Developmental toxicity of cesium in the mouse.

1. Maternal intake of 1 mEq CsCl in drinking water at conception until weaning the offspring mice resulted in certain maternal mediated neonatal and developmental toxicity. 2. Initial reduction in body and brain weights were determined in male offspring due to maternal exposure to Cs salt before they attained the control levels. 3. Offspring from both sexes showed increased spleen weight from control as a consequence of maternal exposure to Cs. This may precipitate delayed immunotoxicity. 4. Maternal Cs exposure did not alter litter size or specific activities of offspring heart lactate dehydrogenase isoenzymes from respective controls. 5. Maternal exposure to Cs altered specific activities of offspring liver alcohol- and aldehyde dehydrogenase during development compared to controls. 6. The results indicate neonatal and developmental toxicity of Cs as a function of maternal intake of CsCl during pregnancy and breast feeding.

Pharmacological aspects of gonadal alcohol and aldehyde-dehydrogenase.

1. A brief overview of gonadal alcohol dehydrogenase (ADH) and aldehyde-dehydrogenase (ALDH) is presented and their relationships to gonadal toxicity of ethanol has been discussed. 2. The distributions of ADH and ALDH among major reproductive tissues of rodents, their subcellular localization and kinetic properties were summarized. 3. The sensitivity of testicular ADH and ALDH to ethanol intake, various psychoactive agents and steroidal compounds was assessed and the implication of these enzymes in gonadal ethanol-drug interaction has been suggested. 4. The possible role of testicular ALDH in tumorigenesis and in high altitude endocrine sensitivity to ethanol has been addressed.

beta-Casomorphin-immunoreactivity in the brain stem of the human infant.

Using a peptide extraction procedure, reversed phase high performance liquid chromatography, and a radioimmunoassay that utilized an antibody raised specifically against human beta-casomorphin-8 (BC8), BC-immunoreactivity (BCIR) was detected in rostrocaudally increasing levels in nineteen microscopically distinct and functionally relevant areas of mesencephalon, pons cerebri, and medulla oblongata of eight infants. On the basis of the methodology used, it can be concluded, that the BCIR present in their brain stem was due to BC8 and/or to some of its congeners. Data in the literature together with those of this study indicate that beta-casomorphins could be transported by specific mechanisms from the blood into the brain stem and that they could play a role in the central regulation of various physiological phenomena.

Fluoxetine: a spectrum of clinical applications and postulates of underlying mechanisms.

The antidepressant efficacy of fluoxetine in major depression has been briefly reviewed. A brief outline of dose selection, therapeutic onset, and pharmacokinetics of fluoxetine were made. The potential use of the drug in management of various psychiatric conditions has been examined. These include obsessive-compulsive disorder and related variances, anorexia nervosa, bulimia nervosa, Tourette's syndrome, and trichotillomania. The suggested use of fluoxetine in pain relief in certain diabetics, premenstrual syndrome, and migraine headache were assessed. The reports on the use of fluoxetine in panic disorders, paraphilias, and related conditions and in the management of substance abuse, alcoholism, and cocaine abuse, were summarized and elaborated upon. A composite of preliminary reports cited in literature pertinent to the potential of fluoxetine in treatment of abusing injurious behavior, dysthymic disorder, fibrositis, postanoxicaction myoclonus, pathologic jealously, personality disorder, pseudobulbar affect, and social phobia were also reviewed. Fluoxetine pharmacological profile may be extended to cover a relative wide range of application, provided future controlled studies confirm the preliminary data found in the literature.

Classifying cytostatics on the basis of their angiocidal and angiostatic effects.

This study describes the effects of ten clinically used cytostatics [bleomycin (BLM), cytarabine (Ara-C), cyclophosphamide (CTX), doxorubicin (DOX), etoposide (VP-16), 5-fluorouracil (5-FU), methotrexate (MTX), mitoxantrone (MXN), vincristine (VCR), and vinblastine (VLB)] on the chorioallantoic membrane vessels--especially on vessel counts--and on the weight of the chicken embryo. A significant reduction of vessel counts (VC) due both to angiocidal and an angiostatic action, was induced by DOX, MXN, VP-16, VCR, and VLB. 5-FU and BLM induced only a (weak) angiostatic effect. MTX, Ara-C, and CTX were neither angiocidal nor angiostatic. The classification of cytostatics presented here might have implications for their use in the clinical treatment of malignant tumors.

Fluoxetine: adverse effects and drug-drug interactions.

This overview summarizes the major and minor side effects and drug interactions of fluoxetine. The adverse reactions include the "serotonin syndrome", cardiovascular complications, extrapyramidal side effects such as akathisia, dyskinesias, and parkinsonian-like syndromes and an apparently increased risk of suicidality. Fluoxetine-induced mania and hypomania, seizures and sexual disorders are evaluated along with minor symptoms of allergic reactions, stuttering, hematological changes, psoriasis, and inappropriate secretion of the antidiuretic hormone. The major fluoxetine-drug interactions involve the amino acids L-dopa and L-tryptophan, anorexiants, anticonvulsants, antidepressants, anxiolytics, calcium channel blockers, cyproheptadine, lithium salts, and drugs of abuse. The underlying mechanism and the paradoxical effects of fluoxetine are addressed.

Maternally-mediated developmental lithium toxicity in the mouse.

1. Breast fed maternally-mediated developmental LiCl toxicity was determined in mice offspring as a function of offspring's gender and duration of maternal intake of LiCl (1 mEq). 2. The female offspring were more sensitive than the males to major organ weight changes by maternal exposure to LiCl. 3. Maternal intake of LiCl from preconception until weaning of the nurslings induced offspring hepatic alcohol dehydrogenase and heart lactate dehydrogenase in both sexes which was isoenzyme specific for the latter. 4. The offspring also showed induction of liver aldehyde dehydrogenase but only as consequences of postnatal exposure to LiCl. 5. The results indicate offspring developmental toxicity as a consequence of maternal exposure to Li salts and breast feeding.

Alcohol- and aldehyde-dehydrogenase: modulation by biogenic amine metabolites, neuropeptides and psychoactive agents.

The results suggest the feasibility of metabolic and behavioral interrelationships between ethanol (ET), certain neurotransmitter substances and major metabolites, some neuropeptides and/or psychoactive agents. This was indicated by the in vivo and in vitro effects of such authentic compounds on certain ET-elicited behavioral responses and on hepatic ET and acetaldehyde metabolizing enzymes in rats and mice.

Behavioral and enzymatic interactions between benzyl alcohol and ethanol.

Acute IP injection of benzyl alcohol but not benzaldehyde (0.5 g/kg) caused aversion to voluntary drinking of 5% ethanol solution by male rats with preference to ethanol. Benzyl alcohol noncompetitively inhibited hepatic alcohol dehydrogenase of rats maintained for a short term on 5% ethanol compared to control. The results suggest an adverse interaction between benzyl alcohol and ethanol underlying the observed aversion to ethanol.

A novel two-site enzyme immunoassay for the sensitive detection of beta-endorphin in specific human brain stem regions.

On the line of experiences previously made in the development of a two-site immunoradiometric assay (TS-IRMA), we generated, in the present study, a novel, sequential, noncompetitive two-site immunoenzymometric assay (TS-IEMA) for the determination of the non-acetylated form of human beta-endorphin (beta h-EP). At variance with other assays reported in the literature, but in analogy to the TS-IRMA, the TS-IEMA does not require previous separation of beta h-EP. The TS-IEMA detects beta h-EP in central nervous tissues at a very low detection limit, and to a high degree of reproducibility, precision, sensitivity, and accuracy. The newly developed assay was then used to determine beta h-EP levels in the tissues of distinct brainstem regions. Tissues were collected, by the Palkovits's punching technique, from a series of victims of "Sudden Infant Death Syndrome" and of miscellaneous infections. The TS-IEMA, combined with the punching technique, has revealed, in the measure of its application in the present study, an unprecedented high degree of resolution of the neurochemical architecture of beta h-EP in the human infantile brainstem.

Effects of a secondary and a tertiary amine tricyclic antidepressant on cerebral biogenic amines as a function of mouse strain: a comparative neurotoxicological evaluation.

The effect of equal-dose regimens of amitriptyline and nortriptyline on the concentrations of serotonin, dopamine and major acidic metabolites was compared in 5 distinct brain regions as a function of inbred mouse strain. Amitriptyline increased to a greater extent the regional brain serotonin levels in the albino BALB/c mouse than did nortriptyline. Both drugs increased serotonin levels but decreased cerebral 5-hydroxyindoleacetic acid levels in some distinct brain regions of the black C57BL/6 mouse strain. The results suggest a strain-dependent differential increase in brain serotonin turnover in specific mouse strain brain regions which may account for the greater incidence of amitriptyline-induced sedation and seizures. The BALB/c mouse was also found to be more sensitive than the C57BL/6 strain to the action of both drugs on dopamine and major acidic metabolites with amitriptyline showing more regional brain potency than nortriptyline. The data suggest an increase in dopamine turnover particularly in brain areas associated with motor function and posture which may account for tricyclic-antidepressant-induced extrapyramidal disorders. The results also indicate that the C57BL/6 mouse strain may be of experimental value for studying the mechanism underlying tricyclic-induced adverse reactions relevant to sedation and movement disorders as a function of genetic predisposition.

Behavioral and metabolic interaction between gossypol and ethanol.

The effects of gossypol on ethanol-elicited responses pertaining to liver ethanol, acetaldehyde-metabolizing enzymes and alcohol preference were studied in rodents. Intraperitoneal injection of a single dose of gossypol, 100 mg/kg, inhibited hepatic alcohol dehydrogenase for 50 h in mice from both sexes. The acute gossypol treatment produced earlier inhibition of mouse liver cytoplasmic aldehyde dehydrogenase in male than female mice. Acute gossypol administration initially inhibited mouse liver subcellular mitochondrial aldehyde dehydrogenase in both sexes which was not evident 50 h later. Administration of gossypol, 10 mg/kg i.p., to male rats with preference for ethanol caused aversion for ethanol drinking. The enzymatic determinations indicate gender sensitivity of subcellular mouse liver aldehyde dehydrogenase to gossypol. The behavioral study suggests adverse metabolic interaction between gossypol and alcohol which may underlie the rat aversion to voluntary ethanol drinking.

Effect of tremorogenic and antitumor agents on enzymes regulating a minor metabolic pathway of biogenic amines: an hypothesis for the underlying mechanism.

The effects of some tremor-producing and antitremor agents on the enzymes sequentially metabolizing ethanol and acetaldehyde in addition to biogenic-amine-derived aldehyde intermediates were studied in mouse liver preparations. Aldehyde but not alcohol dehydrogenase was differentially stimulated by the compounds studied in vitro. This effect was confined to the mitochondrial enzyme and was isoenzyme-dependent. The results indicate difference between in vitro and in vivo effects and suggest a role for mitochondrial aldehyde dehydrogenase in metabolic detoxification of endogenous biogenic aldehydes in the presence of alcohol which may explain the worsening of drug-induced tremor by ethanol.

Genotype-treatment interaction between amantadine and chlorpromazine in the mouse.

1. Repeated administration of amantadine prior to chlorpromazine to two different strains of mice altered both locomotor activity, concentrations of brain biogenic amines and selected major metabolites as a function of mouse strain. 2. Amantadine antagonized chlorpromazine effect on motility which was associated with increases in whole brain levels of homovanillic acid in the CDF-1 but not C57BL/6 mice. 3. Conversely, the treatment with amantadine prior to chlorpromazine reduced whole brain normetanephrine and 5-hydroxyindoleacetic acid levels from respective controls in the C57BL/6 and CDF-1 mice, respectively. 4. The results suggest that genetic factors underly differential alteration of brain dopamine and serotonin which may underly the mechanism of amantadine efficacy in neuroleptic-induced extrapyramidal disorders and to the variable responses to amantadine therapy.

Effect of gossypol on kinetics of mouse liver alcohol and aldehyde dehydrogenase.

1. Gossypol, an antifertility ingredient of the cotton plant, altered specific activity of mouse liver alcohol dehydrogenase (L-ADH) and subcellular aldehyde dehydrogenase (L-ALDH) in mice of both sexes. 2. Intraperitoneal injection of a single gossypol dose, 50 mg/kg, inhibited both male and female L-ADH and cytoplasmic L-ALDH from saline controls 21 hr after drug treatment. 3. Gossypol inhibited female but not male mouse mitochondrial L-ALDH isoenzymes. 4. Gossypol-produced enzyme inhibition was determined as noncompetitive. 5. The results suggest gender-dependent sensitivity of mitochondrial L-ALDH to the gossypol inhibition. A toxic metabolic interaction between ethanol and gossypol has been indicated which suggests the contraindication of alcoholic beverages during gossypol use.

Opioid receptor proteins in human brain. Detection with monoclonal anti-idiotypic antibodies.

In order to identify opioid receptor proteins, we first ascertained the presence of mu-receptors in membranes of the human cerebral frontal cortex, using binding studies performed with sufentanil. Sufentanil binding was reversed by naloxone and prevented by an anti-idiotypic opioid receptor-specific antibody. This antibody was bound specifically by proteins (molecular weights of 66 and 68 Kda) detected in frontal cortex membrane preparations by sodium dodecyl sulphate-polyacrylamide-gel electrophoresis in combination with western blot analysis. Binding of the same antibody was achieved in dot blots of homologous cerebral and cerebellar cortex preparations.

Benzyl alcohol adverse effects in the rat: implications for toxicity as a preservative in parentral injectable solutions.

1. Short-term intake of a 2% benzyl alcohol in the rat drinking fluid resulted in sex-dependent inhibition of hepatic alcohol dehydrogenase. 2. Benzyl alcohol intake also inhibited female but not male mitochondrial aldehyde dehydrogenase isoenzymes with the apparent low and high Km. 3. The benzyl alcohol inhibition kinetics were found non-competitive with the major differences in Vmax being confined to the cytoplasmic enzymes. 4. The velocity of the enzymatic reaction was greater for the substrate benzaldehyde than benzyl alcohol. 5. The results suggest sex-dependent hepatic alcohol dehydrogenase-substrate competition between benzyl alcohol and ethanol which may precipitate adverse metabolic interaction particularly in the susceptible female subject. 6. Modulation of the activity of this enzyme by benzyl alcohol may contribute to its toxicity as preservative in parentral injectable solutions.

Cerebral and peripheral neurotoxicity of chlorpromazine and ethanol interaction: implications for alcohol and aldehyde dehydrogenase.

The effects of certain experimental variables on rodents brain and liver alcohol--(ADH) and aldehyde-dehydrogenase (LALDH) were evaluated. The in vivo and in vitro effect of chlorpromazine on these enzymes was determined. Short-term housing under complete darkness differentially inhibited ADH and ALDH in distinct brain regions with ADH showing more sensitivity than ALDH. The hepatic enzymes studied were not affected by such housing conditions but a non-competitive inhibition of L-ALDH occurred as a consequence of exposure to UV lighting for 3 consecutive weeks. Short-term treatment with chlorpromazine inhibited striatal ADH which was not affected by experimentally-induced hypothermia. Likewise, both hepatic and testicular ADH were noncompetitively inhibited in vitro by chlorpromazine. The results suggest sensitivity of brain and hepatic ADH to environmental housing conditions and indicate a similarity between peripheral and cerebral ADH responses to chlorpromazine. The modulation of ADH and/or ALDH may facilitate the formation of endogenous biogenic amines derived alkaloids which have been implicated in alcohol and extrapyramidal side effects.

Neurotoxicity of chlorpromazine and modulation by amantadine as a function of mouse strain.

The separate and combined effects of successive administration of amantadine, 100 mg/kg, i.p., and chlorpromazine, 0.2 mg/kg, i.p., on motor activity and whole brain levels of certain biogenic amines and major metabolites were studied in four strains of mice. These were the albino ICR, the inbred BALB/C, C57BL/6 and the hybrid CDF-I mice. Amantadine produced a strain-dependent behavioral stimulation subsequent the fourth dose. This was apparent in ICR and C57BL/6 mouse strains and was followed by a behavioral depression phase occurring during the night in C57BL/6 mice which was antagonized by chlorpromazine. Administration of chlorpromazine alone affected only CDF-1 mouse mobility. Chlorpromazine reduced only ICR mouse brain dopamine without concomitant changes in major acid metabolites. Repeated administration of amantadine prior to chlorpromazine negated this effect. Chlorpromazine enhancement of BALB/C brain serotonin and 5-hydroxyindoleacetic acid was antagonised by pretreatment with amantadine. This antagonism was also evident in BALB/C mouse brain dihydroxyphenylacetic acid. The results suggest genotypic-dependent behavioral and cerebral effects by the drugs studied. The antagonism between amantadine and chlorpromazine on brain amines may explain the therapeutic efficacy of amantadine in modulating chlorpromazine-induced extrapyramidal disorders.