RU2281099C2 - Treatment of herpetic neurological viral diseases by using 1,4-dihydropyridine blockers of calcium channels - Google Patents

Abstract

FIELD: medicine, neurology, virology.

SUBSTANCE: invention relates to treatment of neurological diseases caused by herpes virus, such as Bell's paralysis, Hunt's disease, herpetic encephalitis accompanying with damage of cerebral nerves. Invention involves using 1,4-dihydropyridine blockers of calcium channels, such as felodipine, nifedipine, nimodipine, nisodipine being taken preferably in combination with herpes virus antagonist. Invention provides repairing damaged cerebral nerves by topical expanding arteriols and recovery of local microcirculation based on specific competitive interaction of definite groups of calcium blockers of 1,4-dihydropyridine type with vasoconstrictor endothelin.

EFFECT: enhanced effectiveness of treatment.

47 cl, 2 dwg, 1 ex

Description

Field of Invention

The present invention relates to the treatment of certain neurological diseases caused by the herpes virus in mammals, mainly Bell palsy, facial nerve palsy, and the use of calcium channel blockers, preferably in combination with a herpes virus antagonist, in the treatment of these diseases. Other diseases associated with the herpes virus include Ramsay Hunt syndrome (hereinafter referred to as Hunt syndrome) and other neurological diseases caused by the herpes virus, such as encephalitis caused by the herpes simplex virus.

BACKGROUND OF THE INVENTION

This patent claims the priority of provisional application 60/065145, filed November 12, 1997

Bell palsy (originally described by Charles Bell in 1812) is regarded as facial paralysis, usually the seventh cranial nerve. It most often affects one side of the face, can be partial or complete and has a progression period of 7 to 10 days. In the past, it was regarded as an idiopathic disease, but there has recently been compelling evidence that its cause is a herpes simplex virus, a type of herpes simplex virus. Some doctors assure patients that over a period of 3 weeks to 6 months, the disease is most likely to go away (that is, some doctors advocate a policy of inaction rather than treating facial nerve damage, this is sometimes called "therapeutic nihilism") , but the fact remains that approximately 24% of patients suffering from this disease, using the currently available treatment methods, retain some residual paralysis or other consequences, such as a half-face spasm, synkinesia or loss of functions such as the formation of tear fluid or blinking.

An understanding of probable physiological processes (without identifying their causes) was comprehensively promoted by the works of Hilger (Hilger J, The Nature of Bell's Palsy. Laryngoscope, 54: 228-235, 1949) and Blunt (Blunt M, Possible Role of Vascular Changes in the Etiology of Bell's Palsy, J. Laryngol Otol, 70: 701-713, 1956), in which they argued that facial paralysis causes narrowing of the arterioles inside the canal of the facial nerve of the temporal bone. It was believed that this narrowing of the vessels led to primary ischemia (tissue anemia), which caused swelling of the nerve sheath, and secondary ischemia due to compression of the nerve. K.Adour opposed such an opinion and, instead, put forward a viral theory (Adour KK, Cranial Polyneuritis and Bell's Palsy, Arch Otolaryngol, 102: 262-4, 1976) based on the reactivation of the herpes simplex virus, and argued that paralysis Bella is a polycranial disease that is not consistent with the ischemic scenario. However, confirmation of the previous ischemic concept was obtained as a result of anatomical and electromyographic and histopathological studies, which were summarized by U. Fisch (Fisch U. And Felix, H, On the Parthenogenesis of Bell's Palsy. Acta Otolaryngol, 95: 532-538, 1983)) . Further, the description of events from the point of view of ischemia fits well with the later causal analyzes conducted by M. Ikeda (Ikeda M et al, Plasma Endothelin Level in the Acute Stage of Bell Palsy, Arch Otolaryngol Head Neck Surg, 122: 849-852 1996 Aug), including the discovery of endothelin; and the author of the invention by analysis linked the results of a study of the immunological role of endothelin with the ischemic scenario (which requires the role of the herpes virus), as will be explained below.

The currently used treatment mainly includes the administration of steroids, in particular prednisone (see US patent No. 2897216) within the first 3 days from the start, with the standard initial dosage of prednisone being about 30 mg and gradually decreasing over 5- daily period to the level of 10 mg. In some regions of Japan and Europe, steroid treatment has taken the form of treatment with higher dosages of steroids, mainly cortisone, included in a low molecular weight dextran solution for intravenous administration (Kinishi M et al., Conservative Treatment of Hunt Syndrome, Nippon Jibinkoka Gakkai Kaiho, 95: 1, 65-70, 1992) (See US Patent No. 2841578). The theory behind steroid or prednisone treatment, or with a higher dosage method, is to improve microcirculation, which has been impaired due to inflammation affecting the seventh cranial nerve. It can be noted that treatment with high doses of steroids brings its share of risk, including serious liver and kidney disorders, which makes many doctors uncomfortable.

Recently, as a result of research by Dr. Kedar Adour, who for many years has advocated that herpes simplex virus is the causative agent of Bell's palsy, a new approach has emerged that is related to steroid therapy. Based on this view, Adour advocated the use of acyclovir (see US Pat. No. 2,593,963) (commonly used to treat herpes virus infections) for the treatment of Bell's palsy. To this end, he conducted a double-blind study (Adour KK et al., Bell's Palsy Treatment With Acyclovir And Prednisone Compared With Prednisone Alone: A Double-Blind, Randomized Controlled Trial. Otol Rhinol. Laryngol 1996; 105: 371-378) (Kaiser Permanente Medical Cetnter), which confirms the effectiveness of the use of acyclovir, which is an established inhibitor of the herpes virus. The study compared the group of subjects treated with acyclovir-prednisone with the prednisone-placebo group, and the following results were obtained: the recovery rate of voluntary movements of 92% in the acyclovir group, compared with 76% in the prednisone-placebo group, and the frequency of preventing degenerative changes nerve 87% in the acyclovir-prednisone group, compared with 70% in the prednisone-placebo group. Although the number of subjects was one hundred people, approximately equally divided into 2 groups, the results are statistically significant and are consistent with other studies confirming the origin of the Bell paralysis agent from herpes simplex or the herpes virus family. Such studies include Siguta (Siguta T et al., Facial Nerve Paralysis Induced by Herpes Simplex Virus in Mice: An Animal Model of Acute Transient Facial Paralysis, Ann Otol Rhinol Laryngol 104 (7): 574-581, 1995 July), in which Bell's apparent paralysis was caused in mice by the herpes simplex virus, and Murakami's work, pointing primarily to the role of the herpes simplex virus, but sometimes pointing to other herpes viruses.

Further, a recent significant study by M. Ikeda (Nihon University School of Medicine, Tokyo, Japan), linking endothelin, a 21-amino acid peptide with Bell's palsy, was recently conducted. This study has not yet been studied carefully enough, but it, however, sheds important light on some of the immediate causal phenomena underlying Bell's paralysis. Endothelin is an extremely powerful agent that constricts blood vessels, especially small ones, and Ikeda claims that Bell’s paralysis is responsible for microcirculation disorders due to primary and secondary ischemia in the facial nerve canal (which goes back to the earlier publication of Hilger and Blunt), but the novelty is that the occurrence of this is associated with the role of endothelin. However, Ikeda views the etiology of Bell's palsy as unknown or idiopathic and does not offer any causal hypotheses regarding high levels of endothelin.

In addition to steroids, there are currently some other types of treatments, but they are not as popular, although they are sometimes used in combination with them. These methods include surgical decompression, which was more common in previous decades since the thirties, although it is sometimes still used (Jabor MA, Management of Bell's Palsy, J LA State Medical Soc, 146 (7): 279-283, 1996), when the lesion is assessed as extensive. In addition, treatment includes electrical stimulation (also used in previous decades (Devrese PP at al., Electrotherapy in Facial Paralysis, ORL Otorhinolaryngol Relat Spec, 1974; 36 (2): 94-99), acupuncture and biological feedback (May M , et al, Bell's Palsy: Management of Sequelae Using EMG. Rehabilitation, Bottulinum and Surgery, Am J Otol, 10 (3): 220-229, 1989 May)). It turns out that, according to these methods, no final studies have been conducted, and the data on their effectiveness that are questionable are mixed at best. As for surgical treatment, it is associated with a particular risk, although it is based on the ischemic hypothesis.

In addition to the treatment methods discussed, designed to alleviate or minimize nerve damage, in order to avoid permanent damage to the eyes, therapeutic approaches are almost invariably offered, including the use of eye linings and artificial tear fluid. Conductivity studies are also used, which play a significant role in assessing permanent damage and degenerative changes in the nerve. Facial massage is sometimes also recommended to facilitate blood circulation and to avoid atrophy after restoration of muscle movements.

Since 1971, there have been 4 patents (Nos. 5589183, 5542437, 5148477 and 4817628), which relate to Bell paralysis. Of the four, two relate to the treatment of facial nerve lesions with mechanical devices, and two relate to electrical diagnostics for assessment.

Hunt syndrome (also known as "herpes zoster oticus") is also caused by the herpes virus, but in this case the herpes zoster virus, as claimed by Ramsay Hunt in 1907. Hunt syndrome often leads to facial paralysis, which affects the seventh cranial nerve (like with Bell paralysis), but also usually affects other cranial nerves, including the 5th, 9th, 10th and 11th). (In addition, it should be noted that Hunt syndrome, referred to in the present invention as Hunt syndrome I, should not be confused with Ramsay Hunt syndrome II, a completely different disease, which is a rare degenerative neurological disorder characterized by seizures of epileptic type and myoclonus) . Hunt's syndrome is often accompanied by blistering rashes on the ears, sometimes also found on the face, neck or scalp, and often leads to hearing loss (48.2% according to S. Murikami) (Murikami et al., Clinical features and Prognosis of Facial Palsy and Hearing Loss in Patients With Ramsay Hunt, Nippon Jibiinkoka Gakkao, 99:12, 1772-1779, 1996 Dec). Frequent manifestations are also intense pain in the ears, dizziness and ringing in the ears. Hunt syndrome for facial paralysis of the seventh cranial nerve (as in Bell palsy) is found to have a less favorable recovery profile than the latter (Robillard RB et al., Ramsay Hunt Facial Paralysis: "Clinical Analysis of 185 Patients, Otolaryngol Head Neck Surg, 95 (3pt1): 292-297, 1986 Oct.) The estimated recovery rate is about 52% (Murakami S. Nippon Jiinkoka Gakkai Kaiho, 1996 Dec 99:12, 1772-9), compared with 76% at paralysis of Bell.

In connection with the early theory of J. Ramsay, the presence of shingles-chickenpox virus was later confirmed in patients with Hunt syndrome, according to Robillard studies ((Robillard RB et al., Otolaryngol Head Neck Surgery: 292-297, 1986 Oct) and Wachym (Wachym, PA, Molecular Temporal Bone Pathology: II Ramsay Hunt Syndrome, Laryngoscope, 1997; 107: 9, 1165-75, 1997 Sept). The Wachym study confirmed the presence of DNA in the cranked ganglia on sections of the temporal bone, which is significant confirms the hypothesis put forward by Ramsay, and the DNA in detectable amounts is within the areas of the temporal bone, which, according to Hilger and Blunt are affected by Bell's paralysis, namely, in the stony and styloid arteries. In recent years, the use of acyclovir has often been used in combination with prednisone (Murakami, S et al., Treatment of Ramsay Hunt Syndrome with Acyclovir Prednisone, Significance of Early Diagnosis and Treatment, Ann. Neuro; 41 (3): 353-357, 1997 Mar) for the treatment of Hunt's syndrome, in parallel with the currently used treatment for Bell palsy. Steroid therapy was also used (Adour KK and Hetzler DG, Current Treatment for Facial Palsy, Am J Otol, 5 (6): 499-502, 1984 Oct), as well as other treatments discussed for Bell's palsy, i.e. surgical decompression and electrical stimulation. As for Bell's paralysis, no final studies have been carried out according to these methods, and the data on their effectiveness that are questionable are mixed at best. As with Bell paralysis, they included treatments using eye linings due to the loss of a blinking reflex. In addition, with regard to dizziness in Hunt's syndrome, diazepam was used to combat this symptom. In conclusion, there is a clear overlap between Hunt's syndrome and Bell's palsy in relation to past theory and proposed treatment.

SUMMARY OF THE INVENTION

The present invention aims to alleviate the effects of Bell's paralysis and Hunt syndrome, as well as other neurological diseases caused by the herpes virus, by providing a treatment that is directly directed to the mechanisms that are believed to cause this disease. The invention was carried out by analyzing the existing medical literature on the disease and developing what, according to the author, is a new consistent perspective, identifying the most significant causative factors, and determining the pharmacology aimed at influencing these factors. Thus, although the invention was achieved without experiments in humans, it presents the results of an analysis of the medical and pharmacological aspects that were not previously reported for the treatment of a very serious and disabling disease. Although logical considerations led to the invention, it is not the result of merely following the advances reflected in the literature and leading to its discovery.

The treatment disclosed in this application will be based on the proposed causal hypothesis, which considers the involvement of both endothelin and herpes simplex virus in the occurrence of Bell's palsy and other herpes viruses in the onset of other conditions (see the role of shingles virus in the development of Hunt syndrome) . Calcium channel blockers, which belong to the class of 1,4-dihydropyridine derivatives, in particular felodipine, including also nifedipine, nimodipine (see US patent No. 3799934), nizoldipine (see US patent No. 4154839) or alenodipine, can be used to treat paralysis Bella and other herpesvirus infections that cause neurological diseases. It was suggested that treatment be continued until the tenth day of progression, but should be started as early as possible. Treatment is based on the proposed dynamics of the pathological process underlying Bell's paralysis and other diseases. The proposed treatment is intended to counter the effects of this pathological process, as well as inhibiting the process itself. In yet another embodiment, acyclovir, an herpes virus antagonist that can counteract herpes virus DNA replication, can be used to support treatment with dihydropyridine (DHP) drugs.

A supported pathological process is a pathological process described by Hilger and Blunt, in which vascular narrowing of arterioles in the canal of the facial nerve of the temporal bone occurs; however, it is assumed here that this process in itself is caused by an immune response to the herpes virus, mainly to the herpes simplex virus. This reaction causes the production of the endothelin peptide, one of the most powerful natural vasoconstrictor agents known. Endothelin performs its vasoconstrictive effect by releasing calcium ions (Ca ²⁺ ) into the smooth muscle tissue of arteries, in particular small arteries (arterioles). The resulting vasoconstriction disrupts the microcirculation of the facial nerve (seventh cranial nerve) through primary and secondary ischemia.

The use of DHP calcium channel blockers, in particular felodipine, nifedipine, nimodipine or nizodipine, should lead to (1) rapid expansion of the arterioles of the channel, (2) reduced resistance of arterioles, (3) blockade of the same channel through which endothelin acts, and therefore functional impairment of the mechanism of action of endothelin to generate vasoconstriction. An adequate blood and oxygen circulation to the seventh cranial nerve should then follow. Then, the restoration of adequate microcirculation should prevent further damage and enable direct blood flow to promote healing. This treatment should have advantages in comparison with the modern popular approach with the use of steroids in that it accurately focuses on the pathological process, and not on the use of a common anti-inflammatory agent to achieve expansion. The use of steroids should be effective only to the extent that it counteracts the effects of high levels of endothelin, and they have this effect only indirectly as an anti-inflammatory agent. Felodepine is particularly suitable for a more direct and effective role, since in comparative studies with other DHP calcium channel blockers in the treatment of hypertension, it is more effective in its action on arteries. In addition, it was shown that it acts on arterioles of the size found in arterioles in the channels of the facial nerve. Further, it is intended for selective action on smooth muscle, in contrast to the action on the heart and smooth muscles (nifedipine), which is the main component of the small arteries (i.e. arterioles) contained in the channel of the facial nerve. In addition, the use of prednisone, as well as other steroids, is associated with a known risk, including hepatic and renal disorders. Steroids are also immunosuppressive and inhibit the processes necessary to fight any infection caused by the herpes virus. Moreover, unlike other types of treatment proposed, such as electrical stimulation and biofeedback, therapy with calcium channel DHP blockers is based on a modern understanding of the pathological process of Bell's paralysis and its dynamics. Surgical intervention is also associated with various risks, has limited success, and its use as a result has decreased over recent years.

The similar dynamics and treatment regimen using 1,4-dihydropyridine calcium channel blockers, proposed here for Bell's palsy, could also be useful for the treatment of Hunt syndrome. Narrowing of the arterioles in the canal of the facial nerve would lead to primary and secondary ischemia with all the indicated microcirculatory problems in both diseases, although with Hunt's syndrome, the initiating causative factor is herpes zoster virus rather than herpes simplex virus. However, the same 1,4-dihydropyridine calcium channel blockers must counteract the pathological process and inhibit it in light of the parallel narrowing of the same arterioles mentioned earlier in the studies of P. Wackmyn and Rb Robillard. Further, there is some evidence that endothelin (ET-1) may be specifically associated with an immunological response to herpes zoster virus and other herpes viruses (Smith RF and Smith TF, Identification of New Protein Kinase in Three Herpes Viruses, J Virol, 63 : 1,450-455, 1989 Jan), and may also involve astrocytes in the process (Kuo-Chun Ma et al., Reactive astrocytes in Viral Infections of the Human Brain Express Endothelin-Like Immununeoactivity, J Neurol Sci, 126, 184-182, 1994 Nov) as vital agents.

Similarly, the invention strongly suggests that other diseases caused by the herpes virus, such as encephalitis caused by the herpes simplex virus, can be treated in the same way, since in these cases the same viruses may be involved, similar to vasoconstriction, endothelin and astrocytes ( Kuo-Chun Ma).

Brief Description of the Drawings

Figure 1 is a diagram of the progression of the pathological process in Bell paralysis and can also serve as a model of the process of infection with other herpes viruses that cause neurological diseases, Hunt syndrome is an example.

Figure 2 is a diagram of the proposed treatment for Bell paralysis with DHP calcium channel blockers and a model of infection with other herpes viruses that cause neurological diseases, such as Hunt syndrome.

Detailed Description of Preferred Embodiments

The proposed treatment should be prescribed as soon as possible after the first diagnosis of Bell's paralysis or infection with other herpes viruses that cause neurological diseases, and continue until the tenth day after the onset of the first symptoms. As indicated, damage can be considered as caused by primary and secondary ischemia, developing as a result of narrowing of blood vessels in the channel of the facial nerve; therefore, the earlier microcirculation of the seventh cranial nerve inside the canal can be restored, the sooner it is possible to prevent further damage, as well as activate the processes of natural healing. Endothelial vasoconstriction may involve arteries and their branches such as stony artery branches (Fisch U. and Felix H., On the Parthenogenesis of Bell's Palsy, Acta Otolaryngol, 95: 532-538, 1983 May; Blunt M, J. Laryngol Otol, 70: 701-713, 1956) and the styloid artery (Blunt MJ Laryngol Otol., 1956; Hilger J, Laryngoscope., 54: 228-235, 1949). DHP calcium channel blockers are preferred because of their vasodilating ability and the reduced peripheral resistance that they create for blood flow as a result of their blocking effect on calcium ion channels, the channels themselves being stimulated by endothelin to produce calcium ions.

A preferred embodiment is the use of felodipine, which is selective for smooth muscle vascular tissue, the same tissue that is contained in arterioles (consisting mainly of smooth muscle tissue), vessels that are most prone to narrowing with Bell's paralysis. Due to the selectivity of felodipine and other characteristics, felodipine is particularly suitable as a promising treatment for Bell palsy. These characteristics include its effect on smaller arterioles that are found in the fallopian artery network, as well as its constantly observed higher efficacy (Hagiwara S et al., Effects of Felodipine, Nifedipine and Verapamil on Cystolic Ca ²⁺ on Contraction of Smooth Muscle Tissue, Eur Journal Pharmacol, 234 (1): 1-7, 1983 Mar) with respect to vasodilatation, detectable by a decrease in blood pressure caused by felodipine compared with nifedipine. As confirmed by clinical observations, felodipine also penetrates quite well through the blood-brain barrier, which can limit the effectiveness in reaching these arteries (also to some extent borderline in their location).

Another embodiment of the present invention is the use of nifedipine, which has been shown to be effective against angina pectoris in terms of eliminating spasm of arteries or arterioles, as well as exhibiting selectivity for both coronary arteries and smooth muscles.

Nizodipine, another DHP calcium channel blocker acting on the same sites, is effective at much lower dosage levels than felodipine, and also bypasses coronary sites.

Nimodipine, dihydropyridine (DHP), used to treat subarachnoid hemorrhage, is most effective for this disease. In addition, it can be noted that trials in counteracting the effects of endothelin were primarily carried out with respect to nifedipine (Kiowaski W. et al., Endothelin-induced Vasoconstriction in Man; Variable Modification caused by endothelium-Derived Relaxing Factor, Schweiz Med Worchenschr, 122: 15: 559-562, 1992 April; Meyer, P et al., Effects of Calcium Channel Blockers on the Response to Endothelin-1, Bradykinin and Sodium Nitroprusside in Porcine Ciliary Arteries., Exp Eye Res, 60: 5: 505-10 1995 May). However, it is significant that there is a 1996 study (Drimal J. And Koprda V., Endothelin 1 Significantly Increased Number of 1,4-Dihydropyridine Binding Sites Photolabelled on Vascular Smooth Muscle Cells with (-) {3H} -Azidopine, Physiol Res, 45 (1): 51-58, 1996), which shows that endothelin binding sites have high affinity for calcium channel DHP blockers and, therefore, a group of calcium channel DHP blockers can share this advantage.

As mentioned above, Hilger in the 1940s and Blunt in the 1950s offered a physiological explanation for the destructive vascular process that occurs with Bell's paralysis. This process, although viable and accepted by some experts, but disputed by Adour, can now be considered as compatible and confirmed by studies of endothelin conducted by M. Ikeda (Ikeda M. et al., Plasma Endothelin Level in the Acute Stage of Bell's Palsy, Arch Otolaryngol Head Neck Surg, 122: 849-852, 1996 Aug). In addition, these studies of endothelin, when considered along with other studies of endothelin (including immunological mechanisms), as well as recently obtained data on the herpes virus, can now be considered as confirming the consistent pattern of Bell's paralysis dynamics developed by the author of the invention, and, according to According to the author of this invention, justifying the use of DHP calcium channel blockers as a highly active treatment. Therefore, the inventor considers it appropriate to conduct treatment based on the first causative agent (herpes virus) and the associated underlying process involving endothelin (an intermediate causative agent) in relation to the physiological phenomena described by Hilger and Blunt. In essence, the ongoing process is consistent with the action of the herpes virus, but an action that Adour mistakenly considered to be inconsistent with ischemia caused the viral concept to be rejected.

1 and 2 schematically represent the corresponding process and treatment.

There is strong evidence that herpes virus infection results in the production of the protein tyrosine kinase necessary for herpes virus replication (Yura, Y et al., Inhibition of Herpes Simplex Virus Replication by Genestein, an Inhibitor of Protein Tyrosine Kinase, Arch Virol, 132: 3-4: 451-461, 1993 Mar). There is also strong evidence (Grabham P. And Cunningham DD, Thrombin Receptor Activation Stimulates Astrocype Proliferation and Reversal of Stellation by Distinct Pathways: involvement of Tyrosine for Phosphorylation, J Neurochem, 64: 2: 583-91, 1995 Feb) and ( Stanmirouvic DB, The Role of Intercellular Calcium and Protein Kinase in Endothelin stimulated Proliferation of rat type I Astrocytes, Glia, 15: 2, 119-130, 1995 Oct), that protein tyrosine kinase, necessary for the replication of the herpes virus, is mainly involved in stimulation immunological reaction for the production of astrocytes. Astrocytes are the main cells found in certain tissues of the peripheral nervous system. In addition, it was shown that the proliferation of immunoreactive astrocytes in the brain leads to the production of endothelin (ET-1) (K.Ma), and, as was observed in 5 out of 9 cases examined by Ma, this proliferation was stimulated by confirmed inflammatory infections caused by the simple virus herpes. Moreover, endothelin is a known mitogen and in itself leads to the production of many astrocytes. This causes an effect such as a loop or joint effect, whereby endothelin and astrocytes synergistically produce elevated levels of endothelin and astrocytes. As mentioned, endothelin, in particular ET-1, is an extremely powerful vasoconstrictor agent and its vasoconstrictor effect is achieved by stimulating precisely those sections of calcium channels through which DHP calcium channel blockers (Hayes, Drimal) act. Therefore, DHP calcium channel blockers facilitate the process of vasoconstriction itself, although by appropriate dosage adjustment it is even possible to achieve vasodilation beyond just counteracting the effects of endothelin.

The effect of felodipine on eliminating the contraction process and replacing it with the process of expansion and reduction of blood resistance is selective for smooth muscle of blood vessels with little or no effect on the heart muscle. In addition, felodipine can penetrate the blood-brain barrier to such an extent that this barrier can interfere with effective contact with the arteries.

Nimodipine is also selective and especially selective for cerebral arteries, but clinical trials of other aspects of its effectiveness, such as expansion and reduced resistance of small arteries, are not so extensive. However, nimodipine can be considered particularly suitable for the possible treatment of encephalitis caused by the herpes simplex virus, since this disease is associated with infection of the herpes simplex virus in the inner regions of the cerebral cortex. The reactive immunoreactivity of endothelin in this area (Kuo-chun Ma et al., J. Of Neurological Sciences 126: 184-192, 1994 June) also suggests possible treatment approaches using felodipine and nifedipine.

Nizodipine is more active per unit dosage than nifedipine, and its effect lasts longer, and, unlike nifedipine, it is selective in counteracting the effects of vascular smooth muscle contraction, in contrast to the heart muscle. In addition, it has been effectively used in the treatment of hypertension.

The effect of felodipine on arterioles even smaller than the arterioles of the facial nerve canal has been experimentally confirmed (Lindbom L et al., Effects of Felodipine on Microvascular Resting Tone and Responses to Nerve Stimulation and Perfusion Pressure Reduction in Rabbit Skeletal Muscle, J Cardiovasc Pharmacol: 15 ( 4), 592-597, 1990 April). The diameter of the arterioles in the channel of the facial nerve is in the range of 25 to 76 μm (Ogawa A and Sando I, Spacial Occupancy of Vessels and Facial Nerve in Facial Canal, Ann Otol Rhinol Laryngol, 91: 14-19, 1982). Endothelin has been shown to constrict arterioles of this magnitude (Kuo, KC et al. Effects of Endothelin-1 on skeletal Muscle Microcirculation, Microcirculation Annual: 1992: 45-46). In the experiments of Lindbom it was shown (Lindbom L et al. J. Cardiovasc. Pharmacol, 14 (4): 593-597, 1990 April) that felodipine expands even smaller arterioles: 10-20 μm transverse type and 4-8 μm terminal type. Felodipine is known to lead to an expansion of arterioles at oral dose levels of 2.5 to 20 mg 1 time / day in sustained release tablets in the treatment of hypertension, and this range is the dosage range proposed in the present invention for the treatment of Bell palsy and Hunt syndrome ; a daily single dose of 10 mg is most effective in the treatment of hypertension and is the preferred level according to the invention for the treatment of Bell palsy and Hunt syndrome. However, it should be noted that more attention can be paid to higher levels of this range (for example, 15 mg) for the treatment of Hunt syndrome, given the more severe neurological lesions caused by it. After oral administration, it is almost completely absorbed and reaches peak levels after 2-5.5 hours. When treating it with hypertension, administration once a day is enough to treat the disease, and this seems to be good practical guidance in the treatment of Bell's paralysis and Hunt syndrome.

If nifedipine is used, peak levels are reached after 30 minutes at dosage levels of 10 mg as the preferred level for immediate release tablets, and dose ranges of 10 to 20 mg can be administered 3 times / day for effective treatment for Bell palsy and Hunt syndrome, or 1 once / day for sustained release tablets at a dosage level of 30 to 60 mg at a preferred level of 30 mg. The indicated suggested levels and dosage ranges fit into the dosage levels and ranges with the effective treatment of hypertension and angina pectoris and are associated with an adequate expansion of arterioles.

Side effects of DHP calcium channel blockers are minimal, with headaches being the most common (in 14.7% of cases when using felodipine, in 19% when using nifedipine prolonged release at a dose of 30 mg) and slight peripheral edema (17%) for felodipine and occasionally - redness of the skin (6.9% for felodipine, 4% for nifedipine) or dizziness (5.8% for felodipine, 4% for nifedipine). To the extent that the DHP group is used to treat hypertension, in individuals treated with felodipine at a dosage level of 10 mg over a 4-week period, the average drop in systolic blood pressure may average 5.3 / 7.2, and diastolic - 2.7 / 2.5 mm Hg The average decrease over a 6-week period with the use of nifidepine at a dose of 30 mg was 5.5 / 2.9 (systolic / diastolic), and at a dose of 60 mg - 8.0 / 4.1. Nimodipine as a preferred embodiment is recommended in a dosage of 60 mg every 4 hours. The indicated dosage coincides with the standard dosage prescribed for subarachnoid hemorrhage from a torn congenital aneurysm and recommended for the effective treatment of this disease. A decrease in blood pressure was observed in 4.4% of individuals, according to a study of 823 patients (1998 Handbook for Physicians). Therefore, its use avoids the usual drop in blood pressure observed with other DHP drugs. The most common side effect was nausea and rash (1.2% for each). Other side effects were observed in less than 1% of cases, and included hepatitis, itching, and gastrointestinal irritation. Its selectivity for smooth muscles, in contrast to the heart muscle (with a positive comparison with nifedipine), and the safety of its use in patients without hypertension, makes it especially attractive. However, the success rate of its use, compared with placebo groups, was not particularly high. Nizoldipine as an implementation option is a prolonged-release DHP drug, and its recommended daily dosage for the treatment of Bell palsy and Hunt syndrome is 10-20 mg / day. This coincides with its therapeutic dosage in case of low to moderate severity of hypertension. Side effects include mainly peripheral edema and headache with a frequency of 22% each (pharyngitis occurs in 5% of cases, sinusitis in 2%). Treatment with DHP class drugs should be avoided in individuals with existing hypotension or in those who are sensitive to this class of calcium channel blockers. There is a potential risk associated with the drugs of this group for the fetus in expectant mothers, conclusions about the risk are based on some animal studies, on the basis of which these drugs are classified in obstetric practice as group C drugs, and future mothers should be given appropriate recommendations. In addition, the additional administration of acyclovir should be prescribed at a dosage of 2000 mg / day (400 mg 5 times / day) for 10 days (such was the dosage of K.Adour in his study of acyclovir-prednisone) as a means of additional inhibition of the effect of the virus on the launch endothelin production sequences. Alternatively, 500 mg of famciclovir taken every 8 hours for 7 days can be used.

An example of treatment with DHP calcium channel blockers

Treatment of Bell's palsy or Hunt's syndrome with 1,4-dihydropyridine (DHP) calcium channel blockers is suggested with the recommended administration, starting from the first signs and continuing until the 10th day. Felodipine is likely to be especially effective. The introduction of DHP calcium channel blockers is based on the dynamics of the disease, which begins with invasion of the herpes virus (simple) and, ultimately, leads to primary and secondary ischemia of the seventh cranial nerve in the facial nerve canal. Ischemia causes physiological processes of the type described by Hilger and Blunt in the 1940s and 1950s, essentially causing severe narrowing of the vessels of local arterial branches in the canal area, for example, stony artery branches. A key intermediate phenomenon is the production of previously unknown endothelin (ET-1) as a vasoconstrictor peptide through the action of calcium ions generated as an immunoreactive by-product.

The use of 1,4-dihydropyridine (DHP) calcium channel blockers as one of the 5 classes of calcium channel blockers is proposed here as particularly suitable for the treatment of Bell paralysis, as well as other herpetic infections that cause neurological diseases (for example, Hunt syndrome) in light of their vasodilator and resistance-reducing properties by which they counteract and inhibit the described pathological condition associated with vasoconstriction. The DHP group is particularly suitable for the action on vascular smooth muscle by calcium channel blockade, because smooth muscle is the main component of the small arteries, i.e. arterioles, in the area of the channel of the facial nerve. DHP has been shown to be effective in the treatment of hypertension and angina pectoris. Felodipine should be especially effective in treating Bell palsy, because it is selective for smooth muscle of blood vessels (and not selective for heart vessels), as well as cerebral arteries and specifically for arterial elements involved in the pathological process, such as stony and styloid arteries. Further, it turned out to be effective in expanding even smaller arteries than arteries, which account for the development of Bell's paralysis, and it can penetrate quite well through the blood-brain barrier. The constancy of its vasodilating effect is also superior to other remedies. These facts make felodipine a particularly suitable promising treatment. However, nifedipine is also promising, as there is the greatest amount of experimental evidence regarding its opposition to endothelin. Felodipine also has this confirmation, but to a lesser extent. Nimodipine is promising because of its particular effectiveness in penetrating the blood-brain barrier and its connection with improving the neurological state by eliminating ischemia in patients with subarachnoid hemorrhage from ruptured aneurysms. In addition, it has been used safely in patients without hypertension and does not cause a significant decrease in blood pressure. Nizodipine has an unusually long-term effectiveness in a standard dosage form and maintains selectivity for vascular smooth muscle. However, in this group, felodipine appears to be particularly suitable for acting on the corresponding arteriole regions in Bell palsy and Hunt syndrome and even for herpes simplex encephalitis, although nimodipine is also quite suitable for treating the latter.

An appropriate dosage of felodipine for the treatment of vasoconstriction for hypertension would be from about 2.5 g to 20 g sustained release tablets daily for a 10-day period of disease progression. Nifedipine could be prescribed in one sustained release tablet containing 30-60 mg / day for a comparable period. Possible side effects are generally minimal, with minor swelling in the case of felodipine and dizziness or headaches in the case of felodipine or nifedipine being the most common. The combined use of acyclovir as a supplement in the fight against virus replication should be carried out at a dose of 400 mg 5 times / day for a 10-day period. The proposed use of DHP calcium channel blockers is intended to affect the core of the pathological process in Bell paralysis and, thereby, stop and eliminate its progression.

Despite the fact that certain embodiments of this invention have been proposed here, the authors claim a broader understanding of it. Therefore, the invention should not be limited solely to the described embodiments, but should be determined by the following claims.

Claims (47)

1. A method of treating a patient having Bell palsy, comprising administering to the patient a therapeutically effective dosage of a 1,4-dihydropyridine calcium channel blocker. 2. The method according to claim 1, which is a method of enhancing the flow of blood and oxygen to the seventh cranial nerve. 3. The method according to claim 2, where the specified calcium channel blocker is selected from the group consisting of felodipine, nifedipine, nimodipine, nizodipine and alenodipine. 4. The method according to claim 2, where the specified calcium channel blocker is felodipine, and the indicated therapeutically effective dosage is sufficient to affect the arterioles in the channel of the facial nerve. 5. The method according to claim 2, where the specified calcium channel blocker is felodipine, and the indicated therapeutically effective dosage is a daily dose of from 2.5 to 20 mg. 6. The method according to claim 2, where the specified calcium channel blocker is felodipine, and the indicated therapeutically effective dosage is a daily dose of 10 mg. 7. The method according to claim 2, wherein said administration of the 1,4-dihydropyridine derivative of the calcium blocker is continued for 10 days. 8. The method according to claim 2, further comprising administering a therapeutically effective dosage of a herpes virus antagonist to counteract viral DNA replication. 9. The method according to claim 3, where the specified calcium channel blocker is nizodipine administered at a dosage of from 10 to 20 mg / day. 10. The method according to claim 3, where the specified calcium channel blocker is nimodipine, administered in a dosage of 60 mg every 4 hours 11. The method according to claim 3, where the specified felodipine is administered in the form of a sustained release nifedipine in a daily dose in the range of about 30 to 60 mg. 12. The method according to claim 3, where the specified felodipine is administered in the form of a sustained release nifedipine in a daily dose in the range of about 30 mg. 13. The method according to claim 3, wherein said felodipine is administered as nifedipine immediate release 3 times / day in dosages from 10 to 20 mg. 14. The method according to claim 3, wherein said felodipine is administered as immediate release nifedipine at a dose of 10 mg 3 times / day. 15. The method of claim 8, wherein said herpes virus antagonist is acyclovir or famciclovir. 16. A method of treating a patient with Hunt syndrome or other neurological diseases caused by the herpes virus, comprising administering to the patient a therapeutically effective dosage of 1,4-dihydropyridine calcium channel blocker. 17. A method of treating a patient having Hunt syndrome or other neurological diseases caused by a herpes virus, comprising administering to the patient a therapeutically effective dosage of a 1,4-dihydropyridine calcium channel blocker to enhance blood and oxygen flow to the seventh cranial nerve. 18. The method according to 17, where the specified calcium channel blocker is selected from the group consisting of felodipine, nifedipine, nimodipine, nizodipine and alenodipine. 19. The method of claim 17, wherein said calcium channel blocker is felodipine, and said therapeutically effective dosage is sufficient to affect arterioles in the facial nerve canal. 20. The method according to 17, where the specified calcium channel blocker is felodipine, and the indicated therapeutically effective dosage is a daily dose of from 2.5 to 20 mg. 21. The method of claim 17, wherein said calcium channel blocker is felodipine and said therapeutically effective dosage is a daily dose of 10 mg. 22. The method according to p. 18, wherein said felodipine is administered in the form of nifedipine immediate release 3 times / day in dosages of 10-20 mg. 23. The method of claim 18, wherein said felodipine is administered as immediate release nifedipine at a dose of about 10 mg 3 times / day. 24. The method of claim 17, wherein said administration of the 1,4-dihydropyridine derivative of the calcium blocker is continued for 10 days. 25. The method of claim 17, further comprising administering a therapeutically effective dosage of a herpes virus antagonist to counteract viral DNA replication. 26. The method of claim 18, wherein said calcium channel blocker is nizodipine administered at a dosage of 10 to 20 mg / day. 27. The method of claim 18, wherein said calcium channel blocker is nimodipine administered at a dosage of 60 mg every 4 hours. 28. The method according to p. 18, where the specified felodipine is administered in the form of nifedipine in a daily dose of from about 30 to 60 mg. 29. The method of claim 18, wherein said felodipine is administered as nifedipine in a daily dose of about 30 mg. 30. The method according A.25, where the specified antagonist of the herpes virus is acyclovir. 31. A method of enhancing blood circulation to the seventh cranial nerve in case of its violation caused by the endothelin vasoconstriction mechanism by introducing a 1,4-dihydropyridine calcium channel blocker. 32. The method according to p, where the specified calcium channel blocker is selected from the group consisting of felodipine, nifedipine, nimodipine and nizodipine. 33. The method according to p, where the specified calcium channel blocker is nizodipin administered at a dosage of 10-20 mg / day. 34. The method according to p, where the specified calcium channel blocker is nimodipine, administered in a dosage of 60 mg every 4 hours 35. The method according to p, where the specified calcium channel blocker is felodipine, administered orally in amounts from 2.5 to 20 mg. 36. The method of claim 35, wherein said felodipine is orally administered at a dosage of about 15 mg. 37. The method according to p, in which the specified introduction is continued, from the moment of diagnosis of Bell's paralysis or Hunt syndrome to the tenth day after the onset of the first symptoms. 38. The method according to clause 36, in which the specified dosage of felodipine is administered daily for a 10-day period. 39. The method according to clause 36, wherein said felodipine is administered in the form of nifedipine in three daily doses from about 10 to 20 mg. 40. The method according to clause 36, where the specified felodipine is administered in the form of nifedipine in a daily dose of from about 30 to 60 mg. 41. The method according to clause 36, where the specified felodipine is administered in the form of nifedipine in a daily dose of approximately 30 mg. 42. The method of claim 35, wherein the acyclovir or other viral antagonist, such as famciclovir, is also administered in therapeutically effective dosages. 43. The method of claim 42, wherein said acyclovir is administered at a dosage of about 400 mg. 44. The method according to § 42, wherein said acyclovir is administered approximately 5 times / day for a approximately 10-day period. 45. The method according to item 43, wherein said acyclovir is administered approximately 5 times / day for about a 10-day period. 46. The method according to clause 36, wherein said felodipine is administered in the form of nifedipine immediate release 3 times / day in dosages of 10-20 mg. 47. The method according to clause 36, wherein said felodipine is administered in the form of immediate release nifedipine 3 times / day at a dose of 10 mg.

Images