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.

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.

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.

[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.

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.

[Metronidazole in the treatment and prevention of infections in gynecology and obstetrics]. / Metronidazol bei der Behandlung und Prophylaxe von Infektionen in der Gynäkologie und Geburtshilfe.

Metronidazole which has been widely used in the treatment of trichomoniasis urogenitalis is the most active agent available against obligate anaerobes.--In this review the present data about antimicrobial activity, mode of action, pharmacokinetic behaviour, dosage, clinical use in gynecology and obstetrics and side effects of metronidazole are outlined.

[The transfer of drugs into the amniotic fluid]. / Zum Ubertritt von Arzneimitteln in das Fruchtwasser

On the basis of the present literature and our own results a review will be given about the importance of the physico-chemical properties of drugs and of different factors of biological system "mother, fetus and amniotic fluid" for the passage of drugs into amniotic fluid. The amniotic fluid is relieved as a possible distribution volume for drugs.

[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.

[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.

[Pharmacokinetics of metronidazole during short-term therapy of trichomoniasis urogenitalis]. / Pharmakokinetik von Metronidazol während der Kurztherapie der Trichomoniasis urogenitals.

Serum and urine levels after single oral dose of 1 g Metronidazole were effective against trichomonades and anaerobic bacteria too at least 24 hr p. appl. The mean binding to serum albumin was 20%. The urinary recovery within first 24 hr was about 50% of the administered dose.

Pharmacokinetics and therapeutic efficacy of metronidazole at different dosages.

Metronidazole, a drug effective against certain protozoal and anaerobic infections, was given female patients with Trichomoniasis urogenitalis. Group I received twice daily 250 mg of metronidazole (supplied as 250 mg tablets Vagimid). Group II received in a single dose 1.0 g (4 tablets); and group III, 2.0 g (8 tablets). Serum and urine metronidazole levels were measured polarographically. Kinetic parameters were determined from the measured values of the concentration time curve by a computing program. An exact control of the therapeutic result was carried out. In all patients peak serum levels occurred within 1-3 hr and averaged 5.1 +/- 1.7 microgram/ml after 250 mg doses, 19.6 +/- 3.8 microgram/ml after 1.0 g doses and 40.6 +/- 9.3 microgram/ml after 2.0 g doses. About 35% of the administered dose was recovered in the urine in 12 hr and about 50% in 24 hr. Metronidazole shows protein binding of 10-20% equally in vivo and in vitro. Minimum trichomonacidic concentrations of nearly 1 microgram/ml were still present 12 hr after oral application of 250 mg metronidazole, and 24 hr to 36 hr, respectively after 1.0 g and 2.0 g daily doses. The cure rate was 100%. No serious side effects ocurred in any of the patients.

[Metronidazole for treatment of puerperal mastitis (author's transl)]. / Behandlung der Mastitis puerperalis mit Metronidazol?

Pathogenic anaerobic bacteria may be among the causes of puerperal mastitis which, therefore, was treated by the authors with metronidazole (Vagimid) and with antibiotics, such as penicillin, oxacillin, erythromycin, and oxytetracycline. Best results were obtained by administration of metronidazole to patients in early mastitis. The frequency of incisions was reduced. The therapeutic results obtained from the use of metronidazole on patients with advanced mastitis were identical with those obtained from antibiotics.--Metronidazole concentrations were equal in serum and milk. No side effects were observed.

Enzymatic activity in carbohydrate metabolism in human liver during development.

The age dependence of the enzymatic activities hexokinase, glucose-6-phosphate dehydrogenase, and glutathione reductase in the fetal human liver was estimated and the activities were compared with the same enzymatic activities in adult human liver.

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.

[Distribution of salicylic acid and hydrolysis of acetylsalicylic acid in the human fetus in early pregnancy]. / Verteilung von Salizylsäure und Hydrolyse der Azetylsalizylsäure bei menschlichen Feten in der Frühschwangerschaft.

The materno-fetal transfer of salicylic acid and its distribution in the fetal organism was investigated in women of early pregnancy. Acetylsalicylic acid (Acesal) was administered orally in a single dose or in repeated doses at different times before legal interruption. The mean passage rates were about 6-15%. They were independent of the maternal serum concentrations of salicylic acid. The distribution of salicylic acid on the fetal liver, intestine, kidneys, lungs and brain was different. All fetal organs (9th to 15th week of gestation) studied exhibit an acetylsalicylic acid-splitting esterase activity. The esterase activity of the fetal liver was about 30% of the hydrolytic activity of the adult liver. The esterase activity was mainly located in the 105 000 X g-supernatant of cell homogenates.

Effect of theophylline on the riboflavin-sensitized photodegradation of bilirubin in vitro.

Under in vitro conditions, theophylline accelerates the rate of bilirubin photodestuction sensitized by riboflavin, but does not do so in absence of this dye. The effect depends on the concentrations of theophylline and/or riboflavin, on the bilirubin/albumin ratio, and seems to implicate bilirubin unbound to serum albumin. Possible causes of the theophylline action and clinical implication regarding thephototherapy of neonatal jaundice are discussed.

Investigation of drugs in ambulant patients.

In contrast to the drug testing under clinical conditions, many other problems appear in regard to outpatients. These investigations were carried out on 49 outpatients with various degrees of angina pectoris under the conditions of an intraindividual comparison with d,l-oxyfedrine (Myofedrin), l-oxyfedrine (ildamen) or placebo for a period of 16 weeks and a daily dose of 48 mg applied orally altogether. The severity degrees of the angina pectoris were diminished after the chronic application of l- and d,l-oxyfedrine. There are no differences in the activity and side-effects.

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.