Drug for the treatment of acquired immunodeficiency syndromes, including hiv-related

 

(57) Abstract:

The invention relates to medicine, namely to the production of medicines on the basis of [N-methyl-N -/ D-glyukopiranozil/ammonium-2-/acridin-9-one-10-Il/acetate] -cycloferon, and can be used for the treatment of acquired immunodeficiency syndromes (AIDS), including HIV-related. The objective of the invention is to create high quality, effective, low-toxic remedies for the treatment of AIDS, including HIV-related. The problem is solved in that the medicinal product containing the active substance and the solvent, as the active substances used, the compound N-methyl-N/a, Dr. glyukopiranozil/ammonium-2-/acridin-9-one-10-Il/acetate as solvent to water in the following ratio, wt.%:

active substance - 18 - 22,5

water - the rest. 10 table.

The invention relates to medicine, namely to the production of medicines on the basis of [N-methyl-N -/ D-glyukopiranozil/ammonium-2-/acridin-9-one-10-Il/acetate] -cycloferon (application trademark N 93006831/50 from 24.03.93), and can be used for the treatment of acquired immunodeficiency syndromes (AIDS), including HIV-related.

Known is the Danon (U.S. patent N 3681360, class. WITH 07D 37/20, Appl. 09.04.71, publ. 01.08.72) adopted for the prototype structure. The prototype has the following composition:

as active substances substituted acridine sodium salt of 10-carboxymethyl-9-acridinone structural formula

,

surfactant,

sodium hydroxide,

the water solvent.

The tool is not used to treat AIDS.

Known means at the specified prototype has the following disadvantages: strong irritating and painful action, due to the high pH (9); the risk of necrosis and gemokoagulyatsii; insufficient concentration of the active substance (50 mg/ml 5%), which requires an increase in the volume of injectate for the manifestation of therapeutic effect (up to 10 ml or more).

In order to reduce pain effect with the drug were trying stabilization specified in the prototype dosage forms allowed in the Pharmacopoeia by means of, for example, buffer solutions and complexing agents. During the experiment, we tried to reduce the pH of the dosage form below 8, but this has not led to a positive result. At pH below 8 there was a gradual deposition of sediment acre">

Currently, for the treatment of HIV infected and AIDS patients using various inhibitors of viruses (suramin, ribavirin, interferon, and others), which inhibit the replication of HIV (1-5). However, the above-mentioned drugs or have insufficiently expressed specific activity, or highly toxic.

The only permitted at the present time to use the drug for the treatment of HIV/AIDS is the drug 3-azido-3-deoxythymidine (azidothymidine) that have a specific inhibitory effect on reverse transcriptase of the virus (6) prototype therapeutic effect.

However, treatment with azidothymidine is not effective and does not prevent the emergence of a number of severe complications of HIV infection and AIDS, has inhibitory and toxic effects with long-term therapy on bone marrow and blood, gives strong side effects.

The objective of the invention to create high quality, effective, low-toxic remedies for the treatment of AIDS, including HIV-related.

The problem is solved in that the medicinal product containing the active substance and the solvent, as the active substance isolezwe solvent water in the following ratio of components, wt.

active substance 18,0 22,5

water the rest

Currently, biomedical experiments have shown that the effective daily dose of cycloferon is 360-450 mg per person in a single dose. In accordance with the proposed therapeutic dose of the applicant has been a lot of work to create effective and high-quality pharmaceutical form. The development of the dosage form was carried out for vials with a volume of 1.2 and 5 ml applied to obtain standard legform.

To obtain a parenteral dosage form, the applicant used a specified number of greenexpo acid and water for injections and different amounts allowed in the Pharmacopoeia of the N-methylglucamine.

Dosage form was obtained by the method described below.

The results of the studies are given in table. 1.

From table. 1 shows that when using N-methylglucamine less of 96.5 g dosage form is not stable: formed turbidity or precipitation during storage. When using N-methylglucamine more of 96.5 g of the solution has a pH above 9 and has a strong local irritant effect. Thus, the optimal ratio coatom optimal ratio of components of the dosage form, optimal therapeutic daily dose of 360-450 mg per person, single administration, as well as manufactured standard vials (1,2 and 5 ml) was obtained the optimal concentration of active substance in again the type of 18.0-22.5 wt.

The results of the studies are given in table. 2.

As follows from the table. 2, when use vials with a volume of 5 ml with a concentration of active substance of 7.2-9.0% of the volume of solution is too large for a single injection. When using vials in 1 ml with a concentration of active substance 45% dosage form low-tech due to the high viscosity and gives infiltrates with parenteral administration of the drug.

In table. 3 shows the comparative characteristics of qualitative indicators of the claimed dosage forms and prototype structural entity.

As follows from the table. 3, the claimed medicinal product has the following advantages:

the complete absence of irritating and painful steps in injecting drug due to close to physiological (blood pH 7,3);

in 5-20 times higher concentration of active substance in the solution, allowing to obtain a pronounced therapeutic effect in the mini is

upon receipt of the dosage form does not require special equipment for sealing ampoules under inert gas.

A formulation was prepared as follows.

In chemical beaker with a capacity of 2 litres pour 1 liter of water for injection, load 193 g N methylglucamine, stir until dissolved and add 250 g greenexpo acid and again stirred until dissolution. Control potentiometric pH of the solution to bring the volume of the solution to 2 l with water for injection, filtered the solution through Millipore and poured into ampoules and vials. The sealed ampoules and autoclave. Vials sealed with rubber stoppers, practicing aluminum caps and autoclave.

The results of biomedical research has been proved to be highly effective drugs in the treatment of immune disorders, including HIV-related.

Examples confirming therapeutic activity of the drug.

Example 1. Patient Z. 15 years. Diagnosis: acquired immunodeficiency syndrome HIV IIIB. After amputation of the right tibia in the middle third.

Comorbidities: displacenent without exacerbation, bilateral hydronephrosis. Complications: osteomyelitis of the right heel and ankle and left ischial bone in remission, ARI (acute respiratory viral infection).

Diagnosis of HIV infection is confirmed by the results of enzyme immunoassay and immunoblotting.

Estimated date of HIV infection September-October 1988

Complaints received at a fetid purulent discharge from the wound on the right heel region, non-healing wound of the left buttock. A state of moderate severity, the power is reduced. On the left buttock wound size 4.5 x 2 cm depth 8 cm In the right heel linear wound 4 cm with purulent malodorous discharge. Increased all groups of lymph nodes. Borders of the heart extended to the left by 1 cm, the colours are slightly muted, intermittent systolic murmur at the apex. Single dry and not euphonic moist rales in the basal zones of both lungs. Stomach, soft, painless. Liver at 1.5 cm below costal arch (sizes karlovu 12, 11, 4), its consistence is soft, smooth edge. Muscle atrophy of the lower limbs, tendon reflexes diminished, reduced pain sensitivity in the middle of the thighs.

23.06.92 performed amputation of the right tibia in the middle third.

Thus, the hemogram and immune status have undergone a clear positive dynamics: improved indicators of red blood increased number of lymphocytes (2 times), including T3, T4, T8lymphocytes, improved ratio of T4/T8(between 0.46 to 0.61). Objective changes in immune status in hemo-grams in the direction of improvement was accompanied by significant improvement in overall health and status: became much calmer, appetite, normalized sleep, the condition was satisfactory, the wound after amputation of the lower leg healed by first intention.

Example 2. Patient B. 3 years. Diagnosis at admission: chronic picomaviridae infection, severe generalized form. Acquired immunodeficiency syndrome (AIDS), HIV-infection, agammaglobulinemia, stomatitis, chronic hepatitis, cirrhosis of the liver, urinary tract infection, exacerbation of chronic laryngotracheobronchitis, pneumocystosis, necrosis prianalnoy region, normocapnia anemia, a severe form. The deficit of body weight to about 30% of the Complaints of weakness, sudden weight loss S="ptx2">

Therapy with broad-spectrum antibiotics (claforan in combination with gentamicin, then lincomycin in combination with Biseptol intravenous and oral), infusion therapy, 2nd year prednisolone parenteral, vitamins, inderal. Against this background, was conducted therapy inventive product 2 ml of 22.5% solution (3 intramuscular injections: 15, 19, 23. 07. 92 g) (table. 6 and 7).

6 hours after the 1st injection, the child has pain in the area of pressure sores on the buttocks, as well as in the liver, through the day improved appetite. At discharge, improved health and status, gained weight 1.8 kg, disappeared grey colour of the skin, decreased effects of infiltration in the lungs, decreased anemia, erythrocyte sedimentation rate, increased number of platelets (from 60 to 136 thousand). The number of gamma globulin was increased more than 3 times (from 4 to 13% ).

Example 3. Patient, 23 years. Diagnosis: HIV IIIB stage. Chronic diffuse neurodermatitis, complicated strepto-stphiladelphia, genital warts anal area, lymphadenopathy, hepatosplenomegaly, chronic recurrent herpetic infection (exacerbation), acute tracheobronchitis, encephalopathy (atrophy of the cerebellum with ataxia).

The automotive technician is data laboratory tests (ELISA, IB), clinical manifestations.

Complaints about increasing weakness, sweating, constipation, bubble skin rash with subsequent suppuration and the formation of crusts. Suffering from atopic dermatitis since childhood, in November 1991 he had acute pneumonia (right). A state of moderate severity, the power is reduced, the skin is dry, with lots of bubble festering rash (diffuse). Whitish overlay on the mucous membranes of the cheeks and the soft palate. Diffuse lymph node enlargement, elastic, painless on palpation. In the lungs breathing hard. The liver increased (+ 2.5 cm), dense, palpated the lower pole of the spleen. A bit laggy. Carefully examined the clinical, laboratory and instrumental methods, including ultrasound and computed tomography of the brain, the thoracic and the abdominal cavity.

Therapy with all the usual means (broad-spectrum antibiotics, virolex, paracetamol, Cinnarizine, multivitamins, suprastin, gemodez, Panangin, immunoglobulin and local treatment of skin lesions). Against this background, was conducted therapy claimed the drug (3 intramuscular injections of 2 ml of 22.5% solution 22, 26, 30. 10) (table. 8, 9 and 10). Consultation by a dermatologist and a neurologist.

This example demonstrates the positive effect of the drug in adult patient with AIDS: HIV IIIB stage with diffuse neurodermatitis, complicated stabillo and streptococcal infection.

Thus, the application of cold for the treatment of AIDS infections, including HIV-related, has the following advantages over known drugs: high therapeutic efficacy in the treatment of HIV/AIDS infections, including the most severe and complications; low toxicity; fold the course of treatment, the duration of antovic/AIDS the effects of the drug; no side effects; the combination with known drugs.

All these advantages will allow you to get a significant positive result, as it will increase the effectiveness of treatment of cases of HIV/AIDS at all stages in all forms of the disease and will reduce the costs of this treatment.

Drug for the treatment of syndromes acquired immunodeficient active substance contains a compound N-methyl-N (D-glyukopiranozil (ammonium-2-acridin-9-one-10-yl)acetate formula

< / BR>
and as a solvent water in the following ratio, wt.

Active substance 18,0 22,5

Water Ostalnoe

 

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