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L Singh

Publications and source records attributed to L Singh.

At least 73 records · Page 4Linked to original sources
PubMed1998

Evaluation of PD 154075, a tachykinin NK1 receptor antagonist, in a rat model of postoperative pain.

PD 154075 ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3) Ph) is a selective tachykinin NK1 receptor antagonist. Its effect on development and maintenance of thermal and mechanical hypersensitivity was examined in a rat model of surgical pain. When administered 30 min before surgery, PD 154075 dose-dependently (3-100 mg/kg, s.c.) prevented the development of thermal and mechanical hypersensitivity with respective minimum effective doses of 10 and 30 mg/kg. These antihypersensitivity effects lasted for 72 h. In contrast, the administration of PD 154075 (30 mg/kg, s.c.) after surgery had little or no effect on these nociceptive responses. PD 154075 antagonised thermal hypersensitivity induced by intrathecal administration of substance P, over the same dose range that blocked surgical hypersensitivity. However, it only partially blocked the thermal hypersensitivity induced by the selective NK2 receptor agonist [betaAla8]neurokinin A-(4-10). Morphine dose-dependently (1-6 mg/kg, s.c.) lengthened isoflurane and pentobarbitone-induced sleeping time in the rat. In contrast, PD 154075 (3-100 mg/kg, s.c.) did not interact with these anaesthetics. It is suggested that tachykinin NK1 receptor antagonists, such as PD 154075, may possess therapeutic potential as pre-emptive antihypersensitive agents.

Anesthetics↗
PubMed1998

Second generation "peptoid" CCK-B receptor antagonists: identification and development of N-(adamantyloxycarbonyl)-alpha-methyl-(R)-tryptophan derivative (CI-1015) with an improved pharmacokinetic profile.

We have previously described the design and development of CI-988, a peptoid analogue of CCK-4 with excellent binding affinity and selectivity for the CCK-B receptor. Due to its anxiolytic profile in animal models of anxiety, this compound was developed as a clinical candidate. However, during its development, it was determined that CI-988 had low bioavailability in both rodent and nonrodent species. In the clinic, it was further established that CI-988 had poor bioavailability. Thus, there was a need to identify an analogue with an improved pharmacokinetic (PK) profile. The poor bioavailability was attributed to poor absorption and efficient hepatic extraction. We envisaged that reducing the molecular weight of the parent compound (5, MW = 614) would lead to better absorption. Thus, we synthesized a series of analogues in which the key alpha-methyltryptophan and adamantyloxycarbonyl moieties, required for receptor binding, were kept intact and the C-terminus was extensively modified. This SAR study led to the identification of tricyclo[3.3.1.1(3,7)]dec-2-yl [1S-[1 alpha(S*)2 beta]-[2-[(2-hydroxycyclohexyl)amino]-1-(1H-indol-3- ylmethyl)-1-methyl-2-oxoethyl]carbamate (CI-1015, 31) with binding affinities of 3.0 and 2900 nM for the CCK-B and CCK-A receptors, respectively. The compound showed CCK-B antagonist profile in the rat ventromedial hypothalamus assay with a Ke of 34 nM. It also showed an anxiolytic like profile orally in a standard anxiety paradigm (X-maze) with a minimum effective dose (MED) of 0.1 microgram/kg. Although the compound is less water soluble than CI-988, oral bioavailability in rat was improved nearly 10 times relative to CI-988 when dosed in HP beta CD. The blood-brain permeability of CI-1015 (31) was also enhanced relative to CI-988 (5). On the basis of the overall improved pharmacokinetic profile as well as enhanced brain penetration, CI-1015 (31) was chosen as a development candidate.

Adamantane↗
PubMed1998

A summary of mechanistic hypotheses of gabapentin pharmacology.

Although the cellular mechanisms of pharmacological actions of gabapentin (Neurontin) remain incompletely described, several hypotheses have been proposed. It is possible that different mechanisms account for anticonvulsant, antinociceptive, anxiolytic and neuroprotective activity in animal models. Gabapentin is an amino acid, with a mechanism that differs from those of other anticonvulsant drugs such as phenytoin, carbamazepine or valproate. Radiotracer studies with [14C]gabapentin suggest that gabapentin is rapidly accessible to brain cell cytosol. Several hypotheses of cellular mechanisms have been proposed to explain the pharmacology of gabapentin: 1. Gabapentin crosses several membrane barriers in the body via a specific amino acid transporter (system L) and competes with leucine, isoleucine, valine and phenylalanine for transport. 2. Gabapentin increases the concentration and probably the rate of synthesis of GABA in brain, which may enhance non-vesicular GABA release during seizures. 3. Gabapentin binds with high affinity to a novel binding site in brain tissues that is associated with an auxiliary subunit of voltage-sensitive Ca2+ channels. Recent electrophysiology results suggest that gabapentin may modulate certain types of Ca2+ current. 4. Gabapentin reduces the release of several monoamine neurotransmitters. 5. Electrophysiology suggests that gabapentin inhibits voltage-activated Na+ channels, but other results contradict these findings. 6. Gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions. 7. Gabapentin prevents neuronal death in several models including those designed to mimic amyotrophic lateral sclerosis (ALS). This may occur by inhibition of glutamate synthesis by branched-chain amino acid aminotransferase (BCAA-t).

Acetates↗
PubMed1998

Aggressive NK cell lymphoma preceded by a ten year history of neutropenia associated with large granular lymphocyte lymphocytosis.

We report a case of aggressive natural killer (NK) cell lymphoma in an 82 year old man who first presented 10 years earlier with neutropenia in association with a large granular lymphocyte (LGL) lymphocytosis. The diagnosis of NK cell lymphoma was made on the basis of morphological and immunological characteristics (CD3-CD56+) found on skin biopsy of one of multiple skin nodules which subsequently developed in association with splenomegaly, thrombocytopenia and continuing neutropenia. In addition there was BM infiltration and a cytogenetic abnormality [add(6)(p25)] was detected. Combination chemotherapy led to an initial clinical response but a relapse occurred shortly afterwards and the patient died 8 months later from infection whilst neutropenic following re-introduction of chemotherapy. Previously reported cases of aggressive NK cell lymphoma have shown a young male predominance with a rapidly progressive clinical course and without evidence of a preceding chronic phase of LGL lymphocytosis and neutropenia.

Aged↗
PubMed1998

Involvement of the central tachykinin NK1 receptor during maintenance of mechanical hypersensitivity induced by diabetes in the rat.

Our study examines the role of central and peripheral neurokinin1 (NK1) receptors in diabetes-induced mechanical hypersensitivity. Glycine, N, N-dimethyl-, 2-[[2-[[(2-benzofuranylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2 -me thyl-1-oxopropyl] amino]-2-phenylethylester, bisulfate, [R-(R*,R*)] (PD 156982) is a selective NK1 receptor antagonist with nanomolar affinity for the human (IC50 = 1.4 nM) and guinea pig (IC50 = 9.6 nM) NK1 receptors. However, it has approximately two orders of magnitude lower affinity for the rodent NK1 receptor (IC50 = 820 nM). In electrophysiological studies, PD 156982 inhibited NK1 receptor-mediated responses in the guinea pig locus ceruleus, in a competitive manner, with an equilibrium constant of 13.9 nM. The intracerebroventricular (10-100 microg/animal) but not systemic administration of PD 156982 (1-100 mg/kg, s.c.) blocked the [Sar9, Met(O2)11] substance P-induced gerbil foot tapping response. This indicates that PD 156982 is unable to penetrate into the central nervous system. However, PD 156982 (10-100 mg/kg, s.c.) blocked the mechanical hypersensitivity induced by administration of substance P into the plantar surface of a rat paw. This suggests that PD 156982 can effectively antagonize peripheral NK1 receptors in vivo. The chemically related compound carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]et hyl ]-, 2-benzofuranylmethyl ester, [R-(R*,S*)] (CI-1021) is also a selective NK1 receptor antagonist but can penetrate into the central nervous system. PD 156982 (10-100 mg/kg, s.c.) failed to block streptozocin (75 mg/kg, i.p.) induced mechanical hypersensitivity. In contrast, CI-1021 dose-dependently (3-100 mg/kg, s.c.) blocked this hypersensitivity state with a minimum effective dose of 10 mg/kg. At these doses CI-1021 also antagonized mechanical hypersensitivity mediated by central NK1 but not NK2 receptors in the rat. It is suggested that the central NK1 receptor may play an important role in diabetes-induced hypersensitivity.

Animals↗
PubMed1997

The role of conserved amino acid motifs within the integrin beta3 cytoplasmic domain in triggering focal adhesion kinase phosphorylation.

Integrin-mediated adhesion of cells to extracellular matrix proteins triggers a variety of intracellular signaling pathways including a cascade of tyrosine phosphorylations. In many cell types, the cytoplasmic focal adhesion tyrosine kinase, FAK, appears to be the initial protein that becomes tyrosine-phosphorylated in response to adhesion; however, the molecular mechanisms regulating integrin-triggered FAK phosphorylation are not understood. Previous studies have shown that the integrin beta1, beta3, and beta5 subunit cytoplasmic domains all contain sufficient information to trigger FAK phosphorylation when expressed in single-subunit chimeric receptors connected to an extracellular reporter. In the present study, beta3 cytoplasmic domain deletion and substitution mutants were constructed to identify amino acids within the integrin beta3 cytoplasmic domain that regulate its ability to trigger FAK phosphorylation. Cells transiently expressing chimeric receptors containing these mutant cytoplasmic domains were magnetically sorted and assayed for the tyrosine phosphorylation of FAK. Analysis of these mutants indicated that structural information in both the membrane-proximal and C-terminal segments of the beta3 cytoplasmic domain is important for triggering FAK phosphorylation. In the C-terminal segment of the beta3 cytoplasmic domain, the highly conserved NPXY motif was found to be required for the beta3 cytoplasmic domain to trigger FAK phosphorylation. However, the putative FAK binding domain within the N-terminal segment of the beta3 cytoplasmic domain was found to be neither required nor sufficient for this signaling event. We also demonstrate that the serine 752 to proline mutation, known to cause a variant of Glanzmann's thrombasthenia, inhibits the ability of the beta3 cytoplasmic domain to signal FAK phosphorylation, suggesting that a single mutation in the beta3 cytoplasmic domain can inhibit both "inside-out" and "outside-in" integrin signaling.

Amino Acid Sequence↗
PubMed1997

The tachykinin NK1 receptor antagonist PD 154075 blocks cisplatin-induced delayed emesis in the ferret.

The activity of a selective tachykinin NK1 receptor antagonist, PD 154075 ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3) Ph), was examined in radioligand binding studies, in a [Sar9,Met(O2)11]substance P-induced foot-tapping model in the gerbil, and in cisplatin-induced acute and delayed emesis in the ferret. In radioligand binding studies, PD 154075 showed nanomolar affinity for the human, guinea-pig, gerbil, dog and ferret NK1 receptors with an approximate 300 times lower affinity for the rodent NK1 receptor. Using NK2,NK3 receptors and a range of other receptor ligands, PD 154075 was shown to exhibit a high degree of selectivity and specificity for the human type NK1 receptor. Following subcutaneous administration PD 154075 dose dependently (1-100 mg/kg) antagonised the centrally mediated [Sar9,Met(O2)11] substance P-induced foot tapping in the gerbil with a minimum effective dose (MED) of 10 mg/kg. The ability of PD 154075 to readily penetrate into the brain following oral administration was confirmed by its extraction and high performance liquid chromatography assay from the rat brain. PD 154075 was shown to achieve a relatively fast and sustained brain concentration (brain/plasma ratios ranged from 0.27 to 0.41 during the time period of 0.25-12 h). Further pharmacokinetic studies revealed that the absolute oral bioavailability of PD 154075 in the rat was (mean +/- S.D.) 49 +/- 15%. PD 154075 (1-30 mg/kg, i.p.) dose dependently antagonised the acute vomiting and retching in the ferret measured for 4 h following administration of cisplatin (10 mg/kg, i.p.) with a MED of 3 mg/kg. The administration of a lower dose of cisplatin (5 mg/kg, i.p.) in the ferret induces both an acute (day 1) and delayed (days 2 and 3) phase of emesis. The i.p. administration of PD 154075, 10 mg/kg three times a day for 3 days, almost completely blocked both the acute and delayed emetic responses. In the same study, the 5-HT3 receptor antagonist ondansetron (1 mg/kg, i.p., t.i.d.) was also very effective against the acute emetic response observed during the first 4 h following cisplatin, but it was only weakly active against the delayed response. In conclusion, PD 154075 is a selective and specific high affinity NK1 receptor antagonist with good oral bioavailability which is effective against both acute and delayed emesis induced by cisplatin in the ferret.

Animals↗
PubMed1997

Gabapentin, ineffective in normal rats, markedly reduces C-fibre evoked responses after inflammation.

Gabapentin (Neurontin) is a novel anticonvulsant with an as yet unknown mechanism of action. This electrophysiological study investigated the potential antinociceptive actions of systemically administered gabapentin in normal animals and after inflammation induced by the injection of carrageenan. Gabapentin facilitated the noxious evoked responses of dorsal horn neurones recorded in normal animals. In complete contrast, gabapentin strongly and dose-dependently inhibited the C-fibre evoked response and post-discharge, but not the A beta-fibre evoked response, of neurones recorded in animals 3 h after the injection of carrageenan. This unique and selective profile of gabapentin may provide a novel treatment for clinical inflammatory pain states.

Acetates↗
PubMed1997

Assessment of genetic diversity by DNA profiling and its significance in silkworm, Bombyx mori.

Silkworm genetic resources that are being maintained in different countries are yet to be adequately tapped to develop elite varieties that are suited to different agro-eco-climatic conditions of countries like India. This is mostly due to unavailability of efficient protocols that could uncover usable genetic variability in silkworms. Molecular markers are known to provide unambiguous estimates of genetic variability of populations since they are independent of confounding effects of environment. The DNA fingerprinting assays, based on random amplified polymorphic DNA (RAPD) and banded krait minor satellite DNA (Bkm) 2(8) multilocus probes, which successfully characterise the diverse silkworm genotypes at their DNA level, are described. The use of these two DNA fingerprinting assays in estimation of within- and between-population genetic diversity is discussed.

Animals↗
PubMed1997

Genetic variation in Asiatic lions and Indian tigers.

Previous reports have suggested that Asiatic lions and tigers are highly inbred and exhibit very low levels of genetic variation. Our analyses on these species have shown much higher degrees of polymorphism than reported. Randomly amplified polymorphic DNA (RAPD) analysis of 38 Asiatic lions, which exist as a single population in the Gir Forest Sanctuary in India, shows an average heterozygosity of 25.82% with four primers. Sperm motility studies by our colleagues corroborate this data. In Indian tigers, microsatellite analysis of five CA repeat loci and multilocus fingerprinting using Bkm 2(8) probe on a population of 22 individuals revealed a heterozygosity of 22.65%. Microsatellite analysis of loci Fca 77 and Fca 126 revealed polymorphism amongst the Asiatic x African lion hybrids, which has enabled us to use these as markers to discriminate the pure Asiatic lions from the hybrids. A similar analysis was used to identify hybrids of Indian and Siberian tigers through polymerase chain reaction (PCR) amplification of hair samples. To ascertain the variation which existed before the population bottleneck at the turn of the present century, microsatellite analysis was performed on 50- to 125-year-old skin samples from museum specimens. Our results show similar levels of genetic variability as in the present population (21.01%). This suggests that low genetic variability may be the characteristic feature of these species and not the result of intensive inbreeding. DNA fingerprinting studies of Asiatic lions and tigers have helped in identifying individuals with high genetic variability which can be used for conservation breeding programs.

Animals↗
PubMed1997

Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents.

1. Gabapentin (neurontin) is a novel antiepileptic agent that binds to the alpha 2 delta subunit of voltage-dependent calcium channels. The only other compound known to possess affinity for this recognition site is the (S)-(+)-enantiomer of 3-isobutylgaba. However, the corresponding (R)-(-)-enantiomer is 10 fold weaker. The present study evaluates the activity of gabapentin and the two enantiomers of 3-isobutylgaba in formalin and carrageenan-induced inflammatory pain models. 2. In the rat formalin test, S-(+)-3-isobutylgaba (1-100 mg kg-1) and gabapentin (10-300 mg kg-1) dose-dependently inhibited the late phase of the nociceptive response with respective minimum effective doses (MED) of 10 and 30 mg kg-1, s.c. This antihyperalgesic action of gabapentin was insensitive to naloxone (0.1-10.0 mg kg-1, s.c.). In contrast, the R-(-)-enantiomer of 3-isobutylgaba (1-100 mg kg-1) produced a modest inhibition of the late phase at the highest dose of 100 mg kg-1. However, none of the compounds showed any effect during the early phase of the response. 3. The s.c. administration of either S-(+)-3-isobutylgaba (1-30 mg kg-1) or gabapentin (10-100 mg kg-1), after the development of peak carrageenan-induced thermal hyperalgesia, dose-dependently antagonized the maintenance of this response with MED of 3 and 30 mg kg-1, respectively. Similar administration of the two compounds also blocked maintenance of carrageenan-induced mechanical hyperalgesia with MED of 3 and 10 mg kg-1, respectively. In contrast, R-(-)-3-isobutylgaba failed to show any effect in the two hyperalgesia models. 4. The intrathecal administration of gabapentin dose-dependently (1-100 micrograms/animal) blocked carrageenan-induced mechanical hyperalgesia. In contrast, administration of similar doses of gabapentin into the inflamed paw was ineffective at blocking this response. 5. Unlike morphine, the repeated administration of gabapentin (100 mg kg-1 at start and culminating to 400 mg kg-1) over 6 days did not lead to the induction of tolerance to its antihyperalgesic action in the formalin test. Furthermore, the morphine tolerance did not cross generalize to gabapentin. The s.c. administration of gabapentin (10-300 mg kg-1), R-(-) (3-100 mg kg-1) or S-(+)-3-isobutylgaba (3-100 mg kg-1) failed to inhibit gastrointestinal motility, as measured by the charcoal meal test in the rat. Moreover, the three compounds (1-100 mg kg-1, s.c.) did not generalize to the morphine discriminative stimulus. Gabapentin (30-300 mg kg-1) and S-(+)-isobutylgaba (1-100 mg kg-1) showed sedative/ataxic properties only at the highest dose tested in the rota-rod apparatus. 6. Gabapentin (30-300 mg kg-1, s.c.) failed to show an antinociceptive action in transient pain models. It is concluded that gabapentin represents a novel class of antihyperalgesic agents.

Acetates↗
PubMed1997

Structure-based design in drug discovery--the application of a peptoid drug design strategy for the development of non-peptide neuropeptide receptor ligands.

Over the last decade the increasing availability of metabolically- stable non-peptide antagonists targeted at neuropeptide receptors has led directly to a more thorough understanding of the role of neuropeptides in mammalian physiology. By far the majority of these non-peptide neuropeptide receptor antagonists thus far disclosed have been developed from leads identified from broad screening of company compound files or natural product collections, and may thus bear little obvious structural resemblance to the endogenous peptide ligand. This review will focus on an alternative structure-based approach to non-peptide neuropeptide receptor ligand design, referred to as the 'peptoid' drug design strategy, in which an appreciation of the structure of the neuropeptide is the key to the success of this approach. The development and current clinical progress of peptoid cholecystokinin and tachykinin receptor ligands that have thus far resulted from this process will be highlighted and used to exemplify the importance of this novel approach.

Journal Article↗
PubMed1997

Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain.

Gabapentin and S-(+)-3-isobutylgaba are anticonvulsant agents that selectively interact with the alpha2delta subunit of voltage-dependent calcium channels. This report describes the activities of these two compounds in a rat model of postoperative pain. An incision of the plantaris muscle of a hind paw induced thermal hyperalgesia and tactile allodynia lasting at least 3 days. Postoperative testing was carried out using the plantar test for thermal hyperalgesia and von Frey hairs for tactile allodynia. A single s.c. dose of gabapentin, 1 h before surgery, dose-dependently (3-30 mg/kg) blocked the development of allodynia and hyperalgesia with a minimum effective dose (MED) of 10 and 30 mg/kg, respectively. The highest dose of gabapentin prevented development of hyperalgesia and allodynia for 24 and 49 h, respectively. Similar administration of S-(+)-3-isobutylgaba also dose-dependently (3-30 mg/kg, s.c.) prevented development of hyperalgesia and allodynia with MED of 3 and 10 mg/kg, respectively. The highest dose of S-(+)-3-isobutylgaba completely blocked development of both nociceptive responses for 3 days. The administration of S-(+)-3-isobutylgaba (30 mg/kg s.c.) 1 h after surgery also completely blocked the maintenance of hyperalgesia and allodynia, but its duration of action was much shorter (3 h). The administration of morphine (1-6 mg/kg s.c.) 0.5 h before surgery prevented the development of thermal hyperalgesia with a MED of 1 mg/kg. However, unlike gabapentin and S-(+)-3-isobutylgaba, it had little effect on the development of tactile allodynia. It is suggested that gabapentin and S-(+)-3-isobutylgaba may be effective in the treatment of postoperative pain.

Acetates↗
PubMed1996

Detection and purification of sequence-specific DNA binding protein.

A simple assay for identifying DNA-binding proteins is described that involves loading of protein fractions onto nitrocellulose membrane using a slot-blot apparatus, incubating with 32P-labeled DNA probe in buffer in the presence of excess of nonspecific E. coli DNA at room temperature, and washing with increasing concentration of NaCl (from 50 to 500 mM) to obtain optimum signal. A simple and rapid scheme of purification of a sex and tissue-specific DNA-binding protein, which binds specifically to the GATA repeats of Bkm (banded krait minor satellite DNA), designated as Bkm-binding protein (BBP), is also described. This requires only a DNA affinity column after the initial ammonium sulfate precipitation. The insert (545 bp) of the Drosophila clone 2(8) containing 66 copies of GATA repeats was used to prepare the sequence-specific DNA-Sepharose affinity column. The slot-blot-binding assay and the simple scheme of purification described here may be used for routine screening and purification of sequence-specific DNA-binding proteins in general.

Animals↗
PubMed1996

Modulation of the in vivo actions of morphine by the mixed CCKA/B receptor antagonist PD 142898.

The ability of a mixed CCKA/B receptor antagonist PD 142898 (benzenebutanic acid, beta-[[3-(1 H-indol-3-yl)-2-methyl-2-[[[(2-methyl- cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-[1 S-[1 alpha [S*(R*)]-2 beta]]) to modulate the antinociceptive, positive reinforcing and gastrointestinal actions of morphine was investigated in the rat. PD 142898 antagonised the development and maintenance of morphine (2.0 mg/kg, s.c.) induced conditioned place preference at 0.1 mg/kg, i.p. However, it potentiated the antinociceptive action of a subthreshold dose of morphine in the radiant tail flick model at doses of 0.001 and 0.01 mg/kg, s.c. Furthermore, PD 142898 (0.0001-1.0 mg/kg, s.c.) also potentiated the antinociceptive action of morphine (1.0 mg/kg, s.c.) against the late phase of formalin response associated with inflammation at the dose of 0.001-1.0 mg/kg. PD 142898 (0.001 mg/kg, s.c.) blocked the development of tolerance to morphine in the formalin test. It failed (0.001-1.0 mg/kg, i.p.) to modulate the inhibitory action of morphine (5.0 mg/kg, s.c.) on gastrointestinal transit as measured using the charcoal meal test. It is argued that the effect of PD 142898 in the conditioned place preference test involves antagonism of CCKA receptors, whilst the potentiation of the antinociceptive action of morphine is mediated via blockade of CCKB receptors. These results suggest that the mixed CCKA/B receptor antagonist may potentiate the analgesic action of morphine, block the development of tolerance without a concomitant increase in constipation and may also reduce the abuse potential of the opiate.

Animals↗
PubMed1996

The antiepileptic agent gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed by D-serine.

This report describes the activity of the antiepileptic agent gabapentin (Neurontin) in animal models predictive of anxiolysis and analgesia. Gabapentin displayed anxiolytic-like action in the rat conflict test, the mouse light/dark box and the rat elevated X-maze with respective minimum effective doses (MEDs) of 3, 10 and 30 mg/kg. Furthermore, gabapentin also induced behavioural changes suggestive of anxiolysis in the marmoset human threat test with a MED of 30 mg/kg. In the rat formalin test of tonic nociception, gabapentin dose-dependently (30-300 mg/kg) and selectively blocked the late phase with a MED of 100 mg/kg. However, it failed to block carrageenan-induced paw oedema. The intracerebroventricular (ICV) administration of the glycine/NMDA receptor agonist D-Serine, dose-dependently (10-100 micrograms/animal) reversed the antinociceptive action of gabapentin (200 mg/kg, SC). D-Serine (30 micrograms/animal, ICV) also reversed the anxiolytic-like effects (in the light/dark box and the rat elevated X-maze) of gabapentin (30 mg/kg). In contrast, L-Serine (100 micrograms, ICV) failed to block the antinociceptive action of gabapentin. The antinociceptive action of (+)-HA-966 (25 mg/kg, SC), a partial agonist at the glycine/NMDA receptor, was reversed by D-Serine (100 micrograms/animal, ICV). However, D-Serine (100 micrograms/animal, ICV) failed to affect the antinociceptive action of a competitive NMDA receptor antagonist CGS 19755 (3 mg/kg, SC). Gabapentin has negligible affinity for the strychnine insensitive [3H]glycine binding site. This indicates that the interaction between gabapentin and D-Serine may not involve the NMDA receptor complex. Gabapentin may represent a novel type of anxiolytic and analgesic agent.

Acetates↗
PubMed1996

Recurrent duplication and deletion polymorphisms on the long arm of the Y chromosome in normal males.

Deletion of the 50f2/C (DYS7C) locus in interval 6 of Yq has previously been reported as a polymorphism in three males. We describe a survey of worldwide populations for further instances of this deletion. Of 859 males tested, 55 (approximately 6%) show absence of the 50f2/C locus; duplication of the locus was also detected in eight out of 595 males (approximately 1.4%). Populations having the deletion are confined to Asia, Australasia, and southern and northern Europe; of those of reasonable sample size, Finns had the highest deletion frequency (55%; n = 21). The deletions vary in size and the larger ones remove some of the RBM (RNA Binding Motif) genes, but none of the deletion males lack DAZ (Deleted in AZoospermia), a candidate gene for the azoospermia factor. On a tree of Y haplotypes, 28 deletion and eight duplication chromosomes fall into six and four haplotypic groups respectively, each of which is likely to represent an independent deletion or duplication event. Microsatellite and other haplotyping data suggest the existence of at least two further classes of deletion. Thus duplications and deletions in this region of Yq have occurred many times in human evolution, but remain useful markers for paternal lineages.

Asia↗