Psychiatric education in Eastern Europe.

Psychiatry and psychiatric education in the Eastern European countries are determined by the cultural practices and tradition of the region and the organizational principles of the U.S.S.R. Medical schools have been separated from the universities and are under the jurisdiction of the Ministry of Health. Soviet psychiatry is less developed in medical education as compared to the West. A unique feature of Soviet medical education is the development of student scientific societies where opportunities exist for more in-depth work in a specialty. Except for a few select students, postgraduate psychiatric training is shorter and less rigorous than in the West. Refresher education at a facility far advanced training is required at 5-year intervals.

Extended sleep (hypersomnia) in young depressed patients.

To test the hypothesis that young depressed patients have prolonged rather than shortened sleep, 14 depressed patients aged 17-25 and age-matched normal control subjects were allowed to sleep as long as they wanted. All subjects increased their sleep over baseline values, but the extended sleep period of the depressed patients was almost twice as long as that of the control subjects. The distribution of sleep stages in the extended period did not differ. The depressed patients had changes in the length of REM periods similar to those of older subjects. The findings suggest an interaction between age, sleep, and depression.

Major mental illness and childbearing. A role for the consultation-liaison psychiatrist in obstetrics.

Considerable attention has been paid to psychiatric disorders arising in the postpartum period. However, there has been very little systematic study of mental illness during pregnancy. Although quantitatively not a major problem, it can pose several difficulties for mother and fetus. This article reviews the existing literature and along with illustrative cases discusses the management of mental illness related to pregnancy. The relationship between the consultation-liaison psychiatrist and the obstetrician-gynecologist in caring for such problems is emphasized.

Toxicology studies of linear alkylbenzene sulphonate (LAS) in rhesus monkeys. II. The disposition of [14C] LAS after oral or subcutaneous administration.

The disposition of radioactivity has been studied after administration of single and repeated oral or subcutaneous doses of [14C] LAS to rhesus monkeys. After single 30 mg/kg oral doses the radioactivity was rapidly excreted, mostly during the first 24 h. Means of 71.2% and 23.1% of the dose were excreted in the urine and faeces respectively during 5 days. Similarly, after single 1 mg/kg subcutaneous doses, means of 64.1% and 10.9% were excreted in urine and faeces respectively during 5 days, mostly during the first 24 h. After single oral doses of 30, 150 and 300 mg/kh peak plasma concentrations, at 4 h in all cases, were very similar representing 34, 41 and 36 micrograms/ml respectively. After single subcutaneous doses of 0.1, 0.5 and 1 mg/kg, peak plasma concentrations increased almost proportionately and represented 0.16, 0.72 and 1.13 micrograms/ml respectively. During 7 consecutive daily oral (30 mg/kh/day) or subcutaneous (1 mg/kg/day) doses, there was no accumulation of radioactivity in plasma. Mean peak concentrations and biological half-lives were similar after the first and seventh doses. After 7 doses of [14C]LAS, there was no localisation of radioactivity in any tissue. No unchanged LAS was detected in urine samples after oral or subcutaneous doses. About 5 major radioactive components were detected in urine extracts; all were apparently more polar than LAS, but were not sulphate or glucoronide conjugates.

Electrographic analysis of the sleep cycle in young depressed patients.

Electrographic (EEG) patterns of nocturnal sleep were investigated in young psychiatric patients during unipolar depressive episodes. EEG-sleep data was recorded in 20 non-psychotic depressed patients all under 26 years old individually matched with a normal control group. All 20 subjects slept in the laboratory for 1-3 consecutive baseline nights from 12-8:00 a.m. During a subsequent extended condition 14 in each group were allowed to sleep ad-lib. Although the mean total time asleep on baseline nights was about the same between groups (greater than 7.1 hr), the depressives had a statistically significant reduction in REM time, increased transitions into stage 1, but most especially averaged: (a) less stage 4; and (b) more stage 1. Compared with the prior eight-hour night 27/28 subjects among both groups exhibited elevated time asleep during the extended condition, but the patients' mean total 10.3 hr sleep was significantly greater by 1.5 hr than the controls (X = 8.8 hr). Sleep exceeding 9 hr on the ad-lib night was a consistent phenomenon which occurred in significantly more (11/14) young depressed patients contrasted to 4/14 control subjects. These findings indicate that young persons with primary affective disorders do not exhibit nocturnal EEG disturbances of comparable severity to most older depressed patients such as reduced time asleep, increased wakefulness or lowered slow-wave (stages 3 and 4) sleep. Although no direct evidence of symptomatic 'hypersomnia' in these patients was provided, the present results demonstrated that some young persons with clinical depression have the capacity to sleep for sustained periods.

Dermal absorption and disposition of musk ambrette, musk ketone and musk xylene in rats.

Dermal doses of carbon-14 labelled musk ambrette (MA), musk ketone (MK) or musk xylene (MX) to male Sprague-Dawley CD rats were applied at a nominal dose level of 0.5 mg/kg (11 microg/cm2 of skin) and excess material removed at 6 h. Means of about 40, 31 and 19% of the applied doses of MA, MK and MX, respectively, were absorbed. Most of the absorbed material was excreted within 5 days with only 1-2% of the applied dose remaining in the animal at this time. Tissue concentrations of radiolabel were similar for all three compounds with peak concentrations occurring at 6-8 h. In general, fat and liver contained the highest concentrations at around 0.2 microg nitromusk equivalents/g but concentrations in fat declined fairly rapidly to around 0.005 microg equiv./g at 120 h. Most of the absorbed dose was eliminated in bile mainly in the form of polar conjugated metabolites. Structural characterisation of the major aglycones for MA and MX indicated that they were hydroxylated analogues formed by oxidation of the ring methyl. Repeated daily dosing for 14 days resulted in little bioaccumulation for musk xylene and accumulation of about three-fold for musk ketone.

The systemic exposure to the polycyclic musks, AHTN and HHCB, under conditions of use as fragrance ingredients: evidence of lack of complete absorption from a skin reservoir.

7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexa-methylcyclopenta-gamma-2-be nzopyran (HHCB) are two large volume fragrance ingredients widely used in consumer products. As part of the risk evaluation, the systemic exposures to these materials was determined in rats under occlusion and in humans under simulated conditions of exposure. Ring 14C-labeled AHTN or HHCB were applied dermally in alcoholic solutions to rats at doses of 4.5 mg/kg and occluded for 6 h. Urine, feces and air were collected for up to 120 h and analyzed for radioactivity. Pairs of rats were sacrificed periodically for analysis of tissues and organs. The total amount absorbed was approximately 19% for AHTN and 14% for HHCB. In both cases, significant amounts diffused into the skin, most of which was further absorbed but a significant amount of which was lost to surface dressing by reverse diffusion and/or desquamation. Ring 14C-labeled AHTN or HHCB were applied in alcoholic solutions without occlusion to three male volunteers at concentrations approximating that which might be encountered in a typical cologne type product. After a 6-h period, all material was removed from the surface of the skin. Blood, feces and urine were collected over a 5-day period. For both materials, levels in blood and plasma were below limits of detection at all times. Based on excretion, primarily in the urine, the total absorbed dose was approximately 1 and 0.1% for AHTN and HHCB, respectively. However, over the 5-day period, 14.5% of AHTN and 19.5% of HHCB was recovered from the skin in dressings over the site of application indicating that a 'reservoir' had formed in the skin but the material in the reservoir was lost, by desquamation and/or by reverse absorption, and not available systemically. A mean of 24% (AHTN) and 22% (HHCB) was shown to evaporate under the conditions of exposure.

Absorption and elimination of a branched-chain alkylpolyethoxylate surfactant in rats.

Oral doses (100 mg/kg/day) of a 14C-labelled branched-chain alkylpolyethoxylate [( C5H11]2CH14CH2O[CH2CH2O]6H; abbreviated [14C]A12E6) were extensively absorbed from the gastrointestinal tract of rats. During a multiple dosing regime, a proportion of 14C equivalent to one daily dose was excreted each day. This 14C was excreted in urine and faeces in equal proportions; less than 1% of the dose was expired as 14CO2. Almost all the faecal 14C came from the bile and had undergone enterohepatic circulation. After cutaneous application of [14C]A12E6 to rats (8 mg, 333 micrograms/cm2) under occluded conditions, about 25% of the dose was absorbed, mainly during the first 12 h. After dosing by both routes, the A12E6 was biotransformed to several metabolites that were more polar than the parent compound. Less than 15% of the dose was excreted unchanged.

Pharmacokinetics of pyridostigmine in dogs.

The pharmacokinetics of the cholinesterase inhibitor pyridostigmine has been studied in six male Beagle dogs after iv infusion and after oral doses as an immediate-release syrup and as an extended-release tablet, all at a level of approximately 0.6 mg/kg. Pyridostigmine was characterized as a drug of relatively long terminal half-life (8.3 h +/- 2.1 SD), low systemic clearance (13 mL/min/kg +/- 1 SD) and high volumes of distribution (Vd lambda z, 8.7 L/kg +/- 1.9 SD and Vdss, 3.9 L/kg +/- 0.9 SD). The ratio of mean residence times in tissues and plasma was greater than 4, indicating a high affinity of peripheral tissues for the drug. This ratio was about twofold higher in three of the dogs than in the others. Pyridostigmine was slowly and incompletely bioavailable in these dogs; the systemic availability was 44.4% +/- 4.3 SD from the syrup and 33.6% +/- 9.5 SD from the tablet. Pyridostigmine disposition in these dogs was largely determined by distribution processes.

The pharmacokinetics and metabolism of sucralose in the dog.

The pharmacokinetics and metabolism of sucralose were investigated in dogs following intravenous or oral administration. Oral doses of (14)C-sucralose were rapidly absorbed, although there was some variation in the extent of absorption (range 18-48% of the dose). After intravenous or oral administration, radioactivity excreted in the urine was associated mainly with unchanged sucralose. One urinary metabolite was detected after both intravenous and oral doses and was identified by mass spectrometry as a glucuronic acid conjugate of sucralose. This metabolite accounted for about 15-20% of the intravenous dose but for only about 2-8% of the oral dose.

The pharmacokinetics and metabolism of sucralose in the mouse.

The excretion and metabolism of (14)C-sucralose has been investigated in mice following intravenous and oral administration. A 20mg/kg intravenous dose was rapidly excreted mainly in the urine (80% in 5 days). After 100, 1500 and 3000mg/kg oral doses of (14)C-sucralose, means of 23%, 15% and 16% of the dose, respectively, were excreted in the urine during 5 days. Comparison with the intravenous dose indicated that 20-30% of the oral doses was absorbed. Sucralose was excreted almost entirely unchanged and represented more than 80-90% of the radioactivity in all urine and faeces samples. Only two minor metabolites were detected, representing 2-8% of urine radioactivity.

The pharmacokinetics and metabolism of sucralose in the rabbit.

The excretion and metabolism of (14)C-sucralose has been investigated in non-pregnant and pregnant rabbits after administration of single 10mg/kg oral doses. Means of 22% and 55% of the dose were excreted in urine and faeces, respectively, by non-pregnant animals during 5 days. Excretion was similar in pregnant animals with means of 22% and 65% of the dose in urine and faeces, respectively, during the same time. Following a single oral dose, a mean of approximately 7% of the dose was still being excreted during the 96-120-hr collection period. Only one major radioactive component was detected in urine samples which corresponded to unchanged sucralose.

The pharmacokinetics of dichloromethane. I. Disposition in B6C3F1 mice following intravenous and oral administration.

The tissue distribution and metabolism of dichloromethane (DCM; CH2Cl2) was investigated in B6C3F1 mice following iv or oral administration. The route of exposure and the composition of the dosing solution were found to have a significant effect on the pharmacokinetics. Following single iv doses of 10 or 50 mg [14C]DCM/kg dose-dependent metabolism to 14CO2 and 14CO and rapid pulmonary clearance of unchanged 14CH2Cl2 characterized the elimination of DCM from the body. The highest concentrations of 14CH2Cl2 were found in the liver, lung and kidney, with more than 50% of the total radioactivity in these tissues represented by the parent compound. When DCM was administered orally in single gavage doses for 14 consecutive days at treatment levels of 50 mg/kg in water or 500 and 1000 mg/kg in corn oil, rapid absorption and elimination of DCM characterized the treatment in water while distinctly slower trends were found for the doses in corn oil. No observable pharmacokinetic or metabolic effect resulted from repeated oral dosing over the 2-wk treatment period.

The pharmacokinetics of dichloromethane. II. Disposition in Fischer 344 rats following intravenous and oral administration.

The tissue distribution and metabolism of dichloromethane (DCM; CH2Cl2) was investigated in Fischer 344 rats following iv or oral administration. The route and level of exposure were found to have a significant effect on the disposition characteristics. A two-compartment model was used to describe the elimination of DCM from blood following single iv doses. The estimates of t1/2,beta were 11.9 and 23.5 min for doses of 10 and 50 mg/kg, respectively, and the disposition rate constants, beta were found to differ significantly at P less than 0.05. When DCM was administered orally (by gavage) in a daily dose of 50 or 200 mg/kg for 14 consecutive days, rapid absorption and distribution to the tissues characterized the disposition. Dose-dependent metabolism to 14CO2 and 14CO and rapid pulmonary clearance of unchanged 14CH2Cl2 were the dominant routes of elimination of DCM from the body following both iv and oral doses. No observable pharmacokinetic or metabolic effect resulted from repeated oral dosing.

The in vivo dermal absorption and metabolism of [4-14C] coumarin by rats and by human volunteers under simulated conditions of use in fragrances.

The disposition and metabolic fate of [4-14C]coumarin in a 70% aqueous ethanol solution was studied in male Lister Hooded rats after occluded dermal application and in three male volunteers after an exposure designed to simulate that which may be encountered when using an alcohol-based perfumed product. In both cases, the 6-h exposure was 0.02 mg/cm(2) (rats 0.023 mg/kg and humans 0.77 mg/kg). In both, coumarin was quickly absorbed, distributed and excreted in urine and feces, although fecal excretion of coumarin in humans was only 1% of the applied dose as opposed to 21% in rats. Total absorption was 72% of the applied dose with rats and 60% with humans. Peak plasma radioactivity in both was at 1 h. The mean plasma half-life of coumarin and metabolites was approximately 1.7 h for humans and 5 h for rats. In humans, coumarin was primarily metabolized to and excreted in urine as 7-hydroxycoumarin glucuronide and 7-hydroxycoumarin sulfate. Small amounts of unconjugated 7-hydroxycoumarin and o-hydroxyphenylacetic acid (o-HPAA) were also excreted. In rats, about twenty metabolites were present, but only o-HPAA was identified. These studies show the rat is a very poor model for humans and toxicity in the rat cannot be extrapolated to humans.

Comparative metabolism and kinetics of coumarin in mice and rats.

Coumarin, a well recognized rat hepatotoxicant, also causes acute, selective necrosis of terminal bronchiolar Clara cells in the mouse lung. Further, chronic oral gavage administration of coumarin at 200 mg/kg, a dose that causes Clara cell death, resulted in a statistically significant increased incidence of alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice. In contrast, mouse lung tumors were not observed at the 100 and 50 mg/kg dose levels in the oral gavage study, or in CD-1 mice following chronic intake of coumarin at levels equivalent to 276 mg/kg in diet. The current studies were designed to determine the impact of oral gavage vs dietary administration on the pharmacokinetics and metabolism of coumarin in CD-1 and B6C3F1 mice and F344 rats. Following the administration of 200 mg/kg 14C-coumarin via oral gavage, lung C(max) values (total 14C-associated radioactivity) were five- and 37-fold greater than those resulting from a 50 mg/kg oral gavage dose or 1000 ppm in diet, respectively. Coumarin (200 mg/kg) pharmacokinetics and metabolism was also examined in F344 rats following oral gavage dosing. Total 14C-coumarin associated radioactivity in plasma was 3.5-fold lower than in the mouse, and the plasma half-life in rats was five-times longer than in mice. Using non-radiolabeled compound (200 mg/kg), coumarin and products of the coumarin 3,4-epoxidation pathway were quantitated in plasma and urine after oral gavage administration to mice and rats. 7-Hydroxycoumarin (7-HC) was quantitated in mouse plasma and urine. o-Hydroxyphenylacetic acid (o-HPAA) reached a concentration of 37 microg/ml in plasma, and accounted for 41% of the dose in the urine, whereas the C(max) for 7-hydroxycoumarin was 3 microg/ml, and represented 7% of the administered dose. In the rat, the plasma C(max) for o-HPAA was 6 microg/ml, and accounted for 12% of the dose. The coumarin C(max) in rat plasma was comparable to that in mouse. Coumarin 3,4-epoxide (CE) and its rearrangement product o-hydroxyphenylacetaldehyde (o-HPA) and o-hydroxyphenylethanol (o-HPE), were not detected at any time point in plasma or urine. This analysis of coumarin and CE pharmacokinetics in rodents suggests that the differential tumor response in the mouse oral gavage and dietary bioassays is a function of the route of exposure, whereas species differences in lung toxicity between mice and rats result from heightened local bioactivation in the mouse lung.

The use of 13C-nmr spectroscopy for the detection and identification of metabolites of carbon-13 labelled amitriptyline.

The antidepressant drug amitriptyline and two of its metabolites, nortriptyline and desmethylnortriptyline, each containing two 13C atoms, have been used to determine the sensitivity and selectivity of 13C-nmr spectroscopy for the detection of unchanged amitriptyline and N-desmethyl metabolites in the urine of animals dosed orally with the labelled drug. The resonance signals from the 13C atoms detected in the 13C-nmr spectrum of entire extract from a control 12 h rat urine sample to which 1 mg of each labelled compound had been added were easily detected, using an instrument accumulation time of 1 h. The 13C-nmr spectrum of an extract of hydrolysed urine from a dog that had received an oral dose of [13C2]amitriptyline (30mg) exhibited signals that could be assigned to metabolites resulting from N-dealkylation and N-oxidation, as well as those bearing the intact amitriptyline side-chain. These assignments were confirmed by analysis of the same extract by g.c.--ms and h.p.l.c.

Effect of the triazolobenzodiazepine estazolam on hepatic drug-metabolizing enzyme activity in rats.

Oral doses of the sedative/hypnotic estazolam (500 mg kg-1 day-1) to rats for 21 days caused statistically significant increases in liver weight, ascorbate excretion, cytochrome P-450 concentrations, and in aniline hydroxylase, ethylmorphine N-demethylase and glutathione S-transferase activities, as did approximately equivalent doses of flurazepam hydrochloride. Histologically, the centrilobular hepatocytes were enlarged. Some of these parameters were also increased after doses of estazolam of 100 mg kg-1 day-1, but not after 5 mg kg-1 day-1, which is about 50-fold greater than a clinical dose. Estazolam was a much less potent enzyme inducer than phenobarbitone under the conditions of these studies.

A novel conjugate as a major metabolite of bromperidol in man.

The major urine metabolites of the neuroleptic drug, bromperidol, after oral doses to rats and dogs are p-fluorophenylacetic acid and its glycine conjugate resulting from oxidative N-dealkylation. While the same metabolites were also detected in human urine, also present was a major unknown component representing 50% of the total urine metabolites, which apparently was not formed by rats and dogs to any extent. Mass spectroscopic investigations a substituent attached to the tertiary hydroxyl group. The mass spectrum of the metabolite after trifluoroacetylation was consistent with an O-glucofuranosiduronolactone conjugate of bromperidol.

Dietary energy density and frame size effects on composition of gain in feedlot cattle.

Experiments were conducted to evaluate the effects of dietary energy density or genetic background on protein and fat gain of growing cattle. In Exp. 1, 24 Limousin steers were used in a growing-finishing trial. A 2 X 2 factorial arrangement was used with steers randomly allotted to four treatment combinations and fed the following diets: 80% concentrate, high moisture corn-corn silage diet (HI) or a corn silage diet (LO) during both the growing (GRO) and(or) the finishing (FIN) phases. Body composition for both experiments was determined by a deuterium oxide dilution technique. Empty body weight gains were greater (P less than .05) for HI during GRO, FIN and the total trial. Daily protein gains (DPG) were greater (P less than .05) for HI during GRO and FIN, while cattle receiving HI during at least FIN had the greatest (P less than .05) overall DPG. Daily fat gains (DFG) followed the pattern of DPG, being more rapid (P less than .05) for cattle fed HI during either GRO or FIN. Cattle fed the HI diet also tended to be more energetically efficient. In Exp. 2, large frame (LG) and small frame (SM) cattle were used for the evaluation of frame size effects on protein and fat deposition. Steers were individually fed an 80% concentrate, corn-based diet during the entire trial. Average daily gains and daily dry matter intake (P less than .05, P less than .01) were greater for LG, while feed efficiency was similar for both cattle types. Large cattle had greater (P less than .05) DPG than SM cattle, however, DFG were not different. Small frame steers were energetically more efficient (P less than .05), apparently due to composition of gain difference.