Phytotherapeutic Approach in the Management of Cisplatin Induced Vomiting; Neurochemical Considerations in Pigeon Vomit Model.

Cisplatin induced vomiting involves multiple mechanisms in its genesis and a single antiemetic agent do not cover both the phases (acute & delayed) of vomiting in clinics; necessitating the use of antiemetics in combination. Cannabis sativa and other selected plants have ethnopharmacological significance in relieving emesis. The aim of the present study was to investigate the intrinsic antiemetic profile of Cannabis sativa (CS), Bacopa monniera (BM, family Scrophulariaceae), and Zingiber officinale (ZO, family Zingiberaceae) in combinations against vomiting induced by highly emetogenic anticancer drug-cisplatin in pigeons. We have analysed the neurotransmitters which trigger the vomiting response centrally and peripherally. Electrochemical detector (ECD) was used for the quantification of neurotransmitters and their respective metabolites by high performance liquid chromatography in the brain stem (BS) and area postrema (AP) while peripherally in the small intestine. Cisplatin (7 mg/kg i.v.) induced reliable vomiting throughout the observation period (24 hrs). CS-HexFr (10 mg) + BM-MetFr (10 mg)-Combination 1, BM-ButFr (5 mg) + ZO-ActFr (25 mg)-Combination 2, ZO-ActFr (25 mg) + CS-HexFr (10 mg)-Combination 3, and CS-HexFr (10 mg) + BM-ButFr (5 mg)-Combination 4; provided ~30% (30 ± 1.1), 70% (12 ± 0.4; P < 0.01), 60% (19 ± 0.2; P < 0.05) and 90% (05 ± 0.1; P < 0.001) protection, respectively, against cisplatin induced vomiting as compared to cisplatin control. Standard MCP (30 mg) provided ~50% (23 ± 0.3) protection (P > 0.05). CS Hexane fraction (10 mg/kg), BM methanolic (10 mg/kg) and bacoside rich n-butanol fraction (5 mg/kg) and ZO acetone fraction (25 mg/kg) alone provided ~62%, 36%, 71%, and 44% protection, respectively, as compared to cisplatin control. The most effective and synergistic combination 4 was found to reduce 5HT and 5HIAA (P < 0.05-0.001) in all the brain areas area postrema (AP)+brain stem (BS) and intestine at the 3rd hour of cisplatin administration. In continuation, at the 18th of cisplatin administration reduction in dopamine (P < 0.001) in the AP and 5HT in the brain stem and intestine (P < 0.001) was observed. The said combination did not change the neurotransmitters basal levels and their respective metabolites any significantly. In conclusion, all the tested combinations offered protection against cisplatin induced vomiting to variable degrees, where combination 4 provided enhanced attenuation by antiserotonergic mechanism at the 3rd hour while a blended antidopaminergic and antiserotonergic mechanism at the 18th hour after cisplatin administration.

Metabolic dysregulation in early onset psychiatric disorder before and after exposure to antipsychotic drugs

Antipsychotic Drugs (APDs) are being widely prescribed to treat various disorders, including schizophrenia and bipolar disorder; however, abnormal glucose metabolism and weight gain have been reported with Atypical Anti-Psychotic drugs (AAPDs) that can lead to insulin-resistance and type 2 diabetes mellitus. The study was designed to assess various biochemical parameters including insulin and blood sugar before and after exposure to APDs in order to exclude the involvement of psychiatric disorders and certain other factors in metabolic dysregulations. Fifty seven APDs-naïve patients with first episode psychosis were divided into six groups who received olanzapine, quetiapine, risperidone, aripiprazole, haloperidol or combination of olanzapine with escitalopram and haloperidol. The serum samples were taken before the intake of the first dose and then on follow-up. Decrease in the level of elevated insulin and glucose was observed post-treatment in some patients, while others were observed whose insulin and glucose levels increased post-treatment, yet some patients did not show any disturbance in the insulin and glucose levels. It is concluded that psychiatric disorders by itself, narcotics, cigarette smoking and use of oral snuff may be also be implicated in metabolic dysregulations. The effects of APDs on insulin and glucose in healthy volunteers might be different than in patients with psychiatric disorders.

Short-term oral administration of risperidone induces pancreatic damage and hyperamylasemia in Sprague-dawley rats

Risperidone is an atypical antipsychotic acting mainly as a dopamine D2 and serotonin 5-HT2 receptors antagonist prescribed in the treatment of schizophrenia and various affective disorders. Risperidone has been reported to be associated with weight gain, panreatitis and type 2 diabetes mellitus. Various mechanisms of risperidone-induced toxicities have been reported but the histology of tissues especially pancreas has never been studied. Therefore, the current study was designed to elucidate the toxic effects of chronic administration of risperidone on pancreas, liver and kidneys. Animals (rats) of either gender were divided into two groups, the risperidone and control groups. Risperidone was administered in a dose of 2.5 mg/kg/d for three weeks. The controls received acidified saline only. Both the groups received restricted diet (20 g/12 h). The body weight and level of random blood sugar (RBS) were measured on a weekly basis. The levels of lipase and amylase were determined at the conclusion of the experiment. At the end of the experiment, the tissues were dissected out for histopathological evaluation. Risperidone showed no weight gain, hyperglycemia or rise in the level of lipase (P> 0.05); however, the level of amylase was raised (***P<0.05). Histological examination under light microscope showed no hepatotoxicity, nephrotoxicity but did show damage to the pancreas. The findings of this study indicated that the incidence of adverse effects associated with risperidone could be prevented/alleviated/delayed by allowing restricted diet.

Comparative evaluation of pancreatic histopathology of rats treated with olanzapine, risperidone and streptozocin

Olanzapine and risperidone are widely prescribed atypical antipsychotics used in the treatment of schizophrenia and various other psychiatric disorders. Both of these drugs have been extensively reported to cause Type 2 diabetes mellitus and pancreatitis, however, the mechanism of olanzapine and risperidone-induced toxicity has not been so far unveiled. We, therefore, compared the streptozocin-induced pancreatic damage with that of pancreas isolated from olanzapine and risperidone treated rats. It was noticed that fibrotic growth, necrosis and derangement of the pancreatic islet cells caused by streptozocin were more pronounced than olanzapine and risperidone.

Olanzapine induced biochemical and histopathological changes after its chronic administration in rats.

Objective: Olanzapine is a second generation antipsychotic acting mainly as a dopamine D2 and serotonine 5-HT2 receptors antagonist prescribed in the treatment of schizophrenia and various other psychiatric illnesses. Even though olanzapine is widely used in psychiatry, its effects on the architecture of pancreas, liver and kidneys are little known. The histology of pancreas especially has never been studied. For these reasons, the current study was designed to elucidate the toxic effects of chronic administration of olanzapine on pancreas, liver and kidneys and the enzymes released by these tissues in an escalating dose manner. Methods: Fourteen male rats were divided into two groups equally, the olanzapine group and the controls. Olanzapine was administered in a dose of 5 mg/kg/d for the first eight weeks, 10 mg/kg/d for next four weeks and 15 mg/kg/d through the last two week period of 14 weeks experiment. The controls received acidified saline only. Both the groups received restricted diet (20 g/12 h). The body weight and level of random blood sugar (RBS) were measured on a weekly basis. The levels of lipase, amylase, alanine transaminase (ALT) and aspartate transaminase (AST) were determined terminally. At the end of the experiment, the tissues were dissected out for histopathological evaluation. Results: Significant loss in body weight, change in the level of random blood sugar (∗∗P < 0.05, ∗∗∗P < 0.001) and significant rise in amylase and lipase levels (∗P < 0.05, ∗∗∗P < 0.001) were observed. However, the same treatment has shown no significant change in the levels of alanine and aspartate transaminases (P > 0.05). The pancreas has shown derangement of beta cells and fibrotic growth. A mild to moderate focal increase in glomerular cellularity, cellular proliferation and glomerular capsules with negligible basement membranes were observed in the kidneys. No changes were observed in the architecture of the liver. Conclusion: The findings of this study indicated that the incidence of adverse effects associated with olanzapine could be prevented/alleviated/delayed by allowing restricted diet.

Beneficial effects of Bacopa monnieri extract on opioid induced toxicity.

The present study examined the hepatotoxicity and nephrotoxicity of morphine and illicit street heroin and their amelioration by a standardized methanolic extract of Bacopa monnieri (L.) (mBME) in rats. Morphine or street heroin was administered at a dose of 20 mg/kg for 14 and 21 days. mBME (40 mg/kg) or ascorbic acid (50 mg/kg) was administered two hours before morphine or street heroin. High performance liquid chromatography (HPLC) was used for the standardization of bacoside-A major components in mBME. The antioxidant potential of mBME was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. Administration of morphine and street heroin resulted in marked elevation of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine. Histopathological changes induced by morphine and street heroin after 14 days were of reversible nature while treatment for 21 days was associated with irreversible changes. Pretreatment with mBME or ascorbic acid restored the elevation of serum ALT, AST and creatinine and protected liver and kidneys from the toxicological influence of morphine and street heroin. HPLC analysis showed that mBME contained bacoside-A major components i.e. bacoside-A3 (37.5 µg/mg), bacopaside-II (4.62 µg/mg) and bacopasaponin-C (1.91 µg/mg). The EC50 for the DPPH free radical scavenging assay revealed that mBME possessed strong antioxidant potential. These results concluded that as compared to morphine, street heroin was associated with severe biochemical and histopathological changes in the liver and kidneys. Bacopa monnieri having strong antioxidant potential may provide a beneficial herbal remedy for the efficient management of opioid related hepatotoxicity and nephrotoxicity.

Anti-emetic mechanisms of Zingiber officinale against cisplatin induced emesis in the pigeon; behavioral and neurochemical correlates.

BACKGROUND: Zingiber officinale (ZO, family Zingiberaceae) has been reported for its antiemetic activity against cancer chemotherapy induced emesis in animal models and in clinics. Current study was designed to investigate ZO for potential usefulness against cisplatin induced vomiting in pigeon and its effects on central and peripheral neurotransmitters involved in the act of vomiting. METHODS: Zingiber officinale acetone fraction (ZO-ActFr) was investigated for attenuation of emesis induced by cisplatin in healthy pigeons. Neurotransmitters DA, 5HT and their metabolites DOPAC, HVA and 5HIAA were analyzed using High Performance Liquid Chromatography system coupled with electrochemical detector in area postrema, brain stem and intestine. Antiemetic effect of ZO-ActFr was correlated with central and intestinal neurotransmitters levels in pigeon. RESULTS: Cisplatin (7 mg/kg i.v.) induced emesis without lethality upto the observation period. ZO-ActFr (25, 50 & 100 mg/kg) attenuated cisplatin induced emesis ~ 44.18%, 58.13% (P < 0.05) and 27.9%, respectively; the reference drug, metoclopramide (MCP; 30 mg/kg), produced ~ 48.83% reduction (P < 0.05). ZO-ActFr reduced (P < 0.05 - 0.001) 5-hydroxytryptamine (5HT) concentration in the area postrema, brain stem and intestine at 3(rd) hour of cisplatin administration, while at the 18(th) hour ZO treatments attenuated the dopamine upsurge (P < 0.001) caused by cisplatin in the area postrema and 5HT concentration (P < 0.01 - 0.001) in the brain stem and intestine. ZO treatments alone did not altered the basal neurotransmitters and their metabolites in the brain areas and intestine. CONCLUSION: The behavioral study verify the antiemetic profile of ZO against cisplatin induced emesis in the pigeon, where central and peripheral neural evidences advocate the involvement of serotonergic mechanism at initial time point (3(rd) hr), while the later time point (18(th) hr) is associated with serotonergic and dopaminergic component in the mediation of its antiemetic effect.

Comparative evaluation of gastroulcerogenic potential of nitrogen isoforms of salicyl alcohol and aspirin in rats: biochemical and histological study.

The aim of the current study was to explore in vivo any relative gastroulcerogenic prospective propensity of newly synthesized nitrogen containing derivatives of salicyl alcohol; compound (I) [1-(2-hydroxybenzyl)piperidinium chloride], compound (II) [4-carbamoyl-1-(2-hydroxybenzyl)piperidinium chloride] and aspirin in albino rats. The experimental groups received the following oral treatments daily for 6 days: group I saline control; group II, standard (aspirin) treatment group [150 mg/kg of body weight]; group III, test (compound I) treatment group [100, 150 mg/kg]; group IV, test (compound II) treatment group [100, 150 mg/kg]. The results showed that in the case of the aspirin treated group and compound (I) [150 mg/kg], there was a significant increase in gastric volume, free acidity, total acidity, ulcer score and a decrease in gastric pH. Furthermore, histopathological examination of gastric mucosa of these treated groups revealed detectable morphological changes. Utilizing the same protocol, synthetic compound (I) [100 mg/kg] and (II) [100, 150 mg/kg] exhibited no statistically significant ulcerogenic or cytotoxic properties. A cyclooxygenase (COX) selectivity test indicated the preferential inhibition of COX-I and COX-II enzymes by compounds (I) and (II). This study therefore indicates that these synthetic compounds may possess reduced ulcerogenic potential and could be a functional substitute to aspirin.