The pharmacokinetics of a 25:1 combination of ticarcillin and clavulanate were studied in nine pre-term and seven full-term neonates. Pre-term neonates with a gestational age ranging from 30 to 36 weeks received 83.3 mg of ticarcillin and 3.3 mg of clavulanate per kg bw and full-term neonates with a gestational age from 39 to 43 weeks received 100 mg of ticarcillin and 4 mg of clavulanate per kg bw 8-hourly, each by a slow infusion over 10 min. Serum was sampled 15, 30, 60, 120, 240 and 480 min after the first dose and trough samples were additionally obtained on the fourth day of treatment. The patients were allocated to Groups 1-3 on the basis of the pharmacokinetic characteristics obtained. Group 1 comprised seven full-term babies. Group 2 contained seven pre-term neonates with a birth weight between 1915 and 2650 g and Group 3 consisted of two pre-term neonates of low birth weight (1400 g and 1640 g). Mean (+/- S.E.) pharmacokinetic characteristics of Group 1 patients for ticarcillin were: Cmax = 404.9 mg/l (36.0); T = 2.68 h (0.23); AUC = 1287 h.mg/l (69); Vd = 266 ml/kg (28) and for clavulanate: Cmax = 15.0 mg/l (1.2); T = 1.39 h (0.12); AUC = 30.1 h.mg/l (1.7); Vd = 263 ml/kg (22). Corresponding parameters for Group 2 patients for ticarcillin were: Cmax 278.7 mg/l (30.4); T = 4.20 h (0.49); AUC = 1107 h.mg/l (57); Vd = 338 ml/kg (35) and for clavulanate: Cmax = 8.4 mg/l (0.56); T = 2.56 h (0.18); AUC = 27.1 h.mg/l (2.0); Vd = 414 ml/kg (29). Drug accumulation was not observed in patients of Groups 1 and 2. Each of the two patients of Group 3 presented a pharmacokinetic profile which was considerably different from those observed in Groups 1 and 2. While in patients of the latter group the peak serum concentrations were achieved at 15-30 min after the end of infusion, these concentrations occurred between 120 and 240 min in one of the Group 3 patients. In the other Group 3 patient a remarkable drug accumulation was noted but was not associated with clinical or laboratory evidence of toxicity. These data show that ticarcillin and clavulanic acid in these dose ranges achieved adequate peak and trough concentrations in pre-term and full-term neonates.
A two-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased WBC levels, a class effect of benzimidazole anthelminthics, returned to normal during the recovery period. The NOAEL was determined to be >5 but < 25 mg/kg/d and the MTD 100 mg/kg/d. The highest dose, 200 mg/kg/d resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after seven days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma or rat micronucleus assays, nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases.
The pharmacokinetics of amoxycillin and potassium clavulanate were studied in 15 sick children after a 30 min iv infusion of 50 mg/kg amoxycillin and 5 mg/kg clavulanic acid as the potassium salt. Levels of both compounds in plasma were assayed microbiologically. Mean peak concentrations at the end of the infusion were 121.0 mg/l of amoxycillin and 12.0 mg/l of clavulanate, falling to a mean of 15.8 and 1.92 mg/l respectively after 2 h. Mean beta phase T 1/2 was 0.88 h for amoxycillin and 0.79 h for clavulanate. The elimination half-life of clavulanate in some individuals was much shorter because of higher plasma clearance. The data suggest that the treatment of some infections due to beta-lactamase producing organisms in such severely ill children may require more frequent iv administration of amoxycillin and potassium clavulanate, than in less severely affected children.
The effect of probenecid on the combination of amoxycillin/clavulanic acid has been compared with the effect on amoxycillin alone and it has been shown that probenecid, whilst producing its expected effect on amoxycillin, did not affect the clavulanic acid concentration of the combination. A possible minor role for tubular secretion of clavulanic acid is discussed.
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