Nitrosation of amines by stimulated macrophages

Rats and mice treated in vivo with Escherichia coli lipopolysaccharide (LPS) synthesize and excrete large quantities of nitrate. Murine peritoneal macrophages, elicited in vivo with thioglycolate and stimulated in vitro with LPS and/or gamma-interferon (IFN), produce copious amounts of nitrate and nitrite. We report here experiments showing N-nitrosamine formation by macrophages immunostimulated in vitro. Macrophage cell lines J774.1, PU5-1.8, WEHI-3 and RAW 264 and freshly isolated macrophages from C3H/He mice were used. Macrophages were cultured in Dulbecco's modified Eagle's medium (pH 7.5) supplemented with calf serum (10%). Supernatant NO2- and NO3- were measured. N-Nitrosamines were extracted with dichloromethane and the extracts analyzed by a gas chromatography--thermal energy analyzer. Cells (1.5 X 10(6)/ml) were incubated with LPS (10 micrograms/ml) and morpholine (15 mM) for 72 h at 37 degrees C. Under these conditions, all of the cell types listed above produced nitrite (40-70 microM) and N-nitrosomorpholine (NMOR; 114-940 nM). LPS was required for both processes, and this effect was enhanced by IFN. Nitrite (150 microM) incubated with morpholine in cell-free medium did not form NMOR nor did cells plus morpholine and NO2-. The rate of NMOR formation in the J774.1 cell line was highest in the middle incubation period (24-36 h) although [NO2-] was highest in the final incubation period (48-72 h). Thus, the cells do not catalyze nitrosamine formation per se, rather the amine traps out a reactive nitrosating species prior to the formation of NO2- and NO3-. These results suggest that immunostimulated macrophages may be capable of nitrosamine formation under physiological conditions.     

Pharmacokinetic interactions of cimetidine 1987

The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but the metabolism of at least 30 other drugs is affected. Recent evidence indicates negligible effects of cimetidine on liver blood flow. Cimetidine reduces the renal clearance of drugs which are organic cations, by competing for active tubular secretion in the proximal tubule of the kidney, reducing the renal clearances of procainamide, ranitidine, triamterene, metformin, flecainide and the active metabolite N-acetylprocainamide. This previously unrecognised form of drug interaction with cimetidine may be clinically important for both parent drug, and metabolites which may be active.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effects of caffeine on various body systems: a review

Caffeine is the most widely consumed drug in Western society. The intake of caffeine-containing beverages in many adults and children often reaches levels that can induce pharmacological effects. Ninety-nine percent of ingested caffeine is absorbed and distributed to all tissues and organs. The effects of caffeine intake differ greatly according to acute or chronic intake, level of intake, and the development of tolerance. Caffeine administered acutely to non-users or recent abstainers can induce hypertension, arrhythmias, altered myocardial function, increased plasma catecholamine levels, plasma renin activity, serum cholesterol levels, increased production of urine, gastric acid secretion, and alterations in mood and sleep patterns. Tolerance to chronic caffeine intake develops in most individuals, with the cessation of its effects on the renal system, the cardiovascular system, the gastrointestinal system and, to some extent, the central nervous system. Moderate caffeine consumers probably need to have little concern for the effect of caffeine intake on their health if their other life-style habits are also moderate.     

Influence of pregnancy, lactation, litter size and diet energy density on the stomach and intestine of sows

In the first experiment, 52 sows, each having raised one litter, were randomly assigned to the five following groups: control (nongravid) for pregnancy (CP), 110 d pregnancy (P110), control (nongravid) for lactation (CL), 4-wk lactation with 8 (L8) and with 12 (L12) piglets. In a second experiment, 36 sows, each having raised three litters, were randomly assigned to the following groups: control group (nongravid) fed a low-energy-density, 1% tallow diet (CLED) and two lactating groups, one fed the low-energy-density diet (LLED) and one fed a high-energy-density, 10% tallow diet (LHED). At slaughter, the stomach, small and large intestine and cecum were excised, emptied and freed from fat. Lengths and pre- and post-defatting weights were measured. Portions of tissues were homogenized and analyzed for protein, pepsin, maltase, RNA and DNA. Pregnancy had no effect on the weights of the different components of the gastrointestinal tract. Liver and small intestine weights were larger in lactating sows than in the CL group. Sows nursing 12 piglets had heavier livers than those nursing 8. The fundic mucosa of the latter had higher total pepsin activity and total protein and RNA contents than that of L12 sows. LHED sows had heavier small intestine and lower total pepsin content of the fundic mucosa than LLED sows.     

Diagnoses of the relatives of schizotypal outpatients

Relatives of 22 schizotypal probands were evaluated for lifetime psychiatric diagnoses. Forty-four (N = 44) of the 97 available relatives were interviewed directly using the Diagnostic Interview Schedule. The rates of psychiatric diagnoses were compared with those of sixty-six (N = 66) of 140 relatives of 30 depressed patients. Family history of mental illness was ascertained by the informant method on the remainder of relatives of both proband groups. The rate of depression found in the relatives of schizotypal patients was 52% in those directly interviewed and 25.7% when informants' reports on unavailable relatives are pooled with direct interview data. These rates were not significantly higher than those found for the relatives of depressed probands (34.8% by direct interview and 21% including reports from informants). The high rates of depression in the relatives of schizotypal probands may indicate that schizotypal personality is associated with affective disorder and not only with schizophrenia. However, the high rates may be due to the presence of depressive character traits in relatives, which inflate the rates of dysthymic disorder and other chronic depressive disorders in the relatives of borderline patients.     

Intra-urban variations of neonatal and post-neonatal mortality in a developing city

Numerous surveys at the national and regional level have demonstrated that large inequalities in infant health status exist in Southern Africa. Few studies have assessed infant mortality at the intra-urban scale of geographic analysis. Comparisons between infant mortality rates from different areas are made even more meaningful if the data are divided into two primary categories based on period-of-death; these being the neonatal and post-neonatal components. This study presents the results of a survey undertaken in Metropolitan Cape Town (population 1.6 million) during 1982. The aim was to determine the spatial variation of neonatal and post-neonatal mortality at the suburb (or community) level within the city. Overall, a total of 36,789 live births and 928 infant deaths were recorded; 53.4% in the neonatal period and 46.6% in the post-neonatal period. The mean infant mortality rate was 25.2 per 1000 live births; the neonatal mortality rate and post-neonatal mortality rate being 13.5/1000 and 11.7/1000, respectively. A marked range in death rates was evident for both components. For the neonatal category it was 0.0-49.9/1000 and 0.0-40.0/1000 for the post-neonatal period. The generally low post-neonatal mortality rate among the 69 suburbs studied has made the neonatal component the dominant contributor to the infant mortality rate. However, in the lowest socio-economic areas the post-neonatal mortality rate was responsible for over 60% of infant deaths.(ABSTRACT TRUNCATED AT 250 WORDS)     

An enzyme-linked immunosorbent assay for the detection of Entamoeba histolytica antigens in faecal material

This paper describes a method for the detection of Entamoeba histolytica antigens in stool samples using a multi-layer ELISA. The method is sensitive and specific, showing no interference with other intestinal parasites, e.g. E. coli, E. hartmanni, Endolimax nana, Iodamoeba buetschlii, Hymenolepis nana, Giardia lamblia, Trichomonas and Ascaris. The method provides a rapid and simple screening assay for E. histolytica infections and should assist in diagnosis and epidemiological studies of the disease.