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The activities of the conjugative enzymes, glutathione S-transferase and UDP-glucuronyl-transferase, have been measured in vitro in the livers of camels, guinea-pigs and rats. Some sex differences were observed in the levels of these conjugative enzymes. In rats and guinea-pigs, females had higher UDP-glucuronyltransferase activity than males. In camels, females had higher glutathione S-transferase activity than males. In these species, the cytochrome P-450 isozymes observed between the 50,000 and 60,000 mol. wt regions have been separated and characterized by SDS-polyacrylamide gel electrophoresis. Camels showed lower levels of all types of cytochrome P-450 isozymes, while guinea-pigs showed higher levels of most of these isozymes. In general, camels seemed to have the lowest drug-metabolizing enzyme activity when compared to rats and guinea-pigs.

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1. The activities of the drug-metabolizing enzymes, benzphetamine N-demethylase, 7-ethoxycoumarin O-deethylase and dicoumarol oxidation have been measured in vitro in the liver of camels, guinea pigs and rats. 2. In these species, levels of hepatic microsomal parameters namely microsomal protein, cytochrome P450, cytochrome b5 and NADPH-cytochrome c reductase have also been determined. 3. In general, camels seemed to have the lowest enzyme activity when compared to rats and guinea pigs. 4. Some sex differences were observed in the levels of enzymes studied. In rats and guinea pigs, males had higher benzphetamine N-demethylase than females. However, in camels and guinea pigs, females had higher 7-ethoxycoumarin O-deethylase when compared to males.

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An agar dilution technique was used to compare the antimicrobial activities of lomefloxacin, norfloxacin, ofloxacin, ciprofloxacin and enoxacin against 544 strains of bacterial isolates. Among the five quinolone agents tested, ciprofloxacin was the most active. Enoxacin was the most active after ciprofloxacin against Escherichia coli, Enterobacter aerogenes, Proteus mirabilis, Shigella spp., Yersinia enterocolitica, and Haemophilus influenzae with an MIC90 of < or = 0.25 micrograms/ml. Ofloxacin was the most active agent after ciprofloxacin against Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter diversus, and Legionella pneumophila with an MIC of < or = 0.25 micrograms/ml. Ciprofloxacin inhibited Staphylococcus spp. and Streptococcus spp., at < or = 0.5 micrograms/ml and 2 micrograms/ml, respectively. Norfloxacin and enoxacin had the same antimicrobial activity (MIC90) against Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae and some other Gram-positive species, but these activities were weak when compared with ciprofloxacin. The results of this in vitro study show that ciprofloxacin is very active against Gram-negative and Gram-positive species.

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Heat stroke is a medical emergency where quick diagnosis and management of victims are essential for positive prognosis. Several biochemical, physiological and hematological changes were observed in heat stroke. It seems that all of these changes are a consequence of induced tissue damage, or may have been a compensatory action by the body. Induction of hyperthermia and temperature measurement are important components in heat stroke studies to determine the stage of progression or regression of heat stroke. Several animal models have been established by investigators in heat related studies. Rats, dogs, monkeys, baboons, cows, rabbits, sheep and chicks have all been used in such studies that allow manipulation of exposure conditions and various designs of experiments. Amongst these species, rats, rabbits and sheep are the most suitable models because of their similarity to man in response to high temperature and in relation to their availability, cost and simplicity of handling. Such models may be used to study various pharmacological and biochemical parameters and functions concurrently. Further informations could also be obtained from isolated organ studies. The present review is to analyse and compare the available methodology for heat stroke studies.

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Change in body temperature is reported to induce changes in muscle contraction by unconfirmed mechanisms. Therefore, the changes in isolated rat ileal muscle contractions at different surrounding temperatures were studied. The contraction was decreased by increase of the surrounding temperature from 37 degrees C to 40 degrees C, while it was increased by decrease of the temperature to 30 degrees C. Further, bathing the muscle in a conditioned medium prepared by incubation of the ileal muscle at 40 degrees C caused a decrease in contraction at a surrounding temperature of 37 degrees C. This indicates that increase of the temperature around muscles induces a release of the substance that causes a decrease in the contractile response. The effects of this heat-released substance were not blocked by propranolol, phentolamine and naloxone, or edrophonium, which indicates that these effects are not produced through an interaction with cholinesterase enzyme, alpha or beta adrenergic receptors or opiate receptors.

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Dantrolene and theophylline have in common pronounced actions on several muscular systems. Therefore we investigated the interaction of these 2 drugs in rats. Normal cases of dantrolene (4 or 2 mg/kg) caused an increase in the lethality produced by theophylline, but without showing the expected seizures of theophylline toxicity. This may be caused by a synergistic action on the heart or blood vessels. On the other hand, a small dose of dantrolene decreased theophylline-induced seizures and death. This may be due to the effect of dantrolene on calcium release in skeletal muscles. The dosage of dantrolene should be decreased when used with theophylline.

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Dantrolene is effective in the management of malignant hyperpyrexia. Due to the similarities of malignant hyperpyrexia and heat stroke, we have investigated the effect of dantrolene on heat stroke in sheep. Our study indicates that dantrolene pretreatment decreases the extent of heat stroke signs and some of the induced changes in enzymes and hormones. These results indicate that dantrolene may be a valuable drug in the prophylaxis against heat stroke attack in susceptible individuals.

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Heat stroke is a medical emergency. Quick diagnosis, and sorting of victims for severity is very important for positive prognosis. Tympanic membrane thermometry was introduced as a good index for core body temperature. Therefore, we have used a sheep model for heat stroke, to study the reliability of measuring body temperature at the tympanic membrane, as a diagnostic index in heat stroke management. This was compared to measuring body temperature at the skin and the rectum. We have observed no major superiority of tympanic over rectal thermometry in regard to its ability to sort out heat stroke cases according to severity. On the other hand, skin thermometry was found not to be a reliable index in this regard.

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Measurement of digoxin serum concentration can be useful as a direct guide to the dose appropriate to individual patients. Therefore, we have attempted to predict digoxin serum concentration in 62 patients with a wide range of body weight, age and renal function, using creatinine clearance and individual digoxin dose. Creatinine clearance in each patient was determined by the Cockroft and Gault method (1). Digoxin clearance was determined by Scheiner's method (2). Once digoxin clearance was determined, the predicted steady-state serum concentration was calculated using general pharmacokinetic principles. Each patient was on digoxin therapy for at least 1 month. Digoxin serum concentration was measured by the newly developed fluorescence polarization immunoassay (FPIA). A linear regression analysis was performed on the data from the predicted and measured serum level which yielded a slope of 0.9463, intercept of 0.0950 and a correlation coefficient (r) of 0.9600. The method was found to be very useful to predict digoxin serum levels in overdosed and underdosed patients.

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We have applied a multi-stage computer algorithm for normalization of distributions and calculation of reference intervals of some urine characteristics and constituents. The study analyzed 24-h urines, collected from adult male Saudis from different socioeconomic classes, for volume, pH, osmolality, specific gravity, creatine, creatinine, urea and uric acid. Frequency distributions, for each analyte, were found to be nongaussian as judged by the coefficients of skewness and kurtosis, chi 2 and Kolmogorov-Smirnov tests, and from probability plots. Data were transformed to gaussian distributions by multistage log-power transformation. Stepwise, this procedure removed skewness and residual kurtosis. Using the gaussian transformed data the reference intervals were estimated parametrically as the mean +/- 2 SD. In addition, the non-parametric percentile technique was applied to estimate these values. The former intervals were found to have narrower 0.90 confidence limits than the latter. When established limits were compared with those reported for Western subjects urine volume and uric acid showed the most marked variation.

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The performance of the fluorescence polarization immunoassay (FPIA) was compared with that of a microbiological assay for the measurement of serum gentamicin concentrations. Within-run precision from duplicate assays of two concentrations (4 and 8 micrograms/ml) using FPIA and the microbiological assay yielded coefficients of variation (r) of 2.62%, 1.76% (n = 12) and 8.06%, 6.87% (n = 12), respectively. Day-to-day precision was estimated by repetitive analysis of 4 and 8 micrograms/ml control samples over a 3-week period. Coefficients of variation (r) were 2.57%, 3.09% (n = 8) and 10.71%, 14.20% (n = 8) for FPIA and the microbiological assay, respectively. Linear regression analysis performed on data from parallel determinations on 143 patient samples by the two methods showed correlations in the order of 0.74. The FPIA offers a rapid, efficient, and accurate system for therapeutic monitoring of gentamicin serum levels.

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The functional decline of memory in the aging human brain has been partially attributed to defects in cholinergic transmission. Therefore, we have investigated various components of the cholinergic system in cerebra of Fischer 344 male rats, ages 3-33 months. Choline acetyltransferase (ChA), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) activities were determined in homogenates of the cerebra using specific radiometric assays. For measuring the release of acetylcholine (ACh), cerebral slices were incubated for one hour in Krebs buffer containing 3H-choline chloride to label ACh formed in situ, washed, and transferred to a microbath for superfusion. 3H-ACh released into the superfusate was determined. The levels of ChA in the cerebra of 9- to 27-month-old rats were lower (33%) than those in 3-month-old rats. Only 1% of these rats survive to the age of 33 months. In rats of this age, there was no decrease in ChA levels. AChE decreased while BChE increased with advancing age. The rate of spontaneous release of 3H-ACh decreased gradually by 63% from 3 to 33 months of age. The evoked release of ACh decreased by 50% in 33-month-old rats. Alterations in the levels of ChA, AChE (or BChE) and cholinergic receptors are not large enough to account for losses in cholinergic transmission in the cerebrum. The large decreases in the rates of spontaneous or evoked release of ACh in the aging cerebrum indicates that the functional defect in the cholinergic transmission of the aging cerebrum is possibly due to a defective release mechanism of this transmitter.

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The occurrence of methionine enkephalin (379 pg/g tissue), beta-endorphin (448 pg/g tissue) and Substance P (2.4 pg/g tissue) in human placental villus were demonstrated by sensitive and specific radioimmunoassays. Conditions for the bioassay of placental extracts for enkephalin-like activities using the rat vas deferens were described. Substance P did not interfere in this bioassay. Comparison of the enkephalin-like activities determined by bioassay and the content of beta-endorphin and methionine enkephalin determined by radioimmunoassays indicated that placental villus extracts contain other unidentified potent opioid-like peptides or substances. It is suggested that methionine enkephalin and/or beta-endorphin and Substance P regulate release of acetylcholine or hormones from placental villus. Alternatively, these peptides may regulate sensory transmission (pain impulses) locally from the distended uterus during pregnancy or from the vaginal tract during childbirth.

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