Demographics and host-kill parameters of Diglyphus horticola Khan against Chromatomyia horticola (Goureau).

The pea leafminer, Chromatomyia horticola (Goureau) (Diptera: Agromyzidae) is a polyphagous and serious pest of peas. In India, this pest is attacked by many parasitoids and among them Diglyphus horticola Khan (Hymenoptera: Eulophidae) is an important one, however, demographics and pest-kill potential of this parasitoid has not been studied so far. This study presents the first report on its demographics and pest-kill potential on C. horticola. The parasitoid showed three modes of host-killing behaviour viz. host-feeding, parasitism and host-stinging. The parasitoid females killed more number of hosts by parasitism than host-feeding or host-stinging. The pre-adult survival, net reproductive rate, intrinsic rate of increase (rm) and finite rate of increase (λ) were higher on the 5-days old host larvae than those reared on the 3-days old larvae. Demographics and pest-kill parameters of D. horticola were also better on 5-days old host larvae than on 3-days old host larvae. Based on the study, D. horticola appeared to be a promising biocontrol agent for the suppression of C. horticola in peas and could be promoted through conservation biological control. Further studies are required to standardize the mass production protocol and release rates to use the parasitoid by augmentation.

An Innovative Root Inoculation Method to Study Ralstonia solanacearum Pathogenicity in Tomato Seedlings.

In this study, we report Ralstonia solanacearum pathogenicity in the early stages of tomato seedlings by an innovative root inoculation method. Pathogenicity assays were performed under gnotobiotic conditions in microfuge tubes by employing only 6- to 7-day-old tomato seedlings for root inoculation. Tomato seedlings inoculated by this method exhibited the wilted symptom within 48 h and the virulence assay can be completed in 2 weeks. Colonization of the wilted seedlings by R. solanacearum was confirmed by using gus staining as well as fluorescence microscopy. Using this method, mutants in different virulence genes such as hrpB, phcA, and pilT could be clearly distinguished from wild-type R. solanacearum. The method described here is economic in terms of space, labor, and cost as well as the required quantity of bacterial inoculum. Thus, the newly developed assay is an easy and useful approach for investigating virulence functions of the pathogen at the seedling stage of hosts, and infection under these conditions appears to require pathogenicity mechanisms used by the pathogen for infection of adult plants.

Effect of combination of renin inhibitor and Mas-receptor agonist in DOCA-salt-induced hypertension in rats.

To investigate the combined effect of aliskiren, a renin inhibitor, and AVE 0991, a Mas-receptor agonist, in experimental hypertension (HT) in rats. HT was produced by administration of deoxycorticosterone acetate (DOCA) and mean arterial blood pressure (MABP) was assessed by tail-cuff method. Treatments were started from 4th week onwards and were continued for 9 days. A significant increase in MABP was noted after 1 week in DOCA control rats, as compared with the base line value. A stable HT developed after 4 weeks of DOCA administration. Treatments with aliskiren and AVE 0991 alone, dose-dependently decreased MABP in DOCA-treated rats. Further, combination of low doses of aliskiren and AVE 0991 significantly reduced MABP, as compared with DOCA control rats and with either drug alone in low doses. It may be concluded that treatment with aliskiren produced down-regulation of both harmful Ang II-AT1-receptor and survival Ang(1-7)/Mas-receptor axis of RAAS. Treatment with combination of low doses of aliskiren and AVE 0991, for the first time, has been shown to produce synergistic blood pressure lowering effect. Therefore, combination of renin inhibitor with Mas-receptor agonist may prove beneficial for the treatment of hypertensive patients.

Stimulation of accumbens shell cannabinoid CB(1) receptors by noladin ether, a putative endocannabinoid, modulates food intake and dietary selection in rats.

Stimulation of cannabinoid CB(1) receptors in nucleus accumbens shell has been shown to stimulate feeding and enhance positive 'liking' reactions to intraoral sucrose. This study examined the behavioural effects of noladin ether and 2-arachidonoylglycerol following infusion into accumbens shell, on chow intake and food preference in high-carbohydrate and high-fat preferring rats. Noladin ether, potently and dose-dependently stimulated chow intake as compared with 2-arachidonoylglycerol in free-feeding rats. In the diet preference paradigm, in which rats were given free access to both, high-carbohydrate (HC) and high-fat (HF) diets simultaneously, an intra-accumbens administration of noladin ether as well as 2-arachidonoylglycerol, preferentially enhanced fat consumption over carbohydrate in both HF- and HC-preferring rats. These effects were significantly attenuated by the CB(1) receptor antagonist, AM 251. These results suggesting that, the endocannabinoids through CB(1) receptors, affects appetite for specific dietary components. Both these agents exert a specific action on eating motivation and possibly promoting eating by enhancing the incentive value of food. Altogether these findings reinforce the idea that the endogenous cannabinoid system in the accumbens shell may be important to augment reward-driven feeding via modulation of CB(1) receptor signalling pathways.

Protective effect and potential mechanism of Ginkgo biloba extract EGb 761 on STZ-induced neuropathic pain in rats.

Diabetes induced neuropathic pain is recognized as one of the most difficult types of pain to treat with conventional analgaesics. EGb 761 is a standardized extract of Ginkgo biloba that has analgaesic and antiinflammatory properties and modulatory effects on key pain-related molecules. We examined the effect of EGb 761 on streptozotocin (STZ)-induced neuropathic pain behaviours and assessed its mechanism of action. Streptozotocin (20 mg/kg i.p for 5 days) was administered to induce experimental diabetes. Pain hypersensitivity to radiant heat was measured using the Dynamic Plantar Aesthesiometer to test the pain threshold. Diabetic rats exhibited mechanical allodynia and thermal hyperanalgaesia after the third week of STZ injection and concomitantly increased thiobarbituric acid reactive substance and nitric oxide concentration. The antioxidant enzymes level of superoxide dismutase and catalase was markedly reduced in STZ-diabetic rats (p < 0.05). Systemic administration of EGb 761 (25, 50 and 100 mg/kg), starting after the third week following STZ injection, dose-dependently reversed STZ-induced thermal hyperanalgaesia and mechanical allodynia. Moreover, it reduced oxidonitrosative stress and concomitantly restored the level of antioxidant enzymes (p < 0.05) as compared with untreated diabetic rats. These results suggest that EGb 761 attenuated STZ-induced neuropathic pain behaviours by inhibiting oxidative and nitrosative stress and may constitute a new approach for treatment of painful diabetic neuropathy.

Comparison of master two-step exercise stress test versus six-min walk test in patients tested positive for SARS-CoV-2.

Background and Aim: There has been a lack of uniformity on how to triage coronavirus disease 2019 (COVID-19) patients visiting the emergency units of hospitals. Triage tools are themselves spreading the pandemic in hospital areas. The present study compared a master two-step (M2ST) exercise stress test versus a 6-min walk test (6MWT) in COVID-19-positive patients visiting the emergency unit of a hospital. Materials and Methods: Thirty-nine patients underwent 6MWT followed by M2ST, while another set of 38 patients underwent M2ST followed by 6MWT in this randomized, crossover, open-label, and noninferiority study. The exercise tests assessed the change from baseline in SpO2, heart rate (HR), respiratory rate, blood pressure, exertion, and dyspnea on the modified-Borg scale. Results: Noninferiority was established for SpO2 (P < 0.05), systolic blood pressure (SBP; P < 0.001), and diastolic blood pressure (DBP; P < 0.05), but not for HR (P = 0.3) and respiratory rate (P = 0.6). The difference between the pretest and posttest (delta change) values for the parameters SpO2, respiratory rate, HR, SBP, and DBP correlated significantly (P < 0.001) with Pearson correlation coefficient (r = 0.764, 0.783, 0.473, 0.838, and 0.783, respectively). The delta change values of modified-Borg scale for dyspnea (P = 0.291) and exertion (P = 0.208) were statistically insignificant between the two exercise tests. However, the correlation between the tests was statistically significant (P < 0.001). Conclusion: M2ST, a timesaving, cost-effective, and easy to perform exercise stress test, has been identified as a reliable alternative for 6MWT.

Involvement of vascular endothelial nitric oxide synthase in development of experimental diabetic nephropathy in rats.

Endothelial nitric-oxide synthase (eNOS) acts as a common pathogenic pathway in diabetic nephropathy (DN). However, its functional consequences are still not fully understood. Caveolin, a membrane protein, inhibits the eNOS by making caveolin-eNOS complex, and its expression is upregulated during diabetes mellitus (DM). This study was designed to determine the role of caveolin in eNOS-mediated NO synthesis and release in DN. DM in rat was induced by feeding of high-fat diet (HFD) for 2 weeks, followed by single dose of streptozotocin (STZ) (35 mg/kg, ip) further followed by HFD for further 8 weeks. Serum nitrite/nitrate ratio was measured to determine the plasma level of NO. Diabetic rat, after 6 weeks of STZ, developed elevated level of BUN, protein in urine, urinary output, serum creatinine, serum cholesterol, kidney weight, kidney weight/body weight, and renal cortical collagen content, while serum nitrite/nitrate concentration was significantly decreased as compared to normal control group. Treatment with sodium nitrite (NO donor), L: -arginine (NO precursor), daidzein (caveolin inhibitor), and combination of L: -arginine and daidzein for 2 weeks markedly attenuated these changes and increased serum nitrite/nitrate ratio. However, treatment with L-NAME, a eNOS inhibitor, significantly attenuated the L: -arginine-, daidzein-, or combination of L: -arginine and daidzein-induced ameliorative effects in DN. The finding of this study suggests that caveolin plays a vital role in the eNOS-mediated decrease in renal level of NO, which may be responsible for the development of DN in rats.

Pharmacokinetic-pharmacodynamic equivalence of three gliclazide formulations in healthy human male subjects.

AIMS: To find out the pharmacokinetic (PK) and pharmacodynamic (PD) parameters for assessing the bioequivalence of three marketed products. To study the relationship between the pharmacokinetics of gliclazide and pharmacodynamic effect in healthy male volunteers. METHODS: This was an open label, balanced, randomized, 3-treatment, 3-sequence, 3 period, single-dose, cross-over bioavailability study in which 18 healthy adults were randomized to receive gliclazide 80 mg with 7 days wash out between treatments. The drug was administered with 240 ml of 20% glucose solution after a 10 h overnight fasting. Pharmacokinetic parameters like t(max), C(max), AUC(0-t), AUC(0-∞), AUC(0-t) / AUC(0-∞) and t(1/2) and pharmacodynamic parameters like maximum effect (minimum glucose level in the body, C(minglu)), time to minimum glucose level in the body (T(cminglu)) and partial AUC were calculated for all the products. RESULTS: The values for mean ± SD for age, height and weight of the volunteers were 28.00 ± 22.68, 165.78 ± 5.56 and 56.78 ± 13.37 respectively. There were total 4 withdrawn subjects and 1 drop out. Within batch accuracy of the method were in the range of 95.5 - 101.7%, 99.1 - 106.1% and 96.2 - 104.2% for three consecutive batches. The 90% CI for log transformed data of the PK and PD were within the acceptance range of 80.0 - 125.0%. CONCLUSIONS: This population PKPD analysis has characterized the relationship between the exposure to gliclazide and its hypoglycemic effect. The test products A & B compared to reference product R were bioequivalent on the basis of pharmacokinetic and pharmacodynamic parameters. Finally it is recommended that the more costly product R can be safely switched with less costly products i.e. A and B.

Involvement of GSK-3ß in attenuation of the cardioprotective effect of ischemic preconditioning in diabetic rat heart.

Ischemic preconditioning (IPC) produces cardioprotection by phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) that inhibits the opening of mitochondrial permeability transition pore (MPTP). The activity of glycogen GSK-3ß is elevated during diabetes mellitus (DM). This study investigated the role of GSK-3ß in attenuation of cardioprotective effect of IPC in diabetic rat. DM was induced by single administration of streptozotocin (STZ, 50 mg/kg, i.p.). Isolated perfused heart was subjected to 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size was estimated by triphenyltetrazolium chloride (TTC) staining and lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) was analyzed in coronary effluent. IPC significantly decreased myocardial infarct size and release of LDH and CK-MB from normal rat heart. The cardioprotective effect of IPC was significantly attenuated in diabetic rat. Four episodes of preconditioning by either of GSK-3ß inhibitors, lithium chloride (LiCl, 20 mM), indirubin-3 monooxime (1 µM), and SB216763 (3 µM) significantly reduced the LDH and CK-MB release and decreased infarct size in diabetic rat heart. Perfusion of atractyloside, an opener of MPTP, significantly attenuated, the cardioprotective effect of IPC in normal rat heart, and of GSK-3ß inhibitor induced preconditioning in the DM rat heart. Our results suggest that preconditioning with GSK-3ß inhibitors in diabetic rat heart may provide a more consistent cardioprotection, as compared to IPC. Also, the mechanism of diabetes mellitus-induced attenuation of cardioprotective effect of IPC involves activation of GSK-3ß, due to impaired protective upstream signaling pathways and opening of MPTP during reperfusion.

Ameliorative potential of angiotensin1-7/Mas receptor axis in streptozotocin-induced diabetic nephropathy in rats.

The present study was designed to investigate the effects of angiotensin(1-7) (Ang(1-7)) a Mas receptor agonist, and A-779, a Mas receptor antagonist, in streptozotocin-induced diabetic nephropathy (DN). A single administration of streptozotocin (STZ) (50 mg/kg i.p.) to rats produced diabetes, and diabetic nephropathy developed after 8 weeks of STZ administration. The extent of DN was assessed biochemically and morphologically by measuring serum creatinine, creatinine clearance, blood urea nitrogen (BUN), proteinuria, urinary N-acetyl-beta-D glucosaminadase activity, renal collagen contents, lipid profile, serum nitrite/nitrate concentration and kidney weight/body weight (%). Treatments with Ang(1-7) (576 microg/kg/day i.p. for 4 weeks) and Ang(1-7) plus A-779 (744 microg/kg/day i.p. for 4 weeks) were started after 4 weeks of STZ administration. The treatment with Ang(1-7) attenuated STZ-induced nephropathy in rats by decreasing proteinuria, renal collagen content and by improving endothelial functions without preventing tubular damage. It has been shown for the first time that treatment with Ang(1-7) decreases dyslipidemia and BUN in diabetic rats, implying a renoprotective effect of the peptide. However, serum creatinine, creatinine clearance and kidney weight/body weight (%) remained unaffected with Ang(1-7) treatment. It may be concluded that activation by specific agonists of the Mas receptor may be useful in combating glomerular damage in DN.

The effects of rosuvastatin on the serum cortisol, serum lipid, and serum mevalonic acid levels in the healthy Indian male population.

In this open-label, balanced, randomized, placebo-controlled, parallel study, healthy male volunteers were randomly divided into two groups. Each group received either a single oral dose of rosuvastatin 20 mg or placebo. Estimations were done at predose on day 1 of dosing (baseline) and 24 h postdose after days 7 and 14. Serum cortisol and serum lipid levels were estimated using enzyme-linked immunosorbent assay kits and serum mevalonic acid (MVA) levels were measured using validated liquid chromatography-tandem mass spectrometry method. Rosuvastatin produced a statistically significant (P < 0.05) decrease in total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and triglycerides. However, the increase in high-density lipoprotein cholesterol and decrease in cortisol and MVA were not statistically significant when compared to the placebo-treated group. The study showed that rosuvastatin at a dose of 20 mg/day for a period of 14 days was very potent as cholesterol-lowering agent, without any significant change in serum cortisol level in the healthy Indian male population.

The effect of four different types of diet on the bioavailability of loracarbef.

This randomized open-label single-dose crossover pharmacokinetic study was carried out to assess the effect of different diets on the bioavailability of loracarbef in 24 healthy male volunteers. A single dose of loracarbef in 200-mg tablet form was administered at 5 different times: after overnight fasting, after two vegetarian (high-fat and low-fat) diets, and following two non-vegetarian (high-fat and low-fat) diets. Serial blood samples were collected up to 10 h post-dose. Serum loracarbef concentrations were determined by a validated high performance liquid chromatographic (HPLC) method. Area under curve (AUC) values were significantly affected only by non-vegetarian diets; however the time to reach maximum serum concentration (Tmax) was prolonged and the maximum serum concentration (Cmax was decreased by all types of meals. The non-vegetarian diets affected the rate of absorption of loracarbef more than the vegetarian diets. The lowest decrease in Cmax was produced by the high-fat vegetarian diet, while the maximum was produced by the low-fat non-vegetarian diet. The results of this study indicate that while the rate of loracarbef absorption is significantly decreased by all diets, the extent of absorption is only reduced significantly by the non-vegetarian diets. The rate of elimination (k(el)) was not found to be significantly decreased by any of the diets. As compared to the high-fat non-vegetarian diet, the time beyond minimum inhibitory concentration (MIC90) concentration was significantly increased by the high-fat vegetarian diet. The implications of these findings for the large Indian vegetarian population are considerable.

Hemin, a heme oxygenase-1 inducer, restores the attenuated cardioprotective effect of ischemic preconditioning in isolated diabetic rat heart.

BACKGROUND: Attenuated cardioprotective effect of ischemic preconditioning (IPC) by reduced nitric oxide (NO) is a hallmark during diabetes mellitus (DM). Recently, we reported that the formation of caveolin-endothelial nitric oxide synthase (eNOS) complex decreases the release of NO, which is responsible for attenuation of IPC-induced cardioprotection in DM rat heart. Heme oxygenase-1 (HO-1) facilitates release of NO by disrupting caveolin-eNOS complex. The activity of HO-1 is decreased during DM. This study was designed to investigate the role of hemin (HO-1 inducer) in attenuated cardioprotective effect of IPC in isolated diabetic rat heart. METHODS: DM was induced in male Wistar rat by single dose of streptozotocin. Cardioprotective effect was assessed in terms of myocardial infarct size and release of lactate dehydrogenase and creatine kinase in coronary effluent. The release of NO was estimated indirectly by measuring the release of nitrite in coronary effluent. Perfusion of sodium nitrite, a precursor of NO, was used as a positive control. RESULT: IPC-induced cardioprotection and increased release of nitrite were significantly attenuated in a diabetic rat as compared to a normal rat. Pretreatment with hemin and daidzein, a caveolin inhibitor, alone or in combination significantly restored the attenuated cardioprotection and increased the release of nitrite in diabetic rat heart. Zinc protoporphyrin, a HO-1 inhibitor, significantly abolished the observed cardioprotection and decreased the release of nitrite in hemin pretreated DM rat heart. CONCLUSION: Thus, it is suggested that hemin restores the attenuated cardioprotective effect in diabetic rat heart by increasing the activity of HO-1 and subsequently release of NO.

Murine models for evaluating antiretroviral therapy.

The pandemic of the acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus type 1 (HIV-1), requires rapid development of effective therapy and prevention. Analysis of candidate anti-HIV-1 drugs in animals is problematic since no ideal animal model for HIV-1 infection and disease exists. For many reasons, including small size, availability of inbred strains, immunological reagents, and lymphokines, murine systems have been used for in vivo analysis of antiretroviral agents. Here we review currently available murine models involving HIV-1 in transgenic mice and in chimeric mice reconstituted with human cells, as well as murine systems using retroviruses of the subfamily Oncovirinae rather than Lentivirinae. We report our results on various antiretroviral treatment strategies, including chemoprophylaxis after acute retroviral exposure, therapy of chronic viremia, quantitative analysis of combination therapy, and therapy during pregnancy and in the neonatal period aimed at preventing viremia in the offspring. Due to our highly effective postexposure treatment protocols with 3'-azido-3'-deoxythymidine (zidovudine) combined with recombinant human interferon-alpha A/D, retrovirus-inoculated mice developed immunity to the virus to which they were exposed, which will allow us to determine the nature of protective antiretroviral immunity in inbred mice.

Pleiotropic effects of statins: new therapeutic targets in drug design.

The HMG Co-enzyme inhibitors and new lipid-modifying agents expand their new therapeutic target options in the field of medical profession. Statins have been described as the most effective class of drugs to reduce serum cholesterol levels. Since the discovery of the first statin nearly 30 years ago, these drugs have become the main therapeutic approach to lower cholesterol levels. The present scientific research demonstrates numerous non-lipid modifiable effects of statins termed as pleiotropic effects of statins, which could be beneficial for the treatment of various devastating disorders. The most important positive effects of statins are anti-inflammatory, anti-proliferative, antioxidant, immunomodulatory, neuroprotective, anti-diabetes, and antithrombotic, improving endothelial dysfunction and attenuating vascular remodeling besides many others which are discussed under the scope of this review. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil-containing protein kinase (ROCK), and their agonistic action on peroxisome proliferator-activated receptors (PPARs) can be viewed as the principle mechanisms underlying the pleiotropic effects of statins. With gradually increasing knowledge of new therapeutic targets of statins, their use has also been advocated in chronic inflammatory disorders for example rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE). In the scope of review, we highlight statins and their pleiotropic effects with reference to their harmful and beneficial effects as a novel approach for their use in the treatment of devastating disorders. Graphical abstract Pleiotropic effect of statins.

Effect of pioglitazone on the abrogated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart.

OBJECTIVES: The signaling pathways upstream of glycogen synthase kinase-3ß (GSK-3ß) get reduced during ischemic preconditioning (IPC) in hyperlipidemic rat heart. Pioglitazone, an insulin sensitizer, exerts cardioprotection through GSK-3ß. The objective of the study is to investigate the role of pioglitazone on the attenuated cardioprotective effect of IPC in hyperlipidemic rat heart. MATERIALS AND METHODS: The rats were administered high-fat diet for 8 weeks to induce experimental hyperlipidemia (HL). After mounting on a Langendorff apparatus, isolated perfused hearts were given four cycles of IPC; each consists of 5 min of both ischemia and reperfusion followed by 30 min of ischemia and 120 min of reperfusion. Insulin (50 mU/ml) was perfused alone and in combination with pioglitazone (2 µM), while in other groups, this combination was repeated with wortmannin (100 nM), a selective PI3K inhibitor and rapamycin (1 nM), a selective mammalian target of rapamycin (mTOR) inhibitor, separately, and in combination. Myocardial injury was assessed by measuring infarct size and the levels of creatinine kinase-myocardial band (CK-MB) and lactate dehydrogenase (LDH) in the coronary effluent. RESULTS: IPC significantly decreased the infarct size and levels of LDH and CK-MB in normal but not in HL rat heart. Perfusion of insulin along with pioglitazone significantly reduced the infarct size and release of CK-MB and LDH in IPC-treated HL rat hearts. Perfusion of wortmannin or rapamycin alone significantly and in combination almost completely abolished the pioglitazone-induced restored cardioprotection (P < 0.05). CONCLUSION: Cardioprotective effect of IPC gets lost in hyperlipidemic rat heart. The results suggest that perfusion of pioglitazone restored the cardioprotective effect of IPC in hyperlipidemic rat heart, an effect that may be via PI3K and mTOR.

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.

Simian immunodeficiency virus infection via amniotic fluid: a model to study fetal immunopathogenesis and prophylaxis.

The rising prevalence of infection with the human immunodeficiency virus type 1 (HIV-1) in young women will increase the number of infected children worldwide. Because HIV-1 seems to be transmitted mostly intrapartum, fetal infection probably occurs mainly via skin or mucous membrane exposure. A model for this route of fetal infection has been established in primates. After injecting the simian immunodeficiency virus (SIV) into amniotic fluid during late gestation, six of seven rhesus monkeys were born infected. All infected neonates were viable and showed signs of disease, such as low birth weights, lymphadenopathy, and rashes. Cytotoxic T-cell responses to SIV were absent in neonates, but present in mothers. The high fetal infection rate allows studies of lentiviral immunopathogenesis during ontogeny and the development of strategies to prevent maternal HIV-1 transmission.

Development of antiviral treatment strategies in murine models.

Murine models with type C murine leukemia viruses have been used to develop major new prophylactic and therapeutic strategies in vaccination, drug therapy of acute virus exposure and chronic viremia, combination therapy, prevention of maternal transmission, and therapy targeted to the central nervous system. Transgenic mice expressing either the whole human immunodeficiency virus type 1 (HIV-1) provirus or subgenomic sequences allow the in vivo analysis of selected HIV-1 functions. The full replicative cycle of HIV-1 can be studied in human/mouse chimerae which were created by transplanting human hematolymphoid cells into SCID mice. The chimeric SCID mouse models have been used successfully to evaluate anti-HIV-1 drugs. The role of the various murine retrovirus systems in the development of anti-HIV-1 and anti-AIDS therapies is summarized.

Effect of peripheral administration of cinnarizine and verapamil on the abstinence syndrome in diazepam-dependent rats.

The effects of two calcium channel blockers (verapamil and cinnarizine) were evaluated on diazepam withdrawal symptoms. Rats were made diazepam dependent by chronic treatment with daily injections of the drug, 20 mg/kg IP for 3 weeks. On abrupt termination of the drug, animals showed withdrawal hyperactivity that was assessed by autonomic, behavioural and motor signs. The peak effect was seen 3 days after the withdrawal of diazepam. On IP administration, verapamil and cinnarizine (10, 20 and 40 mg/kg) given on eight occasions at an interval of 12 h reversed the withdrawal-induced increase in spontaneous motor activity. Cinnarizine in higher doses (20 and 40 mg/kg) was found to be effective in suppressing the behavioural signs but verapamil did not show any protective effect against startle response and irritability. These results suggest that modulation of the calcium influx in the CNS might influence withdrawal.