The influence of organophosphate and carbamate on sperm chromatin and reproductive hormones among pesticide sprayers.

This study is aimed at evaluating the association between occupational exposure to organophosphate (OP) and carbamate (CB) pesticides and semen quality as well as levels of reproductive and thyroid hormones of pesticide sprayers in Malihabad, Lucknow, Uttar Pradesh, India. Thirty-five healthy men (unexposed group) and 64 male pesticide sprayers (exposed group) were recruited for clinical evaluation of fertility status. Fresh semen samples were evaluated for sperm quality and analyzed for DNA fragmentation index (DFI) by flow cytometry. Pesticide exposure was assessed by measuring erythrocyte acetylcholinesterase and plasma butyrylcholinesterase (BuChE) with a Test-mate ChE field kit. Serum levels of total testosterone (Tt), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and free thyroxine (FT4) were analyzed using enzyme immunoassay kits. Evidence of pesticide exposure was found in 88.5% of sprayers and significant increments were observed in sperm DFI with significant decrease in some semen parameters. DFI was negatively correlated with BuChE, sperm concentration, morphology, and vitality in these pesticide sprayers. The levels of Tt, PRL, FT4, and TSH appeared to be normal; however, there was a tendency for increased LH and FSH levels in exposed workers. The results confirm the potential impact of chronic occupational exposure to OP and CB pesticides on male reproductive function, which may cause damage to sperm chromatin, decrease semen quality, and produce alterations in reproductive hormones, leading to adverse reproductive health outcomes.

Conformational Dynamics of o-Fluoro-Substituted Z-Azobenzene.

A conformational analysis of o-fluoro Z-azobenzene reveals a slight preference for aromatic C-F/π interaction. Density functional theory (DFT) indicates that the conformation with a C-F/π interaction is preferred by approximately 0.3-0.5 kcal/mol. Ground-state conformations were corroborated with X-ray crystallography. (Z)-Azobenzene (Z-AB) with at least one o-fluoro per ring displays (19)F-(19)F through-space (TS) coupling. 2D J-resolved NMR was used to distinguish through-bond from TS coupling ((TS)JFF). (TS)JFF decreases as the temperature is lowered and the multiplets coalesce into broad singlets. We hypothesize that the coalescence temperature (Tc) corresponds to the barrier for phenyl rotation. The experimentally determined barrier of 8-10 kcal/mol has been qualitatively verified by DFT where transition states with a bisected geometry were identified with zero-point energies of 6-9 kcal/mol relative to ground state. These values are significantly higher that values estimated from previous theoretical studies but lie within a reasonable range for phenyl rotation in hydrocarbon systems.

Caput medusae in alcoholic liver disease.

Caput medusae and palmar erythema are cardinal signs in cirrhosis of liver with portal hypertension. Palmar erythema is described more often as a marker for alcoholic etiology of chronic liver disease. The peripheral stigmata of chronic liver disease are not routinely seen now a days due to early diagnosis and better therapy. We recently encountered an interesting patient of alcoholic liver disease with two classical signs of the disease and report the same for this unusual presentation.

Biomonitoring of organochlorines, glutathione, lipid peroxidation and cholinesterase activity among pesticide sprayers in mango orchards.

BACKGROUND: Pesticide sprayers in mango orchards of Malihabad, Lucknow (India) are generally exposed to organophosphate (OP) and pyrethroid pesticides. We determined the pesticide exposure levels along with their biochemical and clinical effects in 31 sprayers, compared with 18 controls. METHODS: Assay of acetyl and butyrylcholinesterases (AChE, BChE respectively) as an indirect measurement of OP exposure and levels of malondialdehyde (MDA) and glutathione (GSH) were estimated in blood samples to determine their impact on redox potential. Organochlorines were estimated by GLC-ECD. RESULTS: Significantly inhibited AChE, BChE activities and higher MDA level were found among sprayers compared to controls (p<0.05). Mean of total organochlorines were surprisingly higher (97.65+/-13.38 ppb) in sprayers than in those of controls (20.42+/-3.56 ppb) (p<0.05). Respiratory morbidity (32.4%), ocular problems (8.8%), gastrointestinal (17.6%) and skin problems (23.5%) were found in sprayers. There was significant correlation between AChE and GSH (r=0.29, p<0.05) and AChE with MDA (r=-0.34, p<0.05). CONCLUSION: Results indicated the significantly enhanced lipid peroxidation in sprayers correlated with cholinesterases inhibition. A small sample size limits the significance of this study. However, it paves the way for a larger Indian study with extended practical significance.

Working conditions and health among employees at information technology--enabled services: a review of current evidence.

Workers in information technology (IT)-enabled services like business process outsourcing and call centers working with visual display units are reported to have various health and psycho-social disorders. Evidence from previously published studies in peer- reviewed journals and internet sources were examined to explore health disorders and psycho-social problems among personnel employed in IT-based services, for a systematic review on the topic. In addition, authors executed a questionnaire- based pilot study. The available literature and the pilot study, both suggest health disorders and psychosocial problems among workers of business process outsourcing. The details are discussed in the review.

Effects of cholinergic and GABAergic drugs on apomorphine-induced gnawing behavior in rats.

The effects of cholinergic and GABAergic agonist and antagonist were studied on the apomorphine-induced gnawing behavior in rats. Physostigmine (0.5 mg/kg) decreased the biting scores, whereas atropine (5 mg/kg) had an opposite effect. Picrotoxin potentiated the physostigmine inhibitory action on gnawing responses. This inhibitory gnawing effect was antagonized by prior treatment with atropine. Pretreatment with amino-oxyacetic acid (25 mg/kg) also potentiated the inhibitory effect of physostigmine on gnawing behavior in animals. Such an additive inhibitory response could be antagonized by simultaneous pretreatment with cholinergic and GABAergic blockers such as atropine and picrotoxin, respectively. These findings indicate that the modulatory action of cholinergic neurons on DA system is probably influenced by changes in the GABAergic system.

Identification of enzyme inhibitors using combinatorial libraries.

Potent enzyme inhibitors have long been recognized as powerful tools for assessing the physiological roles of enzymes and have led to the therapeutic drugs able to modulate their activities in vivo. However, to be valuable tools such inhibitors should be selective so that they do not interfere with other members of the particular enzyme family. Combinatorial chemistry has proven to be a novel approach for the identification of molecules with a desired selectivity profile from the libraries of several million compounds. In recent years it has been extensively used in conjunction with computational methods for the development of potent inhibitors of therapeutically interesting targets. This review describes the various structurally diverse enzyme inhibitors identified by screening combinatorial libraries of peptides and small organic molecules.

Anticonvulsant profile of drugs which facilitate GABAergic transmission on convulsions mediated by a GABAergic mechanism.

The effects of selected modulators of GABAergic transmission, either alone or in combination, were tested for their potency on the seizure pattern and mortality induced by convulsant drugs in rat. Pentobarbital and diazepam were effective against both tonic and clonic seizure components induced by bicuculline and picrotoxin. The anticonvulsant profile of ethanol closely resembled that of pentobarbital. Pentobarbital, diazepam and ethanol did not modify seizures induced by strychnine. In contrast, progabide, a central gamma-aminobutyric acid (GABA) receptor agonist, caused significant protection only against convulsions induced by strychnine and its lethality, but did not protect against seizures induced by bicuculline or picrotoxin. Data on interaction of drugs with subprotective doses of these agents clearly demonstrated potentiation of the anticonvulsant actions of these modulators. Thus, seizures induced by bicuculline were more sensitive to the inhibition by pentobarbital in combination with diazepam or ethanol, while pentobarbital with progabide was equally effective against convulsions induced by GABA antagonists. Diazepam, in combination with progabide, blocked only convulsions induced by picrotoxin. Ethanol, in combination with either pentobarbital or with diazepam, was effective against all the three convulsant drugs. These results are consistent with the concept that drugs which facilitate GABAergic transmission are effective against seizures related to an impairment of GABA transmission. Further, the present data indicate that tonic seizures are more susceptible to the actions of drugs than the clonic component. Smaller doses of these drugs, alone or in combination, modified the seizure patterns and mortality, whereas at larger doses, the possible involvement of a nonspecific depressant action cannot be ruled out.

Effect of chronic treatment of ethanol on benzodiazepine and picrotoxin sites on the GABA receptor complex in regions of the brain of the rat.

Ethanol has been shown to enhance gamma-aminobutyric acid (GABA)ergic transmission. In this study an examination was made of the effect of chronic treatment with ethanol and its withdrawal at 24 h on the binding of [3H]flunitrazepam and [35S]t-butylbicyclophosphorothionate (TBPS) to brain regions in rat. Rats were rendered tolerant to, and dependent on, ethanol by an intragastric intubation method. The affinity (KD) or the binding capacity (Bmax) of [3H]flunitrazepam or [35S]TBPS was not altered by chronic treatment with ethanol or during withdrawal from ethanol. Neither the enhancing effect of GABA on the binding of [3H]flunitrazepam nor its inhibitory effect on the binding of [35S]TBPS were affected by chronic treatment with ethanol or its withdrawal at 24 h. These results suggest that the sensitivity of benzodiazepine and picrotoxin sites on the oligomeric GABA receptor complex is not affected during tolerance to, or withdrawal from ethanol. It is suggested that the effects of ethanol on GABAergic transmission may be produced at the level of coupled chloride ion channels.

The muscle relaxant activity of methaqualone and its methyl congener.

Studies with methaqualone and dimethylquinazolone showed them to possess both central and peripheral muscle relaxant activity, the latter only at high dose levels. They selectively inhibited polysynaptic reflexes and were more potent than mephenesin.

A global comparison of predicting equations on spirometry in the male population.

A multiple regression model considering dependent variables like vital capacity (VC), forced expiratory volume in one second (FEV1) and peak expiratory flow rate (PEFR) and age and height as independent variables for the adult male population, which includes whites of European descent and non-whites was reviewed to evaluate the role of lung function status following standardization of age and height. Non-whites showed 0.19 litre decline in VC per decade of life as compared to 0.24 litres observed in the whites of European descent. Mean VC increased 0.05 litres per centimetre in non-whites and whites. The variation in the constant term in the regression equation determined the difference between the racial groups. Like VC, FEV1 showed ethnic differences similar to those of VC. However, the magnitude of the variation in the predicted values of FEV1 was found to be less than that observed in VC. When related to VC, FEV1 showed little difference between most European populations, New Guyanaese, Indians, Negroes, Africans and Chinese because FEV1/FVC ratio had a very narrow range between 77 and 80%.

Involvement of central cholinoceptors in Metrazol-induced convulsions.

Atropine sulphate (10 mg/kg IP) afforded 90% protection against clonic convulsions induced by standard doses of metrazol (80 mg/kg SC) in mice, whereas atropine methonitrate (10 mg/kg IP) did not offer any protection. Furthermore, physostigmine (1 mg/kg IP) caused recurrence of convulsions in atropinzed metrazol-treated mice and converted the subconvulsive dose of metrazol (40 mg/kg SC) into a 100% convulsive dose. However, neostigmine (1 mg/kg IP) did not antagonize the protection afforded by atropine sulphate against metrazol. The results of the study suggest an involvement of central cholinergic mechanisms in metrazol-induced convulsions.

Identification of novel alpha-glucosidase inhibitors by screening libraries based on N- [4-(benzyloxy) benzoyl] alanine derivatives.

A library of 72 compounds related to N- [4-(benzyloxy) benzoyl]alanine (I) was synthesized, prepared and screened for alpha-glucosidase inhibitory activity. Four compounds showed potent inhibition, six compounds moderate inhibition, and 16 were weak inhibitors. One compound, N- [4-(benzyloxy) benzoyl] serine, was found to be a potent inhibitor of alpha-glucosidase with 100% inhibition at 1 micro M. This inhibitor was at least five times more potent than the lead compound I.

Identification of inhibitors of DNA topoisomerase II from a synthetic library of glycoconjugates.

A library of 24 glycoconjugates related to glycosylated beta-amino acid derivative (I) was been prepared and screened against DNA topoisomerase-II of the filarial parasite S. cervi. Among these, compound 6 was found to be a potent inhibitor of DNA topoisomerase-II with 95% inhibition at 1.09 microM. Furthermore, compound 6 was at least three times more potent than the lead compound, glycosylated beta-amino acid derivative I.

Separate site(s) of action of optical isomers of 1-methyl-5-phenyl-5-propylbarbituric acid with opposite pharmacological activities at the GABA receptor complex.

The behavioral profile of the optical isomers of 1-methyl-5-phenyl-5-propylbarbituric acid (MPPB) and their interaction with the convulsant binding site at the GABA receptor complex were investigated. R(-)-MPPB produced dose-related loss of righting reflex, whereas S(+)MPPB produced convulsions in a dose-dependent manner. Subconvulsive doses of S(+)MPPB were proconvulsant with a subeffective dose of picrotoxin. S(+)MPPB-induced seizures were blocked by R(-)MPPB and pentobarbital. In contrast, S(+)MPPB did not block the loss of righting reflex produced by R(-)MPPB or pentobarbital. S(+)MPPB inhibited the binding of [35S]t-butylbicyclophosphorothionate (TBPS), a ligand that binds to the picrotoxin site on the oligomeric GABA receptor complex, to rat brain membranes competitively, whereas R(-)MPPB inhibited it noncompetitively. Thus, the optical isomer of MPPB, which have opposite pharmacological effects, interact differently with the convulsant (TBPS) site at the GABA receptor complex. These results suggest that the convulsant S(+)MPPB and the depressant R(-)MPPB may produce their behavioral effects by acting via convulsant and anticonvulsant sites, respectively, at the GABA receptor complex.

Behavioural and biochemical alterations following haloperidol treatment and withdrawal: the animal model of tardive dyskinesia reexamined.

Behavioural and biochemical studies were carried out in rats given a single daily dose (1 mg/kg, i.p.) of haloperidol for 30 days and subsequently withdrawn for 7 days. Long-term administration of haloperidol resulted in supersensitivity of dopamine receptors. This was manifested by enhanced stereotypic biting, rearing, locomotor and floor activity of haloperidol withdrawn rats when challenged to a low dose of apomorphine (0.5 mg/kg, s.c.) on the 8th day. Chronic haloperidol treatment significantly decreased dopamine synthesis and release as evidenced by low activity of tyrosine hydroxylase and low level of homovanillic acid in striatum. Dopamine levels did not change in the frontal cortex, striatum and midbrain. Haloperidol treatment significantly increased striatal gamma-aminobutyric acid content and glutamic acid decarboxylase activity by 17% and 16% respectively. The decreased tyrosine hydroxylase activity and homovanillic acid level in corpus striatum might, in part, be due to an inhibitory effect of GABAergic neurons on dopaminergic system. Rats withdrawn from chronic haloperidol treatment showed significant increases in GABA level and glutamic acid decarboxylase activity. This probably resulted in further inhibition of dopamine release as evidenced by marked accumulation of dopamine in the corpus striatum and midbrain. No significant alterations in the endogenous levels of norepinephrine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were observed in haloperidol-treated and subsequently withdrawn rats. These data suggest that chronic haloperidol treatment and subsequent withdrawal results in the development of behavioural dopamine supersensitivity as well as biochemical alterations in dopaminergic and GABAergic system. The changes in these two neuronal systems seem to be interrelated.

Bromocriptine-induced changes in dopamine and gamma aminobutyric acid in haloperidol withdrawn rats.

1. Daily administration of haloperidol (2 mg/kg, i.p.) for 35 days significantly decreased tyrosine hydroxylase activity as well as homovanillic acid in the corpus striatum of rats. 2. Long-term treatment with haloperidol significantly elevated (17%) glutamic acid decarboxylase activity as well as gamma-aminobutyric acid level in the corpus striatum. 3. Withdrawal of rats for 3 and 5 days after 32 and 30 days of haloperidol treatment increased the locomotor activity to 279% and to 211%, respectively, of control values. While haloperidol withdrawal decreased tyrosine hydroxylase activity, it produced no further change in glutamic acid decarboxylase activity and gamma-aminobutyric acid. 4. Daily injection of bromocriptine (2 mg/kg, i.p.) for 5 days in haloperidol-withdrawn rats decreased locomotor activity and dopamine release as evidenced by increased endogenous levels of dopamine and decreased homovanillic acid in striatum of rats. No further increase in striatal glutamic acid decarboxylase activity and GABA levels were reported after bromocriptine treatment. 5. Our data suggest that bromocriptine may elicit its beneficial effect in tardive dyskinesia patients by modifying dopamine turnover in the striatum.

Combinatorial chemistry: polymer supported synthesis of peptide and non-peptide libraries.

In recent years, combinatorial chemistry has emerged as a powerful tool for accelerating drug discovery. While industry is rapidly embracing the technology, researchers continue to develop novel library methods including resins, linkers, tagging and deconvolution techniques. Newer strategies involving computer-customized combinatorial libraries offer enormous potential for the design of more "focused" and "smart" chemical libraries with maximal diversity. In addition, miniaturized systems for synthesizing chemical libraries are also being developed, which has made it possible to carry out reactions at submicroliter volumes.

Involvement of a GABAergic mechanism in the anticonvulsant effect of pentobarbital against maximal electroshock-induced seizures in rats.

The interaction between pentobarbital and other modulators of GABAergic transmission (diazepam, ethanol and progabide) was investigated on maximal electroshock seizures and on the loss of righting reflexes in rats. Pentobarbital, diazepam and ethanol produced a dose-dependent protection against electroshock seizures, with pentobarbital being more potent (3- and 50-times) than diazepam and ethanol. Progabide neither provided protection nor caused loss of righting reflex. Subprotective doses of pentobarbital and diazepam, together or when combined with a single ineffective dose of ethanol or progabide, caused protection against seizures and loss of righting reflex for variable durations, while ethanol and progabide combination did not provide protection. The protective effect of diazepam was antagonized by RO15-1788, picrotoxin and bicuculline pretreatments. The antagonism of pentobarbital protection by a specific GABA receptor antagonist, bicuculline suggests involvement of the GABAergic system in the anticonvulsant effect of pentobarbital. These results indicate that, like diazepam, the anticonvulsant effect of pentobarbital appears to be mediated through a GABAergic mechanism.

A possible role of a GABAergic mechanism in the convulsant action of RO5-4864.

The purpose of the present investigation was to determine the possible role of GABAergic mechanism in the convulsant action of RO5-4864. Benzodiazepines (BZ) and other agents which facilitate central GABAergic transmission delayed the onset of facial and forelimb clonus, whereas tonic hind limb extension was blocked in a dose-dependent manner. RO5-4864-induced convulsions were blocked by diazepam, clonazepam, pentobarbital, ethanol and amino-oxyacetic acid (AOAA). RO5-4864-induced convulsions were not blocked by the BZ antagonist RO15-1788. Specifically, RO15-1788 caused a decrease in the onset of severity component of tonic seizures, which tended to become generalized and precipitated in a tonic extension of the hindlimbs. Further, subconvulsive doses of a direct GABA receptor antagonist, bicuculline, enhanced the proconvulsant action of RO5-4864, indicating thereby a potential antagonism of the central GABAergic transmission. These observations strongly suggest that RO5-4864 probably elicits convulsions by selective impairment of the GABAergic transmission.