Therapeutic Drug Monitoring of Voriconazole in Children with Hematologic Malignancy and Invasive Fungal Infections: An RCT from a Tertiary Care Centre in India.

INTRODUCTION: Voriconazole is a triazole anti-fungal with non-linear kinetics and a narrow therapeutic range. The objective of our study was to monitor the voriconazole serum levels in children with hematological malignancy and clinically suspected invasive fungal infections. METHODS: The study was a prospective, randomized controlled trial conducted from June 2016 to December 2017. All children who had haematologic malignancies with clinically suspected invasive fungal infections and received voriconazole as the only anti-fungal were included in the study. The children were randomly allotted into two groups; one was the group that underwent TDM, and the other, TDM, was not done. Bioassay was the method employed for TDM. The trough levels were evaluated on a sample obtained on the fifth day of starting the drug. The institute's ethics committee approved the study. RESULT: A total of 30 children were included in the study: 15 in the TDM group and 15 in the non-TDM group. The most common underlying malignancy was AML. Neutropenia due to chemotherapy sessions was these patients' most common risk factor. A favorable outcome was seen in 13/15 (86.7%) in the TDM group and 11/15 in the non-TDM group (73.3%). CONCLUSION: Only five out of 15 (33.3%) children had voriconazole serum levels within the therapeutic range. Alterations in dose had to be done in the remaining to achieve the recommended serum levels. Thus, we recommend TDM for all children of hematologic malignancy receiving voriconazole for better management. Our findings also revealed that children with AML had lower than recommended levels of voriconazole on TDM evaluation, whereas those with ALL had normal to elevated levels of voriconazole.

Tideglusib Ameliorates Ischemia/Reperfusion Damage by Inhibiting GSK-3ß and Apoptosis in Rat Model of Ischemic Stroke.

OBJECTIVES: Glycogen synthase kinase-3ß (GSK-3ß), a serine/threonine protein kinase, gets activated and worsen stroke outcome after ischemia/reperfusion (I/R) injury by inducing inflammation and apoptosis. In this study, tideglusib, a selective irreversible and non-ATP competitive inhibitor of GSK-3ß, was explored in cerebral I/R damage using middle cerebral artery occlusion (MCAo) model in rats. MATERIALS AND METHODS: MCAo was done for 90 min in male Wistar rats (250-280 g) using doccol suture. In pre-treatment group, tideglusib (50 mg/kg) was administered once daily for 2 days and on the day of surgery, 30 min before MCAo. Next day, rats were examined for neurobehavioral parameters and MRI was performed to assess brain damage. In post-treatment group, tideglusib was started at 30 min after MCAo and continued for the next 2 days. After 72 h of MCAo, behavioral parameters and brain damage by MRI were assessed. Further, oxidative stress markers (MDA and GSH), inflammatory cytokines (TNF-α, IL-1ß and IL-10) and expression levels of pGSK-3ß S9, Bcl-2 and Bax were estimated in pre-treatment group. RESULTS: Tideglusib pre-treatment but not post-treatment significantly improved neurobehavioral parameters (p < 0.05) and reduced brain damage (p < 0.01) when compared with MCAo group. I/R induced changes in MDA (p < 0.01), TNF-α and IL-1ß (p < 0.05) were significantly attenuated by pre-treatment. Further, tideglusib pre-treatment ameliorated MCAo induced altered expressions of pGSK-3ß S9, Bcl-2 and Bax. CONCLUSION: The results of our exploratory study indicated prophylactic potential of tideglusib in I/R injury by modulating pGSK-3ß S9, apoptosis and neuro-inflammation.

Dihydromyricetin alleviates cerebral ischemia-reperfusion injury by attenuating apoptosis and astrogliosis in peri-infarct cortex.

OBJECTIVES: In ischemic stroke, reperfusion after thrombolysis is associated with secondary brain damage. Dihydromyricetin (DHM), a flavonoid, has shown neuroprotective effects through anti-oxidant, anti-inflammatory and anti-apoptotic properties. This study investigates the potential of DHM, given postreperfusion in middle cerebral artery occlusion (MCAo) model of stroke in rats. METHODS: MCAo surgery was performed in male Wistar rats. Reperfusion was performed after 90 min of ischemia. DHM (50 and 100 mg/kg) was administered 10-15 min and 2 h postreperfusion followed by daily dosing for 2 more days. Neurobehavioral parameters and infarct size (TTC staining) were assessed after 72 h. The effective dose (100 mg/kg) was then used to study reduction in infarct size (measured by MRI) and effect on apoptosis (evaluated by protein expression of Bax, Bcl-2 and cleaved caspase-3 and TUNEL assay) in peri-infarct cortex. Furthermore, effects of DHM on neuronal damage and activation of astrocytes were studied by immunofluorescence. RESULTS: Poststroke DHM (100 mg/kg) administered for 3 days showed significant improvements in motor-coordination and infarct damage (TTC staining and MRI). MCAo-induced altered apoptotic proteins were normalized to a significant extent in peri-infarct cortex with DHM treatment. Data from TUNEL assay were complementary to the effects on apoptotic proteins. Additionally, DHM caused a significant reduction in the number of reactive astrocytes when compared with the MCAo group. DISCUSSION: This study demonstrated the efficacy of subacute DHM treatment in ischemia/reperfusion injury by modulating apoptosis and astrogliosis in the peri-infarct cortex. This suggests the potential of DHM in attenuating disease progression.

Antibody-drug conjugates, cancer immunotherapy, and metronomic chemotherapy as novel approaches in cancer management.

Treatment of cancer is a major challenge even though the pathophysiology is becoming clearer with time. A number of new chemical entities are developed to target cancer growth inhibition, but the targeted delivery of these products still needs novel research. This is of utmost importance not only for higher efficacy but also for a reduction in systemic toxicity and cost of treatment. Although multiple novel targets and molecules are being researched, most of them could not pass the regulatory approval process, due to low benefit-risk ratio and lack of target specificity. Failure of a majority of these drugs was in part due to their superiority claimed via surrogate markers. Despite these, currently, more than 100 chemotherapeutic agents are in practice. This review paper discusses in detail the molecular basis, drug discovery, and pros and cons over conventional treatment approaches of three novel approaches in cancer therapy, i.e., (i) antibody-drug conjugates, (ii) cancer immunotherapy, and (iii) metronomic chemotherapy. All the drugs developed using these three novel approaches were compared against the established treatment regimens in clinical trials with clinical end points, such as overall survival, progression-free survival, and quality of life.

Panchagavya Ghrita, an Ayurvedic formulation attenuates seizures, cognitive impairment and oxidative stress in pentylenetetrazole induced seizures in rats.

Panchagavya Ghrita (PG), according to Ayurvedic formulary of India (AFI), is used to treat epilepsy (apasmara), fever (jvara), mania (unmade) and jaundice (kamala). In the present study, we examined its effect on convulsions, oxidative stress and cognitive impairment in pentylenetetrazole (PTZ) induced seizures in rats. PG @ 250, 500, 1000, 2000 and 4000 mg/kg was administered orally for 7 days to male Wistar rats. On day 7, PTZ (60 mg/kg) was injected intraperitoneally 2 h after the last dose of PG. Sodium valproate (300 mg/kg) was used as positive control. Latency to myoclonic jerks, clonus and generalized tonic clonic seizures (GTCS) were recorded for seizure severity. Cognitive impairment was assessed using elevated plus maze and passive avoidance tests. Malondialdehyde and reduced glutathione levels were measured in rat brain. The results have shown that pretreatment with PG @ 500, 1000, 2000 and 4000 mg/kg exhibited 16.6, 33.3, 50 and 100% protection against occurrence of GTCS. The pretreatment with PG has significantly improved cognitive functions and the oxidative stress induced by seizures demonstrating its protective effect against PTZ induced seizures, and further, use of PG as an anticonvulsant in Ayurvedic system of medicine.

Protective effect of thymoquinone against high-fructose diet-induced metabolic syndrome in rats.

PURPOSE: Thymoquinone (TQ), a bioactive constituent of Nigella sativa (Linn.) seed, which is commonly used as a spice in Asian food, has been reported to possess a wide range of biological effects. The present study evaluated the effect of TQ on high-fructose diet (HFD)-induced metabolic syndrome (MetS) in male Wistar rats. METHODS: MetS was induced by 60% HFD over 42 days. TQ (25, 50 and 100 mg/kg, p.o. once daily) was administered along with HFD for 42 days. Pioglitazone (10 mg/kg, p.o. once daily) was used as a standard drug. Plasma glucose, triglycerides, total cholesterol and HDL-cholesterol were estimated on days 0 and 42. Change in blood pressure, oral glucose tolerance and insulin resistance were measured. Hepatic thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase levels were estimated as measures of hepatic oxidative stress. Hepatic mRNA of PPAR-α and PPAR-γ was also studied. RESULTS: TQ prevented the characteristic features of HFD-induced MetS, such as hyperglycaemia, hypertriglyceridemia, hypercholesterolaemia and elevated systolic blood pressure. TQ also prevented impaired glucose tolerance and insulin resistance. It also ameliorated HFD-induced increase in hepatic TBARS and depletion of SOD, catalase and GSH. TQ prevented reduction in hepatic mRNA of PPAR-α and PPAR-γ in HFD rats, and the effects were comparable to those of pioglitazone. CONCLUSIONS: This study demonstrates protective effect of TQ against HFD-induced MetS on rats which might have been mediated via PPAR mechanism.

Effect of Anacyclus pyrethrum on pentylenetetrazole-induced kindling, spatial memory, oxidative stress and rho-kinase II expression in mice.

Anacyclus pyrethrum (A. pyrethrum) has been reported to exhibit anticonvulsant activity. In the present study, the effect of hydro-alcoholic extract of A. pyrethrum root (HEAP) on pentylenetetrazole (PTZ) induced kindling, spatial memory, oxidative stress and rho kinase (ROCK II) was assessed. Male albino mice (25-30 g) were used in the study. PTZ (35 mg/kg, i.p. on alternate days) was injected to induce kindling and PTZ (70 mg/kg, i.p) challenge was given 7 days post-kindling. HEAP was administered orally daily in the doses of 100, 250 and 500 mg/kg along with PTZ injections during the kindling process and continued till PTZ challenge post kindling. Spatial memory was assessed using Morris water maze test. Oxidative stress parameters [malondialdehyde (MDA) and reduced glutathione (GSH)] and ROCK II expression were estimated in whole brain at the end of the study. Pre-treatment with HEAP (250 and 500 mg/kg) showed significant increase in the myoclonic jerk latency and delay in the development of kindling. A significant decrease in mortality was observed at higher doses of HEAP (250 and 500 mg/kg). Pre-treatment with HEAP significantly increased the number of platform crossings and decreased the escape latency, as opposed to the PTZ group, thus showing protection against memory deficit. HEAP pre-treatment also attenuated the oxidative stress induced by PTZ kindling. PTZ induced kindling increased the ROCK II expression whereas, HEAP pre-treatment attenuated the increase in ROCK II expression. To conclude, HEAP pre-treatment showed antiepileptic effect and also showed protection against cognitive impairment by decreasing oxidative stress and ROCK II expression in PTZ kindled mice.

Interaction profile of Zizyphus jujuba with phenytoin, phenobarbitone, and carbamazepine in maximal electroshock-induced seizures in rats.

The antiepileptic effect of hydroalcoholic extract of Zizyphus jujuba (HEZJ) in experimental seizures was demonstrated earlier. The present study aimed to evaluate the pharmacokinetic and pharmacodynamic interactions of HEZJ with phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) in maximal electroshock (MES)-induced seizures in male Wistar rats. Maximal electroshock (70 mA, 9 ms pulse width, 0.2 s) was used to induce seizures. Blood samples were collected at two time points for estimation of serum PHT, PB, and CBZ levels using high-pressure liquid chromatography (HPLC). Co-administration of HEZJ with the sub-therapeutic doses of PHT, PB, and CBZ exhibited 66.7, 66.7, and 50.0% protection against tonic hind limb extension as compared to 33.3, 33.3, and 50% protection respectively, in the groups treated with PHT, PB, and CBZ alone in their sub-therapeutic doses. Co-administration of HEZJ with the sub-therapeutic doses of these antiepileptic drugs (AEDs) showed significant improvement in cognitive functions as compared to MES group as well as these AEDs alone. A significant increase in glutathione levels and decrease in malondialdehyde levels were observed with pretreatment of HEZJ with the sub-therapeutic doses of these AEDs. Co-administration of HEZJ with PHT, PB, and CBZ did not cause any significant changes in the serum concentrations of these AEDs. The results of the present study indicate that the co-administration of HEZJ with sub-therapeutic doses of PHT and PB potentiated the antiepileptic effect of PHT and PB in MES-induced seizures with no change found in the antiepileptic effect of CBZ.

Antinociceptive effect of intrathecal loperamide: role of mu-opioid receptor and calcium channels.

Morphine is a gold standard analgesic commonly used to alleviate pain. However, its use is associated with unavoidable side effects including the risk for addiction. Peripherally administered loperamide lacks effect on the central nervous system as it is a substrate for the permeability glycoprotein (P-gp) efflux pump which blocks its entry into brain. However, when administered intrathecally, loperamide has been reported to produce analgesia. The present study investigates the mechanism of the central analgesic effect of loperamide. Adult male Sprague-Dawley rats were subjected to surgery for catheter placement. Following baseline testing, different groups of rats were administered fixed intrathecal doses (1 µg, 3 µg, 10 µg and 30 µg) of loperamide and morphine. Analgesia was compared employing Hargreaves paw withdrawal apparatus at 15 min, 30 min, 60 min, 90 min and 120 min. Additionally, CTOP, a specific mu-opioid receptor antagonist was co-administered with loperamide to examine the mu-opioid receptor mediated loperamide analgesia. Furthermore, nefiracetam, a calcium channel opener, was co-administered with loperamide or morphine to evaluate the involvement of Ca(2+) channels in Loperamide showed an analgesic effect which was comparable to morphine. However, loperamide produced longer analgesia and the analgesic effect was significantly better at 42 h and 49 h compared to morphine. CTOP completely reversed loperamide analgesia. Though nefiracetam significantly reversed loperamide analgesia, it did not have any effect on morphine induced analgesia. Our findings suggest that loperamide administered intrathecally produces analgesia which is mediated through mu-opioid receptor and subsequent blockade of downstream calcium channels.

Neuroimaging, biochemical and cellular evidence of protection by mycophenolate mofetil on middle cerebral artery occlusion induced injury in rats.

Stroke is a major cause of mortality and disability worldwide. Presently, recombinant tissue plasminogen activator is the only approved drug for the management of acute ischemic stroke. However, it has limitations like narrow therapeutic window and increased risk of intracranial hemorrhage. In previous studies, immunosuppressive agents such as cyclosporine A and tacrolimus have shown neuroprotection by improving neurological functions and infarct volume in models of ischemic stroke. Therefore, the present study was designed to evaluate the effect of mycophenolate mofetil (MMF) on the cerebral ischemic injury in the middle cerebral artery occlusion (MCAo) model in rats. MCAo was carried out in male Wistar rats by inserting an intraluminal thread. One hour after MCAo, the animals were treated with MMF (50, 100, 200mg/kg, i.p.). Reperfusion was done after 2h of occlusion. Thirty minutes after reperfusion, animals were subjected to diffusion-weighted magnetic resonance imaging for assessment of neuroprotective effect of MMF. Twenty four hours after MCAo, motor performance was assessed and the animals were euthanized for estimation of brain malondialdehyde, glutathione, myeloperoxidase and nitric oxide levels. The effect of MMF on apoptosis was also evaluated. MMF significantly attenuated the percent infarct area, apparent diffusion coefficient and signal intensity as compared to a vehicle treated group. Treatment with MMF prevented the motor impairment and significantly reversed the changes in levels of malondialdehyde, glutathione, myeloperoxidase and nitric oxide. MMF treatment significantly reduced the apoptosis. Data of the present study indicate neuroprotective effect of MMF in the experimental model of ischemic stroke.

A pilot study on area under curve of mycophenolic acid as a guide for its optimal use in renal transplant recipients.

BACKGROUND & OBJECTIVES: The immunosuppressants administered to renal transplant subjects are usually monitored therapeutically to prevent graft rejection and drug toxicity. Mycophenolic acid (MPA) is an immunosuppressant. The present prospective study was undertaken to establish the utility of plasma level monitoring of MPA and to correlate it with clinical outcomes in renal transplant receipients. METHODS: MPA plasma level at 2, 4 and 9 h and the area under concentration-time curve (AUC) were estimated using high performance liquid chromatography in 24 renal transplant recipients receiving immunosuppressant MPA plus tacrolimus and steroid. RESULTS: There was wide inter-individual variation in MPA plasma level and the AUC. The incidences of gastrointestinal adverse drug events (diarrhoea and acidity) were significantly more in the high MPA AUC patients. Though biopsy proven acute rejection was not found, of the six subjects with lower MPA AUC (<30 mg.h/l), three were clinically diagnosed to develop tacrolimus nephrotoxicity. The Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI) scores represented better health related quality of life in lower MPA AUC than in the higher MPA AUC (>60 mg.h/l). INTERPRETATION & CONCLUSIONS: The present findings suggest the MPA AUC of 30 - 60 mg.h/l in the maintenance stage of renal transplant patients to have optimum clinical benefit and relegated adverse events profile indicating the usefulness of AUC of MPA with limited sampling strategy in optimizing its use.

Root extract of Anacyclus pyrethrum ameliorates seizures, seizure-induced oxidative stress and cognitive impairment in experimental animals.

In Ayurveda, Anacyclus pyrethrum has been used as a brain tonic. The present study evaluates the effect of hydroalcoholic extract of A. pyrethrum (HEAP) root against seizures, seizure-induced oxidative stress and cognitive impairment in experimental models of seizures. Male Wistar rats were used in the study. HEAP was administered in doses of 50, 100, 250, 500 in pentylenetetrazole (PTZ) model and 250, 500 and 1000 mg/kg in maximal electroshock (MES) model. Myoclonic jerk latency and generalized tonic clonic seizures (GTCS) were noted in PTZ whereas occurrence of tonic hind limb extension (THLE) was observed in MES seizures. Cognitive deficit was assessed using elevated plus maze and passive avoidance tests. Whole brain reduced glutathione, malondialdehyde levels and cholinesterase activity were measured. HEAP showed 50, 66.7, 83.3 and 100% protection at 50,100, 250 and 500 mg/kg, respectively against GTCS in PTZ induced seizures. In MES induced seizures, HEAP produced 16.7, 33.3 and 50% protection against THLE at 250, 500 and 1000 mg/kg, respectively. HEAP administration significantly prevented seizure induced oxidative stress and cognitive impairment in a dose-dependent manner. HEAP also normalized the decrease in cholinesterase activity caused by seizures. Thus, HEAP showed protective effect against seizures, seizure-induced oxidative stress and cognitive impairment in rats.

Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats.

Stroke is a major cause of mortality and disability. The management with thrombolytic therapy has to be initiated within 3-4 h and is associated with limitations like increased risk of intracranial hemorrhage and progression of cerebral injury. Immunophilin inhibitors such as cyclosporine A and tacrolimus have been shown to afford neuroprotection by improving neurological functions and infarct volume in models of ischemic stroke. In the present study, the effect of rapamycin in middle cerebral artery occlusion (MCAo) model of ischemic stroke was evaluated. Ischemic stroke was induced in rats by occluding the MCA using the intraluminal thread. After 1 h of MCAo, animals were administered rapamycin (50, 150, 250 µg/kg, i.p.). After 2 h of occlusion, reperfusion was done. Thirty minutes after reperfusion, animals were subjected to diffusion-weighted magnetic resonance imaging for assessment of protective effect of rapamycin. Twenty-four hours after MCAo, motor performance was assessed, the animals were euthanized and the brains were removed for estimation of malondialdehyde, glutathione, nitric oxide and myeloperoxidase. Significant improvement was observed with rapamycin 150 and 250 µg/kg in percent infarct area, apparent diffusion coefficient and signal intensity as compared to vehicle treated group. Rapamycin treatment ameliorated motor impairment associated with MCAo and significantly reversed the changes in levels of malondialdehyde, glutathione, nitric oxide and myeloperoxidase. The results of the present study indicate neuroprotective effect of rapamycin in MCAo model of stroke. Therefore, rapamycin might be considered as a therapeutic strategy for stroke management.

Gaso-transmitter hydrogen sulphide: potential new target in pharmacotherapy.

Research in the last two decades has transformed the way hydrogen sulphide (H2S) is perceived from a noxious gas to a gaso-transmitter with a vast potential in pharmacotherapy. H2S is synthesized in various body-systems using the enzymes cystathionine beta-synthase and cystathionine gamma-lyase; either of these being the predominat enzyme in a particular system. H2S may be one of the physiological modulators of blood pressure in humans. The gas relaxes the vascular smooth muscle cells by opening up K(ATP) channels. Moreover, it suppresses the proliferation of vascular smooth muscle cells. H2S may also be contributing in the protection afforded by ischaemia-preconditioning. Testosterone is thought to be responsible for the higher central nervous system level of H2S in males. In the central nervous system, H2S is implicated in Alzheimer's disease, epilepsy, stroke and Down's syndrome. Insulin secretion is associated with a decrease in the H2S levels. Raised H2S is detrimental in acute pancreatitis as well as in septic shock. Recently, H2S-releasing derivatives of certain drugs have shown promise in protection against gastric ulcer and in inflammatory bowel disease. The beneficial effects of certain sulphur containing herbs like ginseng and garlic may be mediated via H2S. In future, development of specific drugs modulating H2S levels may prove beneficial in varied disorders.

Protective effect of curcumin against seizures and cognitive impairment in a pentylenetetrazole-kindled epileptic rat model.

AIM: Epilepsy as well as chronic use of most antiepileptic drugs predisposes to cognitive impairment. Curcumin has been reported to possess antioxidant, anticonvulsant as well as neuroprotective potential. Hence, this study was conducted to evaluate the effect of curcumin against seizures, cognitive impairment and oxidative stress in pentylenetetrazole-induced kindling in rats. MAIN METHODS: The effect of pretreatment with curcumin (100, 200 and 300 mg/kg, orally) on pentylenetetrazole (PTZ)-induced kindling, kindling-induced cognitive impairment and oxidative stress was evaluated. Male Wistar rats were injected PTZ (30 mg/kg, i.p.) once every alternate day (48±1h) until the development of kindling. Cognitive impairment was assessed using elevated plus maze and passive avoidance test while the oxidative stress parameters (malondialdehyde and glutathione) were estimated in the whole brain at the end of experiments. KEY FINDINGS: PTZ, 30 mg/kg, induced kindling in rats after 31.0±1.4 days. Curcumin showed dose-dependent anti-seizure effect. Curcumin (300 mg/kg) significantly increased the latency to myoclonic jerks, clonic seizures as well as generalized tonic-clonic seizures, improved the seizure score and decreased the number of myoclonic jerks. PTZ kindling induced a significant oxidative stress and cognitive impairment which was reversed by pretreatment with curcumin in a dose-dependent manner. SIGNIFICANCE: The results indicate that pretreatment with curcumin ameliorates seizures, oxidative stress and cognitive impairment in PTZ induced kindling in rats. These results thus suggest the potential of curcumin as an adjuvant in epilepsy both to prevent seizures as well as to protect against seizure induced memory impairment.

Protective effect of mycophenolate mofetil on mercuric chloride-induced nephrotoxicity in rats.

In the present study the effect of mycophenolate mofetil (MMF), an immunosuppressant, on mercuric chloride (HgCl(2))-induced nephrotoxicity in male Wistar rats was investigated. Animals (200-250 g) were divided into five groups and were subjected to a 6-day treatment schedule. The first (control) group received only vehicle without any active drug. The second to fifth groups were administered HgCl(2) challenge (single dose of 5 mg/kg, s.c.) on the fourth day. Additionally, the second group received distilled water (DW) on all 6 days and the third group was administered DW the initial 3 days and MMF (10 mg/kg b.i.d. by oral gavage) on days 4-6. The fourth group was given DW the initial 2 days and MMF on days 3-6 and the fifth group received MMF all 6 days. All animals were euthanized on the sixth day. It was found that HgCl(2) administration caused significant nephrotoxicity, as indicated by a rise in serum creatinine, blood urea and soluble intercellular adhesion molecule 1 (sICAM-1) concentrations, histopathological injury and increased oxidative stress (altered malondialdehyde and glutathione levels) as compared to the control group. Administration of MMF significantly ameliorated HgCl(2)-induced nephrotoxicity. The results suggest the potential of MMF in preventing the acute nephrotoxicity of HgCl(2).

Curcumin is protective against phenytoin-induced cognitive impairment and oxidative stress in rats.

The present study investigates the effect of chronic curcumin administration on phenytoin-induced cognitive impairment and oxidative stress in rats. Male Wistar rats were administered drugs/vehicle for 21 days. Learning and memory was evaluated using the passive avoidance paradigm and the elevated plus maze. On day 21, serum phenytoin concentrations and whole brain malondialdehyde (MDA) and glutathione (GSH) levels were estimated. Phenytoin (75 mg/kg, i.p.) produced significant deficits in learning/memory as indicated by the significant increase in retention transfer latency in elevated plus maze test and a significant decrease in retention latency in the passive avoidance paradigm. Chronic administration of phenytoin also produced significant elevations in brain MDA and reduction of brain GSH levels. Curcumin (100, 200 and 300 mg/kg, orally), when administered with phenytoin, significantly prevented phenytoin-induced cognitive impairment and oxidative stress in a dose-dependent manner. There were no significant differences in the serum levels of phenytoin in any of the treatment groups. This study demonstrates that curcumin is effective in preventing phenytoin-induced cognitive impairment and oxidative stress in rats without altering the serum phenytoin levels. This suggests the potential of adjuvant curcumin therapy in ameliorating cognitive impairment caused by chronic phenytoin therapy.

Attenuation of the effect of lindane on immune responses and oxidative stress by Ocimum sanctum seed oil (OSSO) in rats.

Present study was done to evaluate the effect of Ocimum sanctum seed oil (OSSO) on the immunotoxicity and oxidative activity of lindane in rats. Rats were divided into four groups (n = 8) and were treated with lindane (10 mg/kg, po) and/or OSSO (1 mg/kg, po) during the study period. Humoral immunity was assessed by measuring haemagglutination titre to sheep red blood cells (SRBC) and delayed type hypersensitivity (DTH) was assessed by measuring foot pad thickness. Lindane showed significant decrease in anti-SRBC antibody titre and also decreased percentage change in foot pad thickness in DTH response as compared to control group. OSSO per se produced significant increase in anti-SRBC antibody titre, but did not produce significant change in the foot pad thickness as compared to control group. However, it significantly antagonized the effect of lindane on the anti-SRBC antibody titre and foot pad thickness parameters. Lindane produced oxidative stress as indicated by increase in the levels of MDA and decrease in GSH levels. Treatment with OSSO per se showed antioxidant activity and also reversed the oxidative stress produced by lindane. The results suggest that OSSO can attenuate the immunotoxicity and oxidative stress produced by lindane.