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Background: Neuropathic pain, a chronic debilitating painful condition, is frequently difficult to manage with the conventional analgesics. Emerging evidence indicates potential role of peroxisome proliferator-activated receptor (PPAR)-γ, a subfamily of nuclear receptors, in regulating inflammation and oxidative stress at transcription level. Therefore, we investigated whether activation of PPAR-γ attenuate established neuropathic pain and to delineate underlying mechanisms. Methods: Neuropathy was induced by chronic constriction injury of sciatic nerve in rats. Behavioral tests were performed to assess pain hypersensitivity and the markers of inflammation and nitroso-oxidative stress were estimated in sciatic nerve. Results: Chronic administration of pioglitazone (10 and 30 mg/kg, i.p.) for 2 weeks starting 14 days after nerve injury did not induce hypoalgesia in contralateral paws and had no effect on locomotor activity. However, pioglitazone significantly mitigated cold allodynia and thermal hyperalgesia in ipsilateral paws after nerve injury. In addition, pioglitazone reduced plasma extravasation and pro-inflammatory cytokines, TNF-α and IL-1β, following nerve injury. These effects of pioglitazone are parallel with the significant reduction in lipid peroxidation, protein carbonyls, nitrite levels as well as marked improvement in GSH and activities of SOD, catalase in injured nerves. BADGE, a PPAR-γ antagonist (30 mg/kg, i.p.) reversed the effects of pioglitazone in chronic constriction injury (CCI) rats. Conclusion: Together, the present results demonstrate that activation of PPAR-γ receptor-dependently exerted antiallodynic and antihyperalgesic effects through inhibition of inflammation and nitroso-oxidative stress in mononeuropathic rats and supporting a key role of PPAR-γ activation in extenuating existing neuropathic pain.

Background: Surgical site infections are a prevalent cause of nosocomial infections that require antibiotic prophylaxis. Emergence and spread of antimicrobial resistance is a major global public health issue that must be addressed. Eventually, antibiotic prescribing pattern should be examined in order to ensure that antibiotics are used appropriately and that their effectiveness is preserved. Objective: To evaluate hospital antibiotic prescribing pattern emphasizing on cephalosporins in general surgery specialty using the WHO Access, Watch, and Reserve (AWaRe) classification. Methodology: A cross-sectional study was carried out in 658 hospitalized patients who received prophylactic antibiotics in general surgery specialty for six months. The data were analysed using the ‘WHO prescribing indicators’ and examined for the WHO ‘AWaRe’ categories. The acquired data was subjected to descriptive statistics. Results: Per encounter, the average number of drugs and antibiotics prescribed were 3.8 and 1.3, respectively. 83.4% encounters were with at least one antibiotic and 94.5% encounters had parenteral antibiotics. 31.3% and 77.8% antibiotics were prescribed by generic name and from the Essential Medicines List, respectively. The most frequently prescribed antibiotics were the third generation cephalosporins (36.8%) wherein ceftriaxone (22.0%) and cefoperazone (7.2%) were the two most commonly prescribed. A total of 14 specific antibiotics, ‘Access’ 5 and ‘Watch’ 9 were prescribed. Based on the WHO AWaRe classification, 42.3% ‘Access’ and 57.7% ‘Watch’ group antibiotics prescribed. All the prescribed cephalosporins (100%) were from the ‘Watch’ category. Amikacin (13.5%) and ceftriaxone (22.0%) were the most commonly prescribed ‘Access’ and ‘Watch’ group antibiotics, respectively. Amoxicillin index was 7.5 and ‘Access-to-Watch’ index was 0.7, which were much below the priority values. Conclusion: The antibiotic prescription pattern seen in this study did not entirely meet the WHO recommendations. Antibiotics from the ‘Watch’ category, notably cephalosporins, were commonly prescribed. To retain antibiotic effectiveness and encourage rational antibiotic use, as well as to overcome antibiotic resistance, changes and surveillance antibiotics prescribing are required.

Background: Neuropathic pain is a chronic incapacitating painful condition for which there is no effective treatment. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that play key roles in modulating immune and inflammatory responses. The antinociceptive properties of PPAR-γ activation on development of neuropathic pain are not fully known. Objective: To determine the role of PPAR-γ activation on the development of neuropathic pain following chronic constriction injury and to elucidate underlying mechanisms. Methodology: Neuropathy was induced by chronic constriction injury of sciatic nerve in rats. Cold allodynia and thermal hyperalgesia were assessed and the markers of inflammation and nitroso-oxidative stress were estimated. Results: Pre-emptive administration of pioglitazone, a PPAR-γ agonist (3, 10 or 30 mg/kg, i.p. 1 hr before surgery and continued once daily for 2 weeks) dose-dependently attenuated paw withdrawal latency to cold (allodynia) and thermal (hyperalgesia) stimuli. Pioglitazone significantly reduced elevated TBARS, protein carbonylation, nitrite levels and markedly restored depleted GSH, and reduction in activities of SOD and catalase in injured nerves. Further, pioglitazone markedly reduced plasma extravasation and levels of pro-inflammatory cytokines TNF-α and IL-1β following nerve injury. Moreover, pioglitazone did not alter the locomotor activity. Pretreatment with PPAR-γ antagonist BADGE (30 mg/kg, i.p.) blocked the beneficial effects of pioglitazone. Essentially, pioglitazone promoted the long-lasing recovery and also prevented the development of neuropathic pain even after treatment termination. Conclusion: Pioglitazone, a PPAR-γ agonist receptor-dependently abolished the development of traumatic neuropathic pain and exerted long-lasting antinociceptive effects through reducing nitroso-oxidative stress and inflammation. Our findings strongly suggest that pre-emptive activation of PPAR-γ prevented or at least delayed the development of nerve injury-induced pain hypersensitivity.

Background: Paclitaxel-induced painful neuropathy is a major dose-limiting side effect and can persist for up to two years after completing treatment that greatly affects both the course of chemotherapy and quality of life in cancer patients. Peroxisome proliferator-activated receptor (PPAR)-γ belongs to a family of nuclear receptors known for their transcriptional and regulatory roles in metabolism, inflammation, and oxidative stress. However, the role of PPAR-γ activation on paclitaxel-induced neuropathic pain is not yet known. Objective: To investigate whether pioglitazone, a PPAR-γ agonist reduce paclitaxel-induced neuropathic pain and to elucidate underlying mechanisms. Methodology: Peripheral neuropathy was induced by administration of paclitaxel (2 mg/kg per injection) intraperitoneally on four alternate days (days 0, 2, 4, 6). Thermal hyperalgesia and mechanical allodynia were assessed and the markers of inflammation and nitroso-oxidative stress were estimated. Results: Pioglitazone did not induce hypoalgesia and had no effect on locomotor activity. Repeated oral administration of pioglitazone (10 and 20 mg/kg,) for 2 weeks started 14 days after paclitaxel injection markedly attenuated paw withdrawal responses to thermal (hyperalgesia) and mechanical (allodynia) stimuli. Further, pioglitazone administration significantly reduced elevated level of pro-inflammatory cytokine, TNF-α, in both the dorsal root ganglia and the spinal cord accompanied by marked decrease in oxidative stress parameters as well as increase in activity of antioxidant defense enzyme, superoxide dismutase, in the spinal cord after paclitaxel injection. Conclusion: The results of the present study demonstrate that pioglitazone, a PPAR-γ agonist exerted antinociceptive effect in paclitaxel-induced neuropathic pain through inhibiting neuroimmune inflammation in both the periphery and spinal cord and by reducing nitroso-oxidative stress in spinal cord. Our findings strongly suggest pharmacological activation of PPAR-g as a promising therapeutic target in paclitaxel-induced peripheral neuropathy and provide rationale for the clinical evaluation.

Background: Bacteria have ability to rapidly evolve, develop strategies to resist antibiotics, and reduce the effectiveness of antibiotics. The emergence and spread of antimicrobial resistance is an important global public health challenge to tackle. Studying antibiotic prescribing practices would allow rational use and preserve effectiveness of antibiotics. Objective: To study prescribing practices of antibiotics in out-patients in primary care settings using the WHO AWaRe framework. Methodology: A prospective cross-sectional study was conducted to evaluate prescribing practices of antibiotics in the primary care facility of three private hospitals using the WHO ‘core prescribing indicators’ and Access, Watch, and Reserve (AWaRe) classification. A systematic sampling technique was employed to collect the prescriptions at each hospital for three months. Descriptive statistics were applied to the collected data. Results: A total of 2685 prescriptions were systematically evaluated. 1280 encounters had at least one antibiotic (47.7%), of which 1041 consist of only one antibiotic (81.5%). Among 1280 antibiotic encounters, the average number of antibiotics per encounter was 1.2 and 14.6% were prescribed with a parenteral antibiotic. 26.6% and 78.6% antibiotics were prescribed using generic names and from the WHO Essential Medicines List, respectively. Amoxicillin/clavulanic acid, ceftriaxone, azithromycin, cefoperazone, and amoxicillin were the five most commonly prescribed antibiotics. According to the WHO AWaRe classification, a total of 27 specific antibiotics (Access 11, Watch 14, and Reserve 2) were prescribed. 38.4%, 53.7%, 0.3%, and 10.5% of antibiotics prescribed were from the ‘Access’, ‘Watch’, ‘Reserve’, and ‘Not Recommended’ categories, respectively. Third generation cephalosporins (24.0%) were prescribed in high rate among ‘Watch’ category. The most commonly prescribed ‘Access’ and ‘Watch’ antibiotics were amoxicillin/clavulanic acid (12.5%) and ceftriaxone (10.6%), respectively. Amoxicillin index was 19.5% and ‘Access-to-Watch’ index was 0.76, which were below the priority values. Conclusion: Except few indicators, still better prescribing practices of antibiotics are needed to fully meet the WHO recommendations. Antibiotic prescribing guidelines as per the WHO AWaRe framework, changes in prescription patterns and preference of “Access” over ‘Watch’ antibiotics are crucial to preserve effectiveness and promote rational use of antibiotics.

Huntington's disease (HD) is characterized by cognitive and psychiatric impairment caused by neuronal degeneration in the brain. Several studies have supported the hypothesis that oxidative stress is the main pathogenic factor in HD. The current study aims to determine the possible neuroprotective effects of nicotinamide on 3-nitropropionic acid (3-NP) induced HD. Male Wistar albino rats were divided into six groups. Group I was the vehicle-treated control, group II received 3-NP (20 mg/kg, intraperitoneally (i.p.) for 4 days, group III received nicotinamide (500 mg/kg, i.p.). The remaining groups received a combination of 3-NP plus nicotinamide 100, 300 or 500 mg/kg, i.p. respectively for 8 days. Afterward, the motor function and hind paw activity in the limb withdrawal were tested; rats were then euthanized for biochemical and histopathological analyses. Treatment of rats with 3-NP altered the motor function, elevated oxidative stress and caused significant histopathological changes in the brain. The treatment of rats with nicotinamide (100, 300 and 500 mg/kg) improved the motor function tested by locomotor activity test, movement analysis, and limb withdrawal test, which was associated with decreased oxidative stress markers (malondialdehyde, nitrites) and increased antioxidant enzyme (glutathione) levels. In addition, nicotinamide treatment decreased lactate dehydrogenase and prevented neuronal death in the striatal region. Our study, therefore, concludes that antioxidant drugs like nicotinamide might slow progression of clinical HD and may improve the motor functions in HD patients. To the best of our knowledge, this study is the first to explore the neuroprotective effects of nicotinamide on 3-NP-induced HD.

Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α 2 -adrenergic (α 2 A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α 2 A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α 2 A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain. Perspective This article presents the synergistic antiallodynic effects of combinations of α 2 A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas.

Glia, particularly astrocytes and microglia, are known to play an important role in central sensitization and are strongly implicated in the exaggerated pain states. In the present study, we determined the effect of minocycline, an inhibitor of microglial activation, in acute nociception, peritonitis, and the development and maintenance of hypersensitivity following chronic constriction injury of the sciatic nerve in rats. A single dose of minocycline (30 or 100 mg/kg, i.p.) 30 min before acetic acid or zymosan injection did not attenuate the nociceptive behavior in mice. It had no effect on the early events of peritoneal inflammation (vascular permeability, inflammatory cell infiltration, and release of pro-inflammatory cytokines) in acetic acid or zymosan-injected mice. In addition, minocycline (30 or 100 mg/kg, i.p.) did not alter basal nociceptive responses in the tail immersion test. Chronic administration of minocycline (10 or 30 mg/kg, i.p.) for 7 days started before nerve injury significantly prevented the development of neuropathic pain, interestingly, it further delayed the development of hypersensitivity. In contrast, single injection of minocycline failed to reverse hypersensitivity when administered during the development of neuropathic pain. No significant effects were observed on hypersensitivity when treatment was started once neuropathic state was established. Pre-treatment, but not post-treatment, with minocycline markedly attenuated increased pro-inflammatory cytokines release and oxidative and nitrosative stress in mononeuropathic rats. These results suggest that minocycline had no effect on acute peritoneal inflammation, nociception, and chronic administration of minocycline when started early before peripheral nerve injury could attenuate and further delays the development of neuropathic pain. Concluding, this study clearly shows minocycline, an inhibitor of microglial activation, by inhibiting the release of pro-inflammatory mediators and reducing oxidative stress prevented the development of neuropathic pain.

OBJECTIVE: The 2, 3, 7-trisubstituted quinazoline derivatives (Compound HP1, HP2, HP3 and HP4) in two different concentrations were evaluated for antitumor activity against Ehrlich ascites carcinoma (EAC) and Dalton’s lymphoma ascites (DLA) bearing Swiss albino mice. METHODS: The in vivo antitumor potency of quinazoline bases was measured in EAC model by assessing the increase in mean survival time of the treated drug over untreated control mice and treated standard (Gefitinib) mice. Their toxicity was assessed in vivo in normal, standard and EAC bearing mice by measuring the drug-induced changes in haematological parameters. The in vivo antitumor potency of quinazoline bases was assessed in DLA model by measuring solid tumor volume, solid tumor weight and % inhibition of the tumor weight of the treated drug over untreated control mice and treated standard (Gefitinib) mice. RESULTS: Among the four quinazoline bases studied, HP1, HP3 and HP4 at a dose of 10mg/kg and 20 mg/kg, optimally inhibited the growth of EAC and DLA cells in vivo . Besides, the treatment with HP1 and HP3 (20 mg/kg) significantly restored the deviated haematological parameters in EAC challenged mice. In vivo result authenticates that compound HP3 at a dose of 20mg/kg was most effective. The apoptotic studies shows that, both HP1 and HP3, at 10 and 20 mg/kg body weight showed induction of apoptosis as they significantly restored the deviated haematological parameters in EAC challenged mice. CONCLUSIONS: Further studies are required to explore the mechanism of action of this novel molecule which might bring gifted outcomes in cancer chemotherapy.

Chronic stress precipitates many neuropsychiatric disorders and alters the various oxidative stress parameters in brain. Cyclooxygenase (COX) is reported to play an important role in pathogenesis of various neurodegenerative disorders including stroke and seizures. In the present study, we examined the effect of naproxen (non-selective COX-inhibitor having much potency towards COX-I isoform) or rofecoxib (a selective COX-2 inhibitor) in subchronic immobilization stress. Mice were subjected to immobilized stress for 6 h daily for a period of seven days. Naproxen (7 mg/kg, i.p.) or rofecoxib (2 mg/kg, i.p.) was administered daily for 7 days before challenging them to immobilization stress. Behavioral analysis revealed the hyperlocomotor activity and increased anxiety response. Subchronic stress decreased percent retention of memory and also caused hyperalgesia in mice. Biochemical analysis revealed that chronic immobilization stress significantly increased lipid peroxidation and nitrite levels and decreased the reduced glutathione and adrenal ascorbic acid levels. Chronic treatment with naproxen or rofecoxib significantly attenuated the immobilization stress-induced behavioral and biochemical alterations. These results suggested that the use of COX-inhibitors (naproxen or rofecoxib) could be a useful neuroprotective strategy in the treatment of stress.

The present study was undertaken to determine the effects of cyclooxygenase (COX) inhibitors on the development of neuropathic pain in rats following chronic constriction injury (CCI). A single intraperitoneal administration of naproxen, a nonselective COX inhibitor (10 or 30 mg/kg), or rofecoxib, a selective COX-2 inhibitor (3 or 10 mg/kg) 2 h before nerve injury did not attenuate the development of neuropathic state for 28 days. However, the administration of naproxen [10 or 30 mg/kg, intraperitonelly (i.p.)], but not rofecoxib (3 or 10 mg/kg, i.p.), on day 7 attenuated hypersensitivity but did not alter its development for 28 days. Furthermore, naproxen significantly reduced hyperalgesia and allodynia for 4 h, but the efficacy was not observed 24 h after the treatment, whereas rofecoxib failed to modify the hypersensitivity following perineural (p.n.) or intrathecal (i.t.) administration on day 7. Chronic administration of naproxen (3, 10 or 30 mg/kg), but not rofecoxib (1, 3 or 10 mg/kg), 2 h before, daily for 7 days, after nerve injury significantly attenuated and further delayed the development of hypersensitivity for 21 days following nerve injury. These results suggest that the development of hypersensitivity in the CCI model is not COX-2 dependent and that the chronic administration of naproxen started early before peripheral nerve injury could attenuate the development of hypersensitivity.

Nephrotoxicity associated with cyclosporine A (CsA) administration is characterized by marked renal vasoconstriction, interstitial fibrosis and arteriolar hypertrophy. The molecular mechanisms of CsA nephrotoxicity are not well characterized, but previous studies have demonstrated that angiotensin II (Ang II), the primary mediator of renin-angiotensin system (RAS) cascade plays a role in its pathogenesis. Recent studies also suggest an involvement of reactive oxygen species (ROS) in CsA nephrotoxicity. There is emerging evidence that Ang II induces oxidative stress in vitro and in vivo. The aims of this study were to investigate the role of Ang II-induced oxidative stress in CsA nephrotoxicity, and to examine the effects of the insurmountable Ang II type 1 (AT (1)) receptor antagonist, candesartan on CsA-induced nephrotoxicity in rats. Candesartan cilexetil (1.0 mg kg (-1), perorally (p.o.), once a day) was administered 24 h before and 21 days concurrently with CsA (20 mg kg(-1), subcutaneously (s.c.)). Tissue lipid peroxidation was measured as thiobarbituric acid reacting substances (TBARS). Renal function was assessed by estimating serum creatinine, blood urea nitrogen (BUN), creatinine and urea clearance. Renal morphological alterations were assessed by histopathological examination of Haematoxylin-Eosin, PAS and Mason's trichome stained sections of the kidneys. CsA (20 mg kg (-1), s.c.) administration for 21 days produced elevated levels of TBARS and deteriorated the renal function as assessed by increased serum creatinine, BUN and decreased creatinine and urea clearance as compared to vehicle treated rats. The kidneys of CsA-treated rats showed severe striped interstitial fibrosis, arteriolopathy, glomerular basement thickening, tubular vacuolisation and hyaline casts. Candesartan cilexetil (1.0 mg kg (-1)) markedly reduced elevated levels of TBARS, significantly attenuated renal dysfunction and morphological changes in CsA-treated rats. These results clearly demonstrate the pivotal role of Ang II-induced oxidative stress and the therapeutic potential of AT (1)receptor antagonists in ameliorating CsA-induced nephrotoxicity.

Intracerebroventricular (ICV) administration of streptozotocin (STZ) causes degeneration of hippocampal neurons through unknown mechanisms that further lead to dementia. On assumption that enzyme cyclooxygenase (COX), which catalyzes the production of pro-inflammatory prostaglandins, may be involved in ICV-STZ induced neurodegeneration, the present study was designed to investigate the effects of chronic treatment with selective inhibitor of COX-1, COX-2 or COX-3 on hippocampal neuronal density in ICV-STZ treated rats. Drugs were administered daily for 21 days, intraperitoneally, in sham control as well as ICV-STZ treated rats. After 21 days of treatment, rats were sacrificed and histological changes were observed in Cornus Ammonis (CA)-1 region of hippocampus at light microscopic level. Histopathological evaluation showed that valeryl salicylate (selective COX-1 inhibitor; 5 and 10 mg/kg; i.p.) and etoricoxib (selective COX-2 inhibitor; 5 and 10 mg/kg; i.p.) significantly increased the survival of hippocampus CA1 neurons in a dose dependent manner. On the contrary, phenacetin (selective COX-3 inhibitor; 20 and 40 mg/kg; i.p.) treatment had no effect on reduced neuronal density in ICV-STZ treated rats. In summary, these findings provide the first comprehensive description about the differential role of COX isozymes in ICV-STZ induced neuronal death in hippocampal CA1 regions of the rat brain.

Peroxisome proliferators activated receptor is regarded as potential therapeutic targets to control various neurodegenerative disorders. However, none of the study has elucidated its effect in the treatment of Huntington's disease. We explored whether peroxisome proliferators activated receptor-α agonist may attenuate various behavioral and biochemical alterations induced by systemic administration of 3-nitropropionic acid (3-NP), an accepted experimental animal model of Huntington's disease phenotype. Intraperitoneal administration of 3-NP (20mg/kg., i.p.) for 4days in rats produced hypolocomotion, muscle incoordination, and cognitive dysfunction. Daily treatment with fenofibrate (100 or 200mg/kg., p.o.), 30min prior to 3-NP administration for a total of 4days, significantly improved the 3-NP induced motor and cognitive impairment. Biochemical analysis revealed that systemic 3-NP administration significantly increased oxidative and nitrosative stress (increase lipid peroxidation, protein carbonyls and nitrite level), lactate dehydrogenase activity whereas, decreased the activities of catalase, superoxide dismutase, reduced glutathione, and succinate dehydrogenase. Fenofibrate treatment significantly attenuated oxidative damage, cytokines and improved mitochondrial complexes enzyme activity in brain. In the present study, MK886, a selective inhibitor of peroxisome proliferators activated receptor-α was employed to elucidate the beneficial effect through either receptor dependent or receptor independent neuroprotective mechanisms. Administration of MK886 (1mg/kg, i.p.) prior to fenofibrate (200mg/kg, p.o.) abolished the effect of fenofibrate. The results showed that receptor dependent neuroprotective effects of fenofibrate in 3-NP administered rats provide a new evidence for a role of PPAR-α activation in neuroprotection that is attributed by modulating oxidative stress and inflammation.