Interferon-free regimens containing setrobuvir for patients with genotype 1 chronic hepatitis C: a randomized, multicenter study.

BACKGROUND & AIMS: Setrobuvir is a direct-acting antiviral (DAA) non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study examined interferon-free combinations containing setrobuvir, a ritonavir-boosted protease inhibitor (danoprevir/r) and ribavirin, with/without the nucleoside inhibitor mericitabine in HCV genotype (G)1 patients. METHODS: Non-cirrhotic treatment-naïve patients (N = 110) were randomized to five groups. Three groups received a 14-day mericitabine/ribavirin lead-in followed by treatment with 3 DAAs (setrobuvir, danoprevir/r, mericitabine) plus ribavirin for 12 weeks (Group A: G1a; D: G1b) or 24 weeks (B: G1a), and two groups received 2 DAAs (setrobuvir, danoprevir/r) plus ribavirin for 12 weeks (E: G1b) or 24 weeks (C: G1a). Efficacy was defined as sustained virological response (HCV RNA <25 IU/ml after 12 weeks' follow-up, SVR12). RESULTS: Two groups met predefined futility criteria for breakthrough (C) or relapse (A) and were discontinued. SVR12 rates were 42.9% (3/7) and 74.1% (20/27) in G1a patients in Groups A and B, respectively, and 95.7% (22/23) and 68.2% (15/22) in G1b patients in Groups D and E respectively. All G1a patients assigned to 24 weeks of treatment who experienced a decrease in HCV RNA of ≥2.3 log10 IU by the end of the lead-in period (n = 28) achieved SVR12. Overall, treatment was well tolerated and most adverse events were mild to moderate. No major safety signals were identified. CONCLUSIONS: An interferon-free setrobuvir-based regimen (3 DAAs plus ribavirin) is safe and effective in treatment-naïve G1 patients.

Epidemiological and clinical investigations among employees in a former herbicide production process.

OBJECTIVES: To evaluate cancer incidence among employees assigned to a benzothiadiazin herbicide production facility between 1974 and 1984. METHODS: Retrospective cohort study including 185 employees who had worked at least 3 months in the facility. Cancers were identified by review of occupational medical records and interview. Standardized incidence ratios (SIRs) were computed using comparison data provided by the Saarland Cancer Registry. Separately, a medical examination including sonography of the prostate and thyroid and PSA testing was offered to all cohort members including retirees. RESULTS: Between 1975 and 2002, 12 cancers were observed compared with 10.3 expected cases (SIR 1.2; 95% confidence interval 0.6-2.0). Cancer types (including two prostate, two colon and one rectal cancer) were distributed unremarkably with no clustering of rare cancers. Medical screening and subsequent specialist referrals led to detection of three prostate cancers among 117 participants in the screening examination. CONCLUSIONS: Because of the limited study power, a link between former employment in this herbicide production process and the occurrence of cancer cannot be ruled out with confidence, although the observed incidence and distribution of cancers in this small cohort may be consistent with that expected in the general population. Detection of three prostate cancers via the examination program is also consistent with the experience of cancer screening programs that include PSA testing. Enhanced screening for prostate cancer among men over age 50 can lead to detection of cancers at earlier ages than would otherwise be the case. This likelihood needs to be planned for and addressed in communications with the study population prior to undertaking such initiatives.

Behavioral and olfactory responses to prochloraz, bentazone, and nicosulfuron-contaminated flows in goldfish.

The immediate behavioral responses of goldfish (Carassius auratus) to pesticide-contaminated flows were recorded in a countercurrent olfactometer. In addition, electro-olfactograms were recorded from the epithelial surface of the olfactory rosette as a preliminary check for the olfactory sensitivity of the fish to the pesticides tested. All tests were run on prochloraz (imidazole fungicide), bentazone (diazine herbicide), and nicosulfuron (sulfonylurea herbicide). Behavioral effects were assessed, at four concentrations (10 microg/L, 100 microg/L, 1 mg/L, 10 mg/L), on endpoints related to swimming pattern (preference-avoidance responses, burst swimming reactions), comfort activities (buccal movements, feeding attempts), and social relations (antagonistic acts, grouping). The behavior of the fish appeared particularly sensitive to prochloraz exposure. As a whole, prochloraz-contaminated flows showed significant effects on the six behaviors studied; bentazone and nicosulfuron affected three and five, respectively. At the lowest concentration, prochloraz also showed more effects than the two other pesticides. Some of the behavioral endpoints were found particularly sensitive to a given chemical. Pesticide-contaminated flows also induced significant changes in swimming orientation of the fish. Attraction was observed in response to flowing solutions of prochloraz (1 mg/L, 10 mg/L), bentazone (10 microg/L, 10 mg/L), and nicosulfuron (1 mg/L, 10 mg/L). At a concentration of 1 mg/L, none of the pesticides induced a noticeable depolarization of the olfactory epithelium, suggesting that these chemicals are not detected by the olfactory sense of the fish. These results are discussed in the light of the data concerning effects of pesticides on behavior and chemical communication in fish.

Phototoxicity to sulphonamide-derived oral antidiabetics and diuretics: investigations in hairless mice.

The oral antidiabetics glibenclamide, glipizide, glymidine, tolazamide and tolbutamide and the diuretics bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, furosemide, hydrochlorothiazide, hydroflumethiazide and trichlormethiazide were investigated for phototoxic effects in hairless mice. The back of the animals (hr/hr-c3H/TifBom) was covered with Duoderm dressing, and at the site of two punched out holes 0.05 ml of the test substances at 0.25 mol/l concentration and the solvent alone as control were injected intradermally, respectively. Both test and control sites were irradiated with 6-12 J/cm2 of longwave UVA light from a "Bluelight 2000" apparatus (Hönle, Martinsried, Germany). Skin reactions were read at 24 and 48 h. Compared to the solvent alone, all of the test substances induced reactions (necrosis or oedema)--most frequently seen by macroscopic and histologic investigation and by measurements with a thickness gage. Injection of the test substance or solvent alone without or with subsequent UVA irradiation, as well as UVA alone, did not induce measurable skin changes in this model. Three oral antidiabetics and four diuretics, not yet described to induce photosensitivity in vitro nor in vivo, were detected as potential photosensitizers using our animal model.

[Fibrosing pneumopathy induced by cyclothiazide. Apropos of a case]. / Pneumopathie fibrosante induite par le cyclothiazide. A propos d'un cas.

A diffuse interstitial pulmonary fibrosis associated with an idiopathic hepatic cirrhosis occurred in a 79 years old man treated during five years with cyclothiazide and triamterene for a mild systemic hypertension. The outcome was fatal. A provocation test was positive with BAL lymphocytic reaction. Cyclothiazide induced fibrosis is likely.

[Drug-induced pulmonary diseases: diagnostic, therapeutic and prognostic aspects. Apropos of 10 personal case reports]. / Pneumopathies médicamenteuses. Modalités diagnostiques, thérapeutiques et pronostiques. A propos de 10 observations personnelles.

The authors report ten cases of drug induced lung diseases, complicated by respiratory failure of whom five were attributed to cytotoxic drugs and five to non cytotoxic drugs. The drug induced lung disease presented as acute respiratory distress syndrome in two cases, alveolar interstitial lung disease in three cases, purely interstitial in five cases. There was acute respiratory failure (ARF) in eight cases and chronic respiratory failure (CRF) in two cases. Among the five patients admitted for cytotoxic drug induced lung disease and ARF, four recovered and one died of diffuse destructive pulmonary fibrosis. Among the five patients having non cytotoxic drug induced lung disease, three were in ARF and recovered. The other two had CRF and died of diffuse pulmonary fibrosis. The diagnostic of drug induced lung disease was established in each case with the chronology of the clinical events, the exclusion of other possible causes of the lung disease and the evolution after removal of the incriminated drug. Broncho-alveolar lavage (BAL) had a major diagnostic value. It was contraindicated by respiratory failure in five cases. The predominant alveolar cell type was lymphocyte (four cases), eosinophil (three cases) and neutrophil (one case), BAL was realized with a provocation test and demonstrated the pathogenic role of cyclothiazide in one case. No specific information was given by histology. The prognosis did not seem to be linked to the severity of the initial clinical picture, or to the nature of the underlying neoplastic disorder, but to the degree and evolution of the pulmonary fibrosis.

[Long-term efficacy and side effect profile of a low-dose bemetizid-triamterene combination in patients with essential hypertension]. / Langzeitwirksamkeit und Nebenwirkungsprofil einer niedrigdosierten Bemetizid-Triamteren-Kombination bei Patienten mit essentieller Hypertonie.

As only few data are available on the antihypertensive effectiveness and pattern of adverse reactions to low-dose diuretic treatment, a multicenter study was designed in which 77 patients with essential hypertension (WHO grades I to II) were followed up for one year with a view to answering the above questions. In patients who, at the end of a two weeks' placebo period had diastolic pressure values of more than 90 mmHg treatment was initiated with one daily tablet of a new preparation containing 10 mg bemetizide and 20 mg triamterene, for eight weeks. If, at the end of this interval, the target pressure values of less than 90 mmHg had not been attained, the dose was doubled. Blood pressure measurements (in sitting position) were repeated fortnightly, serum electrolytes, metabolic parameters and urinary triamterene fluorescence determined every four weeks. 56 of the 77 patients stayed on 10/20 mg bemetizide-triamterene for twelve months running. In 13 cases the dose had to be raised. Eight patients dropped out of the study. Average blood pressure values of 56 patients decreased from 169/103 mmHg (at the end of the placebo period) to 145/83 mm Hg after 52 weeks. Diastolic pressure reductions averaged 18 mmHg in 27 patients below the age of 49, 19 mmHg in 22 patients aged between 50 and 65, and 22 mmHg in seven patients older than 65 years. At the end of the 52 weeks' therapy, total serum cholesterol, HDL and LDL cholesterol, triglycerides, glucose and uric acid were unchanged in comparison to the placebo period in the entire group.(ABSTRACT TRUNCATED AT 250 WORDS)

[Case report on the administration of diuretics during pregnancy]. / Kasuistik zum Problem der Diuretikaeinnahme in de Gravidität.

Diuretics potentiate existing hypovolaemia and hämoconcentration in patients suffering from toxemia of pregnancy. This effect also applies to the fetus. A case is presented of an intrauterine spontaneous thrombosis in the inferior vena cava and its tributaries in a fetus with resulting perinatal death during long-term diuretic therapy because of edema in the mother in the third trimester. Basing on this example, the present state of assessment and necessity of treatment of the symptom "edema" in late pregnancy is discussed, with the conclusion that administration of diuretics, if it becomes necessary in a life-threatening state of the pregnant mother (pulmonary edema or oliguria in pre-eclampsia or eclampsia) is indicated only with monitoring of the hematocrit and central venous pressure.

[Detection and diagnosis of drug induced lithiasis]. / Dépistage et diagnostic des lithiases médicamenteuses.

Drug-induced calculi are often mis-diagnosed because of inadequate analysis of the urinary calculi. These stones can only be characterized unambiguously by global physical methods like infra-red spectrophotometry. From a series of 2,000 calculi analysed under infra-red, we identified 22, i.e. 1.1% of cases, which contained, partly or entirely, drug products. Ten other cases are still being studied. Amongst the products identified we found metabolites of glafenine (Glifanan) in 7 cases, triamterene and its derivatives (Cycloteriam) in 7 cases, metabolites of phenazopyridine (Pyridium) in 4 cases, sulphonamides in 2 cases : N-acetylsulphamethoxazole hydrochloride (Bactrim) and N-acetylsulphaguanidine (Guanidan), flumequine (Apurone) in 1 case and calcite (Cal-Mag-Na) in 1 case. The authors estimate that about 100,000 calculi are excreted in France each year and that at least 1,000 of these potentially contain drugs and are not diagnosed. Early recognition of drug induced stones is essential in order to protect the patient from recurrences, the risks of renal complications or, more simply, from useless therapeutic or dietetic regimes.

[Pharmacodynamics and pharmacokinetics of bemetizid in comparison with hydrochlorothiazide. A controlled human pharmacologic study of acute effects]. / Pharmakodynamik und Pharmakokinetik von Bemetizid im Vergleich zu Hydrochlorothiazid. Eine kontrollierte humanpharmakologische Studie der Akutwirkungen.

Pharmacodynamics and Pharmacokinetics of Bemetizide Compared with Hydrochlorothiazide/Controlled clinical study of acute effects Bemetizide in doses of 1, 5, 10, 20, 50 mg versus 25 mg of hydrochlorothiazide were examined in a placebo-controlled randomized single-dose study under standardized conditions in normal male volunteers. The diuretic effects of bemetizide and hydrochlorothiazide were qualitatively equal, though after higher doses bemetizide showed greater maximal, statistically significant effects on the excretion of sodium, chloride and urine volume (relative efficacy). A trend to increased elimination of potassium was detectable. Diuresis of calcium and magnesium and pH of urine were unchanged. The effects of the reference dosis of hydrochlorothiazide were constantly lower than those of higher doses of bemetizide conferring to the 24-h aliquot and the fractioned samples. The action of both substances began within 1 to 2 h after oral application exceeding 24 h. Kinetics of effects and pharmacokinetics were closely correlated. The evidence of dose-dependent kinetics for bemetizide supports the assumption, that it is absorbed incompletely in higher doses. Because of the lack of a parenteral preparation it is not possible to provide reliable information on the maximal potency of bemetizide.

Antihypertensive, saluretic and hypokalaemic effects of cyclothiazide in comparison with hydrochlorthiazide with amiloride supplement.

The antihypertensive, saluretic and hypokalaemic effects of a small dose of cyclothiazide (2.5 mg daily) were compared with those of a conventional dose of an hydrochlorthiazide-amiloride hydrochloride combination (50 + 5 mg daily). Both preparations were given to 13 patients with mild (WHO I) hypertension in a cross-over manner for six weeks, with an intervening wash-out phase of three weeks. The antihypertensive efficacy of cyclothiazide was well comparable to that of the hydrochlorthiazide-amiloride combination, although cyclothiazide tended to inhibit renal sodium reabsorption less than the combination. Cyclothiazide tended to cause hypokalaemia, apparently due to increased potassium loss, but with the present dosage none of the 13 patients developed marked hypokalaemia (serum potassium less than 3.3 mmol/l). Both drugs led to a comparable increase in serum urate concentration. Neither of the preparations affected creatinine or free-water clearance. The results suggest that even in relatively small doses thiazides effectively decrease blood pressure, and combining thiazides with potassium-sparing diuretics is advantageous only in patients with marked hypokalaemia and its associated risks.