1 Using a dihydrofolate reductase inhibition assay, we have conducted either pharmacokinetic stud... more 1 Using a dihydrofolate reductase inhibition assay, we have conducted either pharmacokinetic studies in six patients receiving metoprine. 2 The serum level v time-curve for metoprine equivalents was irregular; first-order elimination was not observed during the study period of 0--120 h. A model-independent analysis was therefore performed, employing the area under the curve during the first 120 h (AUC). 3 At an oral dose of 65 mg/m2 without leucovorin, a peak level of 0.6 microgram/ml and an AUC of 52 micrograms ml-1 h produced significant leukopenia and thrombocytopenia. 4 At doses ranging from 100 mg/m2 to 175 mg/m2 orally, with leucovorin administration 40 mg/m2 intravenously at 24 and 96 h, haematologic toxicity was seen in only 1 patient who received 175 mg/m2. This patient also had the highest peak serum level (2.8 micrograms/ml) and AUC (228 micrograms ml-1 h). 5 One partial response and one minor regression were observed in the studied patients; these two patients had the 175 mg/m2 dose, highest peak levels (2.4 and 2.8 micrograms/ml) and highest AUCs (197 and 228 micrograms ml-1 h). The other patients had lower peak levels and AUCs and had neither therapeutic response nor hematologic toxicity. 6 The AUC and peak serum levels were linearly related to each other (P less than 0.001). 7 Total urinary excretion of dihydrofolate reductase inhibitors (as metoprine equivalents) in the first 120 h ranged from 5 to 17% of the administered dose.
Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecti... more Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis®) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo. We randomized women suffering from NVP to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2-4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through p...
1 Using a dihydrofolate reductase inhibition assay, we have conducted either pharmacokinetic stud... more 1 Using a dihydrofolate reductase inhibition assay, we have conducted either pharmacokinetic studies in six patients receiving metoprine. 2 The serum level v time-curve for metoprine equivalents was irregular; first-order elimination was not observed during the study period of 0--120 h. A model-independent analysis was therefore performed, employing the area under the curve during the first 120 h (AUC). 3 At an oral dose of 65 mg/m2 without leucovorin, a peak level of 0.6 microgram/ml and an AUC of 52 micrograms ml-1 h produced significant leukopenia and thrombocytopenia. 4 At doses ranging from 100 mg/m2 to 175 mg/m2 orally, with leucovorin administration 40 mg/m2 intravenously at 24 and 96 h, haematologic toxicity was seen in only 1 patient who received 175 mg/m2. This patient also had the highest peak serum level (2.8 micrograms/ml) and AUC (228 micrograms ml-1 h). 5 One partial response and one minor regression were observed in the studied patients; these two patients had the 175 mg/m2 dose, highest peak levels (2.4 and 2.8 micrograms/ml) and highest AUCs (197 and 228 micrograms ml-1 h). The other patients had lower peak levels and AUCs and had neither therapeutic response nor hematologic toxicity. 6 The AUC and peak serum levels were linearly related to each other (P less than 0.001). 7 Total urinary excretion of dihydrofolate reductase inhibitors (as metoprine equivalents) in the first 120 h ranged from 5 to 17% of the administered dose.
Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecti... more Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis®) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo. We randomized women suffering from NVP to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2-4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through p...
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