Estudo clínico multicêntrico sobre o efeito metabólico do contraceptivo mensal injetável contendo acetofenido de dihidroxiprogesterona 150 mg + enantato de estradiol 10 mg / A multicenter clinical trial on the metabolic effect of an injectable monthly contraceptive containing dihydroxyprogesterone acetophenide 150 mg + estradiol enanthate 10 mg

O efeito metabólico do contraceptivo mensal injetável contendo acetofenido de dihidroxiprogesterona (DHPA) 150 mg + enantato de estradiol (Een) 10 mg foi comparado ao de outros métodos anticoncepcionais comumente utilizados (pílulas contendo: etinilestradiol (EEn) 0,050 mg + levonogestrel (LNG) 0,250 mg, EE 0,030 + LNG 0,150 mg; e EE 0,030/0,040/0,030mmg + LNG 0,050/0,075/0,0125 mg; enantato de noretisterona (NEE) 200 mg via i.m.; e métodos nao-hormonais. Foram determinados os triglicerídeos séricos, colesterol HDL/LDL, cobre, ceruloplasmina, cortisol total e livre, CBG e testosterona total e livre e SHBG de usu rios crônicas. Este estudo contou com a participaçäo do total de 237 mulheres. As usuárias de métodos nao-hormonais utilizadas como controle apresentaram níveis mais altos de triglicerídeos. Os níveis de testosterona total e livre foram mais baixos em mulheres que utilizavam DHPA 150 mg + Een 10 mg e nas que tomavam pílulas anticoncepcionais (p<0,05 - 0,01). Tais alteraçöes foram levemente menores no grupo que utilizou o injetável. Os efeitos do DHPA 150 mg + EEn 10 mg sobre o colesterol HDL/LDL, cobre, ceruloplasmina, CBG, cortisol total e livre e SHBG foram raros ou inexistentes. Entretanto, com as pílulas anticoncepcionais (mesmo as de formulaçäo de baixa dosagem) ocorreram alteraçöes em todas essas vari eis, que foram altamente significativas na comparaçäo com o método injetável (p< 0,01) e com os métodos nao-hormonais (p<0,01); näo houve diferenças entre estes dois últimos métodos. Os resultados sugerem que o efeito metabólico da injeçäo mensal i.m. de DHPA 150 mg + Een 10 mg näo é superior aos dos anticoncepcionais orais comumente utilizados. Estes resultados também nao sugerem que a dose contida nesse injetável seja excessiva. Nao há qualquer evidência de que ele produza efeito cumulativo no organismo. Esses achados devem ser levados em consideraçäo com relaçäo à segurança do uso a longo prazo desse injetável.

Multicentred clinical study of the metabolic effect of the monthly injectable contraceptive containing dihydroxyprogesterone acetophenide 150 mg + estradiol enanthate 10 mg.

The metabolic effect of the monthly injectable contraceptive containing dihydroxyprogesterone acetophenide (DHPA) 150 mg + estradiol enanthate (EEn) 10 mg was compared to that of other regularly used contraceptive methods (pills containing: ethinylestradiol (EE) 0.050 mg + levonorgestrel (LNG) 0.250 mg, EE 0.030 mg + LNG 0.150 mg; EE 0.030/0.040/0.030 mg + LNG 0.050/0.075/0.0125 mg; norethisterone enanthate (NEE) 200 mg i.m.; non-hormonal methods). Serum triglycerides, HDL/LDL-cholesterol, copper, ceruloplasmin, total and free cortisol, CBG, total and free testosterone and SHBG in chronic users were determined. A total of 237 women took part in this study. Taking users of non-hormonal methods as control, triglyceride levels were higher, and total and free testosterone levels were lower in women using DHPA 150 mg + EEn 10 mg and in those taking contraceptive pills (p less than 0.05 - 0.01). Such modifications were slightly less in the group using the injectable. The effects of DHPA 150 mg + EEn 10 mg on HDL/LDL-cholesterol copper, ceruloplasmin, CBG, total and free cortisol and SHBG were rare or non-existent. Nevertheless, the contraceptive pills (even the low-dose formulations) correlate with modifications of all those variables, which were highly significant in comparison with the injectable (p less than 0.01) and with non-hormonal methods (p less than 0.01); there were no differences between the last two methods. The results suggest that the metabolic effect of DHPA 150 mg + EEn 10 mg is not higher than that of the commonly used oral contraceptives. On the other hand, they do not suggest that the dose contained in this injectable is exaggerated. There is no evidence that it produces accumulation of effects in the organism. These findings should be taken into account when referring to the long-term safety of this injectable.

[Experimental osteoarthritis and its course when treated with S-adenosyl-L-methionine]. / Osteoartritis experimental y su evolución bajo tratamiento con S-adenosil-L-metionina (SAMe).

Degenerative arthropathy was experimentally induced in the right knee of 24 rabbits. The animals were randomly divided in 3 groups of 8 rabbits each. S-Adenosyl-L-Methionine (SAMe) was administered intramuscularly to 2 groups. One group received 30 and 60 mg/kg/day i.m. The remaining group was a control and received only a diluent. After 12 weeks of therapy rabbits were sacrificed and tibial and femoral cartilage specimens of both knees were taken. The latter was stained with hematoxylin -eosine, Masson's trichromic and Safranine 0 stains and was microscopically studied. The thickness and cell density of the lesioned cartilages were significantly greater in both groups treated with SAMe than the group control (p less than 0.001). Statistical differences (p less than 0.05) were found within 60 and 30 mg/kg/day of SAMe. A greater concentration of proteoglycans in the cartilage matrix was found in animals treated were as, a severe reduction was found in controls. The severity of the lesions, based on the histologic-histochemical analysis, was significantly lower in rabbits receiving SAMe (p less than 0.0005). These differences were correlated with the administration of SAMe and the possible mechanisms of action are discussed.

Effect of S-adenosylmethionine on experimental osteoarthritis in rabbits.

Twenty-four rabbits with surgically induced osteoarthritis of the knee were allocated into three treatment groups (placebo, S-adenosylmethionine (SAMe) 30 mg/kg per day, and SAMe 60 mg/kg per day). Intramuscular administration of drug or placebo was begun immediately after surgery and continued for 12 consecutive weeks. At the end of the treatment period, animals were killed, and the articular surfaces of the knees were studied using histologic and histochemical techniques. Microscopic studies showed that the number of cells and the depth of the cartilage were significantly (p less than 0.001) increased in SAMe-treated rabbits in comparison with placebo-treated animals. No difference was found in comparing data in animals given SAMe at the two dosage levels. In conclusion, these results suggest a chondroprotective effect of SAMe in animals with experimental osteoarthritis.

Atividades estrogênicas do enantato de estradiol e etinilestradiol comparados a níveis clínicos / Estrogenic activities of estradiol enantate and ethinylestradiol compared at clinical level

Mulheres sadias na menopausa concordaram em receber dois tratamentos estrogênicos consecutivos: 1. 0,030 mg/d p.o. de etinilestradiol durante 21 dias; 2. uma dose única de 10 mg i.m. de enantato de estradiol (estra-1, 3, 5(10)-triene-3-ol-ß-heptanoato). Um dos componentes do Perlutal ou Topasel. Entre os dois tratamentos houve um período de um mês sem qualquer medicamentos. Os níveis séricos de prolactina, LH e FSH foram medidos em todas as mulheres através do radioimunoensaio antes do início de cada tratamento e pelo menos 14 vezes durante 31 dias. Os dois tratamentos induziram uma diminuiçäo temporária dos níveis de FSH e um aumento temporário dos níveis de prolactina. Com relaçäo a isso, o efeito do enantato de estradiol foi mais precoce, mas a qualidade e a magnitude das respostas foram semelhantes entre as duas substâncias. O perfil de evoluçäo do LH foi diferente: houve uma diminuiçäo com o enantato de estradiol, mas foi observado um aumento rápido na concentraçäo máxima no décimo sétimo dia com o etinilestradiol. Comparando os resultados obtidos, näo foram observadas diferenças estatísticas significativas entre as potências estrogênicas dos dois esquemas terapêuticos

Estudos farmacocinéticos do enantato de estradiol em mulheres na menopausa / Pharmacokinetic studies of estradiol enantate in menopausic women

Mulher sadias na menopausa receberam 10 mg i.mg i.m. de enantato de estradiol (estra-1,3,5(10)-triene-3-ol-17ß-heptanoato, um dos componentes do Perlutal ou Topasel). Os níveis séricos de estradiol foram determinados por radioimunoensaio (RIA) nos dias 1, 2, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, e 31 após a injeçäo da droga. Com base nesses dados, foram calculadas a constante do índice de eliminaçäo (K=0,12445 d*-1), a meia vida de eliminaçäo (t1/2=5,57d), a constante do índice de absorçäo (Kabs= 1,5050d*-1), a meia-vida de absorçäo (t1/2abs= 0,46 d) e o volume de distribuiçäo (Vd=5.087 I). Os resultados foram comparados com outros näo obtidos pelo RIA e foram discutidos a partir de um ponto de vista clínico-terapêutico

Influence of ambroxol on lung tissue penetration of amoxicillin.

Lung amoxicillin levels were assessed in tissue obtained from 16 patients who underwent lung resection due to different pulmonary diseases. In this double-blind placebo controlled study patients were allocated to two groups in randomized order; one group received amoxicillin 1000 mg t.i.d. (n = 8) and the other amoxicillin 1000 mg + ambroxol 60 mg t.i.d. (n = 8). A trend towards higher antibiotic lung tissue levels was observed in patients who received the antibiotic together with the mucolytic agent. The ratio pulmonary tissue/serum amoxicillin levels reached a significant difference being higher in the amoxicillin plus ambroxol group than in the other one (0.411 +/- 0.04 vs 0.672 +/- 0.07; p less than 0.01), even if the amoxicillin plasma levels were lower. A possible effect of ambroxol on lung tissue penetration of amoxicillin is suggested and discussed.

Influence of ambroxol on amoxicillin levels in bronchoalveolar lavage fluid.

Amoxicillin levels were measured in bronchoalveolar lavage (BAL) fluid samples obtained from patients who after randomization were treated in double-blind fashion either with amoxicillin 1000 mg p.o.t.i.d. or with amoxicillin 1000 mg + ambroxol 60 mg p.o.t.i.d. Antibiotic levels were higher in the group receiving ambroxol (0.32 +/- 0.02 micrograms/ml; n = 8) than in the other one (0.19 +/- 0.02 micrograms/ml; n = 6). This difference was statistically significant (p less than 0.001). Comparisons of protein concentrations in BAL fluid samples and of amoxicillin plasma levels did not show significant differences in the two groups. These results seem to prove that ambroxol is able to increase the antibiotics concentration in the lungs, although the mechanism of action is still unclear. In addition it could be shown that the BAL technique is suitable for exploring the lung concentration of antibiotics.

Ambroxol plus amoxicillin in the treatment of exacerbations of chronic bronchitis.

Twenty-three patients with exacerbations of chronic bronchitis were divided in two groups in a randomized fashion receiving either amoxicillin 1500 mg/d (n = 13) or amoxicillin 1500 mg/d associated with the mucolytic drug ambroxol 90 mg/d (n = 10). The improvement in cough, expectoration difficulties and sputum purulence was statistically more evident and occurred earlier in the ambroxol + amoxicillin group than in the amoxicillin only group. Although amoxicillin plasma and sputum levels were similar in both groups, the differences in daily sputum volume, which was also statistically greater in patients receiving ambroxol, suggests that this drug favours the bronchial mucus clearance of the antibiotic which could be related to the more favourable clinical evolution. No changes were observed in lung function tests and blood gases.

Estrogenic activities of estradiol enantate and ethinylestradiol compared at a clinical level.

Healthy menopausic women accepted to receive two consecutive estrogenic treatments: 1. ethinylestradiol 0.030 mg/d p.o. during 21 days; 2. a single dose of estradiol enantate (estra-1,3,5(10)-triene-3-ol-17 beta-heptanoate, one of the components of Perlutal or Topasel) 10 mg i.m. Both treatments were separated by a 1-month wash-out period, without any medicine. FSH, LH and prolactin serum levels were measured in each one of the subjects by radioimmunoassay before the beginning of each treatment and for at least 14 times during 31 days thereafter. A temporary decrease of the FSH levels and a temporary increase of the prolactin levels were induced by both treatments. In this respect the estradiol enantate effect was more precocious but the quality and the magnitude of the responses were similar among the two substances. The LH profile evolution was different: there was a decrease under estradiol enantate, but a very sharp increasing peak was observed on the 17th day under ethinylestradiol. By comparing the obtained results no significant statistical differences between the estrogenic potencies of the therapeutic schemes applied were found.

Experimental findings on the estrogenic activity of estradiol enantate.

In a first attempt to find out the estrogenic activity of the monthly injectable contraceptive composed of dihydroxyprogesterone acetophenide 150 mg + estradiol enantate 10 mg (Perlutal, Topasel), estradiol enantate (estra-1,3,5(10)-triene-3-ol-17 beta-heptanoat), estradiol benzoate and ethinylestradiol were compared in rats of the Chbb: THOM species. Estradiol benzoate potency was significantly higher than that of estradiol enantate: 20.34 (15.57-26.31) times in the vaginal cornification test in castrated females; 2.21 (1.63-2.98) times in the uterine weight test also in castrated rats and 2.91 (1.86-4.54) times in the vaginal opening test in immature rats. Ethinylestradiol, orally administered in the first two tests, was less active than the other two parenterally given substances; it overcame them in the vaginal opening test, when all substances were perivaginally administered. The duration of action of equivalent doses on the vaginal smear in castrated females resulted higher for estradiol enantate: 2.52 times more than estradiol benzoate and 5.2 times more than ethinylestradiol. Based on these results and on preexistent literature, the estradiol enantate dosis which would be sufficient to obtain the endometrial proliferation in women was extrapolated and compared with those already established of estradiol benzoate and ethinylestradiol. Finally, the possibility that the estrogenic potency of the injectable contraceptive treatment can be similar or lower than the oral one with pills containing ethinylestradiol 0.030-0.050 mg is discussed.

Pharmacokinetic studies of estradiol enantate in menopausic women.

Healthy menopausic women received 10 mg i.m. of estradiol enantate (estra-1,3,5(10)-triene-3-ol-17 beta-heptanoate, one of the components of Perlutal or Topasel). Their estradiol serum levels were determined by radioimmunoassay (RIA) on days 1, 2, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29 and 31 after the injection. Based on these data, the elimination rate constant (K = 0.12445 d-1), the elimination half-life (t1/2 = 5.57 d), the absorption rate constant (Kabs. = 1.5050 d-1), the absorption half-life (t1/2 abs. = 0.46 d) and the volume of distribution (Vd = 5087 l) were calculated. These results are compared with others not obtained by RIA and discussed from a therapeutic-clinical point of view.

Influence of ambroxol on the bronchopulmonary level of antibiotics.

Antibiotic levels in bronchopulmonary tissue following oral administration of ampicillin, erythromycin and amoxycillin dosed 50 mg/dg were compared with those obtained by the same treatments n0 mg/dg p.o of trans-4-[(2-amino-3,5-dibromo-benzyl)amino]cyclohexanol (ambroxol, Mucosolvan) in several groups of rats. The addition of ambroxol was correlated with an increase of 234% in the pulmonary average concentration of ampicillin, 27% in that of erythromycin 27% in that of amoxycillin; the statistical evaluation of these differences resulted in less than 0.05 in each case. It may be concluded that ambroxol, through a mechanism still unclear, can increase the antibiotic levels in the lungs of the rat.