the like. The term “analog” refers to a compound having a structure similar to that of another one, but differing from it with respect to a certain component. The compound may differ in one or more atoms, functional groups, or substructures, which may be replaced with other atoms, groups, or substructures. In one aspect, such structures possess at least the same or a similar therapeutic efficacy for a given indication. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. The term “stereoisomer” refers to one of a set of isomers whose molecules have the same number and kind of atoms bonded to each other, but which differ in the way these atoms are arranged in space. The term “polymorph” refers to crystallographically distinct forms of a substance. In addition, an agent can be said to be “derived” from a source containing many compounds or agents, such as a plant, fungus, bacteria, or other organism. In this context, the agent can be described or otherwise referred to in terms of its source, rather than by its own properties, characteristics, name, or attributes per se. For example, an extract obtained from a plant may be described as “derived” from the plant.
The phrase “effective amount,” “therapeutically effective amount.” or “therapeutically effective rate(s)” of an active ingredient refers to a non-toxic, but sufficient amount or delivery rates of the active ingredient, to achieve therapeutic results in treating a disease or condition for which the drug is being delivered. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an “effective amount,” “therapeutically effective amount,” or “therapeutically effective rate(s)” may be dependent in some instances on such biological factors. Further, while the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a subjective decision. The determination of a therapeutically effective amount or delivery rate is well within the ordinary skill in the art of pharmaceutical sciences and medicine.
The term “extract” includes any parts of, or a material derived from, the raw material of a particular source. Extracts may take many forms including but not limited to: solid, liquid, particulate, chopped, distillate, etc. and may be performed by any number of procedures or protocols, such as chopping, grinding, pulverizing, boiling, steaming, soaking, steeping, applying a gas, etc., and may employ any suitable reagents, such as water, alcohol, steam, or other organic materials. A wide number of extraction methods and techniques are known to those of ordinary skill in the art. In some embodiments, extracts can be made from specific parts of a source, such as the aerial parts of a plant, the roots of a plant, the mycelium of a fungus, etc. In some aspects and extract may include one or more active fractions or active agents.
As used herein, a “liquid extract” refers to those substances prepared using a solvent, e.g., ethanol, water, steam, superheated water, methanol, hexane, chloroform liquid, liquid CO₂, liquid N₂, propane, supercritical CO₂or any combination thereof. Liquid extracts, as used herein, can refer to a dried powder or other solid form derived from a source using a liquid extract as a step in the overall extraction protocol. Liquid extracts typically have a given purity percentage and can be relatively to highly pure. In some aspects, the purity of an extract can be controlled by, or be a function of the extraction process or protocol.
As used herein “PDE5-associated pathologies,” “PDE5 related conditions,” “PDE5 related diseases,” and the like are used interchangeably and refer to diseases or conditions related to or caused by the degradation of cellular cGMP by PED5. A number of exemplary PDE5 related conditions are enumerated herein.
As used herein, “oxidative stress” refers to an imbalance between the manifestation of reactive oxygen species (ROS) and a biological system's ability to readily detoxify the reactive intermediates. ROS result in the formation of free radicals. Free radicals (e.g. hydroxyl, nitric acid, superoxide) or the non-radicals (e.g. hydrogen peroxide, lipid peroxide) damage (called oxidative damage) specific molecules with consequential injury to cells or tissue. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. While short term oxidative stress can be beneficial; over time oxidative stress can be involved in the etiology of many diseases, such as atherosclerosis, type 1, type 2, and type 3 diabetes, Parkinson's disease, cardiac arrest, myocardial infarction, Alzheimer's disease, Fragile X syndrome, and chronic fatigue syndrome. Increasing intracellular concentrations of cGMP through the inhibition of PDE5 can have a salutary effect on cells stressed by ROS.
As used herein. “Sceletium” refers to a plant in the plant genus Sceletium, which is a member of the subfamily Mesembryanthemacease of the family Azioacae. Sceletium are low growing succulent herbs commonly found in South Africa. Sceletium spp. (i.e. species) include but are not limited to: S. tortuosum, S. strictum, S. subvelutinum, S. joubertii, and S. namaquense.
As used herein, “Sceletium extract” refers to extracts that are derived from the raw material of any part of a plant in the plant genus Sceletium. Extracts can be made from and/or contain the material of specific species such as S. tortuosum, S. strictum, S. subvelutinum, S. joubertii, and S. namaquense or a combination thereof. Additionally, in some embodiments, extracts can be made or derived from specific parts of a Sceletium plant, such as the aerial parts (i.e. above ground parts, such as leaves, flowers, fruit, stems, seeds, etc.) or the roots.
As used herein, “substantial” or “substantially” when used in reference to a quantity or amount of a material, or a specific characteristic thereof, refers to an amount that is sufficient to provide an effect that the material or characteristic was intended to provide. The exact degree of deviation allowable may in some cases depend on the specific context. Similarly, “substantially free of” or the like refers to the lack of an identified element or agent in a composition. Particularly, elements that are identified as being “substantially free of” are either completely absent from the composition, or are included only in amounts which are small enough so as to have no measurable effect on the composition.
The terms “treat,” “treating,” or “treatment” as used herein and as well understood in the art, mean an approach for obtaining beneficial or desired results, including without limitation clinical results in a subject being treated. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more signs or symptoms of a condition, diminishment of extent of disease, stabilizing (i.e. not worsening) the state of a disease or condition, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. “Treat,” “treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment and can be prophylactic. Such prophylactic treatment can also be referred to as prevention or prophylaxis of a disease or condition. The prophylaxis may be partial or complete. Partial prophylaxis may result in the delayed onset of a physiological condition.
As used herein, “inhibit,” “inhibiting,” “inhibition,” and like terms refer to the act of reducing, minimizing, stopping or arresting a function, role, or activity. When used in connection with phosphodiesterase type I-XI (i.e. PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11) these terms can mean reducing, minimizing, stopping, arresting, or effectively reducing, minimizing, stopping, or arresting physiologic activity of the PDE in a subject. In some embodiments, “significantly inhibiting,” “significant inhibition” and the like can refer to a reduction in activity of the PDE in an amount of at least 30% or more. In some embodiments, the significant inhibition may be a reduction in activity of the PDE in an amount of at least 35%, at least 40%, at least 50%. In other embodiments, the amount of reduction may be in an amount of from 30% to 100%.
As used herein, “pharmaceutically acceptable” refers generally to materials which are suitable for administration to a subject in connection with an active agent or ingredient. For example, a “pharmaceutically acceptable carrier” can be any substance or material that can be suitably combined with an active agent to provide a composition or formulation suitable for administration to a subject. Excipients, diluents, and other ingredients used in or used to prepare a formulation or composition for administration to a subject can be used with such term.
Comparative terms such as “more effectively,” “greater than,” “improved,” “enhanced,” and like terms can be used to state a result achieved or property present in a formulation or process that has a measurably better or more positive outcome than the thing to which comparison is made. In some instances comparison may be made to the prior art.
As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
Any steps recited in any method or process claims may be executed in any order and are not limited to the order presented in the claims unless otherwise stated.
The present disclosure relates to extracts derived from the plant genus Sceletium. Plants of the genus Sceletium can be considered among the most commercially promising plants indigenous to South Africa, with potential for use in dietary supplements, natural medicines, and veterinary and pharmacologic products. Sceletium spp. are found throughout the southwestern portion of South Africa in and environments and are distinguishable on the basis of different vegetative, flower, fruit, and seed characteristics.
Historically, Sceletium was used by local individuals in aboriginal medicinal and tribal practices. In one example, S. tortuosum was chewed, smoked, or used as a snuff that produced euphoria and alertness that gently fade into relaxation. Additionally, the Hottentots of Southern Africa used S. tortuosum as a mood enhancer, relaxant, and empathogen. When chewed in sufficient quantities Sceletium has mild anesthetic properties in the mouth, much like kava. Sceletium was used by the San tribes for tooth extraction, or in smaller doses, for children with colic. Furthermore, a tea made from Sceletium was sometimes used to wean alcoholics off alcohol. Moreover, Sceletium was used as a psychotropic in tincture form and more recently for applications in promoting a sense of well-being, relieving stress in healthy individuals and for treating clinical anxiety and depression.
Alkaloids are one type of active agent in Sceletium. The known alkaloids can be categorized into four groups: (1) 3a-aryl-cis-octahydroindoles (e.g., mesembrine), (2) C-secomesembrine alkaloids (e.g., joubertiamine), (3) alkaloids containing a 2,3-disubstituted pyridine moiety and two nitrogen atoms (e.g., Sceletium alkaloid A4), and (4) a ring C-seco Sceletium alkaloid A4 group (e.g., tortuosamine). The 3a-aryl-cos-octahydroindole group of alkaloids, includes mesembrine, mesembranol, and mesembranone. The pharmacologic activities of this 3a-aryl-cos-octahydroindole group of alkaloids, include anxiolytic or antianxiety effects as well as anti-depressive effects. The mesembrine-like alkaloids have central nervous system effects which include an ability to inhibit serotonin-re-uptake (SSRI).
A phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. The most commonly known PDEs are the cyclic nucleotide PDEs that degrade the phosphodiester bond in the second messenger molecules cyclic adenosine monosphophate (cAMP) and cGMP. In doing so, PDEs regulate the localization, duration, and amplitude of cyclic nucleotide downstream signaling within subcellular domains. PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules. The 21 genes of the superfamily of PDE enzymes have been classified into 11 families designated PDE1-PDE11 in mammals. This classification is based upon amino acid sequences, substrate specificities, regulatory properties, pharmacological properties, and tissue distribution. With respect to substrate specificity, PDE4, 7, and 8 are cAMP-selective hydrolases; PDE5, 6 and 9 are cGMP-selective; and PDE1, 2, 3, 10, and 11 can hydrolyze both cAMP and cGMP. The dual specificity of these later PDEs allows for cross-regulation of the cAMP and cGMP pathways.
FIG. 1 shows exemplary effects of PDE inhibition on cyclic nucleotide degradation in various tissues and physiological processes mediated by cAMP or cGMP. This modulation of the downstream signaling pathways relating to cAMP and cGMP can result in profound alterations in cellular signal transduction pathways and reflects metabolic changes associated with the specific PDE inhibitor.
Phosphodiesterase type V (PDE5) inhibitors increase or prolong concentrations of intracellular cGMP resulting in the inhibition of PDE5 activity. Several diseases and conditions are related to processes mediated via protein phosphorylation through PDE5. These diseases and conditions include but are not limited to include: Addison's disease, alzheimer's disease, asthma, autoimmune diseases, benign prostatic hypertrophy (BPH), bipolar disorders, cancer, cardiomyopathies, cardiovascular conditions and diseases, chronic fatigue syndrome, chronic inflammatory disease, Crohn's disease, congestive cardiac failure, cognitive disorders, cutaneous conditions and diseases, diabetes, diminished exercise capacity, erectile dysfunction, female sexual arousal disorder, fibromyalgia, gastrointestinal diseases, heart failure, heat shock, hypertension, hypoxia, inflammation, inflammatory bowel disease, ischemia, low sex drive, lower urinary tract symptoms (LUTS), lupus, metabolic syndrome, motor dysfunction, multiple sclerosis, nervous system conditions and disorders, osteoarthritis, oxidative stress, premature ejaculation, prostate cancer, prostate hyperplasia, pulmonary arterial hypertension, Raynaud's phenomenon, rheumatoid arthritis, stroke, thyroiditis, and vasculitis among others.
Heretofore, it has been generally thought that Sceletium species or extracts therefrom do not inhibit, or do not appreciably, substantially or significantly inhibit activity of PDE's other than PDE4. To the contrary, the present inventors have discovered that Sceletium extracts, or certain Sceletium species extracts, or formulations or dosages containing such extracts can have an inhibitory effect or significant inhibitory effect on a number of PDE's other than PDE4, for example, PDE5. Accordingly, in one exemplary invention embodiment there is provided a PDE activity inhibiting formulation. The PDE inhibitory formulation comprises a therapeutically effective amount of a Sceletium species that inhibits or significantly inhibits PDE activity in a form suitable for administration to a subject. In one embodiment, the PDE can be PDE5. The Sceletium extract can be derived from any parts of or a material derived from the raw materials of a Sceletium species. In one exemplary embodiment, the Sceletium extract is from at least one of S. tortuosum, S. strictum, S. subvelutinum, S. joubertii, S. namaquense or a combination thereof. In another embodiment, the Sceletium extract can be derived from S. tortuosum. In some embodiments, the extract can be derived from aerial portions of the Sceletium plant. In other embodiments the extract can be derived from the plants roots, stems, leaves, flowers, or a combination thereof. The extract can be a liquid extract, a powder, a compound, or a mixture thereof. The Sceletium extract can be present in the formulation in an amount of from about 1 wt % to about 50 wt %, from about 1 wt % to about 25 wt %, from about 2.5 wt % to about 20 wt %, or from about 3 wt % to about 15 wt %.
In some embodiments, the formulation can include a pharmaceutically acceptable carrier. While the type of pharmaceutically acceptable carrier/vehicle employed in generating the disclosed formulations can vary depending upon the mode of administration of the composition, generally pharmaceutically acceptable carriers are physiologically inert and non-toxic. In some embodiments, the pharmaceutically acceptable carrier can be a pharmaceutical grade compound. Exemplary suitable carriers include water, magnesium carbonate, talc, sugar, lactose, pectin, dextrin, starch (from corn, wheat, rice, potato, or other plants), gelatin, tragacanth, a low melting wax, cocoa butter, sucrose, mannitol, sorbitol, cellulose (such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose), and gums (including arabic and tragacanth), as well as proteins such as gelatin and collagen. In one embodiment, the carrier can comprise cellulose, gelatin, water, or a mixture thereof.
In some embodiments, the formulation comprises a Sceletium extract in combination with at least one activity enhancer. The activity enhancer can be any compound that increases PDE inhibition (e.g. PDE5 inhibition) when combined with the Sceletium extract. In some aspects, the inhibition can become significant inhibition with use of the activity enhancer. The activity enhancer can be in the form of an extract, compound, mineral, pharmaceutically acceptable salt, or any other form that is suitable of being placed in a desired formulation. In some embodiments, the activity enhancer is incapable or substantially incapable of inhibiting PDE- (e.g. PDE5) activity on its own.
A wide range of compounds and agents can be used as activity enhancers for the Sceletium extract. In one embodiment, the activity enhancer can be an amino acid or an amino acid analog. Exemplary amino acids include without limitation, L-theanine, theanine, L-glutamic acid, L-L glutamate, L-glutamine, alanine, arginine, asparagine, ethylamine, glutamate, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, and valine. In another embodiment, the activity enhancer can be a metal or a compound having a metal. Exemplary metals and metal compounds include without limitation, magnesium, calcium, strontium, zinc, magnesium carbonate, magnesium chloride, magnesium citrate, magnesium, hydroxide, magnesium oxide, magnesium sterate, magnesium sulfate, calcium citrate, calcium gluconate, calcium phosphate, calcium stearate, zinc acetate, zinc gluconate, zinc oxide, and zinc sulfate. In yet another embodiment, the activity enhancer can be a vitamin, an analog of a vitamin, a salt of a vitamin, or a phosphorylated derivative of a vitamin. Exemplary vitamins include without limitation, acefurtiamine, acetiamine, allithiamine, beclotiamine, benfotiamine, bentiamine, bisbentiamine, cetotoiamine, cycotiamine, fursultiamine, monophosphothiamine, octotiamine, prosultiamine, sulbutiamine, vintiamol, adenosine thiamine diphosphate, adenosine thiamine triphosphate, thiamine diphosphate, thaimine mononitrate, thiamine monophosphate, thiamine triphosphate, adenine, adenylic acid, biotin, catechol, cobalamins, folic acid, niacin, nicotinic acid, pantothenic acid, pyridoxine, pyridoxal, pyridoxamine riboflavin, thiamine, retinol, ascorbic acid, calciferol, tocopherol, and phylloquinone. In a further embodiment, the activity enhancer can be a polysaccharide. Exemplary polysacharides include without limitation, arabinoxylans, cellodextrins, cellulose, glycogen, hemicellulose, pectins, and starch. In one exemplary embodiment, the activity enhancer can be any member selected from the group consisting of: L-theanine, thiamine, zinc gluconate, magnesium citrate, magnesium stearate, cellulose, or mixtures thereof. In another embodiment, the activity enhancer is L-theanine. In yet another embodiment, the activity enhancer is thiamine. In a further embodiment, the formulation comprises a plurality of activity enhancers. The plurality of activity enhancers can include any combination of the activity enhancer types (i.e. amino acids, metals, vitamins, and polysaccharides) discussed above. In one embodiment, the activity enhancers can include L-theanine and thiamine. In another embodiment, the activity enhancers can include L-theanine, thiamine, magnesium citrate, and zinc. In an additional embodiment, the activity enhancer can include L-theanine, thiamine, magnesium citrate, zinc, and magnesium stearate. The amount of activity enhancer can be selected in view of the specific compound used and the desired properties of the final formulation. However, in one embodiment, the activity enhancer can be present in the formulation in an amount of from about 1 wt % to about 90 wt %, from about 5 wt % to about 85 wt %, from about 10 wt % to about 80 wt %, from about 1 wt % to about 75 wt %, or from about 1 wt % to about 50 wt %.
The combination of the activity enhancer with the Sceletium extract can improve the PDE (e.g. PDE5) inhibiting activity to beyond the level of inhibition that is achieved by administering the Sceletium extract or the activity enhancer alone. In some embodiments, the combination is more effective than the additive effect achieved by administering the Sceletium extract or the activity enhancer alone. In some embodiments, the effect can be about 20% greater, about 30% greater, about 40% greater, about 50% greater, about 55% greater, about 60% greater, about 65% greater, about 70% greater, about 75% greater, about 80% greater, about 85% greater, about 90% greater, about 95% greater, about 100% greater, about 105% greater, about 110%, about 115% greater, about 120% greater, or even about 125% greater than the inhibitory effect achieved by administering either the Sceletium extract or the activity enhancer alone. In other embodiments, the effect can be from about 30% to about 80% greater, from about 40% to about 110% greater, from about 20% to about 125% greater, from about 50% to about 100% greater, from about 30% to about 100% greater, or from about 50% to about 115% greater than the inhibitory effect achieved by administering either the Sceletium extract or the activity enhancer alone. In some embodiments, the enhanced PDE inhibitory effect can be synergistic.
In one exemplary embodiment, the Sceletium extract is present in the formulation in an amount of from about 1 wt % to about 50 wt % and the at least one activity enhancer is present from about 1 wt % to about 90 wt % in the formulation. In another embodiment, the Sceletium extract is present from about 1 wt % to about 25 wt % and the at least one activity enhancer is present from about 5 wt % to about 85 wt % in the formulation. In yet another embodiment, the Sceletium extract is present from about 2.5 wt % to about 20 wt % and the at least one activity enhancer is present from about 1 wt % to about 50 wt % in the formulation. In a further embodiment, the Sceletium extract is present from about 3 wt % to about 15 wt % and the at least one activity enhancer is present from about 1 wt % to about 75 wt % in the formulation.
The formulation can include various ratios of the activity enhancer to the Sceletium extract. In one example, the weight ratio of amount of the activity enhancer to the amount of the Sceletium extract can be from about 1:1 to about 20:1. In another example, the weight ratio of the amount of the activity enhancer to the amount of the Sceletium extract can be from about 2:1 to about 15:1. In a further embodiment, the weight ratio of the amount of the activity enhancer to the amount of the Sceletium extract can be from about 1:1 to about 1:20. In yet another example, the weight ratio of the amount of the activity enhancer to the amount of the Sceletium extract can be from about 0.25:1 to about 20:1. In yet another example, the weight ratio of the amount of the activity enhancer to the amount of the Sceletium extract can be from about 2.5:1 to about 14:1. In yet still another example, the weight ratio of the amount of the activity enhancer to the amount of the Sceletium extract can be from about 0.25:10 to about 14:1.
The formulation can further include a secondary active agent. In some embodiments, the secondary active agent can be a naturally derived plant product or extract. Naturally derived secondary active agents can include arginine, berberine, forskolin, papaverine, yohimbine, Lepidium meyenii extract, Panax ginseng extract, Ginkgo biloba extract, Ferula hermonis boiss. extract, other herbals, or any combination thereof. The secondary active agent does not need to act as a PDE (e.g. PDE5) inhibitor. In some embodiments, the secondary active agent will have a mechanism of action other than PDE5 inhibition.
In some embodiments, the formulations can comprise pharmaceutically acceptable excipients. Exemplary pharmaceutically acceptable excipients can be selected from the group consisting of coatings, isotonic and absorption delaying agents, binders, adhesives, lubricants, disintergrants, coloring agents, flavoring agents, sweetening agents, absorbents, detergents, and emulsifying agents. When the formulation includes an emulsifying agent, the emulsifiers can be added to improve the stability of the final product. Exemplary emulsifiers include, but are not limited to, lecithin (e.g., from egg or soy), or mono- and di-glycerides. Other emulsifiers are readily apparent to the skilled artisan and selection of suitable emulsifier(s) will depend, in part, upon the formulation and final product.
Various formulation embodiments can further include flavorings, coloring agents, spices, nuts, preservatives, antioxidants, vitamins, minerals, proteins, fats, and/or carbohydrates. The amount of other ingredients can vary based on the particular design, intended dosage, and method of administration. The total amount of other ingredients can also depend, in part, upon the condition and weight of the subject.
Flavors, coloring agents, spices, nuts and the like can be incorporated into the product. Flavorings can be in the form of flavored extracts, volatile oils, chocolate flavorings (e.g., non-caffeinated cocoa or chocolate, chocolate substitutes such as carob), peanut butter flavoring, cookie crumbs, crisp rice, vanilla or any commercially available flavoring. Flavorings can be protected with mixed tocopherols. Examples of useful flavorings include but are not limited to pure anise extract, imitation banana extract, imitation cherry extract, chocolate extract, pure lemon extract, pure orange extract, pure peppermint extract, imitation pineapple extract, imitation rum extract, imitation strawberry extract, or pure vanilla extract; or volatile oils, such as balm oil, bay oil, bergamot oil, cedarwood oil, cherry oil, walnut oil, cinnamon oil, clove oil, or peppermint oil; peanut butter, chocolate flavoring, vanilla cookie crumb, butterscotch or toffee. In one embodiment, the formulation can contain berry or other fruit flavors. The food compositions may further be coated, for example with a yogurt coating.
Preservatives can be added to the formulation to extend the shelf life of the product. Exemplary preservatives include potassium sorbate, sodium sorbate, potassium benzoate, sodium benzoate, or calcium disodium EDTA.
The formulation can also include natural or artificial sweeteners. In one embodiment, the potential sweeteners can include glucose, sucrose, fructose, saccharides, cyclamates, aspartamine, sucralose, aspartame, acesulfame K, sorbitol, or a combination thereof.
The formulation can further include pharmaceutically acceptable forms of vitamins, minerals, and other nutrients. The nutrients chosen for inclusion in the formulation can vary depending on the particular design, intended dosage, method of administration, and condition of the subject. Individuals skilled in the art are aware of vitamins, minerals, and other nutrients that can be incorporated into formulations and how to incorporate these.
The components in the formulation can be included as salts. In particular, pharmaceutically acceptable salts of the components are contemplated. A “pharmaceutically acceptable salt” is a combination of a compound and either an acid or a base that forms a salt (such as, for example, the magnesium salt, denoted herein as “Mg” or “Mag”) with the compound. Pharmaceutically acceptable salts can be tolerated by a subject under therapeutic conditions. In general, a pharmaceutically acceptable salt of a compound will have a therapeutic index (the ratio of the lowest toxic dose to the lowest therapeutically effective dose) of 1 or greater. Those skilled in the art recognize that the lowest therapeutically effective dose will vary from subject to subject and from indication to indication, and will thus adjust the formulation accordingly.
The formulation can be provided in any convenient form. For example, the formulation can be oral, transdermal, transmucosal, inhalation, rectal, ophthalmic (including intra-vitreal or intra-cameral), nasal, topical (including buccal and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intra-dermal, and intra-tracheal). When the formulation is formulated in an oral dosage form, the formulation can comprise a capsule, tablet, powder, suspension, gel, liquid, beverage, syrup, or a food. In one embodiment, the formulation may be formulated as powder that can be mixed with consumable liquids, such as milk, juice, sodas, water, or consumable gels or syrups for mixing into other nutritional liquids or foods. The formulation can also be formulated to include pre-measured supplemental foods, such as single serving beverages or bars. In one embodiment, the formulation can be formulated into a nutritional beverage. In yet other embodiments, the formulation can be made in a variety of forms, such as pudding, confections (i.e., candy), ice cream, frozen confections and novelties, or non-baked, extruded food products such as bars. In one embodiment, the manufacture of a food bar can comprise adding the dry ingredients with the liquid ingredients in a mixer and mixing until the dough phase is reached; the dough is then put into an extruder and extruded: the extruded dough is then cut into appropriate lengths; and the product is left to cool. In yet another embodiment, the formulation can be provided as a cream or lotion for topical application. One trained in the art can readily formulate the present composition into any of these convenient forms for administration.
When formulated in an oral dosage form, the formulation can comprise from about 0.01 mg to about 30,000 mg, from about 0.01 mg to about 10,000 mg, from about 0.01 mg to about 5,000 mg, or from about 0.01 mg to about 100 mg of the Sceletium extract.
Also, presented herein is a Sceletium extract dosage form for administration to a subject to inhibit, or significantly inhibit, phosphodiesterase activity, such as phosphodiesterase type V activity. The extract dosage includes an amount of a Sceletium extract that inhibits PDE (e.g. PDE5) activity and is in a form suitable for administration to a subject. While the dosage form can vary, the dosage form can be made appropriate to the route of administration, the disease or condition being treated, and the subject.
The Sceletium extract in the dosage form, can be as described above, and comprise any parts of or material derived from the raw materials of a Sceletium species. In one exemplary embodiment, the Sceletium extract in the dosage form is from at least one of S. tortuosum. S. strictum, S. subvelutinum, S. joubertii, S. namaquense or a combination thereof.
The amount of the Sceletium extract in the dosage can vary from about 0.01 mg to about 30,000 mg, from about 0.01 mg to about 10,000 mg, from about 0.01 mg to about 5,000 mg, or from about 0.01 mg to about 100 mg. In another embodiment, the amount of the Sceletium extract in the dosage can vary from about 0.1 mg to about 100 mg, from about 0.1 mg to about 1,000 mg, from about 0.1 mg to about 5,000 mg, from about 0.1 mg to about 10,000 mg, from about 0.25 mg to about 100 mg, from about 0.25 mg to about 1,000 mg, from about 0.25 mg to about 5,000 mg, from about 0.25 mg to about 10,000 mg, from about 0.5 mg to about 100 mg, from about 0.5 mg to about 1,000 mg, from about 0.5 mg to about 5,000 mg, or from about 0.5 mg to about 10,000 mg. In a further embodiment, the amount of the Sceletium extract in the dosage form can vary from about 1 mg to about 100 mg, from about 1 mg to about 1,000 mg, from about 1 mg to about 5,000 mg, from about 1 mg to about 10,000 mg, or from about 1 mg to about 30,000 mg.
In one embodiment, the Sceletium extract can have a standardized alkaloid content. In one example, the content can be from about 1 mg to about 300 mg. In another example, the amount can be from about 5 mg to about 200 mg. In a further example, the amount can be from about 10 mg to 100 mg. In yet another example, the amount can be from about 20 mg to about 30 mg. In another example, the alkaloid content can be standardized at about 25 mg.
In one embodiment, the dosage form can comprise an activity enhancer. The dosage form when administered to a subject with an activity enhancer can be more effective at inhibiting PDE (e.g. PDE5) than either the amount of Sceletium extract or the amount of the activity enhancer alone. When an activity enhancer is included the Sceletium extract in the dosage form can be present in a therapeutically effective amount without the activity enhancer, or the Sceletium extract can be present in an amount that is not therapeutically effective without the activity enhancer. In other words, the Sceletium extract can be in an amount that is insufficient to provide a therapeutic effect, but with the presence of the activity enhancer, the amount may become sufficient to have a therapeutic effect due to the increased activity provided by the activity enhancer. In some aspects, the presence of the activity enhancer can increase the PDE (e.g. PDE5) inhibition to significant inhibition.
The activity enhancer can be in the form of an extract, compound, mineral, pharmaceutically acceptable salt, or any other suitable form capable of being placed in the dosage form, and can be any compound or agent suitable for use as an activity enhancer for a Sceletium extract, including the exemplary compounds and agents recited herein. In one exemplary embodiment, the activity enhancer can be a member selected from the group consisting of: L-theanine, thiamine, zinc gluconate, magnesium citrate, magnesium stearate, cellulose, or a mixture thereof. The amount of the activity enhancer in the dosage form can vary from about 0.01 mg to about 60,000 mg, from about 0.01 mg to about 40,000 mg, from about 0.01 mg to about 20,000 mg, from about 0.01 mg to about 10,000, from about 0.01 mg to about 5,000 mg, from about 0.01 mg to about 1,000 mg, or from about 0.01 mg to about 125 mg. In another embodiment, the amount of the activity enhancer in the dosage form can vary from about 0.1 mg to about 150 mg, from about 0.1 mg to about 1,000 mg, from about 0.1 mg to about 5,000 mg, from about 0.1 mg to about 10,000 mg, from about 0.25 mg to about 150 mg. from about 0.25 mg to about 1,000 mg, from about 0.25 mg to about 5,000 mg, from about 0.25 mg to about 10,000 mg, from about 0.5 mg to about 150 mg, from about 0.5 mg to about 1,000 mg, from about 0.5 mg to about 5,000 mg, or from about 0.5 mg to about 10,000 mg. In a further embodiment, the amount of the activity enhancer extract in the dosage can vary from about 1 mg to about 125 mg, from about 1 mg to about 500 mg, from about 1 mg to about 1,000 mg, from about 1 mg to about 5,000 mg, from about 1 mg to about 10,000 mg, or from about 1 mg to about 60,000 mg. These amounts can be for a single activity enhancer, or for a combination thereof.
In one exemplary embodiment, the Sceletium extract is present from about 1 mg to about 100 mg and the at least one activity enhancer is present from about 1 mg to about 125 mg. In another embodiment, the Sceletium extract is present from about 0.01 mg to about 10,000 mg and the at least one activity enhancer is present from about 0.01 mg to about 10,000 mg. In yet another embodiment, the Sceletium extract is present from about 1 mg to about 30,000 mg and the at least one activity enhancer is present from about 1 mg to about 60,000 mg. In a further embodiment, the Sceletium extract is present from about 0.25 mg to about 1,000 mg and the at least one activity enhancer is present from about 0.25 mg to about 5,000 mg.
The dosage form can be administered using a dosage unit according to a pre-determined regimen. The term “dosage unit” is understood to mean a unitary, i.e. a single dose which is capable of being administered to a patient. The dosage unit can be readily handled and packed, while remaining as a physically and chemically stable unit dose comprising either the active ingredient or a mixture of active ingredient(s) with a solid or liquid pharmaceutical vehicle. The pre-determined regimen can be administered once per day or multiple times per day. When the regimen is administered multiple times per day, the regimen can be administered once per day, twice per day, three times per day, four times per day, or five times per day. The regimen could also be administered on an every other day, every three days, every five days, every week, every other week or on a monthly basis. The exact regimen can vary based on the amounts of Sceletium extract and activity enhancer in the dosage form, the disease be treated, and the subject's individual characteristics and needs. In some embodiments, the dosing regimen can be on an “as needed” basis. For example, at the time a subject requires relief from a condition (i.e. erectile dysfunction), the subject can administer a suitable dose. In alternative embodiments, the dose can be taken according to a specific pre-set regimen as mentioned herein.
The dosage form can be in any of a wide variety of forms. The dosage form can be an oral, transdermal, transmucosal, inhalation, rectal, ophthalmic (including intra-vitreal or intra-cameral), nasal, topical (including buccal and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intra-dermal, and intra-tracheal) dosage form. When the dosage form is an oral dosage, the formulation can be in the form of discrete units such as capsules, sachets, tablets, soft gels or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid, such as ethanol or glycerol; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be administered in the form of a bolus, electuary or paste. When the dosage form is in the form of a depot, the formulation may be administered by implantation (e.g. subcutaneously, intra-abdominally, or intramuscularly) or by intramuscular injection. Thus, for example, the active ingredient may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in a pharmaceutically acceptable oil), or an ion exchange resin. In addition, the dosage form can be in the form of a sustained release formulation. In one exemplary embodiment, polymers or other ingredients can be added to create the sustained release dosage form.
Also presented herein are methods of inhibiting, or significantly inhibiting, phosphodiesterase (PDE) such as phosphodiesterase type V (PDE5) activity in a subject. Such methods generally comprise administering a therapeutically effective amount of a Sceletium extract, or formulation that inhibits PDE (e.g. PDE5) activity to a subject. As discussed above, the Sceletium extract is any part of or a material derived from the raw materials of a Sceletium species. In one exemplary embodiment, the Sceletium extract is from at least one of S. tortuosum, S. strictum, S. subvelutinum, S. joubertii, S. namaquense or a combination thereof. In another embodiment, the Sceletium extract can be derived from S. tortuosum.
The method can further comprise administering an amount of at least one activity enhancer to the subject. As discussed above, the activity enhancer is any agent that increases PDE (e.g. PDE5) inhibition when combined with Sceletium extract. In one exemplary embodiment, the activity enhancer can be a member selected from the group consisting of: L-theanine, thiamine, zinc gluconate, magnesium citrate, magnesium stearate, cellulose, or mixtures thereof. In some embodiments of the method, the inhibiting effect is greater than an inhibitory effect provided by either the amount of the Sceletium extract or the amount of activity enhancer alone. In one embodiment, the Sceletium extract is present in a therapeutically effective amount, and in another embodiment it is present in an amount that becomes therapeutically effective in the presence of the activity enhancer.
In some embodiments, the formulations and dosage forms can be used to provide treatment of a subject that displays or anticipates signs or symptoms of a disease or condition selected from the group consisting of: prostate cancer, erectile dysfunction, prostate hyperplasia, lower urinary tract symptoms, premature ejaculation, Addison's disease, benign prostatic hypertrophy, female sexual arousal disorder, and low sex drive. In another embodiment, the method can provide treatment of signs or symptoms of a disease or condition selected from the group consisting of: pulmonary arterial hypertension, congestive cardiac failure, cardiomyopathy, shock, heart failure, ischemia, pulmonary hypertension, various cardiovascular diseases, Raynaud's phenomenon, essential hypertension, stroke, and vasculitis. In yet another embodiment, the method can provide treatment of signs or symptoms of a disease or condition selected from the group consisting of: diminished exercise capacity, chronic fatigue syndrome, hypoxia, and asthma. In a further embodiment, the method can provide treatment of signs or symptoms of a disease or condition selected from the group consisting of: motor dysfunction, cognitive disorders including Alzheimer's disease, autoimmune disease, bipolar disorder, nervous system disorders, lupus, fibromyalgia, and multiple sclerosis. In yet a further embodiment, the method can provide treatment of signs or symptoms of a disease or condition selected from the group consisting of: cutaneous conditions and diseases, inflammation, chronic inflammatory disease, osteoarthritis, and rheumatoid arthritis. In one other embodiment, the method can provide treatment of signs or symptoms of a disease or condition selected from the group consisting of: cancer, type 1 and type 2 diabetes, gastrointestinal diseases, metabolic syndrome, obesity, inflammatory bowel disease, thyroiditis, and Crohn's disease. In yet one other embodiment, the method can provide treatment of signs or symptoms of oxidative stress.
The methods disclosed can be used on any subject that would benefit from PDE (e.g. PDE5) inhibition. In one exemplary embodiment, the subject is a mammal. In another embodiment, mammals include humans. In other exemplary embodiments, mammals include non-human mammals. Non-human mammals can include domesticated animals, such as cats and dogs, as well as farm animals such as horses and cows, mice, and rats.
In one embodiment, the present formulations and dosage forms can be administered to a subject that is suffering from a PDE (e.g. PDE5) related condition or disease, or the method can be administered prophylactically in order to prevent the occurrence or progression of a PDE (e.g. PDE5) related condition or disease. The formulation or dosage used can be administered in the form of an oral, transdermal, transmucosal, rectal, ophthalmic (including intravitreal or intracameral), nasal, nasal by inhalation, topical (including buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intratracheal), by implantation, or intramuscularly. In one exemplary embodiment the method administers the formulation orally. The method can include administering the Sceletium extract and the at least one activity enhancer concurrently. When administered concurrently, the Sceletium extract and at least one activity enhancer can be administered from a single formulation. In another embodiment, the Sceletium extract and at least one activity enhancer are administered separately. In yet another embodiment, the Sceletium extract and the at least one activity enhancer are administered sequentially.
In one embodiment a method of treating a PDE (e.g. PDE5) related condition in a subject can comprise administering an amount of a Sceletium extract and an activity enhancer. In one embodiment, the amount of Sceletium extract per dose can be about 25 mg and the daily amount of the activity enhancer per dose can be about 515 mg. In another embodiment, the amount of the Sceletium extract per dose can be about 30 mg and the amount of the activity enhancer per dose can be about 60 mg. In yet another embodiment, the amount of the Sceletium extract per dose can be about 100 mg and the amount of the activity enhancer per dose can be about 125 mg. In a further embodiment, the amount of the Sceletium extract per dose can be about 100 mg and the amount of the activity enhancer per dose can be about 4,000 mg. While exemplary dosage amounts are presented above, the exact dosage amount will vary based on the disease or condition being treated and the individual needs and characteristics of the subject.
In an additional invention embodiment, there is presented a method of increasing the phosphodiesterase, such as phosphodiesterase type V (PDE5) inhibition activity of an amount of a Sceletium extract. In one aspect, such a method comprises adding or combining an amount of at least one activity enhancer with the administration of the Sceletium extract. The Sceletium extract and the activity enhancer can be included in the method as described above. The combination of the Sceletium extract and the activity enhancer inhibits PDE (e.g. PDE5) activity to a greater degree than the amount of the Sceletium extract alone. In some embodiments, the increase in inhibition attained can be greater than the additive effect of each ingredient alone (i.e. synergistic). In one embodiment, the Sceletium extract and activity enhancer can be combined in a single formulation, or can be in separate formulations that are combined upon administration to the subject. For example, the Sceletium and activity enhancer can be administered to a subject in such a manner that they combine or effectively combine in vivo. In one embodiment, they Sceletium extract and the activity enhancer can be administered concurrently. In another embodiment they can be administered sequentially or otherwise at separate times as long as they are still able to provide the enhanced PDE (e.g. PDE5) inhibitory effect. Further presented is a phosphodiesterase, such as phosphodiesterase type V (PDE5) inhibiting system. The inhibiting system comprises an amount of a Sceletium extract, or formulation and in some embodiments includes a delivery vehicle. In one embodiment, the delivery vehicle is a pharmaceutically acceptable carrier. In one embodiment, the system further comprises at least on activity enhancer. Presented more fully above, are exemplary embodiments of the Sceletium extract or formulation and/or the activity enhancer as used in the system, as well as, the PDE (e.g. PDE5) inhibiting activity of the system. The Sceletium extract and the activity enhancer can be separately assembled in the system. In some embodiments the Sceletium extract and activity enhancer are in separate formulations. When the Sceletium extract and activity enhancer are in separate formulations they can be packaged together or packaged individually. In other embodiments, the Sceletium extract and activity enhancer are in a single formulation. Regardless of the embodiment, the formulation can be in a form that masks the taste of the Sceletium extract and/or the activity enhancer (e.g., capsule or pill form) rather than incorporating them into a food or beverage (e.g., powder or bar).
The system can optionally include additional components. In one embodiment, the system can be associated a container(s). In some embodiments, the system can include a notice in the form prescribed by a government agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use of sale for human administration. Furthermore, the system can be labeled with information (i.e. instructions) regarding mode of administration, sequence of administration (e.g., separately, sequentially or concurrently), or the like. Alternatively, such information can be included in a sheet or booklet separate from the product label. The system can also include means for reminding the patient to take the Sceletium extract and activity enhancer. The system can be a single unit dosage of the Sceletium extract and activity enhancer or it can be a plurality of unit dosages.
Further presented is a method for modulating protein kinase activity in a subject. As previously discussed PDE (e.g. PDE5) inhibitors can prolong or enhance the effects of a variety of physiological processes mediated by cGMP. The process can occur in a wide range of tissues through inhibition of cyclic nucleotide degradation. The modulation of the downstream signaling pathways relating to cGMP directly affects protein kinase activity. Certain protein kinases are only activated when cGMP is present. Therefore, the formulations previously discussed can be used in a method for modulating protein kinase activity.
The method includes administering to a subject a formulation having an amount of Sceletium extract that inhibits phosphodiesterase, for example phosphodiesterase type 5, activity in an amount sufficient to modulate a selected protein kinase activity. In one embodiment, the method can further include administering an activity enhancer in combination with the Sceletium extract. In either embodiment the Sceletium extract and/or activity enhancer can be administered in the method as discussed above. In one embodiment when the method is administered to a subject with at least one activity enhancer, the method is more effective at modulating protein kinase activity then either the amount of Sceletium extract or the amount of activity enhancer alone. In one embodiment, the protein kinase activity that is modulated is a protein kinase selected from the group consisting of IGF-1R, IR, Met, B-Raf(V599E), DAPK1, ALK, Itk, Src(T341M), Rse, CDK7/cyclinH/MAT1, DMPK, PKC₁, B-Raf, CHK2, MKK7β, PKCβI, PKA, PKCη, Ax1, EphA8, MST1, Ab1 (Q252H), STK25, and PKCε. In a second embodiment, the protein kinase activity that is modulated is a protein kinase selected from the group consisting of fCLK1, Met, Syk, Aurora, PRAK, Flt4, TrkC, CK2a2, MSSk1, Fms, and GSK3. Regulation of protein kinase activity is useful as a treatment for disease states or conditions because of the relationship between protein kinase activity and disease states and conditions. While not being bound by theory, it is believed that the relationship is either causative of the disease or intimately related to the expression and progression of disease-associated symptomology and pathology.
Further presented is a method of preparing a PDE (e.g. PDE5) inhibiting formulation. The method comprises providing an extract of a Sceletium species that inhibits PDE (e.g. PDE5) activity and concentrating the extract into a therapeutically effective amount sufficient to inhibit PDE (e.g.) PDE5 activity when administered to a subject. In one embodiment, the formulation can include adding the concentrated extract to at least one activity enhancer in a manner suitable for administration to a subject. In all of the embodiments discussed above, the Sceletium extract and/or at least one activity enhancer includes those extracts and enhancers as previously discussed above. The method includes methods of formulating compositions that are well known in the art. All methods include the step of bringing the active ingredient into association with the vehicle that constitutes one or more auxiliary constituents. In one embodiment, the method can include acquiring a source of a Sceletium extract and formulating the Sceletium extract with the activity enhancer(s). The formulation can be further formulated with a pharmaceutically acceptable carrier and/or other excipients, preservatives or additives. In one embodiment, the method further includes the step of extracting the Sceletium extract from a Sceletium sp. or spp. prior to combining the Sceletium extract with the activity enhancer(s). The Sceletium sp. or spp. can be extracted using any known extraction methods. When the extraction is a liquid extraction the extraction can occur using any suitable solvent including, organic solvents, inorganic solvents, ethanol, water, steam, superheated water, methanol, ethanol, hexane, chloroform liquid, liquid CO₂, liquid N₂. propane, supercritical CO₂or any combination thereof. In a further embodiment, the material that the Sceletium extract is derived from can be milled prior to being extracted.
Additionally presented is a method of inhibiting, or significantly inhibiting, cGMP degradation, comprising administering a formulation comprising a therapeutically effective amount of a Sceletium species that inhibits, or substantially inhibits, PDE (e.g. PDE5) activity. Sceletium species that inhibit or substantially inhibit PDE (e.g. PDE5) activity can be used to inhibit, or substantially inhibit, cGMP degradation because PDE5 acts by degrading cGMP. The method can include administering any of the formulations discussed above.
Embodiments of the present disclosure will be described with reference to the following Examples which are provided for illustrative purposes only and should not be used to limit the scope of or construe the invention.

EXAMPLES

Example 1

Formulation of S. tortuosum

Dry aerial parts of S. tortuosum were cultivated and prepared commercially by HG&H Pharmaceutical (Pty) Ltd, South Africa. The air dried S. tortuosum was milled using a conventional industrial milling machine. The milling occurred in a hammer mill with a mesh size adjusted to achieve a particle size >85 microns and ≦3 mm. The milled powder was added to an aqueous ethanoic solution comprising 70% ethanol. The ratio of raw milled plant material to extraction liquid was 1:6 w/w. The solution and milled powder were stirred with an electric stirrer. The temperature of the solution was maintained between 25° C.-50° C. and was continually and slowly stirred for 24 hours. Following the stirring, the solution was filtered through a commercial filter with an appropriate mesh size to yield the desired filtrate. The filtrate was spray-dried onto lactose monohydrate.

Example 2

Phosophodiesterase Inhibition

The ethanoic extract of S. tortuosum was tested for the capacity to inhibit five phosphodiesterases in a concentration dependent manner. The sample was tested at 10 concentrations with 2-fold serial dilutions starting at 125 μg/mL. Each assay was accompanied by a dose-response series of the control compound 3-isobutyl-1-methylxanthine (IBMX); positive controls were also tested at 10-concentrations with 3-fold serial dilutions starting at 100 μM.
The incubation mixture contained 10 mM Tris, pH 7.5, 5 mM MgCl2, 0.01% Brij 35, 1 mM dithiothreitol, and 1% dimethylsulfoxide (DMSO). For PDE1A. 0.2 mM CaCl₂and 0.36 μM calcium/calmodulin were included in the reaction mixture. Test material was added in DMSO, followed by addition of cAMP or cGMP (depending on the PDE enzyme tested, cAMP for PDE1, 2, 3, and 4; cGMP for PDE5) to a final concentration of 1 μM. After one hour at ambient temperature, the reaction was stopped by the addition of a proprietary Stop/detection mixture. Fluorescence polarization was measured after another 90 minutes incubation at room temperature. The adenosine monophosphate (AMP) or guanosine monophosphate (GMP) was quantified for each concentration using the Transcreener® fluorescence polarization assay (BellBrook Labs, Madison, Wis.) with Ex=620 nm FP and Em=688 nm P and S.
The IC₅₀values (concentrations producing half maximal inhibition of control specific activity) and Hill coefficients were determined by non-linear regression analysis of the inhibition curves using Hill equation curve fitting (Y=D+[(A−D)/(1+C/C₅₀)^nH)] using GraphPad Prism software (GraphPad Software, La Jolla, Calif.). Curve fits were performed from the point where the inhibitory activity at the highest concentration of compound was less than 65%. IC₅₀values are presented in Table 1 as μg sample/mL.

TABLE 1

Median Inhibitory Concentration of S. tortousum
against PDE1A, PDE2A, PDE3A, PDE4D, and PDE5A

Median Inhibitory Concentration

IC₅₀Value

S. tortuosom

Controls

	Enzyme	μg/mL	Test Material	μg/nxL

PDE1A	—	IBMX	0.140
PDE2A	—	IBMX	1.78
PDE3A	124	IBMX	0.591
PDE4D	16.7	IBMX	5.63
PDE5A	1.68	Methoxyquinazoline	0.548

The organic extract of S. tortuosum, exhibited a concentration-dependent inhibition of PDE3A, PDE4D, and PDE5A. The inhibition of PDE5 was ten times greater than the inhibition of PDE4 exhibited by the formulation. The inhibition activity of PDE5 was 2.4 times more potent than the reported inhibition of PDE5 by icarrin. (Icarrin inhibition values obtained from, Dell'Agli, M. et al., (2008) Potent inhibition of human phosphodiesterase-5 by icarrin derivatives, J. Natural Products, 71: 1513-1517).

Example 3

Formulations of Sceletium Enhanced by L-Theanine and Thiamine

L-theanine and thiamine were purchased from commercial sources, (available from PureBulk Inc.). Independent testing of L-theanine and thiamine for PDE-inhibitory activity revealed that neither compound possessed inhibitory activity against any of the four PDE isozymes at the concentrations used in the study. Preparation of the alcoholic extract of S. tortuosum was performed as described in Example 1 and combined with the L-theanine and thiamine. The formulation contained 50 mg of the S. tortuosum extract, 52 mg of L-theanine, and 6.25 mg of thiamine.

Example 4

Phosphodieslerase Inhibition by Formulations Containing Sceletium, L-Theanine and Thiamine

The effects of formulations containing S. tortuosum extract, L-theanine, and thiamine on the inhibition of PDE4 and PDE5 compared to the S. tortuosum extract alone were tested. An additional objective was to observe the effects of the multi-component formulation on PDE1A, PDE2A, and PDE3A.
Enzyme assays and calculations were performed as previously described in Example 2 using the formulations prepared in Example 3. Activities were based on S. tortuosum sample content of the reaction mixture, as all other components had demonstrated no effect on PDEs and the alkaloid content of the S. tortuosum and the test formulation of S. tortuosum containing L-theanine and thiamine were balanced.

TABLE 2

Median Inhibitory Concentrations of S. tortousum, L-theanine, and thiamine
against PDE1A, PDE2A, PDE3A, PDE4D, and PDE5A

Median Inhibitory Concentration

IC₅₀Value

tortuosum

L-

thiamine

Controls

Enzyme	extract	theanine*	Thiamine*	sample	Test Material	μg/mL

PDE1A	—	0	0	—	IBMX	0.795
PDE2A	—	0	0	—	IBMX	1.41
PDE3A	—	0	0	—	IBMX	0.869
PDE4D	6.94	0	0	4.43	IIBMX	3.24
PDE5A	2.77	0	0	1.05	Methoxyquinazoline	0.460

*L-theanine and thiamine were tested individually at a different date for their PDE4 and PDE5 inhibitory effect. During that testing L-theanine and thiamine did not exhibit any inhibitory activity.
—No dose-response was exhibited over the 10 concentrations tested.

The extract combining the S. tortuosum, with L-theanine and thiamine exhibited a 36% inhibition in the PDE4 activity and 62% inhibition in the PDE5 activity which is synergistic and unexpected in view of the fact that L-theanine and thiamine do not exhibit any PDE4 or PDE5 inhibitory activity when administered alone. The addition of L-theanine and thiamine to the S. tortuosum preparation unexpectedly increased the PDE4 inhibitory activity 1.57-fold and the PDE5 inhibitory activity 1.97-fold relative to the extract alone.

Example 5

Clinical Results—Nocturnal Penile Tumescence

The formulation from Example 3 was consumed by a sixty-six year old caucasian male. Over a span of two weeks, the subject increased his dose four-fold two hours prior to sleep (2.2 mg/kg body weight). The individual found that several times during the night, each night, he was awakened with nocturnal penile tumescence. The individual discontinued increased dosing after two weeks and his sleep patterns returned to normal. During the individuals normal sleep patterns he did not experience nocturnal penile tumescence.

Example 6

Inhibitory and Stimulator, Effects of Sceletium tortuosum on 295 Protein Kinases

Protein kinases represent a transferase class of enzymes that are able to transfer a phosphate group from a donor molecule (usually ATP) to an amino acid residue of a protein (usually threonine, serine or tyrosine). Kinases are used in signal transduction for the regulation of enzymes, i.e., they can inhibit or activate the activity of an enzyme, such as in cholesterol biosynthesis, amino acid transformations, or glycogen turnover. While most kinases are specialized to a single kind of amino acid residue, some kinases exhibit dual activity in that they can phosphorylate two different kinds of amino acids.
Methods—The inhibitory effect of the organic extract of S. tortuosum of the present invention on human kinase activity was tested on a panel of 295 kinases in the KinaseProfiler™ Assay (Millipore UK Ltd. Dundee, United Kingdom). The assay protocols for specific kinases are well-known. Median inhibitory concentrations were estimated by simple interpolation when a dose-response was observed over the three concentrations that captured the median effective concentration.
The dose responsiveness of the organic extract of S. tortuosum as prepared in Example 1 was tested at 5, 25 and 125 μg/mL on 295 protein kinases are presented as Table 3 below.

TABLE 3

Dose responses of S. tortuosum on 251 protein kinases

	Percent of Solvent
	Control Activity

5

25

125

Kinase†	μg/mL	μg/mL	μg/mL

1	Abl (H396P)	90	95	65
2	Abl (M351T)	100	96	78
3	Abl (Q252H)	121	107	62
4	Abl	98	83	77
5	Abl(T315I)	72	60	45
6	Abl(Y253F)	112	102	69
7	ACK1	91	86	44
8	ALK	88	88	133
9	ALK4	85	79	83
10	AMPKα1	95	83	39
11	AMPKα2	110	97	24
12	Arg	93	84	82
13	ARK5	87	71	53
14	ASK1	108	98	97
15	Aurora-A	91	76	12
16	Aurora-B	76	32	2
17	Aurora-C	92	79	27
18	Axl	122	121	72
19	B-Raf	112	105	124
20	B-Raf(V599E)	92	138	116
21	Blk	92	78	4
22	Bmx	91	88	72
23	BRK	108	92	50
24	BrSK1	92	80	18
25	BrSK2	98	87	31
26	BTK	107	82	31
27	BTK(R28H)	91	82	60
28	c-RAF	97	96	116
29	CaMKI	90	93	95
30	CaMKIIβ	98	101	91
31	CaMKIIγ	93	103	95
32	CaMKIIδ	91	89	48
33	CaMKIV	105	117	108
34	CaMKIδ	98	99	89
35	CDK1/cyclinB	91	82	72
36	CDK2/cyclinA	101	97	81
37	CDK2/cyclinE	102	96	54
38	CDK3/cyclinE	100	93	69
39	CDK5/p25	98	104	87
40	CDK5/p35	114	110	106
41	CDK6/cyclinD3	106	107	89
42	CDK7/cyclinH/MAT1	105	115	128
43	CDK9/cyclin T1	96	100	78
44	CHK1	92	95	89
45	CHK2	123	115	53
46	CHK2(I157T)	105	92	68
47	CHK2(R145W)	106	96	67
48	CK1γ1	97	86	28
49	CK1γ2	81	57	15
50	CK1γ3	96	57	2
51	CK1δ	114	119	64
52	CK2	109	107	38
53	CK2α2	86	54	6
54	cKit(D816H)	88	68	17
55	cKit(D816V)	96	98	71
56	cKit	95	95	54
57	cKit(V560G)	102	79	33
58	cKit(V654A)	99	79	18
59	CLK1	51	13	3
60	CLK2	97	84	20
61	CLK3	97	80	24
62	CLK4	107	87	12
63	CSK	99	96	20
64	cSRC	96	81	66
65	DAPK1	127	134	109
66	DAPK2	91	82	32
67	DCAMKL2	99	104	111
68	DDR2	109	107	98
69	DMPK	116	126	120
70	DRAK1	120	115	92
71	DYRK2	97	99	92
72	eEF-2K	109	99	58
73	EGFR	93	75	45
74	EGFR(L858R)	94	90	97
75	EGFR(L861Q)	95	90	70
76	EGFR(T790M, L858R)	89	93	66
77	EGFR(T790M)	106	93	82
78	EphA1	112	100	94
79	EphA2	96	102	96
80	EphA3	100	96	79
81	EphA4	91	82	52
82	EphA5	95	99	99
83	EphA7	108	109	95
84	EphA8	122	116	117
85	EphB1	106	93	57
86	EphB2	85	62	25
87	EphB3	96	95	93
88	EphB4	84	58	25
89	ErbB4	98	95	77
90	FAK	88	98	109
91	Fer	96	104	85
92	Fes	117	101	76
93	FGFR1	98	79	28
94	FGFR1(V561M)	100	94	61
95	FGFR2	98	93	66
96	FGFR2(N549H)	101	95	81
97	FGFR3	108	98	66
98	FGFR4	94	86	43
99	Fgr	97	95	60
100	Flt1	106	85	30
101	Flt3(D835Y)	95	73	46
102	Flt3	95	71	46
103	Flt4	80	49	4
104	Fms	82	53	16
105	Fms(Y969C)	115	110	88
106	Fyn	86	77	15
107	GCK	94	84	61
108	GRK5	104	103	100
109	GRK6	109	106	90
110	GRK7	105	93	94
111	GSK3α	91	61	6
112	GSK3β	117	60	14
113	Haspin	110	89	42
114	Hck	79	73	45
115	Hck activated	102	112	92
116	HIPK1	97	94	90
117	HIPK2	114	99	83
118	HIPK3	93	92	79
119	IGF-1R	147	199	229
120	IGF-1R activated	100	99	48
121	IKKα	100	104	67
122	IKKβ	110	115	50
123	IKKε	101	103	97
124	IR	97	99	196
125	IR, activated	78	67	34
126	IRAK1	90	96	94
127	IRAK4	97	96	112
128	IRR	100	104	83
129	Itk	112	116	130
130	JAK1	86	93	67
131	JAK2	106	107	99
132	JAK3	110	101	31
133	JNK1α1	102	106	97
134	JNK2α2	106	98	101
135	JNK3	109	103	69
136	KDR	109	114	118
137	Lck	89	82	109
138	Lck(h) activated	100	77	57
139	LIMK1	89	86	44
140	LKB1	96	95	83
141	LOK	101	94	70
142	LRRK2	115	110	106
143	Lyn	81	73	4
144	MAPK1	106	93	57
145	MAPK2	99	104	87
146	MAPKAP-K2	77	98	71
147	MAPKAP-K3	118	110	96
148	MARK1	100	86	28
149	MEK1	98	93	92
150	MELK	89	88	50
151	Mer	111	105	105
152	Met(D1246H)	55	12	2
153	Met(D1246N)	82	47	1
154	Met	146	114	91
155	Met(M1268T)	78	48	5
156	Met(Y1248C)	80	38	−1
157	Met(Y1248D)	97	58	4
158	Met(Y1248H)	81	55	2
159	MINK	97	98	84
160	MKK6	92	98	101
161	MKK7β	109	123	99
162	MLCK	115	120	120
163	MLK1	83	77	75
164	Mnk2	102	100	81
165	MRCKα	91	96	98
166	MRCKβ	105	100	85
167	MSK1	100	119	108
168	MSK2	81	79	34
169	MSSK1	76	51	22
170	MST1	101	121	103
171	MST2	109	108	84
172	MST3	98	96	23
173	MST4	84	86	80
174	mTOR	104	80	65
175	mTOR/FKBP12	105	84	55
176	MuSK	104	92	106
177	NEK11	81	84	45
178	NEK2	104	113	75
179	NEK3	115	106	58
180	NEK6	96	96	57
181	NEK7	99	115	103
182	NLK	99	101	106
183	p70S6K	93	96	46
184	PAK1	92	94	98
185	PAK2	101	100	96
186	PAK4	95	94	94
187	PAK5	101	92	78
188	PAK6	98	98	91
189	PAR-1Bα	105	107	37
190	PASK	97	96	93
191	PDGFRα	99	103	107
192	PDGFRα(D842V)	99	90	67
193	PDGFRα(V561D)	102	100	59
194	PDGFRβ	112	92	99
195	PDK1	104	102	65
196	PEK	84	60	15
197	PhKγ2	106	109	88
198	PI3 Kinase (p110a(E542K)/p85a)	94	81	75
199	PI3 Kinase (p110a(E545K)/p85a)	95	90	85
200	PI3 Kinase (p110a(H1047R)/p85a)	95	87	80
201	PI3 Kinase (p110a/p65a)	91	84	84
202	PI3 Kinase (p110a/p85a)	92	86	88
203	PI3 Kinase (p110b/p85a)	91	85	81
204	PI3 Kinase (p110d/p85a)	97	87	88
205	PI3 Kinase (p120g)	96	101	104
206	PI3KC2a	95	85	74
207	PI3KC2g	72	41	63
208	Pim-1	82	79	60
209	Pim-2	100	104	89
210	Pim-3	102	103	111
211	PIP4K2a	79	52	77
212	PIP5K1a	67	49	76
213	PIP5K1g	76	58	68
214	PKA	121	123	115
215	PKBα	119	111	92
216	PKBβ	102	89	50
217	PKBγ	108	119	84
218	PKCα	113	106	95
219	PKCβI	112	123	105
220	PKCβII	101	116	105
221	PKCγ	106	106	74
222	PKCδ	95	91	61
223	PKCε	114	121	102
224	PKCζ	103	72	31
225	PKCη	114	122	114
226	PKCθ	106	112	91
227	PKCι	125	118	82
228	PKCμ	98	90	69
229	PKD2	97	105	78
230	PKG1α	106	105	94
231	PKG1β	110	110	75
232	Plk1	108	107	95
233	Plk3	115	112	98
234	PRAK	79	42	1
235	PRK2	103	92	84
236	PrKX	88	91	84
237	PTK5	95	88	93
238	Pyk2	107	100	79
239	Ret (V804L)	110	88	42
240	Ret	93	77	17
241	Ret(V804M)	102	101	55
242	RIPK2	99	98	97
243	ROCK-I	105	106	98
244	ROCK-II	101	106	97
245	Ron	97	78	14
246	Ros	89	82	53
247	Rse	103	129	50
248	Rsk1	88	78	36
249	Rsk2	101	94	31
250	Rsk3	118	101	55
251	Rsk4	105	111	60
252	SAPK2a	111	110	113
253	SAPK2a(T106M)	103	100	103
254	SAPK2b	106	105	105
255	SAPK3	99	98	91
256	SAPK4	92	100	76
257	SGK	104	102	91
258	SGK2	116	105	82
259	SGK3	107	120	109
260	SIK	92	83	76
261	Snk	90	93	89
262	Src(1-530)	98	84	45
263	Src(T341M)	115	130	72
264	SRPK1	79	63	27
265	SRPK2	87	65	46
266	STK25	89	121	58
267	STK33	109	101	105
268	Syk	72	21	1
269	TAK1	82	86	91
270	TAO1	92	92	81
271	TAO2	106	106	81
272	TAO3	103	103	108
273	TBK1	81	63	48
274	Tec activated	96	86	18
275	TGFBR1	114	108	108
276	Tie2	75	76	42
277	Tie2(R849W)	103	89	47
278	Tie2(Y897S)	114	96	31
279	TLK2	97	100	103
280	TrkA	103	73	11
281	TrkB	96	92	60
282	TrkC	99	43	2
283	TSSK1	102	97	83
284	TSSK2	100	101	53
285	Txk	95	99	96
286	TYK2	98	94	97
287	ULK2	100	95	89
288	ULK3	105	106	95
289	VRK2	102	104	105
290	Wee1	103	107	84
291	WNK2	85	89	90
292	WNK3	91	85	83
293	Yes	110	93	68
294	ZAP-70	114	103	43
295	ZIPK	103	112	85

†Parenthesis identifies a protein encoded by a mutated form of the gene.

The inhibitory effect of the organic extract of S. tortuosum on kinase activity displayed a wide range of effectiveness depending on the specific kinase. Two-hundred-ninety-five human kinases were assayed in a cell-free system. Surprisingly we discovered that the organic extract of S. tortuosum inhibited 71 in a concentration-dependent manner that captured the median inhibitory concentration. The IC₅₀values for these kinases are presented in Table 4.

TABLE 4

Median inhibitory concentrations for 71 protein kinases exhibiting
a concentration-dependent inhibition by the S. tortuosum extract

IC₅₀

	Kinase	[μg/mL]

1	CLK1	3.9
2	Met(D1246H)	4.9
3	Syk	11
4	Aurora-B	14
5	Met(Y1248C)	16
6	PRAK	17
7	Met(M1268T)	19
8	Met(D1246N)	19
9	Flt4	20
10	Met(Y1248H)	21
11	TrkC	23
12	CK2α2	24
13	MSSK1	25
14	Fms	25
15	CK1γ2	26
16	CK1γ3	26
17	GSK3α	28
18	Met(Y1248D)	28
19	Lyn	28
20	PEK	29
21	Blk	33
22	EphB4	34
23	cKit(D816H)	35
24	SRPK1	37
25	EphB2	37
26	Aurora-A	37
27	Fyn	38
28	GSK3β	38
29	TrkA	38
30	Ron	41
31	Ret	42
32	BrSK1	45
33	cKit(V654A)	46
34	CLK4	47
35	Tec activated	50
36	IR, activated	51
37	CLK2	51
38	CLK3	53
39	Aurora-C	55
40	PKCζ	58
41	FGFR1	58
42	CSK	60
43	CK1γ1	65
44	MARK1	65
45	MST3	65
46	BTK	67
47	cKit(V560G)	68
48	DAPK2	68
49	Flt1	68
50	MSK2	68
51	AMPKα2	69
52	BrSK2	77
53	Abl(T315I)	73
54	Rsk1	73
55	Rsk2	80
56	Tie2(Y897S)	81
57	JAK3	87
58	SRPK2	88
59	AMPKα1	90
60	Flt3	97
61	TBK1	98
62	Tie2	101
63	Flt3(D835Y)	102
64	EGFR	102
65	Ret (V804L)	103
66	Haspin	105
67	Hck	110
68	FGFR4	116
69	Src(1-530)	119
70	PAR-1Bα	119
71	CK2	120

†Parenthesis identifies a protein encoded by a mutated form of the gene.

Of the 295 human kinases assayed in cell free system, we discovered that the Sceletium extract tested inhibited 71 of them in a concentration-dependent manner. Of those 71 kinases, 9 had IC₅₀values less than 20 μg/mL and 50 kinases exhibited IC₅₀values of 50 μg/mL or less. These kinases represented signaling pathways in glucose metabolism, inflammation, oxidative stress, organ regeneration, tissue remodeling, brain development, immune responses and the development and repair of the gastrointestinal tract. Thus, inhibition of those kinases would provide a beneficial effect for a subject in need.

TABLE 5

Protein kinases activated by the S. tortuosum extract

	Kinase	Relative Increase

1	IGF-1R	229
2	IR	196
3	Met	146
4	B-Raf(V599E)	138
5	DAPK1	134
6	ALK	133
7	Itk	130
8	Src(T341M)	130
9	Rse	129
10	CDK7/cyclinH/MAT1	128
11	DMPK	126
12	PKCι	125
13	B-Raf	124
14	CHK2	123
15	MKK7β	123
16	PKCβI	123
17	PKA	123
18	PKCη	122
19	Axl	122
20	EphA8	122
21	MST1	121
22	Abl (Q252H)	121
23	STK25	121
24	PKCε	121

†Parenthesis identifies a protein encoded by a mutated form of the gene.

Of the 295 kinases studies, 24 of them exhibited a maximum activation greater than 20% one or more of the three concentrations of the organic extract of Sceletium. Notable among those kinase increases was the greater than two-fold activation of IGF-1R, and IR. This discovery indicates potential use of the organic extract of Sceletium as a IGF1 and insulin mimetics, respectively. As such these extracts, as well as fractions or compounds derived from these extracts, would have uses in metabolic conditions responsive to IGF1 and insulin administration. Non-limiting examples of metabolic disorders benefiting from an IGF mimetic include myopathies, such as age- or disease-related loss of muscle tissue and muscular dystrophies, chronic obstructive pulmonary disease as well as in systemic disorders such as cancer, diabetes, sepsis, heart failure, decreased bone density, and anorexia.
Non-limiting examples of metabolic disorders benefiting from an insulin mimetic include type 1, type 2 and type 3 diabetes, metabolic syndrome, obesity, and cardiovascular diseases.

Exemplary Embodiments

The following exemplary invention embodiments pertain to further aspects of the disclosure.
In one example there is provided, a formulation for inhibiting phosphodiesterase type V (PDE5) activity, comprising:

- a therapeutically effective amount of an extract of a Sceletium species that inhibits PDE5 activity in a form suitable for administration to the subject.

In one example, the Sceletium extract in the formulation is from at least one of S. tortuosum, S. strictum, S. subvelutinum, S. joubertii, and S. namaquense or a combination thereof.
In one example, the Sceletium extract in the formulation is derived from S. tortuosum.
In one example, the Sceletium extract in the formulation is derived from aerial portions of a Sceletium plant.
In one example, the formulation further comprises a pharmaceutically acceptable carrier.
In one example, the Sceletium extract comprises from about 1 wt % to about 50 wt % of the formulation.
In one example, the Sceletium extract comprises from about 3 wt % to about 15 wt % of the formulation.
In one example, the formulation further comprises an amount of at least one activity enhancer.
In one example, the PDE5 inhibiting effect of the formulation, including at least one activity enhancer, when administered to a subject is more than an additive effect achieved by administering the Sceletium extract or the activity enhancer alone.
In one example, the PDE5 inhibiting effect of the formulation on the subject is from about 400/% to about 110% greater than that achieved by administering either the Sceletium extract or the activity enhancer alone.
In one example, the activity enhancer in the formulation is a member selected from the group consisting of: L-theanine, thiamine, zinc gluconate, magnesium citrate, magnesium stearate, cellulose, or a mixture thereof.
In one example, the activity enhancer in the formulation is L-theanine.
In one example, the activity enhancer in the formulation is thiamine.
In one example, the formulation comprises a plurality of activity enhancers.
In one example the formulation comprises a plurality of activity enhancers and the activity enhancers include L-theanine and thiamine.
In one example, the formulation comprises a plurality of activity enhancers and the activity enhancers include L-theanine, thiamine, magnesium citrate, and zinc.
In one example, the formulation above further comprises magnesium stearate.
In one example, the at least one activity enhancer in the formulation comprises from about 1 wt % to about 75 wt % of the formulation.
In one example, the Sceletium extract in the formulation is present from about 3 wt % to about 15 wt % and the at least one activity enhancer is present in the formulation from about 1 wt % to about 75 wt %.
In one example, the at least one activity enhancer in the formulation is in a form of a pharmaceutically acceptable salt.
In one example, the formulation further comprises a secondary active agent member selected from the group consisting of: arginine, yohimbine, lepidium mevenii extract, Panax ginseng extract, Ginkgo biloba L. extract, and Epimedium grandiflonrm flavanol icariin, or a mixture thereof.
In one example, the formulation further comprises at least one member selected from the group consisting of coatings, isotonic and absorption delaying agents, binders, adhesives, lubricants, disentegrates, coloring agents, flavoring agents, sweetening agents, absorbents, detergents, emulsifying agents, preservatives, antioxidants, vitamins, minerals, proteins, fats, carbohydrates, or a mixture thereof.
In one example, the formulation is an oral dosage formulation.
In one example, the oral dosage form comprises a capsule, a tablet, a powder, a beverage, a syrup, a suspension, or a food.
In one example, the formulation comprises from about 0.1 mg to about 10,000 mg of the Sceletium extract.
In one example there is provided, a Sceletium extract dosage form for administration to a subject to inhibit phosphodiesterase type V (PDE5) activity comprising:

In one example, the amount of the Sceletium extract in the dosage form is from about 0.01 mg to about 30,000 mg.
In one example, the amount of the Sceletium extract in the dosage form is from about 0.01 mg to about 10,000 mg.
In one example, the amount of the Sceletium extract in the dosage form is from about 0.1 mg to about 100 mg.
In one example, the dosage form further comprises at least one activity enhancer.
In one example, the amount of the at least one activity enhancer in the dosage form is from about 0.01 mg to about 10,000 mg.
In one example, the amount of the at least one activity enhancer in the dosage form is from about 1 mg to about 125 mg.
In one example, the Sceletium extract is present in the dosage form at an amount of from about 1 mg to about 100 mg and the at least one activity enhancer is present in an amount of from about 1 mg to about 125 mg.
In one example, the dosage form is prepared for administration to a subject according to a predetermined regimen.
In one example, the dosage form is administered in the regimen is a once per day administration.
In one example, the dosage form is administered according to a predetermined regimen that is a multiple times per day administration.
In one example, the dosage form is administered in an oral dosage form, a transdermal dosage form, a transmucosal dosage form, an inhalant dosage form, or a parenteral dosage form.
In one example there is provided, a method of inhibiting phosphodiesterase type V (PDE5) activity in a subject comprising:

- administering a therapeutically effective amount of an extract of a Sceletium species that inhibits PDE5 activity to the subject.

In one example, the therapeutically effective amount of the Sceletium species extract is from about 0.01 mg to about 30,000 mg.
In one example, the amount of the Sceletium species extracts is from about 0.01 mg to about 10,000 mg.
In one example, the Sceletium species is a member selected from the group consisting of: S. tortuosum, S. strictumr, S. subvelutinum, S. joubertii, and S. namaquense, or a combination thereof.
In one example, the Sceletium species is S. tortuosum.
In one example, at least one activity enhancer is administered in addition to the formulation.
In one example, the activity enhancer used in the method is a member selected from the group consisting of: L-theanine, thiamine, zinc gluconate, magnesium citrate, magnesium stearate, cellulose, or a mixture thereof.
In one example, the PDE5 inhibiting effect is greater than an effect provided by either the amount of Sceletium extract or the amount of activity enhancer alone.
In one example, the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: prostate cancer, erectile dysfunction, prostate hyperplasia, lower urinary tract symptoms, premature ejaculation, Addison's disease, benign prostatic hypertrophy, female sexual arousal disorder, and low sex drive.
In one example, the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: pulmonary arterial hypertension, congestive cardiac failure, cardiomyopathy, pulmonary hypertension, various cardiovascular diseases, Raynaud's phenomenon, essential hypertension, stroke, shock, heart failure, ischemia, and vasculitis.
In one example, the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: diminished exercise capacity, chronic fatigue syndrome, hypoxia, and asthma.
In one example, the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: motor dysfunction, cognitive disorders including Alzheimer's disease, autoimmune diseases, bipolar disorder, lupus, fibromyalgia, nervous system disorders, and multiple sclerosis.
In one example, the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: cutaneous conditions and diseases, inflammation, chronic inflammatory disease, osteoarthritis, and rheumatoid arthritis.
In one example, the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: cancer, type 1 and type 2 diabetes, gastrointestinal diseases, metabolic syndrome, obesity, inflammatory bowel disease, thyroiditis, and Crohn's disease.
In one example, the PDE5 inhibition provides treatment of signs or symptoms of oxidative stress.
In one example, is administered to a subject that is a mammal.
In one example, the mammal is a human.
In one example, the mammal is a domesticated or farm animal.
In one example, the treatment is prophylactic.
In one example, the Sceletium extract is administered orally, rectally, ophthalmicly, nasally, nasally by inhalation, topically, vaginally, parentally, by implantation, or intramuscularly.
In one example, the Sceletium extract is administered orally.
In one example, the Sceletium extract and at least one activity enhancer are administered concurrently.
In one example, the Sceletium extract and at least one activity enhancer are administered from a single formulation.
In one example, the Sceletium extract and at least one activity enhancer are administered separately.
In one example, the Sceletium extract and the at least one activity enhancer are administered sequentially.
In one example there is presented, a method of increasing phosphodiesterase type V (PDE5) inhibition activity of an amount of a Sceletium extract comprising:

- adding an amount of at least one activity enhancer, wherein the combination of Sceletium extract and the at least one activity enhancer inhibits PDE5 activity to a greater degree than the amount of Sceletium extract alone.

In one example, the PDE5 inhibition occurs in a subject to whom the Sceletium extract and the at least one activity enhancer are administered.
In one example, the at least one activity enhancer is added to a formulation containing the Sceletium extract.
In one example, the at least one activity enhancer is added to the Sceletium extract upon administration of the activity enhancer to a subject.
In one example, the increase in PDE5 inhibition activity is more than an additive effect of administering the amount of Sceletium extract and the amount of at least one activity enhancer alone.
In one example, the increase in PDE5 inhibition activity is from about 40% to about 110% greater than that achieved by administering either the Sceletium extract or the activity enhancer alone.
In one example, the Sceletium extract is from at least one of S. tortuosum, S. striclum, S. subvelutinum, S. joubertii, and S. namaquense, or a combination thereof.
In one example, the Sceletium extract is from S. tortuosum.
In one example, the at least one activity enhancer is a member selected from the group consisting of: L-theanine, thiamine, zinc gluconate, magnesium citrate, magnesium stearate, cellulose, or mixtures thereof.
In one example, the at least one activity enhancer is L-theanine.
In one example, the at least one activity enhancer is thiamine.
In one example, the amount of at least one activity enhancer is added to the amount of Sceletium extract at a ratio of from about 1:1 to about 20:1.
In one example, the ratio is from about 2:1 to about 15:1.
In one example, the ratio is about 14:1.
In one example, the at least one enhancer is added in an amount of 345 mg to a formulation containing 25 mg of Sceletium extract.
In one example there is provided, a phosphodiesterase type V (PDE5) inhibiting system, comprising:

- an amount of an extract of a Sceletium species that inhibits PDE5 activity; and a delivery vehicle.

In one example, the delivery vehicle is a pharmaceutically acceptable carrier.
In one example, the system further comprises an amount of at least one activity enhancer.
In one example, the Sceletium extract and the at least one activity enhancer are separate from one another.
In one example, the Sceletium extract and the at least one activity enhancer are in separate formulations.
In one example, the Sceletium extract and the at least one activity enhancer are in a single formulation.
In one example, the amount of Sceletium extract and the amount of at least one activity enhancer are more effective at inhibiting PDE5 together than either the amount of Sceletium extract or the amount of at least one activity enhancer alone.
In one example, the PDE5 inhibiting effect of the combined amount of Sceletium extract and the amount of at least one activity enhancer is from about 40% to about 110% greater than that achieved by administering the amount of Sceletium extract or the amount of activity enhancer alone.
In one example, the Sceletium extract is derived from at least one of S. tortuosum, S. strictum, S. subvelutinum, S. joubertii, and S. namaquense or a combination thereof.
In one example, the Sceletium extract is derived from S. tortuosum.
In one example, the amount of the amount of Sceletium extract is from about 0.01 mg to about 30,000 mg.
In one example, the amount of Sceletium extract is from about 0.01 mg to about 10,000 mg.
In one example, the amount of Sceletium extract is from about 1 mg to about 100 mg.
In one example, the amount of the at least one activity enhancer is from about 0.01 mg to about 10,000 mg.
In one example, the amount of the at least one activity enhancer is from about 1 mg to about 125 mg.
In one example, the Sceletium extract and the at least one activity enhancer are packaged together.
In one example there is provided, a method disease-associated protein kinase activity in a subject comprising:
administering to the subject a formulation having an extract of a Sceletium species that inhibits phosphodiesterase type V (PDE5) activity in an amount sufficient to modulate a selected protein kinase activity.
In one example, the Sceletium species extract modulates activity of multiple protein kinases.
In one example, the disease-associated protein kinase is a member selected from the group consisting of: IGF-1R, IR, Met, B-Raf(V599E), DAPK1, ALK, Itk, Src(T341M), Rse, CDK7/cyclinH/MAT1, DMPK, PKC₁, B-Raf, CHK2, MKK7β, PKCβI, PKA, PKCη, Ax1, EphA8, MST1, Ab1(Q252H), STK25, and PKCγ.
In one example there is provided, a method of preparing a phophdiesterase type V (PDE5) activity inhibiting formulation comprising;
providing an extract of Sceletium species that inhibits PDE5 activity; and concentrating the extract into a therapeutically effective amount sufficient to inhibit PDE5 activity when administered to a subject.
In one example, the method further comprises combining the concentrated extract with a pharmaceutically acceptable carrier.
In one example, the method further comprises adding an amount of an enhancing agent to the concentrated extract.
In one example there is provided, a method of preventing cGMP degradation in a subject, comprises administering a therapeutically effective amount of an extract of a Sceletium species that inhibits PDE5 activity in a form that is suitable for administration to the subject
In one example there is provided, a composition for enhancing the PDE (e.g. PDE5) inhibitory activity of Sceletium in a subject comprising a therapeutically effective amount of at least one member selected from the following group comprising:
a. from about 0.01 mg to about 10,000 mg of aerial parts of Sceletium;
b. from about 0.01 mg to about 10,000 mg of an extract of Sceletium tortuosum;
c. from about 0.01 mg to about 10,000 mg of a compound derived from Sceletium;
and at least one member from the following group comprising:
d. from about 0.01 mg to about 10,000 mg of L-theanine;
e. from about 0.01 mg to about 10,000 mg of thiamine;
f. from about 0.01 mg to about 10,000 mg of zinc gluconate;
g. from about 0.01 mg to about 10,000 mg of magnesium citrate;
h. from about 0.01 mg to about 10,000 mg of magnesium stearate;
i. from about 0.01 mg to about 10,000 mg of cellulose.
In one example there is provided, a method for enhancing the PDE (PDE5) inhibitory activity of Sceletium administered to a subject comprising administering a therapeutically effective amount of at least one member selected from the following group comprising:
a. from about 0.01 mg to about 10,000 mg of aerial parts of Sceletium;
b. from about 0.01 mg to about 10,000 mg of an extract of Sceletium tortuosum;
c. from about 0.01 mg to about 10,000 mg of a compound derived from Sceletium;
and at least one member from the following group comprising:
d. from about 0.01 mg to about 10,000 mg of L-theanine;
e. from about 0.01 mg to about 10,000 mg of thiamine;
f. from about 0.01 mg to about 10,000 mg of zinc gluconate;
g. from about 0.01 mg to about 10,000 mg of magnesium citrate;
h. from about 0.01 mg to about 10,000 mg of magnesium stearate;
i. from about 0.01 mg to about 10,000 mg of cellulose.
Thus, there have been disclosed novel compositions of Sceletium and/or Sceletium extract, such as S. tortuosum and methods of synergistically inhibiting PDE5. Methods for the production of these formulations and uses have been described. It will be readily apparent to those skilled in the art, however that various changes and modifications of an obvious nature may be made without departing from the spirit of the disclosed invention embodiments, and all such changes and modifications are considered to fall within the scope of the invention as recited herein, including in the appended claims. Examples of such changes and modifications could include, but not be limited to, the incipient ingredients added to affect the capsule, tablet, powder, lotion, food or bar manufacturing process as well as vitamins, flavorings and carriers. Other examples of such changes or modifications could include the use of herbs or other botanical products containing the combinations of the preferred embodiments disclosed above.

tortousum,

What is claimed is:

1. A formulation for inhibiting phosphodiesterase type V (PDE5) activity in a subject comprising:

a therapeutically effective amount of an extract of a Sceletium species that inhibits PDE5 activity in a form suitable for administration to the subject.

2. The formulation of claim 1, wherein the Sceletium species is a member selected from the group consisting of: S. tortuosum, S. strictum, S. subvelutinum, S. joubertii, and S. namaquense, or a combination thereof.

3. The formulation of claim 2, wherein the Sceletium species is S. tortuosum.

4. The formulation of claim 1, wherein the Sceletium species comprises from about 1 wt % to about 50 wt % of the total formulation.

5. The formulation of claim 1, further comprising an amount of at least one activity enhancer.

6. The formulation of claim 5, wherein the activity enhancer has substantially no PDE5 inhibitory effect of its own.

7. The formulation of claim 5, wherein when administered to the subject, the formulation is more effective at inhibiting PDE5 activity than either the Sceletium species or the activity enhancer alone.

8. The formulation of claim 5, wherein the PDE5 inhibiting effect of the formulation on the subject is more than an additive effect achieved by administering the Sceletium species or the activity enhancer alone.

9. The formulation of claim 5, wherein the PDE5 inhibiting effect of the formulation on the subject is from about 40% to about 110% greater than that achieved by administering either the Sceletium species or the activity enhancer alone.

10. The formulation of claim 5, wherein the activity enhancer, is a member selected from the group consisting of: L-theanine, thiamine, zinc gluconate, magnesium citrate, magnesium stearate, cellulose, or a mixture thereof.

11. The formulation of claim 10, wherein the at least one activity enhancer is L-theanine.

12. The formulation of claim 10, wherein the at least one activity enhancer is thiamine.

13. The formulation of claim 5, wherein the activity enhancer comprises from about 1 wt % to about 75 wt % of the total formulation.

14. The formulation of claim 5, wherein the Sceletium species is present from about 3 wt % to about 15 wt % and the activity enhancer is present from about 1 wt % to about 75 wt %.

15. The formulation of claim 1, further comprising a secondary active agent member selected from the group of consisting of arginine, yohimbine, lepidium meyenii extract, Panax ginseng extract, Ginkgo biloba L. extract, and Epimedium grandiflorum flavanol icariin, or a mixture thereof.

16. The formulation of claim 1, wherein the formulation further comprises a pharmaceutically acceptable carrier.

17. The formulation of claim 16, wherein the formulation is an oral dosage formulation.

18. The formulation of claim 17, wherein the oral dosage form comprises a capsule, a tablet, a powder, a beverage, a syrup, a suspension, or a food.

19. The formulation of claim 17, wherein the consumable formulation comprises from about 0.1 mg to about 10,000 mg of the Sceletium species.

20. A Sceletium extract dosage form for administration to a subject to inhibit phosphodiesterase type V (PDE5) activity comprising:

21. The dosage form of claim 20, wherein the amount of the Sceletium species extract is from about 0.01 mg to about 30,000 mg.

22. The dosage form of claim 20, wherein the amount of the Sceletium species extracts is from about 0.01 mg to about 10,000 mg.

23. The dosage form of claim 20, wherein amount of the Sceletium species extract is from about 0.1 mg to about 100 mg.

24. The dosage form of claim 20, further comprising an amount of at least one activity enhancer.

25. The dosage form of claim 24, wherein the amount of the at least one activity enhancer is from about 0.01 mg to about 10,000 mg.

26. The dosage form of claim 24, wherein the amount of the at least one activity enhancer is from about 1 mg to about 125 mg.

27. The dosage form of claim 24, wherein the Sceletium species extract is present at an amount of from about 1 mg to about 100 mg and the at least one activity enhancer is present in an amount of from about 1 mg to about 125 mg.

28. The dosage form of claim 20, wherein the dosage is prepared for administration to the subject according to a predetermined regimen.

29. The dosage form of claim 28, wherein the regimen is a once per day administration.

30. The dosage form of claim 20, wherein the dosage is one of an oral dosage form, a transdermal dosage form, a transmucosal dosage form, an inhalant dosage form, or a parenteral dosage form.

31. A method of inhibiting phosphodiesterase type V (PDE5) activity in a subject comprising:

administering a therapeutically effective amount of an extract of a Sceletium species that inhibits PDE5 activity to the subject.

32. The method of claim 31, wherein the therapeutically effective amount of the Sceletium species extract is from about 0.01 mg to about 30,000 mg.

33. The method of claim 31, wherein the amount of the Sceletium species extracts is from about 0.01 mg to about 10,000 mg.

34. The method of claim 31, wherein amount of the Sceletium species extract is from about 0.1 mg to about 100 mg.

35. The method of claim 31, wherein the Sceletium species is a member selected from the group consisting of: S. tortuosum, S. strictum, S. subvelutinum, S. joubertii, and S. namaquense, or a combination thereof.

36. The method of claim 35, wherein the Sceletium species is S. tortuosum.

37. The method of claim 31, further comprising administering an amount of at least one activity enhancer to the subject.

38. The method of claim 37, wherein the at least one activity enhancer that is a member selected from the group consisting of: L-theanine, thiamine, zinc gluconate, magnesium citrate, magnesium stearate, cellulose, or a mixture thereof.

39. The method of claim 31, wherein the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: prostate cancer, erectile dysfunction, prostate hyperplasia, lower urinary tract symptoms, premature ejaculation, Addison's disease, benign prostatic hypertrophy, female sexual arousal disorder, and low sex drive.

40. The method of claim 31, wherein the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: pulmonary arterial hypertension, congestive cardiac failure, cardiomyopathy, pulmonary hypertension, various cardiovascular diseases, Raynaud's phenomenon, essential hypertension, stroke, shock, heart failure, ischemia, and vasculitis.

41. The method of claim 31, wherein the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: diminished exercise capacity, chronic fatigue syndrome, hypoxia, and asthma.

42. The method of claim 31, wherein the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: motor dysfunction, cognitive disorders including Alzheimer's disease, autoimmune diseases, bipolar disorder, lupus, fibromyalgia, nervous system disorders, and multiple sclerosis.

43. The method of claim 31, wherein the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: cutaneous conditions and diseases, inflammation, chronic inflammatory disease, osteoarthritis, and rheumatoid arthritis.

44. The method of claim 31, wherein the PDE5 inhibition provides treatment of signs or symptoms of a condition selected from the group consisting of: cancer, type 1 and type 2 diabetes, gastrointestinal diseases, metabolic syndrome, obesity, inflammatory bowel disease, thyroiditis, and Crohn's disease.

45. The method of claim 31, wherein the PDE5 inhibition provides treatment of signs or symptoms of oxidative stress.

46. The method of claim 31, wherein a treatment is prophylactic.

47. The method of claim 37, wherein the Sceletium species extract and at least one activity enhancer are administered concurrently.

48. The method of claim 37, wherein the Sceletium species extract and at least one activity enhancer are administered separately.

49. A method of increasing phosphodiesterase type V (PDE5) inhibition activity of an amount of a Sceletium extract comprising:

adding an amount of at least one activity enhancer, wherein the combination of Sceletium extract and the at least one activity enhancer inhibits PDE5 activity to a greater degree than the amount of Sceletium extract alone.

50. The method of claim 49, wherein the at least one activity enhancer is added to the Sceletium species extract upon administration of the activity enhancer to a subject.

51. The method of claim 49, wherein the increase in PDE5 inhibition activity is more than an additive effect of administering the amount of Sceletium species extract and the amount of at least one activity enhancer alone.

52. The method of claim 49, wherein the amount of at least one activity enhancer is added to the amount of Sceletium species extract at a ratio of from about 1:1 to about 20:1.

53. A phosphodiesterase type V (PDE5) inhibiting system, comprising;

an amount of an extract of a Sceletium species that inhibits PDE5 activity; and

a delivery vehicle.

54. The system of claim 53, wherein the delivery vehicle is a pharmaceutically acceptable carrier.

55. The system of claim 53, further comprising an amount of at least one activity enhancer.

56. The system of claim 55, wherein the Sceletium species extract and the at least one activity enhancer are separate from one another.

57. A method for modulating a disease-associated protein kinase activity in a subject comprising:

administering to the subject a formulation having an extract of a Sceletium species that inhibits phosphodiesterase type V (PDE5) activity in an amount sufficient to modulate a selected protein kinase activity.

58. The method of claim 57, wherein the Sceletium species extract modulates activity of multiple protein kinases.

59. The method of claim 57, wherein the disease-associated protein kinase is a member selected from the group consisting of: IGF-1R, IR, Met, B-Raf(V599E), DAPK1, ALK, Itk, Src(T341M), Rse, CDK7/cyclinH/MAT1, DMPK, PKC₁, B-Raf, CHK2, MKK7β, PKCβI, PKA, PKCη, Ax1, EphA8, MST1, Ab1(Q252H), STK25, and PKCε.