Using telemetry to automate the detection of emesis in the ferret: new vistas for delayed emesis assessment.

INTRODUCTION: Nausea and vomiting are common side effects of cancer chemotherapy. The ferret is a highly appropriate animal species to evaluate both early and delayed emetic events occurring hours and days after administration, respectively. If early emesis can be easily investigated in ferrets by direct observation, alternative methods are required to quantify delayed emesis. This study was designed to validate a new method of automated detection of abdominal pressure changes related to retches or vomits induced by a cytotoxic substance in the ferret. METHODS: Five ferrets implanted with telemetry devices (Data Sciences International) were challenged with cisplatin (8 mg/kg, i.p.) and abdominal pressure was recorded in unrestrained animals for 72 h. The pressure signals were analyzed both manually and automatically using an adapted version of ecgAUTO software (Emka Technologies). Over the first 3 h, the emetic response was also quantified via direct observation of the animals. The data produced by the 3 methods of detection were compared using a Spearman's rank correlation coefficient. RESULTS: Visual, manual and automated detections of early emetic events over the first 3-hour recording period were well correlated when compared per 30-, 15- or 5-minute epoch: correlation coefficients ranging from 0.8640 to 0.9289, p<0.0001 for all comparisons. Manual and automated detections of early and delayed emetic events over the 72-hour recording period were also well correlated when compared per 3-hour epoch: correlation coefficient=0.9190, p<0.0001. DISCUSSION: These findings demonstrate that automated detection of abdominal pressure changes with adapted software is a reliable method for measuring emetic events in the ferret. The results obtained open major possibilities for the rapid, comprehensive and objective analysis of delayed emesis. They should thereby facilitate the development of novel chemotherapeutic agents and anti-emetic therapies.

Continuous evaluation of drug withdrawal in the rat using telemetry: effects of morphine and chlordiazepoxide.

INTRODUCTION: The procedures used to assess withdrawal must be sensitive and widely applicable, i.e. not specific to any particular drug class. Furthermore, the measurements should not be affected by repeat testing. METHODS: We have used implanted telemetry devices to continuously follow body temperature, locomotor activity (LMA), heart rate (HR) and mean arterial blood pressure (mean ABP) in addition to food intake and body weight gain over 20days of treatment and 8days of withdrawal. The effects of morphine (32 and 64mg/kg p.o., b.i.d.) and chlordiazepoxide (16, 32 and 64mg/kg p.o., b.i.d.) were studied in rats. RESULTS: The results show that during the treatment phase chronic morphine reduced food intake and body weight gain, increased body temperature, HR, mean ABP and LMA. These effects continued over the 20days of treatment. In contrast, chlordiazepoxide slightly increased food intake and body weight gain throughout the treatment period. It also decreased body temperature and LMA but increased HR and mean ABP after the first few administrations but these effects disappeared over the 20days of treatment. Following discontinuation, both morphine- and chlordiazepoxide-treated rats showed a dose-related decrease in food intake and loss of weight on days 2 and 3 of discontinuation. Morphine discontinuation also induced a nocturnal hypothermia and a diurnal hypertension (i.e. during the light phase) which lasted for 4-5days and also moderate diurnal increases in locomotor activity and heart rate over the first 3days of discontinuation. Chlordiazepoxide discontinuation induced small increases in telemetry parameters some of which, such as the effect on locomotor activity, lasted for more than 5days. The intensity and duration of effects for both substances were broadly dose-related. DISCUSSION: These data show that telemetry can increase the sensitivity of withdrawal experiments to changes that might otherwise be missed and allows a better definition of the time-course of withdrawal effects. This technique is therefore useful as part of safety pharmacology abuse liability evaluation of novel test substances across a broad range of pharmacological and therapeutic classes.

No altered blood pressure and serum markers of oxidative stress after a long time dietary fish oil in the genetically 9 month-old type-2 diabetes Zucker rat.

In this study, we investigated the effect of a high n-3 fatty acid diet (eicosapentaenoic and docosahexaenoic acids) in Zucker obese and lean rats on blood pressure in association with physiological parameters, serum biochemistry and oxidative stress analysis. After 150 days of treatment, dietary fish oil supplementation in Zucker obese rats (9 months of age) reduces bodyweight gain and serum triglyceridemia and nitrite levels, increases serum glucose and angiotensin converting enzyme activity, but does not alter blood pressure, cholesterol levels and serum markers of oxidative stress (malondialdehyde, glutathione), compared to the Zucker rats fed control diet. According to these results, we can consider that after 150 days of treatment, fish oil is not enough to regulate parameters involved in the metabolic syndrome, such as cholesterolemia and blood pressure, in a 9 month-old genetically type-2 diabetes rat.

Ventilatory function assessment in safety pharmacology: optimization of rodent studies using normocapnic or hypercapnic conditions.

Although the whole body plethysmography for unrestrained animals is the most widely used method to assess the respiratory risk of new drugs in safety pharmacology, non-appropriate experimental conditions may mask deleterious side effects of some substances. If stimulant or bronchodilatory effects can be easily evidenced in rodents under standard experimental conditions, i.e. normal air breathing and diurnal phase, drug-induced respiratory depression remains more difficult to detect. This study was aimed at comparing the responsiveness of Wistar rats, Duncan Hartley guinea-pigs or BALB/c mice to the respiratory properties of theophylline (50 or 100 mg/kg p.o.) or morphine (30 mg/kg i.p.) under varying conditions (100% air versus 5% CO2-enriched air, light versus dark day phase), in order to select the most appropriate experimental conditions to each species for safety airway investigations. Our results showed that under normocapnia the ventilatory depressant effects of morphine can be easily evidenced in mice, slightly observed in guinea-pigs and not detected in rats in any day phase. Slight hypercapnic conditions enhanced the responsiveness of rats to morphine but not that of guinea-pigs and importantly they did not blunt the airway responsiveness of rats to the stimulation and bronchodilation evoked by theophylline, the most widely used reference agent in safety pharmacology studies. In conclusion, hypercapnic conditions associated with the non-invasive whole body plethysmography should be considered for optimizing the assessment of both the ventilatory depressant potential of morphine-like substances or the respiratory stimulant effects of new drugs in the rat, the most extensively used species in rodent safety and toxicological investigations.