TR201903529A2 - USAGE OF HIGH DOSE COENZYME Q10 - Google Patents

Abstract

The present invention relates to the use of high doses of coenzyme Q10 in the treatment of primary, genetically derived coenzyme Q10 deficiencies.

Description

DESCRIPTION USING HIGH DOSE COENZYME Q10 Technical Area This invention is used to treat primary Coenzyme Q10 deficiencies at high doses. related to the oral administration of coenzyme Q10. Prior Art Coenzyme Q10 (KOQ10; ubiquinone, ubidecaquinone, ubidecarenone), common in nature It can be found in almost every cell of the animal and human body, fat-soluble, antioxidant, vitamin, which cells can synthesize de novo It is a similar compound but not a vitamin [1].

The structure of Conezyme Q10 in humans is similar to vitamin K, and 1,4-benzoquinone. It is formed by adding 10 isoprene side units to its ring, so this structure it is named coenzyme Q10 [2].

The chemical formula of Coenzyme Q10 is 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4- It is a benzoquinone and can be found in biological tissues in two biochemical forms: The reduced form (ubiquinol-10) and the oxidized form (ubiquinone-IO) [3].

Coenzyme Q10 is located in the inner membrane of mitochondria and is involved in the electron transfer chain. complexes I, II and 111, which are involved in oxidation-reduction reactions An essential coenzyme necessary for the activities of the named enzyme systems and It acts as a component of lipid membranes. Coenzyme, as it participates in ATP synthesis Q10 is needed by all cells in the body, especially high energy. affect the function of the signifiers. This makes Coenzyme Q10 in all tissues and organs. necessary for its health. In addition, Coenzyme QlO is combined with free oxygen radicals. It acts as an important antioxidant [4].

Cells generally perform biosynthesis to provide Coenzyme Q10. coenzyme Endogenous levels of Q10 are related to the oxidative activity of the organism. regulated by factors [5].

The para-hydroxybenzoic acid in the tyrosine amino acid is a component of Coenzyme Q10 in humans. It is the first aromatic precursor in the biosynthesis pathway and is the quinoid of Coenzyme Q10 molecule. form the ring structure. Tail of ten isoprenoid units, mevalonate It is derived from the pathway [6]. Endogenous Coenzyme Q10 levels increase both production rate and It is also determined by the rate of consumption in the body. These levels are associated with cardiovascular disease and various diseases that have been demonstrated in humans, such as degenerative muscle disorders may vary in their case [7].

Primary and secondary Coenzyme Q10 deficiencies, initochondrial diseases, fibromyalgia, cardiovascular disease, neurodegenerative diseases, cancer, diabetes with Coenzyme Q10 deficiency such as diabetes mellitus, male infertility and periodontal disease. Many associated diseases may benefit from supplementation with Coenzyme Q 10.

Coenzyme QlO, which appeared due to a genetic defect in this application deficiencies should be treated early with high-dose Coenzyme Q10 for treatment. It needs to be started and a patent for use for this indication is required. is requested. Because the existing Coenzyme Q10 preparations are generally used as supplements. as low dose (like 100mg) and mostly as tablets in our country. are available. With the patent that is the subject of application, Coenzyme Q10 is used for therapeutic purposes. In the indication, 2-3 g of Coenzyme Q1 0 should be taken daily.

The use of high-dose coenzyme Q10 in the patent that is the subject of application is genetic. It is used for treatment in case of deficiency of origin coenzyme Q10. Promise Unlike the existing coenzyme Q10 tablets, the subject is high dose. can be used. In current applications, the treatment of high-dose coenzyme Q10 There are no explanations for its intended use because treatment protocols is not standardized. For example, ZOOug/ml coenzyme Q10 easily treated in both pediatric and adult patient populations with doses are provided.

Objectives of the Invention The aim of this invention is to treat primary genetic coenzyme Q 10 deficiencies. It is the use of high doses of coenzyme QlO such as 2-3 gr.

Another aim of this invention is to use high dose eg 20014 g/ml coenzyme Q10 syrup. Easily reduce therapeutic doses in both the pediatric and adult patient population with to use high-dose coenzyme Q10 that provides

Another object of this invention is high dose Coenzyme orally in powder or liquid form. It is the use of Q10 in the treatment of some diseases.

Another aim of this invention is to prevent genetically derived coenzyme Q10 deficiencies. It is the use of high-dose 1-3 gr coenzyme Q10 pills or sachets in the treatment.

Another object of this invention is to produce high-dose powder or liquid coenzyme Q10 both It is used in both pediatric and adult patient populations.

Another object of this invention is to use high doses of coenzyme Q10 as a syrup or tablet or in capsule or sachet form so that treatment doses can be adjusted easily. is to be used.

Brief Description of the Invention Patients with any CoQ10 deficiency should be treated with oral CoQ10 supplementation. showed clinical improvement, but brain symptoms were probably pre-treatment irreversible structural brain damage and across the blood-brain barrier It was partially cured due to poor penetration of coenzyme Q10 [8]. This The first request and other related requests, carried out to achieve the purpose of the invention. The use of high-dose coenzyme Q10 as defined in the claims is as follows: is carried out. The subject of the invention is coenzyme Q10, primary, genetic origin. It can be used in doses of 2-3 grams in the treatment of coenzyme Q10 deficiencies.

The dose rates of the mentioned coenzyme Q10 can be controlled or according to the need. can be changed accordingly. Coenzyme Q10 orally in powder or liquid form can be obtained. The coenzyme Q10 in question is in the form of syrup orally. It can be taken in tablet, capsule or sachet form. stable Coenzyme Q10 plasma levels were increased after 3 to 4 weeks of constant dosing. monitoring of their concentrations may be considered [9]. Coenzyme Q10 as primary genetics The recommended oral supplemental doses in adult patients are 1,200- Up to 2,400 mg, 10-SOmg/kg daily in pediatric patients, dose three times daily is divided [10]. Coenzyme Q10 is different depending on the treatment of a particular disease. can be used for a longer or shorter period of time.

Coenzyme Q10, other pharmaceutically acceptable substances and food supplements can be used with the ingredients. The said pharmaceutical substance It can be selected in a way that is suitable for the purpose of treatment.

Detailed Description of the Invention Primary and secondary Coenzyme Q10 deficiencies, mitochondrial diseases, fibromyalgia, cardiovascular disease, neurodegenerative diseases, cancer, diabetes Coenzyme Q10 deficiency such as diabetes mellitus, male infertility and periodontal disease etc. Many diseases associated with coenzyme Q10 may benefit from supplementation. primary secondary CoQ10 deficiencies, such as coenzyme Q10 deficiencies and mitochondrial diseases Coenzyme in relation to numerous medical conditions, including deficiencies Q10 tissue deficiencies or subnormal serum CoQ10 levels have been reported.

Coenzyme Q10 levels decrease with advancing age. It can partially contribute to the emergence of some signs of aging.

Coenzyme Q10 deficiency can be due to many different reasons. Coenzyme Q10 Coenzyme Q10 synthesis is impaired due to nutritional deficiencies (for example, vitamin B6, an essential cofactor in the synthesis of Coenzyme Q10 deficiency), genetic or acquired, in the synthesis or use of Coenzyme Q10. such as increased tissue needs due to a disorder or a particular disease reasons may arise. Clinical manifestations of severe Coenzyme Q10 deficiency encephalomyopathy, severe infantile multisystemic disease, cerebellar ataxia, diseases such as growth retardation Leigh syndrome and isolated myopathy finds. Oral administration of coenzyme Qlu can increase tissue levels. It is possible to correct Coenzyme Q 1 O deficiency because it can increase

The approach of oral high-dose administration of coenzyme Q10 is life-threatening. It is especially important for infantile encephalopathy.

The most severe Coenzyme Q 10 deficiencies are due to autosomal recessive mutations. when mutations affect Coenzyme Q10 biosynthesis genes (COQ genes) The primary deficiency is called a secondary deficiency if it is due to other genetic disorders. can be classified. In 1989, Ogasahara et al. They identified and published the first example of coenzyme Q10 deficiency [11]. At the moment More than 100 Coenzyme Q10 deficiency diseases have been identified and published.

Most patients with the infantile-onset multisystemic variant are genetically There is a primary Coenzyme Q10 deficiency. who have so far caused CoQlO deficiency nine genes [COQl (PDSSl and PDSSZ), COQZ, COQ4, COQÖ, COQ7, COQSA/ADCK3, COQSB/ADCK4, and COQ9] disorder has been detected.

Secondary deficiencies include genes unrelated to ubiquinone biosynthesis. diseases caused by mutations exist, for example ataxia and oculomotor aprataxin (APTX) gene causing apraxia, electron causing isolated myopathy transfer-Havoprotein dehydrogenase gene (ETFDH) and cardiofaciocutaneous BRAF gene mutations that cause the syndrome can be counted. Coenzyme Qlo deficiency Patients with coenzyme Q10 have shown variable responses to treatment. Many Clinical improvement was reported in the patient after Coenzyme Q10 supplementation. Therefore high dose, especially Coenzyme Q10 deficiencies of genetic origin It can be used for diseases that require coenzyme Q10 support.

The use of high-dose coenzyme Q 1 0 in an application of the invention is as follows: is carried out. Coenzyme Q10 of the invention, primary, genetic origin It can be used in doses of 2-3 grams in the treatment of coenzyme Q]0 deficiencies.

Doses are taken daily. Dose rates of the mentioned coenzyme Q10 It can be controlled or according to the need, the treatment process of the disease. can be changed.

Coenzyme QIO of the invention can be taken orally in powder or liquid form. Promise The subject coenzyme Q10 can be taken orally in syrup form, such as tablets, capsules. or in sachet form.

The coenzyme Q10 in the invention, which is the subject of the application, can be used orally in powder or liquid form. available throughout. In different embodiments of the invention, the treatment process is different. In other words, the duration of use of coenzyme Q10 can be more than 2 or 3 days. Promise The subject coenzyme Q10 is taken orally in powder or liquid form for at least 2 or 3 days. for 4 weeks or more, or for less than 4 weeks can also be used. Coenzyme Q10 depending on the treatment of a particular disease It can be used in different long or short time intervals.

Coenzyme Q10, the subject of the invention, should be at least 50 mg and at most 4 grams per day. can be used.

Cholesterol-lowering drugs such as lovastatin and pravastatin It also inhibits the HMG-CoA reductase enzyme required for the synthesis of coenzyme Q10. causes a decrease in serum COQ10 [12]. beta blockers, of propranolol and metoprolol, [13] phenothiazines and tricyclic antidepressants has also been shown to inhibit CoQ10-dependent enzymes [14]. CoQl O's platelets function, the risk of bleeding in patients taking antiplatelet drugs such as aspirin. can increase [15]. On the other hand, because it acts like vitamin K, warfarin may counteract its anticoagulant effects [16]. with antihypertensive drugs When given, CoQ10 may have an additive antihypertensive effect [17]. C0Q10 beta- insulin requirements for diabetic patients by increasing cell function may improve insulin sensitivity, which may decrease [18].

COQ10 therapy is safe even at the highest doses reported in the literature. Most significant adverse events requiring discontinuation of treatment in the clinical trial. has not been reported [19]. However, abdominal swelling, nausea, vomiting, diarrhea and gastrointestinal effects such as loss of appetite, allergic rash and headache pain has also been reported [20]. In addition, the antiplatelet effect of CoQ10 may increase the risk [21]. C0Q10 undergoes biotransformation in the liver and is excreted from the body. It is primarily excreted via the biliary tract, therefore liver failure or biliary obstruction may accumulate in patients with

In the use of high-dose coenzyme Q10 mentioned in the invention, which is the subject of the application, by minimizing the light contact of coenzyme Q10. It can be stored in a thickened bottle. In addition, the coenzyme in question Q10 can be applied in liquid form, preferably by means of a scaled syringe.

Tests on the invention and a study with a family of two active members water must have been. The first patient was a 26-year-old man and there was no consanguineous marriage. was the subject. The patient's parents were first-degree cousins. In the index case, the patient He had a slowly progressive ataxia and spasticity disease. Patient 8 years old with difficulty walking He survived, 4 years later he had partial epilepsy and lost the ability to walk at the age of 16.

In the neurological examination of the patient, cognitive dysfunction (cognltive deterioration) and dysarthria were detected, the patient could not walk even with support, but He was able to stand with support. Severe spasticity in the patient's lower limbs (spasticity, spasm), moderate spasticity (spasm) in her upper limbs, also moderate weakness in the upper leg muscles, dysmetria (dysmetria) and There was dysdiadocokinesia (dysdiadochokinesia). Oculomotor (oeulomotor) movements symmetrical deep tendon reflexes in both limbs with sphincters and sphincters was normal. However, the Babinski sign was bilaterally positive. Patient's brain MRI evaluation showed; cortical (cortical) and subcortical (subcortical) T2 Hyperintensity (TZ hyperintensity) was a previous study describing COQ4 mutations. it was not limited to a specific vascular region as described in the report. sick day 600 mg of carbamazepine (carbamazepine) twice a day and 2 mg of clonazepam twice a day (clonazepam) was treated.

The symptoms of the patient's 27-year-old sister began when she was 8 years old, but progressed more slowly than that of the male patient. When the patient's sister was 12 years old partly epilepsy. In the physical examination of the female patient; in the lower limbs (extremities) more prominently dysuria, spastic-ataxic and mild in all four limbs spasticity was seen. The female patient could walk without support, her eye movements were normal, dysmetria (dysmetria) and dysdiadocokinesis (dysdiadocokinesis) were present. your patient there was deterioration in cognitive functions (cognition). Babinski sign is two-sided It was positive without sphincter dysfunction. Routine biochemistry, hemogram and metabolic tests were normal. Whole spine MRI, da 111 No pathology was detected. However, in brain MRH, cerebral and cerebellar atrophy (cerebral and cerebellar atrophy) was seen. female patient twice a day treated with 1000 mg of levetiracetam (levetiracetam) once.

The patient in question was diagnosed with ataxia (disorder in bodily processes) and medical genetics. She was referred to the department of genetics, which is the most common cause of ataxia. disorders were examined and genetic counseling was given to patients, relatives of patients. suggested. In terms of the most common genetic disorders that cause ataxia, patients should be for the whole exome sequencing test, which is further investigation after it is found to be normal patient materials sent to University of Michigan with permission of patients' guardians and it worked.

Following the identification of the COQ4 gene mutation in coenzyme Q10 biosynthesis, As a therapeutic, coenzyme Q10 supplementation was tried in the patient. Coenzyme Q10 After the treatment is successful, local health insurances will pay for Coenzyme Q10 treatment. gave consent. Both patients were on long-term treatment and relapsed 1 year later. evaluated.

Plasma Coenzyme Q10 (Q10, 87853) levels, Mayo Clinic (Rochester, MN) analyzed by. Since the samples have been transported for more than 72 hours, only total plasma CoQ10 values are reliable and these values are reported. was done. Coenzyme despite not being treated with sister CoQ10 Q10 levels were measured at the same time as the male patient.

DNA was isolated from whole blood using the Qiagen Gentra Puregene kit. New generation exome sequencing by the University of Michigan DNA core facility done. Exons (exome), SeqCap EZ exome (exome) v Captured and matched ends, averaged 52 X depth on HiSeq2000 lined up. Variables of interest were validated and parental mutations were identified. were tested and verified to determine that they are carriers for Childhood DNA samples of his brother with period-onset ataxia, next generation exon Sent for (exome) sequence. A pedigree that takes into account first cousin mating Common SNPs were used for linkage analysis using Merlin. Model parameters, frequency 0.0001 was chosen for a rare recessive disease. distal only one region on chromosome 9, an LOD above 1.0 under this model show the score. The `region in question contained 51 genes. Only one gene, COQ4, we have identified a homozygous (homozygous) mutation that is presumed to be harmful, exon2: c.G164T; p.G55V. Both parents were heterozygous (heterozygous). This The particular mutation has not been previously reported and the glycine at this position preserved in vertebrates. COQ4 mutations lead to Coenzyme Q10 deficiency. plasma Coenzyme Q10 was measured. Coenzyme Q10 levels are normal was under.

Coenzyme Q10 treatment was recommended to the patient. Ataxia disease, Coenzyme Q10 deficiency It was more common in humans and animals. The neurologist giving the treatment offered treatment with high-dose (2000 mg/day) Coenzyme Q10. One month treatment then the patient was reevaluated and the patient's blood sample was taken and ataxia was measured and evaluated. After 1 month of treatment with coenzyme Q10, Although serum Coenzyme Q10 values did not improve, clinical evaluation and the subjective report showed significant improvement. Total SARA score from 30 to 10 rose; progress was made regarding the patient, being wheelchair bound, from being unable to walk even with support or standing unassisted, now a He can walk with a walker and stand unassisted. Coenzyme Q10 After approximately 1 year of treatment with SARA, the patient had a baseline SARA score of 17. It's gotten to a much better level than the line. Later, long-term in the sister A treatment was started and improvement in SARA score was noted.