The antihypertensive effect of captopril. Evidence for an influence of kinins.

The acute effect of the orally-active converting enzyme inhibitor, captopril, was compared to that of saralasin in 13 patients with various forms of hypertension on ad libitum sodium intake. A significant difference between the effects of the two drugs on mean arterial pressure (MAP) was found (-11 +/- 3 mm Hg with saralasin, -24 +/- 4.5 mm Hg after captopril). This difference was not correlated with control plasma renin activity (PRA). To determine the influence of the endogenous kallikrein-kinin system in the antihypertensive action of captopril, the effect of aprotinin (Apro), an inhibitor of kinin generation, on the MAP level achieved by captopril was assessed in five normal subjects and 15 patients with hypertension on ad libitum sodium intake. In normal subjects, captopril did not alter MAP, nor did Apro have any effect. In six patients with essential hypertension and normal PRA, MAP decreased by 5.5 +/- 2 mm Hg following captopril, and Apro did not modify this level. In nine patients with renovascular hypertension (RVH), MAP fell by 22 +/ 3 mm Hg after captopril administration, and Apro infusion induced a rise in MAP of 13 +/- 1.7 mm Hg. A positive correlation between log control PRA and the effect of aprotinin was obtained ( r = 0.63, p less than 0.005). Apro had no effect in two patients with RVH who experiences a large drop in MAP during salasin. These results suggest that endogenous kinins as well as other substances, the generation of which is inhibited by aprotinin, may participate to the antihypertensive effect of captopril in patients with angiotensin-dependent hypertension. The lack of an aprotinin effect on the MAP level achieved during saralasin infusion suggests that the influence of the kallikrein-kinin system is related to the effect of captopril rather than the fall in arterial pressure resulting from angiotensin blockade.

Objective response and disease outcome in 59 patients with stage D2 prostatic cancer treated with either Buserelin or orchiectomy. Disease aggressivity and its association with response and outcome.

A comparative study was done in 59 recently diagnosed Stage D2 prostatic cancer patients treated with either long-term GnRH-A (Buserelin) (N = 42) or with orchiectomy (N = 17) and followed up for three years. The suppressed limits of plasma testosterone and estradiol levels after eight-week follow-up as well as the objective clinical response and disease outcome were found to be similar with either treatment. Hot flushes and loss of libido were noticed in both groups throughout the follow-up period; however, there were no other side effects. Analysis of Stage D2 patients based on their time of death enables us to identify nonhormonal variables which, in the form of an aggressiveness score, correlated well with both clinical response and disease outcome. These data confirm that (1) Buserelin is an effective and safe alternative to orchiectomy in advanced prostatic cancer, and (2) in clinical studies a multifactor aggressiveness score is useful for analyzing clinical efficacy data. Prospective application of that score may enable predictability of patient response and influence patient management.

Inhibition of serum androgen levels by chronic intranasal and subcutaneous administration of a potent luteinizing hormone-releasing hormone (LH-RH) agonist in adult men.

The effect of chronic treatment with the luteinizing hormone-releasing hormone (LH-RH) agonist Buserelin (Hoechst AG, Frankfurt/Main, West Germany) ([D-Ser(TBU)6,des-Gly-NH2(10)]LH-RH ethylamide) administrered by nasal spray (200 or 500 micrograms, twice daily) or subcutaneously (50 micrograms daily) for periods of 1 to 8 months was studied on serum sex steroids and LH levels in 18 patients with cancer of the prostate. Basal serum testosterone concentration decreases to 71.1 +/- 18.3 (NS) and 28.6 +/- 9.3%, (P less than 0.01) of control in patients receiving the 200-micrograms and 500-micrograms dose by nasal spray, respectively. In patients treated subcutaneously, a more rapid inhibition of serum testosterone levels to 19.6 +/- 6.4% of control (P less than 0.01) is observed. The finding of decreased levels of 17-OH-progesterone, testosterone, and dihydrotestosterone in the presence of unchanged pregnenolone concentration indicates that the decrease in androgen biosynthesis induced by Buserelin treatment is due to a blockage at the level of 17-hydroxylase and 17,20-desmolase activities. The present data indicate that chronic administration of Buserelin could be a safe and effective means of reducing serum androgens in patients with cancer of the prostate.

Total androgen ablation: Canadian experience.

A multicenter randomized, double-blind trial comparing total androgen blockade obtained by the use of castration with a pure anti-androgen (nilutamide) with simple castration was begun. One hundred and five patients received the combined treatment and 103 the orchiectomy plus placebo. Several features were used to evaluate the efficacy. Bone pain responded better to combined treatment at 6 months (P = 0.042). The number of favorable responses, as evaluated by the NPCP criteria, was 61% with simple castration and 78% with the combined treatment (P = 0.013). There was no statistically significant difference between the two groups in time to progression (logrank test P = 0.462) or survival (logrank test P = 0.137) despite an increase in median survival of 5.4 months. All other measures showed no difference between the two treatments. With total androgen blockade, 50% of the patients had disease progression at 1 year, and 45% were dead at 2 years. A review of the results of similar reported studies suggests no improvement or very modest improvement with total androgen blockade over testicular androgen ablation alone.

The assessment of disease aggressivity in stage D2 prostate cancer patients (review).

Suppression of androgen levels in blood of stage D2 prostate cancer patients has been the prominent treatment for advanced prostate cancer. However, the duration of hormone sensitivity of prostate tumor is variable. The type of initial response to hormonal treatment, the length of response and patient's survival are in direct association with disease aggressiveness. Recently, an arithmetic formula expressing disease aggressivity was computed using pretreatment values of prostatic acid phosphatase (P.A.P.), alkaline phosphatase (A.P.), degree of tumor differentiation and number of bone metastases. This aggressiveness score was related to disease response and patients outcome receiving hormonal treatments. The use of an arithmetic formula to express disease aggressivity could result in a subdivision of the disease. The identification of the subgroup of stage D2 patients destined not to benefit from hormonal manipulation could change the strategies employed up until today for the treatment of advanced prostate cancer.

Total androgen blockade for metastatic cancer of the prostate.

This randomized, double-blind study comparing orchiectomy plus placebo to orchiectomy plus a nonsteroid antiandrogen (Anandron) shows that total androgen blockade for metastatic cancer of the prostate provides a significantly better early objective response when compared to castration alone. This response, however, is less apparent at 18 months. The study also suggests a longer survival for the patients with total androgen blockade.

[Evaluation of the acute effect of a converting enzyme inhibitor, captopril, in normal and hypertensive subjects]. / Estimation de l'effet aigu d'un inhibiteur de l'enzyme de conversion, le Captopril, chez le sujet normal et l'hypertendu.

The response to acute oral administration of 50 mg of Captopril was assessed in 17 normal volunteers and 47 patients with hypertension; 17 had renovascular (RVH) abnormalities and 30 patients had essential hypertension (EH). All patients were maintained on ad libitum sodium intake. The effect of Captopril on mean arterial pressure (MAP) was rapid a maximal within 60 minutes. The converting enzyme inhibitor induced a similar decrease in MAP in normal subjects (-5.1 +/- I mm Hg) and patients with EH (-7.2 +/- I mm Hg). Control plasma renin activity (PRA) was similar in both groups; however, the increase in PRA following Captopril was more marked in normals (8.1 +/- 1.7 ng/ml/h) than in EH (1.7 +/- 0.7 ng/ml/h). In patients with RVH a marked fall in MAP occurred (-25.4 +/- 4 mm Hg). A fall in MAP higher than 20 mm Hg was observed in 65% of patients with RVH and none of the EH group. A negative correlation between log PRA and the change in MAP induced by Captopril was obtained (r = 0.65). Assessment of the response to acute administration of Captopril may be useful for screening patients with RVH.

Procalcitonin is not produced by circulating blood cells.

A large number of clinical studies has described procalcitonin (ProCT) as a marker of bacterial infection and a good predictor of disease severity and antibiotherapy efficacy. Nevertheless, the mechanism of ProCT synthesis remains unclear. The aim of this study was to demonstrate potential ProCT production by peripheral blood mononuclear cells as is the case for cytokines involved in sepsis. In a whole blood model, LPS (10 micrograms/ml) stimulation on blood samples from healthy volunteers (n = 14) was tested. Early (TNF-alpha and IL1-beta) and late (IL-6 and IL-8) cytokines were produced in large amounts in contrast to the absence of ProCT. Additional experiments with nitric oxide or detection of intra-cellular ProCT (cell lysis, flow cytometry) had negative results. It was concluded that ProCT is not produced in this model. Data are still needed to investigate the cellular origin of ProCT in order to better define its clinical usefulness.

[Effect of captopril in essential hypertension (author's transl)]. / Effet du captopril dans l'hypertension artérielle essentielle.

The angiotensin I-converting enzyme inhibitor, captopril (SQ 14225) was proposed as first treatment in 12 cases of uncomplicated essential hypertension maintained on unrestricted sodium intake (group I). Arterial pressure was normalized in 7 patients (subgroup Ia) whilst hydrochlorothiazide was added to captopril in 5 patients (subgroup Ib). A significant dose-response curve between the dose of captopril (range 75 to 450 mg/day) and the antihypertensive effect was obtained with a maximum at 300 mg/day. In 8 patients (group II) hydrochlorothiazide was proposed first and the addition of captopril was necessary in 4 cases. No relationship between pretreatment PRA and the maximum effect of captopril was observed (r = -0.34, NS). No disturbance of upright blood pressure regulation was noted. Adverse reaction consisted of 4 cases of benign and spontaneously regressive skin rash or pruritus.

[Renal and perinephritic abscesses in children]. / Abcès rénal et périrénal chez l'enfant.

One child with a pure perinephric abscess and three with renal abscesses, one of which had perinephric extension, are described. All presented with a long course of subacute infection leading to localizing symptoms or signs in the flank. The diagnosis was confirmed by radiologic examination. All the abscesses were surgically drained at various intervals after diagnosis, while the patients were receiving antibiotic therapy. Salvage of renal function was possible in all cases. A rational approach to the diagnosis and management of such abscesses is emphasized.

Protection of the myocardial homograft. 1. The cooling bag.

Because severe cardiac insufficiency follows orthotopic heart transplantation, the authors have evaluated protection of the homograft provided by a cooling and isolating bag during the operative period of ischemia and subsequently its effect on cardiac function. In one group or four dogs hearts were transplanted without using hypothermia. In the second group, seven hearts were excised, immediately cooled by immersion in saline at 4 degrees C and orthotopically homotransplanted. In the third group, six hearts were immersed in saline and then isolated in a cooling bag until transplantation had been completed. Cardiac function in all animals was evaluated at rest, 3, 24 and 48 hours after operation. In group 1, lowering of the temperature was minimal and all animals died immediately after operation. In group 2, the myocardial temperature, which had been lowered to 13 degrees C by immersion, had risen to 25 degrees C after 17 minutes. In group 3, the myocardial temperature was maintained at 13 degrees C up to the time the aortic clamp was removed. Three hours after operation, the cardiac performance of group 3 was much better than that of group 3 was much better than that of group 2 as demonstrated by an increase of cardiac output (39%), stroke volume (44%), mean systolic ejection rate (25%), maximum systolic flow (28%), peak velocity (26%), maximum acceleration (20%), left ventricular power (32%) and left ventricular work (47%). In the following days, cardiac function of groups 2 and 3 improved and the disparity between then decreased. These results demonstrate that the cooling bag, while offering technical advantages, maintains profound hypothermia in the donor heart and substantially improves the performance of the homograft in the immediate postoperative phase.