Efficacy & tolerability of ondansetron compared to metoclopramide in dose dependent cisplatin-induced delayed emesis.

BACKGROUND & OBJECTIVES: Delayed emesis with cisplatin is a significant problem, which is often poorly controlled with conventional antiemetics. There is a relative paucity of data on the control of delayed emesis and rather inconsistent results have been reported. The present study aimed to compare the efficacy and tolerability of ondansetron versus metoclopramide in dose related grades of cisplatin-induced delayed emesis. METHODS: A total of 80 chemotherapy naive patients with malignancy were randomized to receive cisplatin 60 mg/m2 intravenously (iv) either as a single dose on day 1 (high dose regimen) or split into three doses of 20 mg/m2 each on 3 days (low dose regimen) along with bleomycin +5- fluorouracil in 40 patients each. Patients were further randomized in each cisplatin regimen to receive either 20 mg metoclopramide (20 patients) or 8 mg ondansetron (20 patients) iv 30 min prior to cisplatin administration followed by the respective antiemetic orally 8 hourly for five days after the last cisplatin administration. Ten patients receiving high dose cisplatin in each group were also given dexamethasone 8 mg iv with the primary antiemetic. The assessment period started 24 h after last cisplatin infusion and ended at midnight on day 5. RESULTS: In low dose cisplatin regimen, complete suppression of delayed emesis occurred in 55 per cent patients receiving ondansetron and in 30 per cent patients receiving metoclopramide. Neither ondansetron nor metoclopramide could completely suppress delayed emesis in high dose cisplatin regimen. Protection from nausea in the delayed phase was seen in 85 per cent patients receiving ondansetron and in 70 per cent patients receiving metoclopramide in low dose regimen, while nausea protection rates were 70 vs 0 per cent respectively in the high dose regimen. Addition of dexamethasone to metoclopramide significantly augmented its antiemetic efficacy (P<0.02) and the combination of metoclopramide + dexamethasone was found to be as efficacious as ondansetron monotherapy. Twenty out of 80 patients reported 39 adverse events of mild intensity. No significant effects on QOL (quality of life) parameters were observed in any group over the 5-day period. INTERPRETATION & CONCLUSION: The results demonstrate that delayed emesis due to cisplatin is also dose related, and superior antiemetic efficacy of ondansetron compared to metoclopramide is maintained, though its superiority is less marked than against acute emesis. Metoclopramide and dexamethasone combination matched the antiemetic efficacy of ondansetron monotherapy.

Comparison of ondansetron with metoclopramide in prevention of acute emesis associated with low dose & high dose cisplatin chemotherapy.

BACKGROUND & OBJECTIVES: Nausea and vomiting remain the most distressing side effects of cancer chemotherapy. The present study aimed to study the efficacy and tolerability of ondansetron versus (vs) metoclopramide in different dose related grades of cisplatin induced acute emesis. METHODS: A total of 137 patients were enrolled and 80 completed the study. Cisplatin 60 mg/m2 was given intravenously (iv) either as a single dose on day 1 (high dose regimen) or in three doses of 20 mg/m2 each on days 1-3 (low dose regimen) along with bleomycin +5-flurouracil in 40 patients each. Patients were randomized in each cisplatin regimen to receive either 20 mg metoclopramide (20 patients) or 8 mg ondansetron (20 patients) iv 30 min prior to cisplatin administration followed by 20 mg metoclopramide or 8 mg ondansetron orally 8 h respectively for 24 h after the last cisplatin administration. Ten patients receiving high dose cisplatin in each group were also given dexamethasone 8 mg iv with the primary antiemetic. Patients were assessed for 24 h after the last cisplatin injection. RESULTS: In low dose cisplatin regimen, complete suppression of acute emesis occurred in 65 per cent patients receiving ondansetron versus 30 per cent receiving metoclopramide, while in high dose regimen, complete response rate was 20 per cent with ondansetron versus 0 per cent with metoclopramide. Dexamethasone significantly augmented the antiemetic efficacy of metoclopramide but not that of ondansetron. Protection from nausea in the acute phase was seen in 95 per cent patients receiving ondansetron vs 70 per cent receiving metoclopramide in low dose regimen. With high dose the protection rates were 90 vs 0 per cent respectively. Combination of dexamethasone + metoclopramide achieved 70 per cent protection while dexamethasone + ondansetron was effective in 90 per cent. Dropouts and withdrawals were more among patients receiving high dose cisplatin and antiemetic regimens without dexamethasone. Thirty nine adverse events were reported by 20 out of 80 patients. All adverse events were mild. INTERPRETATION & CONCLUSION: The results demonstrate dose related emetogenicity of cisplatin and superior antiemetic efficacy of ondansetron, especially against high dose cisplatin regimen. Dexamethasone potentiated efficacy of metoclopramide but not that of ondansetron. The combination of metoclopramide plus dexamethasone was found to be as efficacious as ondansetron monotherapy.

Correlation of serum and salivary carbamazepine concentration in epileptic patients: implications for therapeutic drug monitoring.

Therapeutic drug monitoring (TDM) of carbamazepine (CBZ) in saliva is an attractive alternative, because its collection is painless, non-invasive and simpler than drawing blood. Salivary drug levels, also closely reflect the free drug concentration. The aim of the study was to evaluate the suitability of saliva in routine TDM of CBZ in adult epileptic patients. Blood and saliva samples were taken simultaneously at 0 hours and 24 hours of CBZ dosing from 31 epileptic patients, receiving CBZ monotherapy for three or more months. Levels of CBZ in both these fluids were measured by high performance liquid chromatography. Strong and highly significant correlation was found between serum and salivary CBZ concentration (r = 0.659, p<0.001). Estimation of CBZ level in saliva is thus a practicable, valid and convenient method of TDM in epileptic patients.

Association of drug levels & pharmacokinetics of carbamazepine with seizure control.

BACKGROUND & OBJECTIVES: A sizeable number of epilepsy patients remain uncontrolled with carbamazepine (CBZ) monotherapy. While the therapeutic plasma concentration range of CBZ is only vaguely defined, pharmacokinetic differences in the disposition of CBZ among subjects could be responsible for the inadequate control of seizures in some. This study was aimed at associating serum CBZ levels with seizure control and elucidating any pharmacokinetic differences between patients with controlled and uncontrolled epilepsy. METHODS: The study was conducted in 16 controlled and 15 uncontrolled adult epileptic patients receiving CBZ monotherapy for the previous 3 or more months, without any dosage change. Blood samples were drawn from the patients before and 0.5, 1, 2, 3, 4, 8, 12 and 24 h after ingestion of their total daily dose of CBZ. Serum CBZ levels were measured by HPLC and the pharmacokinetic parameters were calculated. RESULTS: The uncontrolled epileptic patients were receiving a higher daily dose of CBZ (difference not significant). The trough and peak serum CBZ levels were relatively higher in the uncontrolled group, and at no time point were the drug levels lower in these patients compared to the controlled group. The absorption kinetics, volume of distribution and plasma half life of CBZ were similar in the two groups. Thus, non-attainment or non-maintenance of therapeutic CBZ level or other pharmacokinetic difference was not responsible for occurrence of seizures in the uncontrolled patients. A high percentage of patients with generalised tonic clonic seizures (73%) and simple partial seizures (SPS) with generalisation (66%) were controlled by CBZ, while SPS and complex partial seizures (CPS) were largely uncontrolled. INTERPRETATION & CONCLUSIONS: It appears that pharmacodynamic resistance of the seizure to CBZ rather than pharmacokinetic factors is responsible for lack of efficacy of CBZ in nonresponding epileptic patients.

Curative efficacy of norfloxacin in falciparum malaria.

Fifteen patients of uncomplicated falciparum malaria from Delhi were treated with norfloxacin (10 with 400 mg, 5 with 800 mg, both twice daily) for 3 days and the response was measured according to the WHO extended in vivo test criteria. The lower dose produced S response in two, RII response in five and RIII response in three patients, while the higher dose produced S response in four and RI response in one patient. In patients with S or RI response, the parasite clearance time was 68.6 +/- 9.1 h the defervescence time being 48 h. Thus, norfloxacin did reveal in vivo activity in falciparum malaria, but a dose of 400 mg twice daily proved to be curative only in a small percentage of cases and not consistently. Nausea and bitter taste were the only side effects noted in two patients.

Single dose pharmacokinetics of lithium & prediction of maintenance dose in manic depressive patients.

Pharmacokinetics of lithium was studied in 60 manic-depressive patients after an initial dose of 900 mg, in serial blood samples for 24 h. The values (mean +/- SD) obtained were peak serum Li concentration 0.81 +/- 0.18 mEq/l; time to peak 2.57 +/- 0.87 h; total Li clearance 33.2 +/- 15.5 ml/min; volume of distribution 0.62 +/- 0.26 l/kg; elimination rate constant 0.0514 +/- 0.02 h; area under serum concentration-time curve 16.41 +/- 11.41 mEq/1 h; serum half life 15.34 +/- 6.06 h. Thereafter, the applicability of various dose prediction methods was evaluated vis-a-vis the actual doses needed to attain steady state serum lithium concentration of 0.6-1.2 mEq/l in 46 patients. The method based on body weight was not found suitable. A nomographic method predicted higher doses in 27 patients, while Zetin's mathematical model predicted dose was in the range of +/- 150 mg of the actual dose in 21 patients. A method for predicting maintenance dose based on 24 h serum lithium level and body weight is suggested.