Potentiation of physical dependence on diazepam by ondansetron in rats

The effects of ondansetron, a 5-HT3 antagonist, on the development of physical dependence on diazepam were examined in rats using a drug-admixed food method. Rats were treated with diazepam or diazepam in combination with ondansetron for 26 days. After an abrupt withdrawal from diazepam, the incidence of withdrawal signs, such as jerks, tremors and convulsions, and withdrawal scores, were potentiated by co-administration of ondansetron. On the other hand, rats which had been treated with ondansetron alone for 33 days did not show any withdrawal signs after abrupt withdrawal from ondansetron. These findings suggest that ondansetron does not possess physical dependence liability, but does potentiate the development of physical dependence on diazepam. Regulation of serotonergic neurons through 5-HT3 receptors may affect the development of physical dependence on diazepam.     

Clinical pharmacology of ondansetron

Ondansetron (ODS) is a new carbazole which exerts selective and potent antagonism on serotoninergic neurotransmission at serotonin 3 (5-HT3) receptors. Animal and clinical studies show that ODS reduces the incidence and severity of nausea and vomiting induced by cytotoxic drugs and radiotherapy. The antiemetic properties of this agent have been determined in ferrets against the nausea and vomiting induced by cisplatin, cyclophosphamide and whole-body radiation. The current hypothesis is that there may be both a peripheral and a central site of action for ODS. The lack of antagonist activity on dopamine and other non 5-HT3 receptors indicates that, unlike metoclopramide, ODS will not cause extrapyramidal or other dose-limiting side effects. ODS is rapidly and completely absorbed when administered as a tablet. Preliminary data show that ondansetron can be combined with dexamethasone safely with enhanced antiemetic results.     

Potential anxiolytic-like activity of some amino acid derivatives

This report describes a case of uterine didelphys, lipomeningocele, meatal stenosis, and inguinal hernia presenting in a single individual. This unusual group of birth defects suggests a common mechanism of malformation in tailbud maturation which involves both the müllerian duct and the distal spinal cord.     

Prophylactic administration of ondansetron in emergency intraabdominal operations

Efficiency of ondansetron, a selective 5-HT3 receptor antagonist, in prevention of postoperative nausea and vomiting in 40 ASA I-II patients who will undergo emergency intraabdominal operations is studied in a randomized double-blind and placebo controlled study. Patients of no premedication are administered 4 mg i.v. ondansetron or placebo (saline) before induction. Thiopental (4 mg/kg) was used for induction, succinylcholine (2 mg/kg) for muscular relaxation, and 50% nitrous oxide in oxygen and isoflurance (0.8-1.5%) for the maintenance of anesthesia, and fentanyl and norcuron were administered when necessary. Vital signs were closely monitored and recorded during anesthesia and early postoperative period. Study is carried out during postoperative 0-1 h, 1-2 h and 2-24 h periods. Nausea scores and emesis were recorded during 0-1 and 1-2 h periods. Ondansetron was found significantly more effective than placebo (p < 0.05 and p < 0.05). Although is was effective during 2-24 h period, the difference was not statistically significant (p > 0.05). No significant difference was observed between the groups in terms of vital findings, laboratory findings and side effects (p > 0.05). Therefore it is concluded that administration of prophylactic i.v. ondansetron to patients undergoing emergency intraabdominal operations is effective in prevention of nausea and vomiting without any significant side effects.     

Effects of ondansetron on gastrointestinal symptoms in carcinoid syndrome

The effect of short-term treatment with the highly selective serotonin receptor antagonist ondansetron on symptoms and gastric emptying in 11 carcinoid patients was studied. Diarrhoea improved in 6 of 6 patients, nausea in 3 of 4 patients. Flushing was not affected. The rate of gastric emptying increased during ondansetron treatment (P = 0.08). No changes in serotonin in platelets and urinary excretion of 5-hydroxyindoleacetic acid were found. It is concluded that ondansetron can improve gastrointestinal symptoms in carcinoid patients and possibly slows gastric emptying.     

An antinociceptive effect of the intraperitoneal injection of nifedipine in rats, measured by tail-flick test

The tail-flick (TF) technique was used to assess the antinociceptive properties of nifedipine (NIF) given intraperitoneally (i.p.). First, the most suitable intensity of the noxious stimulus (temperature of the bulb) has been ascertained and used in the main study. Male Sprague-Dawley rats received NIF, dissolved in dimethyl sulfoxide (DMSO) at the doses of 0.0, 0.5, 2, 5, 10 and 15 mg/kg, or control with no injection. For the main study, the noxious stimulus was limited to 15 sec (cut-off time) and TF latencies were recorded up to 120 min. The antinociceptive response was expressed as the area under the curve for each rat and analyzed by one-way ANOVA. The antinociceptive response to the lower doses of NIF (0.5 and 2 mg/kg) did not differ from control (no injection) and DMSO alone. Significance was found at 5, 10 and 15 mg NIF with no difference among the doses. However, there was an increasing tendency of the mean values from 0.5 to 15 mg NIF resulting in a positive correlation. The correlation coefficient was 0.32483 (p = 0.015) and regression equation Y = (19.37) x dose + 1320. Our data suggest that spinal mechanisms are involved in NIF-induced antinociception.     

Influence of ondansetron on thiopental hypnotic requirements

Ondansetron, a selective 5-HT3 antagonist has been proved to be an effective antiemetic agent for prophylaxis of nausea and vomiting after surgery. This study was conducted to determine whether ondansetron changes thiopental requirements for induction of anesthesia in patients unpremedicated and premedicated with diazepam. One hundred sixty eight adult female patients classified as American Society of Anesthesiologists (ASA) physical status I (normal healthy patient) or II (patient with mild systemic disease) participated in this prospective, double blinded, randomized study. Patients were assigned to receive either 0.07 mg/Kg diazepam orally or no premedication. They then received saline and ondansetron 0.1 mg/Kg or 0.2 mg/Kg intravenously 5 minutes before thiopental induction. Thiopental was administered at a rate of 25 mg/min until the patient lost the ability to open eyes on command. Thiopental requirements were not significantly different among groups. The results indicate that ondansetron in clinically used doses does not influence the hypnotic requirements of thiopental.     

Propylene glycol elicits anxiolytic-like responses to the elevated plus-maze in male mice

Propylene glycol is a common solvent often contained in injectable solutions of anxiolytics of low water-solubility, such as diazepam (Valium) and pentobarbital (Nembutal). Several studies have shown that propylene glycol can have an inhibitory effect on the central nervous system. This study, using ethanol for comparison, further examined whether propylene glycol has anti-anxiety properties. Use of the elevated plus-maze test with male mice revealed that propylene glycol at doses (27 or 41 mmol kg-1, i.p.) which did not affect general activity, increased the number of entries into open arms and of head dips over open arm edges, indicative of an anxiolytic effect. In parallel, ethanol (14 and 27 mmol kg-1, i.p.) caused an increase in the amount of time spent on open arms and number of entries into open arms, accompanied by reduction of returns into closed arms. These doses of ethanol had no significant effect on motor ability. The results suggest that propylene glycol can act as an anxiolytic agent and that its anxiolytic potency is weaker than that of ethanol. In addition to previous warnings about the pharmacological effects of propylene glycol, the findings of this study alert investigators to the anxiolytic properties of the compound when it is employed as a solvent in anxiety or anxiety-related studies.     

The antiemetic drug ondansetron intereferes with lithium-induced conditioned rejection reactions, but not lithium induced taste avoidance in rats.

Conditioned rejection reactions displayed in the taste reactivity test are exclusively produced by treatments that elicit nausea. The present experiments demonstrate that pretreatment with the antinausea agent ondansetron interferes with both the establishment and the expression of conditioned rejection reactions. Ondansetron did not interfere with lithium-induced taste avoidance in either a 1-bottle or a 2-bottle test. In fact, when rejection reactions were measured during a consumption test, ondansetron selectively attenuated rejection reactions, with only a slight modification of consumption. These results suggest that conditioned rejection reactions, but not conditioned taste avoidance, reflect nausea in rats that can be attenuated by ondansetron pretreatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stability of ondansetron hydrochloride and 12 medications in plastic syringes

The stability and compatibility of ondansetron hydrochloride with neostigmine methylsulfate, naloxone hydrochloride, midazolam hydrochloride, fentanyl citrate, alfentanil hydrochloride, atropine sulfate, morphine sulfate, meperidine hydrochloride, propofol, droperidol, metoclopramide monohydrochloride, and glycopyrrolate were studied. Ondansetron 1.33 or 1.0 mg/mL was combined with 0.9% sodium chloride injection and each of the 12 drugs in duplicate in plastic syringes (or glass for propofol). The syringes were stored at 21.8-23.4 or 4 degrees C in the dark, except for those containing propofol, which were stored at ambient temperature. Samples were removed at 0, 4, 8, and 24 hours for analysis by high-performance liquid chromatography and pH measurement; the propofol-containing samples were removed at 0, 1, 2, and 4 hours. Syringes were visually assessed for color and clarity, and particulate content was measured with a particle counter at the end of the study period. All solutions containing ondansetron retained more than 90% of their initial ondansetron concentration. Solutions containing each of the other drugs except droperidol retained more than 90% of their initial concentration of these drugs. The solutions containing droperidol retained more than 90% of their initial droperidol concentration for up to eight hours at ambient temperature but precipitated quickly at 4 degrees C. In combinations of ondansetron 1.33 or 1.0 mg/mL and 10 of 12 drugs, all drugs were stable for 24 hours in plastic syringes at 23 and 4 degrees C; ondansetron hydrochloride 1.0 mg/mL and propofol 1.0 and 5.0 mg/mL in admixtures were stable for 4 hours, and droperidol on its own and combined with ondansetron 1.0 mg/mL was stable for no more than 8 hours at ambient temperature.     

Effect of the 5-HT3 antagonist ondansetron on voluntary ethanol intake in rats and mice maintained on a limited access procedure

The effect of the 5-HT3 antagonist ondansetron on ethanol self-administration was examined in a limited access paradigm. Acute administration of ondansetron (0.01 and 0.1 mg/kg) reduced ethanol intake in male Wistar rats by 35%, whilst water intake was unaffected. Both a lower (0.001 mg/kg) and higher dose (1 mg/kg) of ondansetron failed to modify ethanol consumption. Ondansetron did not, however, alter the pharmacokinetic profile of an orally administered dose of ethanol (1 g/kg) over the same dose range. To examine the generality of these findings and to determine if tolerance would develop to the suppressant effects of ondansetron on ethanol intake, male C57BL/6 mice were treated with ondansetron (0.001, 0.01 and 0.1 mg/kg) over 22 days, 30 min prior to scheduled access to ethanol. Both 0.01 and 0.1 mg/kg doses reduced ethanol intake; however, water intake was not altered by either dose. This finding confirms and extends the generality of the effects of 5-HT3 receptor antagonists on ethanol intake across different species and different paradigms of ethanol consumption. More importantly, the present study shows that the reduction in ethanol intake induced by ondansetron was maintained even after a prolonged period of treatment and is not due to an alteration in the absorption or metabolism of ethanol.     

Hypocalcemic effect of zinc and mechanism in rats

The effect of zinc on serum calcium was investigated after a single oral administration of zinc sulfate in rats. Zinc (5, 10, and 20 mg Zn/100 g body weight) administration produced a significant decrease of serum calcium. This effect of zinc was not inhibited by thyroparathyroidectomy. Zinc administration resulted in a significant increase in calcium content of lungs and muscle but it was not significant in liver, kidneys, spleen and heart. Intestinal calcium absorption and bile calcium excretion was not affected by zinc administration. However, the urinary calcium excretion after zinc administration decreased markedly. On the other hand, zinc administration caused a remarkable elevation of calcium content in gastric secretion. This effect was dose-dependent (5 and 10 mg Zn/100 g). However, an increase in gastric calcium after zinc administration was completely prevented by atropine (0.1 micrograms/100 g) treatment, which also showed a marked inhibition of hypocalcemic effect of zinc. Meanwhile, acetylcholine (4.0 micrograms/100 g) administration caused a significant decrease of serum calcium by zinc administration is mainly based on an increase in gastric calcium secretion.     

An apperture effect in hypochondria

The incidence of penicillin in bulk milk supplies to the city has varied from 1,2% to 2,6% over the past five years, and 3,2% of 366 pasteurised milk samples examined in 1975 were found to contain penicillin. Investigation of the sources revealed numerous instances of producers, milkers and veterinarians who had not acted responsibly in regard to the marketing of milk from treated cows. Details are provided. The legal and professional obligations of the veterinarian are emphasized. Reference is made to the dye marking registered intramammary formulations for farmer treatment of mastitis.     

Use of oral and intravenous ondansetron in patients treated with cisplatin

Ondansetron, a selective 5-HT3 antagonist, has been shown to be effective in preventing chemotherapy-induced nausea and vomiting. From July and August 1991, 25 patients were accrued in a phase II study to assess the efficacy of ondansetron in patients receiving cisplatin-containing chemotherapy. Patients received intravenous cisplatin 100 mg/m2, given either as a 24-hour infusion on day 1 or in divided doses as eight-hour infusions daily on days 1 to 3. Each patient received 24 mg of ondansetron per day for six days. Intravenous dexamethasone 24 mg was given daily on the days of cisplatin infusion. The emetic episodes and degree of nausea were evaluated daily. "Good" control of emesis (0-2 episodes of vomiting) and nausea (mild or no nausea) ranged from 64-100% and 88-100% respectively. Failure in emesis control occurred most frequently on days 3 and 4. Ondansetron was generally well tolerated with only minimal side-effects. One patient developed unexplained encephalopathy which resolved completely. Our results suggest that ondansetron is an effective anti-emetic agent with minimal toxicities. Randomised studies comparing ondansetron against "standard" anti-emetics should be conducted.