RU2467749C1 - Method for correction of blood sugar level and treatment of patients with type two diabetes mellitus and cognitive defects - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely endocrinology and psychiatry, and concerns correction of blood sugar level in patients with type two diabetes mellitus and cognitive defects. That is ensured by a conventional complex of antidiabetic therapy added with rivastigmine. The preparation is introduced orally or transdermally. When introduced orally, the preparation is introduced with food 1.5 mg 2 times a day; high tolerability requires higher doses to 3 mg 2 times a day in 2 weeks, and then every 2 weeks to 4.5 and 6 mg/day 1 time a day. A transdermal form is used in an initial dose of 4.6 mg 1 time a day, in case of high tolerability in 4 weeks, a dose is increased to 9.5 mg 1 time a day.

EFFECT: method provides effective decrease of blood glucose level and reduced dose of hypoglycemic drugs used by the patient combined with improving such psychological values as levels of memory, concentration, gnosis, praxis, intellectual operations.

1 ex

Description

The invention relates to medicine, namely to endocrinology and psychiatry, and can be used to optimize treatment regimens for patients with type 2 diabetes mellitus (T2DM) with cognitive impairment.

Rivastigmine is a carbamate derivative that selectively inhibits brain acetylcholinesterase and butyrylcholinesterase. In the Russian Federation, the drug is registered under the trade name Exelon. There are three forms of release of Exelon - capsules for oral administration, a solution for oral administration and a transdermal therapeutic system - a patch. According to the official instructions for the medical use of Exelon capsules, Exelon's solution and transdermal therapeutic system [Instructions for medical use of Exelon (oral capsules). Reg. No. P No. 014495/01, registration date 12/22/2004; Instructions for medical use of the drug Exelon (oral solution). Reg. No. P No. 012952/01, registration date 12/08/2006; Instructions for the medical use of the drug Exelon (transdermal therapeutic system). Reg. No. LSR-007020/08, registration date September 2, 2008], the only indication for the use of the listed forms of rivastigmine release is mild or moderate Alzheimer's type dementia, including suspected Alzheimer's disease. The effects of rivastigmine in dementia of Alzheimer's type include both a direct improvement in the intellectual and mnemonic functioning of patients, and a slowdown in the progression of the disease associated with a decrease in the rate of cerebral atrophy, which allows us to consider rivastigmine as a basic drug (pathogenetic) therapy of dementia of Alzheimer's type [Gavrilova S.I. Pharmacotherapy of Alzheimer's disease. M .: VNTSPZ RAMS, 2007 - 258 p.].

The drug does not have official indications for use in mild to moderate cognitive (intellectual - mental) disorders, including those combined with type 2 diabetes mellitus.

T2DM is one of the most common forms of non-infectious pathology associated with age. A natural manifestation of T2DM is diabetic encephalopathy, accompanied by impaired memory, attention, intelligence, slowing thinking [Chugunov PA, Semenova IV. Diabetes mellitus and cognitive impairment. Diabetes mellitus - 2008 - T.38, No. 1 - S.61-68; Zakharov V.V., Sosina V.B. Possibilities of antihypoxants in the treatment of cognitive impairment in patients with diabetes mellitus. Attending Physician - 2010 - No. 3].

When examined using pathopsychological techniques, these disorders are detected in 70-80% of patients with T2DM [Petrova M.M., Prokopenko S.V., Pronina E.A. Cognitive and emotional impairment in patients with type 2 diabetes mellitus. Siberian Medical Review - 2008 - V.52, No. 4 - P.83-85; Sosina V.B., Zakharov V.V., Yakhno N.N. Non-cement cognitive impairment in patients with type 2 diabetes. Neurological Journal - 2010 - No. 4]. The severity of cognitive impairment in patients with type 2 diabetes is more moderate, but these disorders can progress and lead to the development of dementia (dementia) [Elfimova EV, Elfimov MA Diabetes mellitus and the psyche: etiopathogenetic relationships / Deputy chief physician: medical work and medical examination - 2008 - No. 3]. Cognitive impairment in T2DM is not the result of vascular complications of the disease or side effects of drugs used to treat T2DM, since they are detected in patients with the prodromal stage of T2DM - impaired glucose tolerance - and in T2DM patients who have never received sugar-lowering drugs.

The data presented allow us to state that cognitive intellectual-mnestic disorders, often of moderate and mild severity, but in some cases reaching the degree of dementia, are one of the mandatory clinical manifestations of T2DM. Cognitive impairment significantly reduces the quality of life and the level of social adaptation of patients with T2DM [Zakharov VV, Sosina VB Possibilities of antihypoxants in the treatment of cognitive impairment in patients with diabetes mellitus. Attending Physician - 2010 - No. 3].

It is known from the prior art that in patients with Alzheimer's disease without clinical manifestations of T2DM, the density of insulin receptors in the brain tissue is reduced, the level of insulin in the cerebrospinal fluid is reduced and the plasma insulin level is increased; these indicators correlate with the severity of the disease, which makes it possible to regard Alzheimer's disease as an insulin-resistant state of the brain [Hoyer S. Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J. Neural Transm. - 1998 - Vol.105 - P.415-422; Hoyer S. The aging brain. Changes in the neuronal insulin / insulin receptor signal transduction cascade trigger at lateonset sporadic Alzheimer disease (SAD). J. Neural Transm. 2002 - Vol.109 - No.7-8 - P.991-1002]. Thus, the drugs of the basic pathogenetic therapy of Alzheimer's type dementia, including rivastigmine, can fundamentally have a therapeutic effect not only with respect to cognitive impairment in T2DM, but also with respect to the main symptom of T2DM - hyperglycemia.

In support of these considerations, one can cite a known method for the treatment of hyperinsulinemia, hyperglycemia, insulin resistance and obesity due to T2DM, which consists in the long-term administration of bromocriptine [Pat. US No. 92/11166 from 12/22/92]. Preparations of D2 receptor agonists, for example, pyribedil (Pronoran, Servier), are used to treat cognitive impairment, in particular, in Alzheimer's type dementia. The authors of the method do not provide information on the effect of bromocriptine therapy on the severity of cognitive impairment in patients with T2DM.

In medical practice, for the treatment of cognitive impairment in T2DM, blood glucose level is monitored using monotherapy or combination therapy with hypoglycemic agents - second and third generation sulfonylureas, biguanides, insulin sensitizers, alpha glucosidase inhibitors, prandial glycemic regulators (glinides), if necessary [Antsiferov MB, Volkova A.K. Oral hypoglycemic drugs in the treatment of type 2 diabetes. The Medical Council - 2007 - No. 2], and prescribe treatment with antihypoxic, neuroprotective agents in accordance with one of the methods below.

There is a method of treating neurovascular complications of diabetes, which consists in the appointment of intravenous Mildronate at a dose of 1000 mg / day [application No. 2009103459/14 from 02.02.2009]. The authors state that this method leads to an improvement in the conductivity of sensory and motor fibers of peripheral nerves. Information on the influence of the method on glycemic indices and pathopsychological studies of cognitive functions is not given.

A known method of treating patients with diabetes, combined with a disease of the central nervous system, which consists in the intravenous drip of 5 ml of 5% solution of Mexidol in combination with physiotherapy with transcerebral sinusoidal currents [application No. 2008104564/14 from 02/11/2008]. The authors state that the application of the method improves the functions of memory and attention, reduces the severity of headaches, reduces the severity of anxiety and depression, normalizes sleep, and also leads to a decrease in blood lipids. Data on the effect of the method on glycemic indices in the description of the invention are not given.

There is a method of treating cognitive impairment in T2DM, which consists in administering an Acturogin neuroprotective agent at a dose of 400 mg 3 times a day for three months [Zakharov VV, Sosina VB Possibilities of antihypoxants in the treatment of cognitive impairment in patients with diabetes mellitus. Attending Physician - 2010 - No. 3]. The authors note an improvement in selectivity of attention and auditory-speech memory when using this method. However, data on the effect of the method on glycemia indicators are not given in the publication.

Thus, existing methods of treating cognitive impairment in T2DM are based on the combined use of hypoglycemic drugs and drugs with antihypoxic, neuroprotective effects. Given that such treatment is usually carried out in an elderly patient against the background of an initially high sensitivity to the undesirable effects of pharmacotherapy, a drawback of existing methods is an increase in the number of drugs taken simultaneously by the patient, which is associated with an increased risk of side effects of pharmacotherapy and drug interaction reactions.

The purpose of the invention is the development of a method of pharmacotherapy for patients with type 2 diabetes mellitus with cognitive impairment, which allows to optimize the treatment regimen, improve pathopsychological indicators characterizing the level of memory, attention, gnosis, praxis, mental operations, reduce the risk of side effects of pharmacotherapy and undesirable drug interaction reactions.

The technical result is achieved by supplementing hypoglycemic therapy with the administration of rivastigmine in doses usually used in medical practice - 4-5 mg 1 time per day to a patient with type 2 diabetes mellitus and cognitive impairment of any severity, including mild and moderate, against the background of daily monitoring of blood glucose on an empty stomach, for an indefinitely long time. As the blood glucose level decreases, the patient is reduced in the dosage of previously prescribed hypoglycemic agents or their intake is canceled.

The method allows to reduce blood glucose levels by at least 40% from basal values, increase pathopsychological indicators characterizing the level of memory, attention, gnosis, praxis, mental operations, reduce dosages of hypoglycemic drugs taken by the patient, reduce the number of drugs prescribed to the patient at the same time, reduce the risk side effects of pharmacotherapy and adverse reactions of drug interactions.

The method was tested in 96 patients with type 2 diabetes mellitus and cognitive impairment. Patients were divided into two groups - in the first of 47 people, a hypoglycemic therapy regimen was used, including glimepiride - 4 mg / day in 2 divided doses (morning and evening) in combination with gliclazide with modified excitation - 60 mg / day in 1 divided dose . For the correction of cognitive impairment, cerebrolysin was prescribed in the form of intramuscular injections (5.0 daily for 30 days).

The second group of 49 people on the background of hypoglycemic therapy with glimepiride and gliclazide was prescribed rivastigmine in doses recommended by the manufacturer, namely by mouth, during meals - 1.5 mg 2 times a day; with good tolerance after 2 weeks, it is possible to increase the dose to 3 mg 2 times a day and then with an interval of 2 weeks to 4.5 and 6 mg / day 1 time per day. When using the transdermal form, the initial dose is 4.6 mg 1 time per day (equivalent to a dose of less than 6 mg / day by mouth), after 4 weeks, with good efficacy and tolerability, they switch to 9.5 mg 1 time per day.

It was established that in the group receiving rivastigmine one month after the start of treatment, the blood glucose level had a significantly more pronounced decrease, compared with the group receiving cerebrolysin with almost identical results of correction of memory, attention, gnosis, praxis, and mental operations.

The possibility of achieving the claimed effects is illustrated by a clinical example.

A 62-year-old female patient with type 2 diabetes mellitus combined with moderate cognitive decline (MCI) who has been taking glimepiride for a long time - 4 mg / day in 2 divided doses (morning and evening) in combination with modified-release glycazide - 60 mg / day in 1 reception in the evening, therapy was prescribed with a transdermal (patch) form of rivastigmine at a dose of 4.6 mg once a day, against the background of continued administration of the listed oral hypoglycemic agents. Basal values of the indicators: scale of the intellectual - mnestic functions Mini Mental State Examination (MMSE, KSHPS) - 24 points (norm is not less than 28 points), fasting blood glucose in the morning 7.8 mM / l, in the evening 3 hours after the last meal 9, 2 mM / L.

After 30 days, there was a decrease in blood glucose to 5.2 mM / L in the morning and 6.8 mm / L in the evening, which allowed the abolition of gliclazide. The MMSE score did not change, which allowed increasing the dose of rivastigmine to the highest therapeutic dose - 9.5 mg once a day.

After 45 days during therapy with the indicated dose of rivastigmine and taking glimepiride - 4 mg / day in 2 divided doses (morning and evening), an increase in the overall MMSE score was noted to 26 points, a subjective increase in the level of short-term memory, ability to concentrate, mental performance, decrease in level blood glucose in the morning on an empty stomach to 4.2 mmol / L. The dose of glimepiride was reduced to 2 mg / day in 2 doses (1 mg in the morning and 1 mg in the evening).

Claims (1)

A method for correcting blood sugar levels in patients with type 2 diabetes mellitus with cognitive impairment during hypoglycemic therapy, characterized in that rivastigmine is additionally prescribed orally during meals, 1.5 mg 2 times a day, with good tolerance, after 2 weeks, increase the dose to 3 mg 2 times a day and further with an interval of 2 weeks to 4.5 and 6 mg / day 1 time per day; when using the transdermal form, the initial dose is 4.6 mg once a day, after 4 weeks, with good tolerance, increase the dose to 9.5 mg once a day.