Long-term antihypertensive therapy with isradipine. Improvement of coronary flow reserve in patients with arterial hypertension and microvascular angina

Antihypertensive Long-term Therapy with Isradipine/Improvement of coronary flow reserve in patients with arterial and microvascular angina In patients with arterial hypertension coronary flow reserve is often impaired due to left ventricular (LV) hypertrophy and alterations of the coronary microcirculation. Experimental and clinical studies have shown that calcium channel blockers can induce regression of myocardial hypertrophy. Objective of the present study was to see whether chronic antihypertensive treatment with calcium channel blockers can improve the diminished coronary reserve in patients with arterial hypertension and microvascular angina pectoris. Fifteen hypertensive patients with microvascular angina (61 +/- 7 years, normal coronary angiogram, mild LV-hypertrophy) were treated with isradipine (CAS 75695-93-1) (5.3 +/- 0.9 mg/d) for 12 +/- 2 months. Before and after therapy (after a washout period of 1 week) coronary flow was quantitatively measured by the gas chromatographic Argon method. Coronary reserve was calculated as the quotient of coronary resistance under baseline conditions and after dipyridamole (0.5 mg/kg i.v.). Under isradipine therapy systolic blood pressure was lowered from 165 +/- 20 to 140 +/- 13 mmHg (p < 0.01) and diastolic blood pressure from 98 +/- 8 to 88 +/- 6 mmHg (p < 0.01). The LV muscle mass index decreased by 10% from 154 +/- 33 to 139 +/- 28 g/m2 (p < 0.05). Baseline coronary blood flow (81 +/- 13 versus 83 +/- 16 ml/min x 100 g, n.s.) was identical before and after therapy. There were also no differences in coronary perfusion pressure, heart rate, myocardial oxygen consumption and arterio-coronary venous oxygen difference before and after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

A shape-based machine learning tool for drug design

Building predictive models for iterative drug design in the absence of a known target protein structure is an important challenge. We present a novel technique, Compass, that removes a major obstacle to accurate prediction by automatically selecting conformations and alignments of molecules without the benefit of a characterized active site. The technique combines explicit representation of molecular shape with neural network learning methods to produce highly predictive models, even across chemically distinct classes of molecules. We apply the method to predicting human perception of musk odor and show how the resulting models can provide graphical guidance for chemical modifications.     

3-Alkanoyl-5-hydroxymethyl tetronic acid homologues and resistomycin: new inhibitors of HIV-1 protease. I. Fermentation, isolation and biological activity

In the course of a screening program for HIV-1 protease inhibiting activity, six new homologues of 3-alkanoyl-5-hydroxymethyl tetronic acids (1 approximately 6) and the known natural product resistomycin (7) were isolated from cultures of the Actinomycete strain DSM 7357. The substituted tetronic acids belong to a recently described structural class of secondary metabolites. The HIV-1 activity of resistomycin (7) has not been reported before.     

Thymoma in dogs: 23 cases (1980-1991)

OBJECTIVE: To assess the efficacy of misoprostol for the treatment of chronic erosive gastritis and associated symptoms. METHODS: We performed a double-blind controlled trial, administering 200-micrograms misoprostol tablets or placebo twice daily for 2 months to 48 patients with symptomatic chronic erosive gastritis. Symptomatology was assessed by means of a standard questionnaire at the beginning and at the end of the study, as well as endoscopic and histologic changes of the gastric mucosa. RESULTS: At the end of the treatment period, a significant reduction in symptom score was observed in misoprostol-treated (from 86.6 +/- 66.2 to 17.6 +/- 18.2, p < 0.001) but not in placebo-treated patients. Endoscopic score was significantly reduced at the end of the treatment period in the misoprostol group, compared with that of the placebo group (p < 0.05). A significant reduction in the activity of histologic gastritis was observed only in patients on misoprostol. The prevalence of gastric colonization by Helicobacter pylori was rather low (30%), and no effect of treatment was observed. CONCLUSIONS: Patients with symptomatic chronic erosive gastritis seem to profit from treatment with misoprostol: the treatment with misoprostol, but not with placebo, was effective in significantly reducing the extent of symptoms. Such an improvement was associated with a substantial improvement in the endoscopic and histologic appearance of the gastric mucosa.     

Testicular lymphoma: a population-based study of incidence, clinicopathological correlations and prognosis. The Danish Lymphoma Study Group, LYFO

In a Danish population-based non-Hodgkin's lymphoma registry, 2687 newly diagnosed patients were registered from 1983 to 1992. 39 had testicular involvement (TL) (incidence 0.26/10(5)/year). Median age was 71 years. 24 cases had localised and 15 had disseminated disease. Histologically, all cases were diffuse (65% diffuse centroblastic type). Of the 27 tested, 11% were of T- and 89% of B-immunophenotype. In localised cases, where surgery was supplemented by combination chemotherapy (CCT), the relapse rate was 15.4%. The relapse rate for cases with localised disease treated with other regimens (orchiectomy and/or radiotherapy) was 63.6% (P < 0.05). Median relapse-free survival was 28 and 14 months, respectively. Overall 5-year survival for all cases was 17%. Adverse prognostic factors at the univariate level were stage IV, constitutional symptoms, serum lactic dehydrogenase elevation and performance score (WHO 3-4). It is suggested that the treatment of stage IE/IIE TL should include early CCT and CNS prophylaxis.     

A case-control study of menopausal estrogen therapy and breast cancer

The association between estrogen replacement therapy and female breast cancer was studied in two Los Angeles area retirement communities. The 138 study cases of breast cancer occurring in residents younger than 75 years were compared with age- and race-matched community control subjects. The risk ratio for a total cumulative dose in excess of 1,500 mg was estimated to be 2.5 in women with intact ovaries. This increase was present using various independent sources of drug usage information but was inconsistent at low dose and undetectable in oophorectomized women. No important sources of confounding could be identified, and no risk modifiers could be identified except for a history of surgically confirmed benign breast disease. In such women with intact ovaries, the risk ratio for a high cumulative dose rose to 5.7 relative to nonusers with normal breasts.     

Lorazepam-valproate interaction: studies in normal subjects and isolated perfused rat liver

Valproate (VPA) has been shown to interact with all the major antiepileptic drugs (AEDs) through two mechanisms of action: displacement from albumin binding sites and inhibition of drug metabolism. More recently, evidence showed that VPA inhibits the elimination of drugs metabolized by glucuronide conjugation. Lorazepam (LZP), which is primarily eliminated by conjugation with glucuronic acid, is administered concurrently with VPA both in treatment of epilepsy and in patients treated with VPA for psychiatric disorders. Therefore, a significant drug interaction is likely. We investigated such interaction both in in vitro isolated perfused rat liver (IPRL) and in normal subjects. LZP [2 mg, intravenous (i.v.) bolus] was administered to 8 normal volunteers before and after chronic dosing with VPA. In 6 of 8 subjects, VPA significantly decreased LZP plasma clearance by an average of 40% (p < 0.05) and increased LZP concentrations by decreasing formation clearance of the LZP glucuronide. In the IPRL studies, VPA also significantly decreased formation of LZP glucuronide (from 0.72 +/- 0.14 to 0.22 +/- 0.15 ml/h/kg, p < 0.05), indicating that IPRL is a useful tool for evaluation of the effect of VPA on drugs eliminated by glucuronide conjugation.     

Taste receptor response to sodium chloride and natriuresis in the workers and employees of an industrial enterprise

Studied in the course of one-stage epidemiologic survey of 1191 individuals were the threshold of gustatory sensitivity to table salt and nycterine natriuresis, relation of these indices to dietary habits, some risk factors for cardiovascular disorders and clinical parameters. Differing relations were established between gustatory sensitivity to table salt and natriuresis and age and gender of the examinees, the level of blood pressure, aggravated heredity in respect of arterial hypertension, smoking and alcohol abuse, this enabling one to embark upon a differential approach to dietetic correction of salt consumption.