D-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation.

No abstract

Previously, it has not been possible to address the effect of treatment of postprandial hyperglycemia specifically. We have now shown that the treatment of postprandial hyperglycemia with insulin lispro markedly improves overall glucose control and some lipid parameters in patients with type 2 diabetes.

The high potency and selectivity of new aromatase inhibitors has translated to greater efficacy and improved tolerability in comparison with established second-line hormonal agents for advanced breast cancer in phase III clinical trials. Two pharmacological studies are reported which assess the use of one of these inhibitors, vorozole, in combination or comparison with well-established methods of oestrogen deprivation in pre and postmenopausal patients. When combined with the gonadotrophin-releasing hormone agonist (GnRHa) goserelin in 10 premenopausal patients, vorozole markedly enhanced the suppression of serum levels of oestrone, oestradiol and, oestrone sulphate beyond that achieved by goserelin alone (by a mean 74%, 83%, and 89%, respectively). The combination was well-tolerated and had no significant effects on androgen levels. Vorozole was compared with formestane in 13 postmenopausal women and serum oestrone, oestradiol, and oestrone sulphate levels were suppressed by 47%, 30%, and 70%, respectively, more by vorozole than by the steroidal aromatase inhibitor. Again the tolerability was excellent. The plasma oestrogen levels in the postmenopausal patients on vorozole were lower than in the premenopausal patients on goserelin plus vorozole, indicating that ovarian oestrogen synthesis may be relatively resistant to aromatase inhibition, even during GnRHa treatment. Thus, in both pre and postmenopausal patients substantially greater suppression of oestrogen can be achieved by vorozole compared with alternative approaches. Existing clinical-pharmacological correlates suggest that these increases in pharmacological effectiveness may result in enhanced clinical effectiveness.

It is well known that in vitro the combination of carbenicillin, ticarcillin, or other antipseudomonal penicillins with gentamicin, tobramycin, or other aminoglycoside antibiotics results in the inactivation of the antibacterial activity of the aminoglycoside. To assess the influence of the in vivo interaction of tobramycin and ticarcillin on experimental nephrotoxicity, male Fischer 344 rats were given either tobramycin alone (120 mg/kg per day), tobramycin (120 mg/kg per day) and ticarcillin (250 mg/kg per day) concomitantly, or the combination of these drugs at the same d9ses that had been preincubated for 24 h and at the time of delivery contained but 63 and 25%, respectively, of the initial concentrations of tobramycin and ticarcillin as measured by conventional analytical procedures. Initial experiments were conducted to determine the concentrations of the antibiotics in serum achieved after administration of each test solution. After a single dose of the test solution, ticarcillin concentrations in serum were higher and more prolonged in rats given tobramycin plus ticarcillin than in rats given ticarcillin alone. After 7 days of exposure to the test solutions, inulin clearance in animuals giVen tobramycin alone was 0.15 ± 0.1 (mean ± 2 standard errors) ml/min per 100 g of body weightas compared with 0.53 ± 0.1 in rats given tobramycin and ticarcillin concomitantly, 0.59 ± 0.1 in animals given the partially inactivated tobramycin-ticarcillin mixture, and 0.79 ± 0.1 in control rats. Although there was some improvement in inulin clearance in the group containing tobramycin alone, the three treatment groups maintained the same rank relationship in inulin clearance through 14 days of treatment. Renal histology confirn9ed the attenuation of tubular injury in animals given tobramycin and ticarcillin concomitantly. There was no evidence of toxicity from the presumed inactivation complexes of tobramycin-ticarcillin. These results document an in vivo protective effect of ticarcillin on experimental tobramycin nephrotoxicity.The in vitro inactivation of aminoglycoside antibiotics by carbenicillin, ticarcillin, and other antipseudomonal penicillins is well described (3, 6-9, 12, 16-19). This interaction may have clinical importance when low aminoglycoside concentrations in serum from patients are the result of aminoglycoside inactivation in vitro before drug assay (7,8,18). The in vivo significance of this interaction is not considered important in patients with normal renal function.In patients with preexisting renal impairment and prolonged half-lives of both drugs, the serum half-life of aminoglycosides is decreased by concomitant antipseudomonal penicillin therapy (3, 6, 9).With the notable exception of streptomycin, all of the aminoglycosides used clinically have been shown to accumulate in the renal cortex of experimental animals (5, 15). Since the half-life in the renal cortex is prolonged (14, 15), it was postulated that an interaction between the aminoglycoside and penicillin might take place in or near the ...