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Biomedical subjects

P L Sharma

Publications and source records attributed to P L Sharma.

At least 19 recordsLinked to original sources
PubMed1998

The bis-azo compound FP-21399 inhibits HIV-1 replication by preventing viral entry.

The bis-azo compound FP-21399 inhibits HIV-1 infection. We now show that FP-21399 acts on the HIV-1 envelope glycoprotein to prevent viral replication. This compound targets the entry step of the HIV-1 replication cycle as demonstrated by time-of-addition and single cycle viral entry assays. The entry of SIVmac239, which uses the same coreceptors (CD4/CCR5) as HIV-1, was not inhibited by FP-21399, indicating that the antiviral effect of FP-21399 is specific for the HIV-1 envelope glycoprotein and is not dependent upon the cellular receptors CD4 and CCR5. FP-21399 inhibits neither the activity of HIV-1 reverse transcriptase nor the expression of HIV-1 early mRNA. Finally, this compound inhibits gp120 shedding of the T-tropic virus. Our results suggest that the anti-HIV activity of FP-21399 is due to its interaction with HIV-1 gp120/41 complex during viral entry.

Animals↗
PubMed1997

Topotecan inhibits human immunodeficiency virus type 1 infection through a topoisomerase-independent mechanism in a cell line with altered topoisomerase I.

Topotecan (TPT), a known inhibitor of topoisomerase I, has previously been shown to inhibit the replication of several viruses. The mechanism of inhibition was proposed to be the inhibition of topoisomerase I. We report that TPT decreased replication of human immunodeficiency virus type 1 (HIV-1) in CPT-K5, a cell line with a topoisomerase I mutation. TPT inhibited production of HIV-1 RNA and p24 in CPT-K5 and wild-type cells equally effectively. The antiviral effects of TPT were observed not only in the topoisomerase-mutated CPT-K5 line but also in peripheral blood mononuclear cells (PBMC) acutely infected with clinical isolates and in OM10.1 cells latently infected with HIV and activated by tumor necrosis factor alpha. Little toxicity from TPT was noted in HIV-1-infected PBMC and in CPT-K5 and OM10.1 cells as measured by cell growth and proliferation assays. These observations suggest that TPT targets factors in virus replication other than cellular topoisomerase I and inhibits cytokine-mediated activation in latently infected cells by means other than cytotoxicity. These results suggest a potential for TPT and for other camptothecins in anti-HIV therapy alone and in combination with other antiretroviral drugs.

Camptothecin↗
PubMed1997

Attenuated replication of human immunodeficiency virus type 1 with a didanosine-selected reverse transcriptase mutation.

The Leu-74 to Val (Leu74Val) mutation in human immunodeficiency virus type 1 reverse transcriptase (RT) develops as a consequence of didanosine (ddI) therapy and is associated with a decreased susceptibility to ddI. In this report, we provide evidence that the ddI-associated Leu74Val mutation confers a replication disadvantage to the virus. In a series of experiments, we have shown that (i) a cloned virus with an engineered Leu74Val mutation in RT was attenuated for replication; (ii) a Val-to-Leu revertant of Leu74Val in the pNL4-3 background replicated with an efficiency similar to that of the wild-type virus; (iii) when two isolates from the same patient were compared, a clinical isolate containing mutations Leu74Val and Thr215Tyr was attenuated for replication compared to one in which the Thr215Tyr mutation alone was present; and (iv) the viruses with the Leu74Val mutation showed an 11% loss of fitness in a single passage compared to the wild-type and a mutant virus containing a Lys70Arg mutation. The loss of fitness for viruses grown in drug-free medium could result in an inability to detect a Leu74Val mutant in clinical isolates obtained post-ddI therapy. The decreased replication ability of the Leu74Val mutant virus selected by ddI therapy provides a strong rationale for the lower viral RNA levels observed with ddI therapy compared to zidovudine therapy in clinical trials.

Amino Acid Substitution↗
PubMed1996

AZT-related mutation Lys70Arg in reverse transcriptase of human immunodeficiency virus type 1 confers decrease in susceptibility to ddATP in in vitro RT inhibition assay.

The genetic basis for didanosine (ddl) resistance in human immunodeficiency virus (HIV-1) has previously been shown to be commonly associated with a Leu to Val change at codon 74 in the HIV-1 RT gene. In this study sequential viral isolates were analyzed from five patients with prior zidovudine (AZT) use who received 6 to 16 months of ddl therapy. Following ddl therapy, viral isolates exhibited an increased AZT susceptibility and decreased ddl susceptibility. Sequence and nested PCR analysis of the HIV-1 RT gene revealed that two viral isolates contained the Leu to Val change at codon 74, and three other isolates with reduced susceptibility to ddl each contained changes at codons 65, 70, and 72. Site-directed mutagenesis was employed to insert specific mutations in RT gene of proviral clone pNL4-3. Analysis of virion-associated reverse transcriptase activity indicated that the Lys70Arg mutation resulted in an enzyme with 2- to 4-fold decreased susceptibility to ddATP. Statistical analysis of the inhibitory concentration for RT activity between pNL4-3 and mutant Lys70Arg viruses obtained in three independent RT inhibition assays was significant (P = 0.05) by student t test paired analysis. Drug susceptibility assays on the virus with Lys70Arg mutation showed a marginal decrease in susceptibility to ddl (1.5- to 2-fold) and about 4- to 6-fold decrease in susceptibility to AZT. Mutations Lys65Glu and Arg72Ser resulted in an impaired RT with greatly diminished functional RT activity. The AZT-associated Lys70Arg mutation results in an RT enzyme with decreased susceptibility to ddATP.

Base Sequence↗
PubMed1996

Murine and simian retrovirus models: the threshold hypothesis.

By considering the dynamic relationship between retroviruses and their hosts, we have developed a unifying hypothesis to explain such disparate clinical phenomena as differential pathogenicity of a given virus in adults and neonates, transient infection with clearance of provirus-containing cells, long-term non-progression and vaccine effects of fully pathogenic viruses. The threshold hypothesis predicts that an opportunity exists during acute retroviral infection to influence the ultimate clinical outcome: if virus replication is kept below threshold by any means, including drug therapy or passive immunoprophylaxis with neutralizing antibodies, the host will prevail and win the race.

Animals↗
PubMed1996

Role of noradrenaline uptake inhibition and alpha-adrenoceptors in reperfusion ventricular arrhythmias in vivo and in vitro.

In view of the importance of sympathetic nervous system in the genesis of cardiac arrhythmias during reperfusion following coronary occlusion, the role of noradrenaline uptake inhibitor desipramine in the prevention of reperfusion arrhythmias was investigated in intact rabbit heart and isolated rat heart. For both the paradigms, ischaemia was produced by coronary artery ligation for 30 min followed by reperfusion for 60 min with drug administration at the time of reperfusion. Desipramine was used at three dose levels (0.2, 0.6 and 2.0 mg/kg) in the in vivo study while in vitro it was used at a concentration of 7 microM. Further, to investigate the status of adrenergic receptors during ischaemia and reperfusion, ischaemia was simulated by superfusing lactate physiological solution in isolated rabbit aortic strip preparation, which has well characterized alpha-receptors. Cumulative dose response curves (DRC) of selective alpha 1 agonist, phenylepherine (PE) were recorded during normal, ischaemic and reperfused conditions. Desipramine showed dose dependent anti-arrhythmic effect in vivo as well as in vitro. In intact heart studies desipramine offered protection against reperfusion arrhythmias in a dose related manner i.e. 50, 67.5 and 100% whereas in isolated studies, 50% protection was observed in the overall incidence of arrhythmias. DRC of PE shifted towards right during both ischaemia and reperfusion with a significant elevation of maximal response only during reperfusion.

Adrenergic Uptake Inhibitors↗
PubMed1995

Evaluation of antimuscarinic activity in human volunteers: a teaching aid in clinical pharmacology.

The antimuscarinic activity of oxyphenonium bromide, diphenhydramine hydrochloride and astemizole were evaluated in six volunteers. The parameters used were salivary secretion, heart rate and pupillary size. The results indicated that the changes in heart rate and pupillary size and measurements were not convenient parameters for class room demonstration. However, salivary secretion and dryness of mouth were found to be reliable parameters for measurement. It was concluded that simple procedures like evaluation of antimuscarinic activity could be introduced as teaching aids in clinical pharmacology for undergraduate students.

Adult↗
PubMed1995

Differential effect of selected antiarrhythmic drugs on coronary artery ligation-induced ventricular arrhythmias on the right or left sides.

The differential effect of the antiarrhythmic agents quinidine, propranolol, verapamil and sotalol was studied on right and left sided ventricular arrhythmias induced by ligation of the right coronary artery or anterior descending branch of the left coronary artery, respectively. Quinidine (0.30 mg/kg/min), propranolol (0.30 mg/kg/min), sotalol (0.25 mg/kg/min) and verapamil (0.018 mg/kg/min) were injected in unanesthetized dogs 18-24 h after coronary artery ligation. The doses of test drugs required for suppression of the ventricular arrhythmias were higher in the case of quinidine, sotalol and verapamil, but not in case of propranolol. The potency of the selected drugs in abolishing ventricular ectopics was, in descending order: verapamil, sotalol, propranolol and quinidine. The differential antiarrhythmic effect of these drugs in ventricular arrhythmias is discussed.

Animals↗
PubMed1994

Possible mechanism of endosulfan-induced enhancement of memory acquisition and retention in mice.

The effects of pre-training and post-training administration of endosulfan on retention of a step-down passive avoidance task was studied in mice. Endosulfan at doses of 1.0 mg/kg(ip) and 2.0 mg/kg(ip) enhanced memory acquisition and retention. This effect of endosulfan was possibly mediated by interaction with cholinergic neurotransmission, as scopolamine (0.5 mg/kg, ip) significantly antagonized the memory enhancing effects of endosulfan. Clonidine (0.05 mg/kg, ip) did not have any effect on enhancement of memory produced by endosulfan, thus indicating possibly no role of noradrenergic system.

Animals↗
PubMed1993

Animal models for perinatal transmission of pathogenic viruses.

In earlier work, mouse models have been used to demonstrate the efficacy and lack of toxicity of transplacental and perinatal AZT therapy. These practical small animal models can be useful for evaluating antiviral drugs aimed at common retroviral functions only, since Type C MuLVs are used. A primate model for fetal infection with an immunosuppressive lentivirus, SIV, has been established using ultrasound-guided inoculation of the amniotic fluid. The infection rate was 86% overall and 100% if the fetal SIV exposure occurred at least 19 days before delivery. The suspected major route of vertical HIV-1 transmission, that is, virus entry through fetal mucous membranes or skin, is replicated by our approach. The high fetal infection rate will allow studies of SIV pathogenesis during various stages of fetal development. This model should be well suited to development and evaluation of therapeutic strategies for preventing fetal infection.

Animals↗
PubMed1993

Search for an antidote to electroconvulsion and lethality in aminophylline-sensitized mice.

Diazepam (10 mg/kg i.p.) or MK-801 (0.25 mg/kg i.p.) offered complete protection against corneal electroshock (30 mA x 0.2 s)-induced tonic seizures and lethality but failed to protect from aminophylline (150 mg/kg i.p.) + electroshock (15 mA x 0.2 s)-induced tonic seizures and lethality in mice. The diazepam (2.5 mg/kg i.p.) and MK-801 (0.25 mg/kg i.p.) combination completely protected the mice from aminophylline + electroshock-induced seizures and lethality. Sodium valproate (500 mg/kg i.p.) protected the mice from electroshock (30 mA) per se and aminophylline + electroshock (15 mA)-induced seizure and lethality. The present study established the neurosensitizing potential of a single, non-convulsive dose of aminophylline for electroconvulsion due to subthreshold intensity electroshock and demonstrated the prophylactic efficacy of sodium valproate and the synergistic therapeutic potential of diazepam and MK-801 combination against such seizure attacks.

Aminophylline↗
PubMed1993

A histidine protein kinase is involved in polar organelle development in Caulobacter crescentus.

Mutations having pleiotropic effects on polar organelle development (pod) in Caulobacter crescentus have been identified and shown to occur in at least 13 genes scattered throughout the genome. Mutations at each locus affect a unique combination of polar traits, suggesting that complex interactions occur among these genes. The DNA sequence of one of these genes, pleC, indicates that it is homologous to members of the family of histidine protein kinase genes. Membes of this family include the senor components of the bacterial two-component regulatory systems. Furthermore, in vitro experiments demonstrated that the PleC protein was capable of autophosphorylation. These results suggest that the PleC protein (and perhaps the proteins encoded by the other pod genes as well) regulates the expression of genes involved in polar organelle development through the phosphorylation of key regulatory proteins. The use of a phosphorelay system cued to internal changes in the cell would provide a mechanism for coordinating major changes in gene expression with the completion of specific cell cycle events.

Amino Acid Sequence↗
PubMed1993

Effects of post-training administration of (-)-baclofen and chlordiazepoxide on memory retention in ICRC Swiss mice: interactions with GABAA and GABAB receptor antagonists.

The effects of post-training administration of chlordiazepoxide and (-)-baclofen on memory retention was studied in ICRC Swiss mice by measuring the retest stepdown latency 24 hr after foot-shock in a passive avoidance task. Chlordiazepoxide 20 mg/kg impaired memory retention and a similar effect was produced by 10 mg/kg of diazepam. The effect of chlordiazepoxide was antagonised when combined with picrotoxin but not by the addition of a specific GABAB antagonist CGP 35348. The effect of chlordiazepoxide on memory retention seems to be mediated by action at the GABAA-benzodiazepine receptor complex. (-) Baclofen, the active isomer of the GABAB agonist enhanced memory in ICRC mice and this effect was antagonised by CGP 35348 at a dose of 10 mg/kg. The inactive isomer of baclofen, (+)-baclofen did not produce any effect. This indicates that GABAB receptors contribute to the effects of (-)-baclofen on memory.

Animals↗
PubMed1993

BRL 38227--a potassium channel opener, antagonizes digoxin-induced convulsions.

Experimental evidence suggests that potassium channel openers play an important role in convulsions. In this study, the anticonvulsant activity of BRL 38227, a new potassium channel opener against digoxin-induced convulsions, is reported. Intraventricular administration of digoxin (7.5 micrograms), included "popcorn-type" convulsions in rats. BRL 38227, injected centrally increased the onset time of convulsions and decreased the mortality rate in a dose-dependent manner. Pretreatment with 4-aminopyridine, a potassium channel blocker antagonized the protective effect of BRL 38227. These findings show the involvement of potassium channels in digoxin-induced convulsions. Further these results indicate that in the future potassium channels might be a target for new anticonvulsant drugs.

4-Aminopyridine↗
PubMed1993

Clinical evaluation of the effect of omeprazole, cimetidine, famotidine and ranitidine on histamine induced cutaneous wheal and flare response.

The effect of H2 receptor antagonists on immediate cutaneous response to allergens remain controversial. In the present study, the effect of 7-day administration of omeprazole, cimetidine, famotidine and ranitidine on histamine induced wheal and flare reaction was evaluated. A single blind randomized parallel group study with within patient comparison of responses was planned in non-ulcer dyspepsia patients eligible to receive H2 antagonists or omeprazole. None of the drugs produced any changes in the area of the wheal in comparison to respective baseline values. The area of flare was decreased by all the drugs and the percentage decrease in this parameter caused by omeprazole, cimetidine, famotidine and ranitidine was 2.4, 12.3, 20.2 and 13.2, respectively. Only famotidine caused a significant decrease in flare area (p < 0.05).

Adult↗
PubMed1993

Effects of ranitidine alone and in combination with chlorpheniramine on histamine-induced wheal and flare and psychomotor performance.

Some reports suggest that addition of an H2 antagonist increases the efficacy of H1 antagonist but the influence on the side effect profile of antihistamines are largely unknown. The effects of ranitidine, chlorpheniramine, their combination and placebo on histamine induced wheal and flare, psychomotor performance and subjective symptoms were studied in 6 healthy male volunteers in a double blind randomized and cross-over (Latin square) study. Ranitidine significantly reduced the histamine induced wheal at 4 hrs (P < 0.05). Chlorpheniramine and the combination significantly reduced both histamine induced wheal and flare at 2 hrs and at 4 hrs (P < 0.05). Addition of ranitidine reduced the feeling of sleepiness produced by chlorpheniramine, though other subjective symptoms were not affected. None of the treatment schedules produced any consistent change in the psychomotor performance of the volunteers.

Adult↗
PubMed1993

A study on withdrawal related haemodynamic response in chronic propranolol treated conscious rats.

Single dose of propranolol hydrochloride (5 mg/kg, i.p.) caused significant fall in heart rate (HR) but not in systolic blood pressure (SBP) in normotensive conscious rats. Multiple doses of propranolol (5 mg/kg, i.p., twice-a-day for 5 wk) caused significant fall in both HR and SBP at 2 wk and 4 wk in normotensive conscious rats. Sudden withdrawal of propranolol at 5 wk caused a significant blood pressure upswing and tachycardia between 12-24 h followed by normalization of both blood pressure and heart rate. The study documents a possible model of rebound hypertension in normotensive conscious rats.

Animals↗