The paradox of tPA in ischemic stroke: tPA knockdown following recanalization improves functional and histological outcomes.

Previous studies have demonstrated that endogenous tissue-type plasminogen activator (tPA) is upregulated in the brain after an acute ischemic stroke (AIS). While mixed results were observed in genetic models, the pharmacological inhibition of endogenous tPA showed beneficial effects. Treatment with exogenous recombinant tPA exacerbated brain damage in rodent models of stroke. Despite the detrimental effects of tPA in ischemic stroke, recombinant tPA is administered to AIS patients to recanalize the occluded blood vessels because the benefits of its administration outweigh the risks associated with tPA upregulation and increased activity. We hypothesized that tPA knockdown following recanalization would ameliorate sensorimotor deficits and reduce brain injury. Young male and female rats (2-3 months old) were subjected to transient focal cerebral ischemia by occlusion of the right middle cerebral artery. Shortly after reperfusion, rats from appropriate cohorts were administered a nanoparticle formulation containing tPA shRNA or control shRNA plasmids (1 mg/kg) intravenously via the tail vein. Infarct volume during acute and chronic phases, expression of matrix metalloproteinases (MMPs) 1, 3, and 9, enlargement of cerebral ventricle volume, and white matter damage were all reduced by shRNA-mediated gene silencing of tPA following reperfusion. Additionally, recovery of somatosensory and motor functions was improved. In conclusion, our results provide evidence that reducing endogenous tPA following recanalization improves functional outcomes and reduces post-stroke brain damage.

Tangeretin confers neuroprotection, cognitive and memory enhancement in global cerebral ischemia in rats.

Global cerebral ischemia is commonly associated with neurological deficits, including cognitive and memory impairments. The present study aims to investigate the neuroprotective, cognitive, and memory enhancement effects of Tangeretin, a flavonoid against global cerebral ischemia in rats. Bilateral common carotid artery occlusion (BCCAO) and reperfusion injury method was used to induce global cerebral ischemia in rats. Motor, cognitive, and memory functions were evaluated using rotarod, grip strength, Y-maze, and Morris water maze. Further, acetylcholine esterase (AchE) enzyme activity, acetylcholine (Ach), oxidative stress markers (ROS, SOD, MDA, and CAT), inflammation (IL-6 and TNF-α), and apoptotic markers (cytochrome C, caspase 9, and caspase 3) in BCCAO rats were measured following Tangeretin (5,10, and 20 mg/kg, oral) treatment. Our findings show that Tangeretin treatment significantly improved cognition and memory by enhancing Ach levels through the amelioration of AchE enzyme activity in BCCAO rats. Moreover, Tangeretin exhibited neuroprotective effects through the mitigation of oxidative stress, inflammation, and apoptosis in the BCCAO rats. In summary, the current findings suggested that Tangeretin exhibited neuroprotection, cognitive and memory enhancement against global cerebral ischemia.

The Impact of Social Isolation and Environmental Deprivation on Blood Pressure and Depression-Like Behavior in Young Male and Female Mice.

Background: Social isolation (SI) and loneliness are major adult and adolescent health concerns, particularly in the coronavirus disease 2019 (COVID-19) era. Recent prospective cohort studies indicate that older women who experienced both SI and loneliness had a significantly higher risk of cardiovascular disease (CVD). Hypertension, a well-established risk factor for CVD, is more prevalent in elderly women than men. Furthermore, a lack of social relationships is strongly associated with an increased risk of hypertension in middle-aged and elderly women compared to men. Although this has not been extensively studied, adolescents and young adults who experience loneliness or SI may also be at risk for CVD and depression. The purpose of this study was to examine the effect of SI on blood pressure and depression-like behavior in young male and female mice. Methods: Weaned C57BL/6 mice were randomly assigned (n = 6/group/sex) to either group housing (GH) or SI. Animals in the SI group were housed in individual cages for 8 weeks with no view of other animals. The cages were kept in ventilated racks to prevent pheromone exposure and socially isolated animals had no cage enrichment. Results: SI increased systolic, diastolic, and mean arterial blood pressure in females and elevated heart rate in both sexes. Body weight gain was dramatically increased in socially isolated females but tended to decrease in socially isolated males. In the forced swim test, which detects depression-like behavior, there was no difference between groups in total immobility time. The latency to immobility, however, was significantly decreased in socially isolated females. Serum concentrations of corticosterone and metanephrine did not differ between socially isolated and group-housed females, but corticosterone levels were significantly reduced in socially isolated males. Conclusions: Our results indicate that 8 weeks of SI leads to significant changes in blood pressure and heart rate and mild changes in depression-like behavior in young mice, with females affected more than males.

Tau trajectory in Alzheimer's disease: Evidence from the connectome-based computational models.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an impairment of cognition and memory. Current research on connectomics have now related changes in the network organization in AD to the patterns of accumulation and spread of amyloid and tau, providing insights into the neurobiological mechanisms of the disease. In addition, network analysis and modeling focus on particular use of graphs to provide intuition into key organizational principles of brain structure, that stipulate how neural activity propagates along structural connections. The utility of connectome-based computational models aids in early predicting, tracking the progression of biomarker-directed AD neuropathology. In this article, we present a short review of tau trajectory, the connectome changes in tau pathology, and the dependent recent connectome-based computational modelling approaches for tau spreading, reproducing pragmatic findings, and developing significant novel tau targeted therapies.

Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration.

We recently showed that the post-ischemic induction of matrix metalloproteinase-12 (MMP-12) in the brain degrades tight junction proteins, increases MMP-9 and TNFα expression, and contributes to the blood-brain barrier (BBB) disruption, apoptosis, demyelination, and infarct volume development. The objectives of this study were to (1) determine the effect of MMP-12 suppression by shRNA-mediated gene silencing on neurological/functional recovery, (2) establish the optimal timing of MMP-12shRNA treatment that provides maximum therapeutic benefit, (3) compare the effectiveness of acute versus chronic MMP-12 suppression, and (4) evaluate potential sex-related differences in treatment outcomes. Young male and female Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion and reperfusion. Cohorts of rats were administered either MMP-12shRNA or scrambled shRNA sequence (control) expressing plasmids (1 mg/kg; i.v.) formulated as nanoparticles. At designated time points after reperfusion, rats from various groups were subjected to a battery of neurological tests to assess their reflex, balance, sensory, and motor functions. Suppression of MMP-12 promoted the neurological recovery of stroke-induced male and female rats, although the effect was less apparent in females. Immediate treatment after reperfusion resulted in a better recovery of sensory and motor function than delayed treatments. Chronic MMP-12 suppression neither enhanced nor diminished the therapeutic effects of acute MMP-12 suppression, indicating that a single dose of plasmid may be sufficient. We conclude that suppressing MMP-12 after an ischemic stroke is a promising therapeutic strategy for promoting the recovery of neurological function.

The interplay between MMP-12 and t-PA in the brain after ischemic stroke.

Tissue-type plasminogen activator (t-PA) expression is known to increase following transient focal cerebral ischemia and reperfusion. Previously, we reported downregulation of t-PA upon suppression of matrix metalloproteinase-12 (MMP-12), following transient focal cerebral ischemia and reperfusion. We now present data on the temporal expression of t-PA in the brain after transient ischemia, as well as the interaction between MMP-12 and t-PA, two proteases associated with the breakdown of the blood-brain barrier (BBB) and ischemic brain damage. We hypothesized that there might be reciprocal interactions between MMP-12 and t-PA in the brain after ischemic stroke. This hypothesis was tested using shRNA-mediated gene silencing and computational modeling. Suppression of t-PA following transient ischemia and reperfusion in rats attenuated MMP-12 expression in the brain. The overall effect of t-PA shRNA administration was to attenuate the degradation of BBB tight junction protein claudin-5, diminish BBB disruption, and reduce neuroinflammation by decreasing the expression of the microglia/macrophage pro-inflammatory M1 phenotype (CD68, iNOS, IL-1ß, and TNFα). Reduced BBB disruption and subsequent lack of infiltration of macrophages (the main source of MMP-12 in the ischemic brain) could account for the decrease in MMP-12 expression after t-PA suppression. Computational modeling of in silico protein-protein interactions indicated that MMP-12 and t-PA may interact physically. Overall, our findings demonstrate that MMP-12 and t-PA interact directly or indirectly at multiple levels in the brain following an ischemic stroke. The present findings could be useful in the development of new pharmacotherapies for the treatment of stroke.

mTOR signaling as a molecular target for the alleviation of Alzheimer's disease pathogenesis.

Mechanistic/mammalian target of rapamycin (mTOR) belongs to the phosphatidylinositol kinase-related kinase (PIKK) family. mTOR signaling is required for the commencement of essential cell functions including autophagy. mTOR primarily governs cell growth in response to favourable nutrients and other growth stimuli. However, it also influences aging and other aspects of nutrient-related physiology such as protein synthesis, ribosome biogenesis, and cell proliferation in adults with very limited growth. The major processes for survival such as synaptic plasticity, memory storage and neuronal recovery involve a significant mTOR activity. mTOR dysregulation is becoming a prevalent motif in a variety of human diseases, including cancer, neurological disorders, and other metabolic syndromes. The use of rapamycin to prolong life in different animal models may be attributable to the multiple roles played by mTOR signaling in various processes involved in ageing, protein translation, autophagy, stem cell pool turnover, inflammation, and cellular senescence. mTOR activity was found to be altered in AD brains and rodent models, supporting the notion that aberrant mTOR activity is one of the key events contributing to the onset and progression of AD hallmarks This review assesses the molecular association between the mTOR signaling pathway and pathogenesis of Alzheimer's disease. The research data supporting this theme are also reviewed.

Potentiation of microglial endocannabinoid signaling alleviates neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) isaprogressive neurodegenerative disorder characterized by chronic inflammation due to the presence of neurotoxic Aß and tau proteins. Increased microglial activation and inflated immune response are the other factors to be considered in AD pathology. Microglial cells own biochemical machinery that synthesizes and release endocannabinoids. The exploitation of therapeutic actions of endocannabinoid system has newly emerged in the field of Alzheimer's disease. The activation of cannabinoid receptors/ cannabinoid system modulates inflammatory responses. This review assesses the association between the microglial endocannabinoid system and neuroinflammation in AD. The data supporting the anti-inflammatory role of pharmacological agents modulating cannabinoid system are also reviewed.

Granny Smith Apple Extract Lowers Inflammation and Improves Antioxidant Status in L-arginine-induced Exocrine Pancreatic Dysfunction in Rats

Objectives: Granny Smith is a cultivated hybrid variety of apple with a high antioxidant content relative to all other species of apple. Acute pancreatitis (AP) is an instantly emerging inflammatory condition with a high mortality rate. The preferred treatment is restricted to symptomatic relief and supportive care. The present study was undertaken to evaluate the favorable effects of Granny Smith apple extract (GSAE) as a prophylactic treatment for L-arginine-induced AP in rats. Materials and Methods: Male Sprague Dawley rats were divided in to five groups (n=6): Normal control (saline), disease control (a single dose of L-arginine 2.5 g/kg I.P.), positive control (pelatonin 10 mg/kg I.P.), and GSAE I and II (200 mg/kg and 400 mg/kg, orally, respectively). All groups were treated for 7 days. At the end of the study, blood samples were collected from the retro-orbital plexus, serum separated, and subjected to estimation of biomarker enzymes such as amylase, lipase, antioxidant enzymes, etc. The animals were then sacrificed, and the pancreas was isolated and subjected to estimation of tissue biomarkers, DNA fragmentation assay, and histopathological studies. Results: Serum levels of amylase and lipase were significantly (p<0.001) reduced in L-arginine-treated rats. Similar results were also observed with tissue inflammatory markers such as malondialdehyde, nitrate, etc. There was a dramatic increase (p<0.001) in the overall antioxidant enzyme levels when compared with disease control rats. Histopathological examination of pancreatic tissue showed an intact structural feature of acinar cells in the extract-treated group of rats, which was further in pact with the intact DNA found in the DNA fragmentation assay. Conclusion: Thus, GSAE treatment was found to be beneficial in lowering the inflammatory conditions of AP by improving the overall antioxidant levels, and a further investigation into its exact molecular mechanism is needed.

Stem cell treatment improves post stroke neurological outcomes: a comparative study in male and female rats.

BACKGROUND AND PURPOSE: The therapeutic potential of different stem cells for ischaemic stroke treatment is intriguing and somewhat controversial. Recent results from our laboratory have demonstrated the potential benefits of human umbilical cord blood-derived mesenchymal stem cells (MSC) in a rodent stroke model. We hypothesised that MSC treatment would effectively promote the recovery of sensory and motor function in both males and females, despite any apparent sex differences in post stroke brain injury. METHODS: Transient focal cerebral ischaemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery. Following the procedure, male and female rats of the untreated group were euthanised 1 day after reperfusion and their brains were used to estimate the resulting infarct volume and tissue swelling. Additional groups of stroke-induced male and female rats were treated with MSC or vehicle and were subsequently subjected to a battery of standard neurological/neurobehavioral tests (Modified Neurological Severity Score assessment, adhesive tape removal, beam walk and rotarod). The tests were administered at regular intervals (at days 1, 3, 5, 7 and 14) after reperfusion to determine the time course of neurological and functional recovery after stroke. RESULTS: The infarct volume and extent of swelling of the ischaemic brain were similar in males and females. Despite similar pathological stroke lesions, the clinical manifestations of stroke were more pronounced in males than females, as indicated by the neurological scores and other tests. MSC treatment significantly improved the recovery of sensory and motor function in both sexes, and it demonstrated efficacy in both moderate stroke (females) and severe stroke (males). CONCLUSIONS: Despite sex differences in the severity of post stroke outcomes, MSC treatment promoted the recovery of sensory and motor function in male and female rats, suggesting that it may be a promising treatment for stroke.

Attenuation of the Induction of TLRs 2 and 4 Mitigates Inflammation and Promotes Neurological Recovery After Focal Cerebral Ischemia.

The intense inflammatory response triggered in the brain after focal cerebral ischemia is detrimental. Recently, we showed that the suppression of toll-like receptors (TLRs) 2 and 4 attenuates infarct size and reduces the expression of pro-inflammatory cytokines in the ischemic brain. In this study, we further examined the effect of unsuppressed induction of TLRs 2 and 4 on the expression of its downstream signaling molecules and pro-inflammatory cytokines 1 week after reperfusion. The primary purpose of this study was to investigate the effect of simultaneous knockdown of TLRs 2 and 4 on M1/M2 microglial polarization dynamics and post-stroke neurological deficits and the recovery. Transient focal cerebral ischemia was induced in young adult male Sprague-Dawley rats by the middle cerebral artery occlusion (MCAO) procedure using a monofilament suture. Appropriate cohorts of rats were treated with a nanoparticle formulation of TLR2shRNA and TLR4shRNA (T2sh+T4sh) expressing plasmids (1 mg/kg each of T2sh and T4sh) or scrambled sequence inserted vector (vehicle control) expressing plasmids (2 mg/kg) intravenously via tail vein immediately after reperfusion. Animals from various cohorts were euthanized during reperfusion, and the ischemic brain tissue was isolated and utilized for PCR followed by agarose gel electrophoresis, real-time PCR, immunoblot, and immunofluorescence analysis. Appropriate groups were subjected to a battery of standard neurological tests at regular intervals until 14 days after reperfusion. The increased expression of both TLRs 2 and 4 and their downstream signaling molecules including the pro-inflammatory cytokines was observed even at 1-week after reperfusion. T2sh+T4sh treatment immediately after reperfusion attenuated the post-ischemic inflammation, preserved the motor function, and promoted recovery of the sensory and motor functions. We conclude that the post-ischemic induction of TLRs 2 and 4 persists for at least 7 days after reperfusion, contributes to the severity of acute inflammation, and impedes neurological recovery. Unlike previous studies in TLRs 2 or 4 knockout models, results of this study in a pharmacologically relevant preclinical rodent stroke model have translational significance.

Effect of Chrysin on Mechanical Hyperalgesia in Chronic Constriction Injury-Induced Neuropathic Pain in Rat Model.

OBJECTIVE: The present study aimed to assess the effect of Chrysin on mechanical hyperalgesia in chronic constriction injury (CCI)-induced neuropathic pain in Wistar rats. MATERIALS AND METHODS: Neuropathic pain was induced by CCI to the sciatic nerve in rats. Oral treatment of chrysin was given at doses of 50 mg/kg, 100 mg/kg, and 200 mg/kg in neuropathic rats. Mechanical hyperalgesia (in terms of paw withdrawal threshold [PWT]) was measured using Randall-Selitto analgesy-meter, and percent PWT was determined. Statistical analysis was carried out using GraphPad Prism 5 tool. RESULTS: In mechanical hyperalgesia test, treatment with chrysin 200 mg/kg, naive PWT, predose PWT, 0.5 h, 1 h, 2 h, and 4 h postdose PWT were found to be 141 ± 8.94 g, 60 ± 7.91 g, 107 ± 9.08 g, 113 ± 5.70 g, 106.0 ± 7.42 g, and 97 ± 9.08 g, respectively. The peak effect was observed at 2 h posttreatment for 50 mg and 100 mg while the peak effect for 200 mg was reached at 1 h, and the same was maintained till 2 h posttreatment. Chrysin 200 mg dose has shown maximal percent reversal (74%) at 2 h posttreatment. The percent reversal PWT of 50 mg/kg, 100 mg/kg, and 200 mg/kg at 2 h were 68%, 67%, and 74%, respectively. Chrysin has exhibited dose-dependent efficacy in CCI-induced neuropathic pain. In mechanical allodynia test, In chrysin (200 mg/kg) treatment group, naive PWT, predose PWT, 0.5 h, 1 h, 2 h, and 4 h postdose PWT were found to be 60.0 ± 0.0 g, 5.0 ± 1.10 g, 22.45 ± 6.62 g, 52.64 ± 18.29 g, 37.33 ± 17.56 g, and 29.83 ± 9.22 g, respectively. The percent reversal PWT of 50 mg/kg, 100 mg/kg, and 200 mg/kg at 2 h were 43%, 68%, and 87%, respectively. CONCLUSION: Chrysin attenuates neuropathic pain by ameliorating mechanical hyperalgesia and allodynia. Further studies are warranted to establish the mechanism.

A systematic review on hepatoprotective activity of quercetin against various drugs and toxic agents: Evidence from preclinical studies.

Quercetin is one of the most abundant flavonoids in human diet that has been reported to exhibit a wide range of pharmacological properties. The biochemical and molecular mechanisms involved in the hepatoprotective activity of quercetin were discussed in this review. Quercetin exhibited hepatoprotective activity against 2-butoxyethanol, acrylamide, acrylonitrile, aflatoxin B1, aroclor-1254, arsenic, sodium arsenite, azathioprine, cadmium chloride, carbon tetrachloride, chlorpyrifos, cyclosporine A, diazinon, dimethylnitrosamine, doxorubicin, epirubicin, ethanol, fenvalerate, isoniazide, rifampicin, lead acetate, lindane, D-galactosamine, methotrexate, methylmercury, nickel sulfate, paracetamol, perfluorooctanoic acid, polychlorinated biphenyls, pyrrolizidine alkaloid clivorine, rotenone, sodium fluoride, streptazotocin, tert-butyl hydroperoxide, thioacetamide, titanium dioxide, tumor necrosis factor-α, tripterygium glycoside, triptolide, ultraviolet A light, concavalin A, bisphenol, and ischemia-induced hepatotoxicity in various animal models due to its antioxidant, free radical-scavenging,anti-inflammatory, antiapoptotic, and cytochrome P450 2E1 (CYP2E1) inhibitory activities. In this review, we provide an overview of the possible mechanisms by which quercetin reduced the hepatotoxicity of different hepatotoxicants. This will help the toxicologists, pharmacologists, and chemists to develop new safer pharmaceutical products with quercetin and other hepatotoxicants.

Quercetin reduced the formation of N-acetyl-p-benzoquinoneimine, a toxic metabolite of paracetamol in rats and isolated rat hepatocytes.

N-acetyl-p-benzoquinoneimine (NAPQI) is toxic metabolite of paracetamol formed primarily by cytochrome P4502E1 (CYP2E1) metabolic pathway when administered at therapeutic doses or overdose. The influence of quercetin (flavonoid) on the bioactivation of paracetamol to NAPQI was investigated using rat liver microsomes and rats in vivo. Paracetamol (80 mg/kg) was administered orally without or with silymarin (100 mg/kg), a known inhibitor of CYP2E1, CYP3A4 and quercetin (10 and 20 mg/kg) to rats for 15 consecutive days. Area under the plasma concentration-time curve (AUC0-∞ ) and the peakplasma concentration (Cmax ) of paracetamol were dose-dependently increased with quercetin (10 and 20 mg/kg) compared to paracetamol control group (p < 0.001). On the other hand, the AUC0-∞ and Cmax of NAPQI were decreased significantly with quercetin. The same results were observed with silymarin also. The elevated liver and kidney functional enzymes/compounds were significantly reduced by quercetin and silymarin compared to paracetamol control group. The formation of NAPQI was reduced in the incubation samples in presence of quercetin in experiment using isolated rat hepatocytes. The presentstudy results revealed that quercetin might be inhibited the CYP2E1-mediated metabolism of paracetamol; thereby decreased the formation of NAPQI and protected the liver and kidney.

A comprehensive review on hepatoprotective and nephroprotective activities of chrysin against various drugs and toxic agents.

Chrysin belongs to the flavonoids and has been used as traditional medicine from ancient and has been reported to exhibit a wide range of pharmacological properties. The biochemical and molecular mechanisms involved in the hepato- and nephroprotective activities of chrysin were discussed in this review. Chrysin exhibited hepatoprotective activity against 2,3,7,8-tetrachlorodibenzo-p-dioxin, carbon tetrachloride, cisplatin, d-galactosamine, doxorubicin, ethanol, lipopolysaccharide/d-galactosamine, methotrexate, ammonium chloride, paracetamol, diethylnitrosamine, streptozotocin, tert-butyl hydroperoxide, thioacetamide, 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), ischemia/reperfusion-induced hepatotoxicity and nephroprotective activity against cisplatin, doxorubicin, paracetamol, gentamicin, streptazotocin, N-nitrosodiethyl amine, 5-fluorouracil, adenine, carbon tetrachloride, copper, 2,3,7,8-tetrachlorodibenzo- p-dioxin, colistin, Nω-nitro-l-arginine-methylester and ethanol in various animal models due to its antioxidant, anti-apoptotic activities. In this review, we provide an overview of the possible mechanisms by which chrysin reduced the hepatotoxicity and nephrotoxicity of different toxicants. This will help the toxicologists, pharmacologists and chemists to develop new safer pharmaceutical products with chrysin and other toxicants.

Biochanin-A attenuates neuropathic pain in diabetic rats.

BACKGROUND: Soya supplements are used in the treatment of neuropathic pain. Previous reports reveal that consumption of soy diet before nerve injury prevents the development of neuropathic pain in rats. Biochanin-A, a soy isoflavone, has a naturally occurring inhibitor of fatty acid amide hydrolase (FAAH) that metabolized endocannabinoids. OBJECTIVE: The objective was to evaluate efficacy of biochanin-A in streptozotocin (STZ) induced neuropathic pain in rat model. MATERIALS AND METHODS: Diabetes mellitus was induced by an injection of STZ at a dose of 45 mg/kg, i.v. into tail vein of male albino Wistar rats. Biochanin-A was dosed at 0.1, 1 and 5 mg/kg by intraperitoneal (i.p.) administration in diabetic neuropathic rats. Mechanical hyperalgesia and allodynia was measured using Randall-Selitto analgesymeter and manual von Frey filaments of increasing weights respectively. Paw withdrawal threshold (PWT) and percent PWT was determined with respect to both hyperalgesia and allodynia. RESULTS: Treatment of biochanin-A at three different levels of 0.1, 1 and 5 mg/kg had not significantly altered serum glucose levels throughout the treatment period. In hyperalgesia study, acute treatment with higher dose exhibited 51.1% reversal of paw withdrawal threshold (PWT) while with chronic treatment, efficacy declined to 22.5% reversal of PWT. In allodynia study, acute treatment reversed PWT by 79.4% while with chronic treatment, efficacy was raised to 88.2% reversal of PWT. CONCLUSION: Biochanin-A demonstrated better efficacy in reversing mechanical allodynia than mechanical hyperalgesia. Biochanin-A could be a good drug candidate for further studies to establish the mechanism of attenuation of neuropathic pain.

A study of medication-related problems in stroke patients: A need for pharmaceutical care.

OBJECTIVE: The study was aimed to assess the incidence and characteristics of drug-related problems (DRPs). METHODS: A prospective, observational study was conducted among 133 patients with stroke disease who were aged 18 years or older and admitted to the general medicine ward. During the 6 months study period, the incidence of DRPs was identified using the Pharmaceutical Care Network Europe Foundation classification system, version 6.2. FINDINGS: A total of 133 patients were screened for DRPs. Among them, 120 patients have at least one DRP. A total of 254 DRPs were identified (on average, 2.015 DRPs per each patient case). CONCLUSION: Increasing the evidence of the incidence of medication-related problems in tertiary care hospitals indicates the need for the establishment of a clinical pharmacist in hospital settings.

A prospective study of incidence of medication-related problems in general medicine ward of a tertiary care hospital.

The study is aimed to assess the incidence of drug-related problems (DRPs) and provide pharmacist interventions for identified DRPs. A prospective, observational study was conducted among 189 patients with cardiovascular disease who were aged 18 years or older and admitted to the general medicine in-patient ward. During the 6 months study period, the incidence of DRPs was identified using Pharmaceutical Care Network Europe Foundation classification system version 6.2. A total of 189 patients were screened for DRPs. Among them, 130 patients have at least one DRP. A total of 416 DRPs were identified (on average, 2.2 DRPs per each patient). Of the 416 DRPs, 125 (30.04%) interventions were accepted, 7 (1.68%) interventions were not accepted, while remaining (68.26%) accepted but no action taken. The results of the study indicate that incidence of DRPs is substantial and pharmacist-led interventions resulted in resolution of DRPs. This represents the need for the active role of the clinical pharmacist in the developing countries like India.

Quercetin does not alter the oral bioavailability of Atorvastatin in rats.

The study was undertaken to evaluate the effect of Quercetin on the pharmacokinetics of Atorvastatin Calcium. In-vivo Pharmacokinetic studies were performed on rats in a single dose study and multiple dose study. Rats were treated with Quercetin (10 mg/kg) and Atorvastatin Calcium (20 mg/kg) orally and blood samples were collected at (0) pretreatment and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24 hours post treatment. Plasma concentrations of Atorvastatin were estimated by HPLC method. Quercetin treatment did not significantly alter the pharmacokinetic parameters of atorvastatin like AUC(0-24), AUC(0-α) , T(max), C(max) and T(½) in both single dose and multiple dose studies of Atorvastatin Calcium. Quercetin does not alter the oral bioavailability of Atorvastatin Calcium in rats.

Surgical animal models of neuropathic pain: Pros and Cons.

One of the biggest challenges for discovering more efficacious drugs for the control of neuropathic pain has been the diversity of chronic pain states in humans. It is now acceptable that different mechanisms contribute to normal physiologic pain, pain arising from tissue damage and pain arising from injury to the nervous system. To study pain transmission, spot novel pain targets and characterize the potential analgesic profile of new chemical entities, numerous experimental animal pain models have been developed that attempt to simulate the many human pain conditions. Among the neuropathic pain models, surgical models have paramount importance in the induction of pain states. Many surgical animal models exist, like the chronic constriction injury (CCI) to the sciatic nerve, partial sciatic nerve ligation (pSNL), spinal nerve ligation (SNL), spared nerve injury (SNI), brachial plexus avulsion (BPA), sciatic nerve transaction (SNT) and sciatic nerve trisection. Most of these models induce responses similar to those found in causalgia, a syndrome of sustained burning pain often seen in the distal extremity after partial peripheral nerve injury in humans. Researchers most commonly use these surgical models in both rats and mice during drug discovery to screen new chemical entities for efficacy in the area of neuropathic pain. However, there is scant literature that provides a comparative discussion of all these surgical models. Each surgical model has its own benefits and limitations. It is very difficult for a researcher to choose a suitable surgical animal model to suit their experimental set-up. Therefore, particular attention has been given in this review to comparatively provide the pros and cons of each model of surgically induced neuropathic pain.