Increased hepatotoxicity among HIV-infected adults co-infected with Schistosoma mansoni in Tanzania: A cross-sectional study.

INTRODUCTION: Little is known about hepatotoxicity in patients with schistosome and HIV co-infections. Several studies have reported increased liver enzymes and bilirubin levels associated with schistosome infection. We investigated whether HIV-infected adults on antiretroviral therapy who had S. mansoni co-infection had a higher prevalence of hepatotoxicity than those without. METHODOLOGY/PRINCIPAL FINDINGS: We determined the presence and grade of hepatotoxicity among 305 HIV-infected outpatients who had been on medium-term (3-6 months) and long-term (>36 months) antiretroviral therapy in a region of northwest Tanzania where S. mansoni is hyperendemic. We used the AIDS Clinical Trial Group definition to define mild to moderate hepatotoxicity as alanine aminotransferase, alanine aminotransferase, and/or bilirubin elevations of grade 1 or 2, and severe hepatotoxicity as any elevation of grade 3 or 4. We determined schistosome infection status using the serum circulating cathodic antigen rapid test and used logistic regression to determine factors associated with hepatotoxicity. The prevalence of mild-moderate and severe hepatotoxicity was 29.6% (45/152) and 2.0% (3/152) in patients on medium-term antiretroviral therapy and 19.6% (30/153) and 3.3% (5/153) in the patients on long-term antiretroviral therapy. S. mansoni infection was significantly associated with hepatotoxicity on univariable analysis and after controlling for other factors associated with hepatotoxicity including hepatitis B or C and anti-tuberculosis medication use (adjusted odds ratio = 3.0 [1.6-5.8], p = 0.001). CONCLUSIONS/SIGNIFICANCE: Our work demonstrates a strong association between S. mansoni infection and hepatotoxicity among HIV-infected patients on antiretroviral therapy. Our study highlights the importance of schistosome screening and treatment for patients starting antiretroviral therapy in schistosome-endemic settings. Additional studies to determine the effects of schistosome-HIV co-infections are warranted.

Influence of H2-receptor- and proton pump inhibitors on some functions of the oxydative and conjugative drug metabolism.

There are numerous investigations describing the influence of histamine H2-receptor antagonists and proton pump inhibitors on cytochrome P450-mediated hepatic oxydative and conjugative drug metabolizing enzymes. The aim of this study was to investigate the influence of the H2-receptor blockers cimetidine, ranitidine, famotidine, nizatidine and of the proton pump inhibitors omeprazole and lansoprazole on the acetylation capacity and on different microsomal monooxygenases of the rat liver. The experiments were performed in two randomized studies with male Wistar rats after a 7-day pretreatment of the animals with antisecretory, equipotent doses of the investigational products. The activities of the arylamine N-acetyltransferase (NAT) and the microsomal enzymes were determined in vitro. Cimetidine and ranitidine decreased the activity of NAT significantly, no effect on this enzyme was observed after nizatidine. Small doses of famotidine tended to lower, high doses of famotidine tended to enhance the NAT activity. The proton pump inhibitor omeprazole significantly increased the NAT activity, lansoprazole evoked a small increase of the enzyme activity. Ethyl-resorufin O-deethylase (EROD) and penthlresorufin O-depentylase (PROD) were sensitive to cimetidine, ranitidine and famotidine. Only omeprazole and lansoprazole treatment inhibited the detromethorphan O-demethylase (DXDM) activity.

Effects of nocloprost clathrate on absorption of acetylsalicylic acid.

The cytoprotective prostaglandin E2 analog nocloprost clathrate (NOCLO) is tested as a prophylactic for gastrointestinal lesions of NSAID. The effects of 400 micrograms NOCLO versus respective placebos with and without equivalent amounts of beta-cyclodextrin on the pharmacokinetic behavior of acetylsalicylic acid (ASA), given 30 min after NOCLO, were studied in two single-blind, parallel-group trials. The trials were performed in 15 male healthy volunteers (age 21-25 years, body weight 62-94 kg, body height 172-187 cm) with known N-acetylation and debrisoquine type hydroxylation phenotype. ASA, salicylic acid (SA), and salicyluric acid (SU) in plasma and SA and SU in urine were measured by HPLC. NOCLO delayed the absorption of ASA (increased tmax, lower Cmax) significantly in comparison with both placebos. AUC and clearance values were not changed by NOCLO premedication. There were neither differences between the two placebo groups nor between the two groups pretreated with NOCLO with regard to any pharmacokinetic parameter. The changes in drug absorption are caused by the sum of those cytoprotective effects of prostaglandin which are also determinants of drug absorption.

Effects of nocloprost on some monooxygenases of rat and human liver.

Interactions of the cytoprotective agent nocloprost (9 beta-chloro-16,16-dimethyl-prostaglandin E2, CAS 79360-43-3) with the microsomal monooxygenase system were studied in rat and human liver. Nocloprost did neither bind to human and rat liver cytochrome P-450 nor changed the activities of aniline hydroxylase, aminopyrine demethylase, ethylmorphine N-demethylase, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylase as well as 7-pentylresorufin O-depentylase after in vitro incubation with 1 ng/ml. Premedication of rats with 0.1 and 1.0 mg/kg lacked significant interferences with the monooxygenases studied.

Potential pharmacokinetic interactions of nocloprost clathrate with retarded theophylline and enteric coated diclofenac after single and repeated premedication in healthy volunteers.

Pharmacokinetic interactions of cytoprotective prostaglandin E2 analog nocloprost clathrate with theophylline and diclofenac were studied in two placebo controlled, single-blind studies with parallel groups (n = 8) in healthy male volunteers (age 20-32 years, body weight 63-95 kg, body height 169-193 cm, Broca index 0.81-1.18). Nocloprost (200 micrograms) or placebo tablets were given twice daily (07:00 h a.m. and p.m.) for 8 days. Thirty min after the first administration on the first day (single) and 30 min after the last administration in the morning of the 8th day (repeated premedication), pharmacokinetic examinations with retarded theophylline capsules (250 mg) or enteric coated tablets of diclofenac (50 mg) were performed. Theophylline was measured using an HPLC- and diclofenac with a GC-method. Both single and repeated premedication with nocloprost did not significantly change any pharmacokinetic parameter of theophylline. There was only a tendency towards lower AUC of theophylline after both regimens of premedication. As far as diclofenac is concerned, single premedication increased significantly the rate of absorption and total body clearance but lowered the AUC of the NSAID. After repeated premedication, no parameter was significantly influenced. All pharmacokinetic changes observed are most likely without any clinical importance.

Activation of human blood platelets induced by nocloprost, a stable prostaglandin E2 derivative.

Nocloprost, a 9 beta-chloro-16,16-dimethyl derivative of prostaglandin E2 (PGE2), belongs to the gastric cytoprotective agents that are used in the therapy of gastric ulcer. Since methylated derivatives of PGE2 are known to have proaggregatory effects the influence on platelets was studied. In platelet-rich citrated plasma, nocloprost (> 0.1 mumol/l) caused aggregation with a biphasic course at higher concentrations. Aggregation induced by nocloprost (1 mumol/l) corresponded to that induced by adenosine diphosphate (ADP) (5 mumol/l). Activation of platelets by nocloprost was accompanied by formation of thromboxane A2 and an increase in cytosolic calcium in Indo 1-loaded platelets. At 0.1 mumol/l it potentiated aggregation induced by low concentrations of ADP or adrenaline. The effect of nocloprost on platelets was blocked by iloprost, daltroban and indomethacin. PGE2, which was studied for comparison, at 0.1-1.0 mumol/l inhibited aggregation induced by 1 mumol/l nocloprost. The concentrations of nocloprost required for therapeutic use as antiulcer agent were lower by three orders of magnitude than those which induce human platelet aggregation.

[Nizatidine in therapy and prevention of non-steroidal anti-rheumatic drug-induced ulcers in rheumatic patients]. / Nizatidin in Therapie und Prophylaxe NSAR-induzierter gastroduodenaler Ulzera bei Rheumapatienten.

269 patients with various rheumatic disorders who had been treated with non-steroidal anti-inflammatory drugs (NSAID) for at least three weeks, were enrolled in this randomised double-blind multicenter trial. Entry criteria were both the presence of an ulcer in gastric and/or duodenal mucosa (> 3 mm and < 20 mm in diameter) as well as dyspeptic symptoms. The patients had been treated with 150 mg nizatidine nocte (n = 86), 2 x 150 mg/d (n = 93) and 2 x 300 mg/d (n = 90) nizatidine. All patients continued to take their original NSAID-medication. The three nizatidine-groups had been well matched with respect to important patient characteristics. After 8 weeks of treatment more than 90% of gastric and duodenal ulcers had been healed under all three nizatidine-dosages. There was a tendency for higher healing rates in case of gastric ulcers after 4 weeks following the higher dose of nizatidine. Erosions in stomach and duodenum as well as esophagitis had been improved to a similar degree with all nizatidine doses. The same holds with respect to improvement of clinical symptoms such as epigastric pain, heartburn etc. Consumption of additional antacids was similar in all three groups. In the subsequent prophylactic trial 237/221 patients had been followed for 3/6 months. 116/107 received in addition to their continued antirheumatic medication nizatidine 150 mg nocte and 121/114 patients 2 x 150 mg nizatidine daily. The cumulative relapse rates within 6 months averaged 5.5% in the low and 1.8% in the high dose group (n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of nocloprost (9 beta-chloro-16,16-dimethyl PG E2) on absorption and disposition of antipyrine and sulfamethazine in healthy volunteers.

Prostaglandins are known to interfere with drug metabolizing processes. Nocloprost (9 beta-chloro-16,16-dimethyl PG E2) is a promising new cytoprotective prostaglandin in clinical evaluation for the treatment of ulcer disease and prophylaxis of gastric lesions caused by NSAID. Pharmacokinetic interactions of 400 micrograms nocloprost with 15 mg/kg antipyrine and 500 mg sulfamethazine (all given p.o.) were studied with a controlled, single-blind crossover trial in 16 healthy male volunteers (age 22-25 years, body weight 63-94 kg, body height 175-187 cm) in order to measure potential interferences with oxidative and conjugative drug metabolism. All individuals were extensive metabolizers of debrisoquine, 9 were slow and 7 rapid acetylators of sulfamethazine. Antipyrine and its major metabolites were measured in serum respectively, urine with the HPLC-method, sulfamethazine and its acetylated metabolite with a colorimetric technique. Nocloprost premedication (30 min prior to the test drugs) did neither interfere significantly with the oxidative processes involved in the disposition of antipyrine nor with the N-acetylation of sulfamethazine. Higher metabolic and renal clearance values of sulfamethazine in slow acetylators were most likely the result of the affected drug absorption. Nocloprost significantly reduced absorption rates of antipyrine and sulfamethazine in the group of slow but not of rapid acetylators. The extent of bioavailability remained unchanged. This phenomenon was certainly caused by the effects of the cytoprotective prostaglandin on those gastrointestinal functions which are determinants of drug absorption.

Nocloprost, a unique prostaglandin E2 analog with local gastroprotective and ulcer-healing activity.

Nocloprost (9 beta-chloro-16,16-dimethyl prostaglandin E2 (PGE2)) was examined for gastroprotective and ulcer-healing activity and compared to 16,16-dimethyl PGE2 (dmPGE) in rats. Nocloprost given intragastrically (i.g.) at various doses (0.01-10 micrograms/kg) 30 min before 100% ethanol, acidified aspirin (ASA), acidified taurocholate, water immersion, or restraint stress dose dependently prevented the formation of gastric lesions, the ID50 values being 0.25, 0.58, 0.06 and 0.12 micrograms/kg, respectively. The gastroprotection provided by nocloprost given i.g. was somewhat enhanced by the presence of acid in the stomach and was reduced by inhibition of gastric acid secretion. Nocloprost given s.c. also showed protective activity against ethanol damage but was ineffective when applied intraduodenally. The protective effect of nocloprost lasted about 8 h whereas that induced by dmPGE lasted 6 h. Nocloprost (0.01-100 micrograms/kg) given i.g. failed to affect gastric acid secretion or intestinal secretion (enteropooling) but prevented the increased gastroduodenal alkaline secretion. Nocloprost alone caused only a transient increase in the mucosal blood flow but prevented the fall in blood flow caused by 100% ethanol. [3H]Nocloprost was absorbed from the small intestine but was then taken up and metabolized by the liver and excreted into the bile so that very little reached the systemic circulation in an unchanged form. Nocloprost, unlike dmPGE, accelerated the healing of chronic gastric ulcerations and enhanced mucosal growth. We conclude that nocloprost is a locally active PGE2 analog with high cytoprotective and ulcer-healing efficacy.

Gastric protection by nocloprost against aspirin damage in humans. Possible role of epidermal growth factor.

Ten healthy young male subjects took part in a double-blind, placebo-controlled crossover study to assess the effects of nocloprost on gastric microbleeding and endoscopic mucosal injury induced by the administration of aspirin (2.5 g). In addition, basal and pentagastrin-induced gastric acid and pepsin secretion and salivary and plasma contents of epidermal growth factor (EGF) were measured after placebo plus aspirin or nocloprost plus aspirin treatment in these subjects. Nocloprost (100 micrograms/dose) significantly reduced spontaneous gastric microbleeding and almost completely prevented gastric mucosal injury induced by aspirin. Nocloprost failed to affect basal and pentagastrin-stimulated gastric acid and pepsin secretion but increased significantly the salivary outputs and plasma concentrations of EGF. In conclusion, nocloprost is effective in preventing gastric injury by aspirin even at a non-antisecretory dose, and this protection may involve an excessive release of EGF.

[Biological testing of biomaterials in the framework of permitted procedures. 2]. / Zur biologischen Prüfung von Biomaterialien im Rahmen des Zulassungsverfahrens. 2. Mitteilung.

Submitted is the revised version of a proposal for a guideline for biological testing of materials (biomaterials) which remain temporarily or permanently, resp., at or in the human body or have contact with drugs or body fluids outside the human body.

[Therapy of endometriosis with dienogest]. / Endometriosetherapie mit Dienogest.

Dienogest (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4,9-dien-3-one, VEB Jenapharm, Jena, GDR), an orally active 19-nortestosterone derivative, was used firstly in the treatment of endometriosis. 57 patients (age 17-45 years) have been entered into the study. The diagnosis was confirmed by laparoscopy or laparotomy in 56 cases and in one case clinically. All patients have been treated with 2 mg dienogest per day in a progestin only regimen over a period of 6 month. The day after completing the course of dienogest therapy 51 patients underwent laparoscopy for control. On this basis endometriotic lesions had completely disappeared in 66.7%; in 80.4% a marked improvement was noted, but no effect was visible in 19.6% of the implants. Eighty-four per cent of the women reported symptomatic improvement. The efficacy of dienogest was correlated negative with the age of the treated women. The major side effects were spottings and decrease of libido. Blood pressure as well as mean body weight remained unaltered. No patient discontinued dienogest therapy due to side effects.

[Postcoital contraception with dienogest]. / Postkoitale Kontrazeption mit Dienogest.

Fifty eight fertile female volunteers between 20 to 45 years were enrolled in a clinical trial to evaluate the efficacy and tolerance of the progestin dienogest (17 alpha-cyanomethyl-17 beta-hydroxyestra-4,9-dien-3-one, VEB Jenapharm Jena GDR) as a postcoital contraceptive. An oral dose of 2 mg dienogest was administered immediately after each coitus. The 58 women reported 872 intercourses during 302 cycles. Frequency of ingestion was on average 3 times per cycle. Pregnancy occurred in 14 women corresponding to a Pearl-index of 55.6. The observed pregnancy rate referring to all intercourses was 1.6 per cent. The incidence of expected pregnancies in relation to the coital exposures was 4.04 per cent. As a result the risk of pregnancy was reduced 2.5 times by dienogest. Menstrual disorders occurred in 18.9 per cent in regard of the total numbers of cycles. The results and an overview of literature suggest that neither dienogest nor other progestins are suitable as a sole contraceptive method when used as a postcoital agent. They are only indicated as a risk-reducing method after so-called "contraceptive emergencies".

[Tissue distribution of iso-metronidazole and metronidazole in tumor-bearing C3H inbred mice]. / Zur Gewebeverteilung von iso-Metronidazol und Metronidazol in tumortragenden C3H-Inzuchtmäusen.

Among the group of nitroimidazole radiosensitizers, predominantly misonidazole and metronidazole have so far been submitted to an extensive clinical testing. However, neurotoxic side effects have limited the dose of the substance necessary to obtain a maximal effect of sensibilization. Therefore, extensive efforts are being undertaken in the search for new compounds of equally good radiosensitizing action but with less side effects. One approach is to use substances of lower lipophilicity which will reduce penetration into the cerebral tissue. Proceeding from these considerations, comparative investigations were carried out with metronidazole (1-(2'-hydroxyethyl)-2-methyl-5-nitroimidazole) and iso-metronidazole (1-(2'-hydroxyethyl)-2-methyl-4-nitroimidazole), since in vitro but also in animal experiments the both substances showed an equally good radiosensitizing action while the lipophilicity of iso-metronidazole is much lower. Whereas for the metronidazole about the same distribution of the substance was found in all the organs investigated and also in the tissue of the mammary adenocarcinoma of C3H mice, the maximal concentration of iso-metronidazole in the cerebral tissue reached only about 50% of that in tumor tissue. This property, combined with the improved solubility, make the iso-metronidazole appear more appropriate for clinical testing than metronidazole.

[Gas chromatographic analysis in the detection of anaerobes]. / Gaschromatographische Analysen in der Anaerobier-Diagnostik.

By means of gaschromatography a rapid (ca 30 min) diagnosis of anaerobic infections is possible. The principle of a simple technique regarding the equipment and the laboratory-chemical process is presented.

[Pharmacokinetics of metronidazole during perioperative short-term prophylaxis in cesarean section]. / Pharmakokinetik von Metronidazol während der perioperativen Kurzprophylaxe beim Kaiserschnitt.

Placental transfer and elimination of metronidazole and its main metabolites, 1-(2-hydroxyethyl-)2-hydroxymethyl-5-nitroimidazole (metabolite I) and 2-methyl-5-nitroimidazole-1-acetic acid (metabolite II) were studied in newborn infants and compared with maternal data obtained in 8 high-risk parturients who were subjected to Caesarian section after intravenous infusion of 500 mg metronidazole. Unchanged metronidazole is rapidly transferred across the placental membranes. Its concentrations were the same in maternal venous blood and in both umbilical vessels at delivery. The concentrations of metabolite I were lower in the umbilical vein and artery than in the mother in the first hour after infusion. The elimination half-lives of metronidazole and metabolite I were markedly prolonged in the newborn infants in comparison with the maternal values. No adverse effects were observed in infants or mothers.