DE3533494A1 - Aerosol use of pentamidine (p,p'-(pentamethylenedioxy)-dibenzamidine bis( beta -hydroxyethanesulphonate)) for the treatment of the pneumonia caused by Pneumocystis carinii - Google Patents

Abstract

The use of an aerosol of pentamidine (p,p'-(pentamethylenedioxy)-dibenzamidine bis( beta -hydroxyethanesulphonate)) for the treatment of the pneumonia caused by Pneumocystis carinii as a sequela of AIDS is proposed and leads to 100% cure of the disorder.

Description

Pneumoycystis pneumonia is a common infection of the immune system-weakened body and the most occurring and dangerous infection in AIDS patients. The infection also occurs in cancer and organ transplant patients and was found in epidemic form in premature babies. Reports of Pneumocycstis Pneumonia in otherwise healthy Humans were the first signal of the appearance of the epidemic AIDS disease. More than 70% of AIDS patients develop this infection. For many, it is the first symptom of dysfunction of the immune system and thus provides the basis for diagnosis of AIDS.

Patients can benefit from initial episodes of Pneumocystis Pneumonia recover from earlier and longer treatment. Because a response therapy is usually slow or incomplete, treatment must be continued for 21 days or more. During this period, patients in the hospital must have one experienced intensive treatment.

The compound pentamidine has so far been used essentially for treatment African trypanosis miasis, African sleeping sickness, been applied. There have also been attempts to connect this for the treatment of AIDS by intramuscular administration to apply. However, as explained below, this is unsuccessful, this could lead to the final stage existing pneumonia cannot be effectively combated, and the exitus was only delayed for a short time.

Preventing Pneumocystis caused by Pneumonia Pneumocystis carinii would essentially be the clinical picture and eliminate mortality and a significant reduction of the limited medical resources. Preventing infection could also eliminate a factor the one with an already damaged immune defense system can intensify an underlying disease.

It has now surprisingly been found that aerosol administration from pentamidine to the lungs even in the most severe cases leads to healing of the focus of infection.  

The subject matter of the invention is subsequently carried out using the Investigations explained:

Pentamidine is administered to rats per os, intramuscularly and by aerosol. The pentamidine values in the tissues are determined bioanalytically. After ingestion of 16 mg / kg pentamidine in water within two days, rats have tissue values that are no longer detectable (less than 0.8 µg / g). 24 hours after 1, 2 or 4 daily intramuscular doses of 4.0 mg / kg, the tissue values were less than 0.8, 3.7 ± 2.6, and 9.1 ± 6.6 µg / g in the lungs and 26.9 ± 4.4, 62.4 ± 14.8 and 83.7 ± 48.8 in the kidneys. (mean value ± SA, N = 4). 24 hours after 1, 3 or 4 daily aerosol doses of 0.4 mg / kg, the values are 3.1 ± 1.9, 12.1 ± 3.0 and 17.7 ± 5.5 µg / g in the lungs and less than 0.8 µg / g in the Kidneys. After 1, 24, 48 and 96 hours after a single aerosol dose of 4.0 mg / kg, the values are 50.6 ± 8.7, 39.2 ± 13.3, 28.4 ± 18.3 and 22.5 ± 12.1 µg / g in the lungs. After the aerosol doses, the pentamidine values in the periphery of the lungs are just as high as in the entire lungs.
The measurement results of the tissue concentrations obtained are summarized in Tables I to III below:

Table I

Tissue concentrations of pentamidine in rats after intramuscular injection of 4.0 mg / kg

Table II

Tissue concentrations of pentamidine in rats after administration of aerosol 0.4 mg / kg

Table III

Tissue concentrations of pentamidine in rats after administration of 4.0 mg / kg aerosol

Male Sprague-Dawley rats are subcutaneously twice weekly 50 mg / kg cortisone acetate injected. The same with a 8% protein diet nourished and with tetracycline in their drinking water treated. After 12 weeks the rats are killed and that The extent of infection was assessed by counting the cysts in Toluidine 0 stained smears of the homogenates (1:10) of the lungs.

The extent of Pneumocystis carinii infestation is assessed based on the cysts, their number at a microscopic magnification of 450 × is determined.  

In experiment 1, 8: 4.0 mg / kg pentamidine means once a week starting with the fifth week, 8 aerosol: 0.4 mg / kg pentamidine Once a week, starting with the fifth week.

In experiment 2, 9 means aerosol prophylaxis: 2.0 mg / kg pentamidine once a week starting with week 7. 8: Aerosol treatment: 0.4 mg / kg pentamidine once a day for 4 days starting on the first day of week 11.

The results are summarized in Table IV below:  

Table IV

The results summarized in a table show a surprising result Result. During intramuscular administration while trying leads to a cyst score of 102 according to Table I, conditionally the use of only a tenth of the compound in the form of an aerosol the presence of no cysts at all, i.e. a complete one Recovery. Comparably favorable values result from the test according to Table II regarding aerosol prophylaxis and treatment.

In summary, it can thus be stated that the aerosol administration the pentamidine in an effective manner to the focus of infection is brought and the accumulation in other organs as far as possible is limited. Results from the application according to the invention an extremely effective treatment option lethal opportunistic infection in patients with the AIDS clinical picture caused by Pneumocystis carinii.

The compound p.p ′ - (pentamethylenedioxy) dibenzamidine-bis (β-hydroxyethanesulfonate) can be made by saturating an anhydrous alcoholic solution of 4,4′-dicyanodiphenoxypentane with dry hydrochloric acid and let stand. The so obtained Iminoether hydrochloride is made with a solution of sodium hydroxide treated and the base thus obtained with ammonium β-hydroxyethanesulfonate implemented.

Claims (2)

1. Aerosol application of pentamidine (p, p ′ - (pentamethylenedioxy) - dibenzamidine-bis (β-hydroxyethanesulfonate)) for the treatment of pneumonia caused by Pneumoxystis carinii. 2. Application according to claim 1, characterized in that the solution on which the aerosol is based contains of active ingredient of up to 20%.