The combination of insulin-like growth factor I and insulin-like growth factor-binding protein-3 reduces insulin requirements in insulin-dependent type 1 diabetes: evidence for in vivo biological activity.

Insulin-like growth factor-I (IGF-I) enhances insulin action in normal subjects and in patients with both type 1 and 2 diabetes; however, its administration is associated with significant side effects in a high percentage of patients. The coadministration of IGF binding protein-3 (IGFBP-3, the predominant IGF binding protein in serum) with IGF-I limits IGF-I inducible side effects, but it does not attenuate the ability of IGF-I to enhance protein synthesis and bone accretion; therefore, we determined whether IGF-I/IGFBP-3 would retain biological activity in type 1 DM and limit side effects associated with free IGF-I administration. Twelve patients received recombinant human IGF-I plus IGFBP-3 (2 mg/kg-day) by continuous sc infusion for 2 weeks. Each subject served as his own control; and, during a paired 2-week period, each received a placebo infusion. The order of the treatments was randomized. Subjects were placed on a constant caloric intake but were allowed to adjust insulin doses to maintain appropriate levels of glycemic control. Subjects measured blood glucose four times per day at home and kept a log of their insulin use. Frequent sampling for glucose, insulin, and GH was conducted during four inpatient study periods, one at the beginning and one at the end of each 2-week study interval. During IGF-I/IGFBP-3, insulin doses were reduced by 49%, and mean serum glucose was reduced by 23%. Free insulin levels obtained during frequent sampling in hospital fell 47% on IGF-I/IGFBP-3, compared with control, but showed no change with placebo. Concomitant glucose measurements did not differ in the two treatment groups. There was no change in body weight. Fructosamine levels decreased by 12%, but this was not significant (P < 0.1). Fasting triglyceride was unchanged, but cholesterol declined from 170 +/- 24 to 149 +/- 31 mg/dL (P < 0.05). IGFBP-2 (an IGF-I-dependent responsive variable) rose from 141 +/- 56 to 251 +/- 98 ng/mL (P < 0.01) on IGF-I/IGFBP-3. To analyze the mechanism by which IGF-I/IGFBP-3 might reduce insulin requirements, the change in serum GH was quantified. Mean GH levels were reduced by 72%, from 2.48 to 0.55 ng/mL (P < 0.001). An equal number (40%) of drug- and placebo-treated subjects had minor hypoglycemic episodes at home that required adjustment of insulin doses. No episode was classified as severe. In contrast to previous studies with free IGF-I, there were no cases of edema, headache, jaw pain, retinal edema, or Bell's palsy. No subject withdrew because of drug complications. These findings indicate that IGF-I/IGFBP-3 is biologically active on carbohydrate metabolism, as measured by a decrease in insulin requirements in patients with type 1 diabetes. Further studies will be required to determine the long-term safety and efficacy of this combination in patients with insulin resistance and diabetes.

Pharmacokinetics of repaglinide in subjects with renal impairment.

OBJECTIVE: To evaluate the effect of renal impairment and renal failure on the pharmacokinetics and safety of repaglinide. METHODS: We conducted a phase I, multicenter, parallel-group, pharmacokinetic comparison trial with single and multiple doses of repaglinide in subjects with various degrees of renal impairment. Subjects with normal renal function (n = 6) and subjects with renal impairment (mild to moderate, n = 6; severe, n = 6) received treatment with 2 mg repaglinide for 7 days. Subjects in the hemodialysis group (n = 6) received two single doses of 2 mg repaglinide separated by a 7- to 14-day washout period. All subjects had repaglinide serum pharmacokinetic profiles measured for the first and last doses administered. Serum steady-state levels, urine levels, and dialysate levels were also measured. RESULTS: Pharmacokinetic parameters did not show significant changes after single or multiple doses of repaglinide, although the elimination rate constant in the group with severe renal impairment decreased after 1 week of treatment. Subjects with severe impairment had significantly higher area under the curve values after single and multiple doses of repaglinide than subjects with normal renal function. No significant differences in values for maximum serum concentration or time to reach maximum concentration were detected between subjects with renal impairment and those with normal renal function. Hemodialysis did not significantly affect repaglinide clearance. CONCLUSIONS: Repaglinide was safe and well tolerated in subjects with varying degrees of renal impairment. Although adjustment of starting doses of repaglinide is not necessary for renal impairment or renal failure, severe impairment may require more care when upward adjustments of dosage are made.

Reduction of transmission stages concomitant with increased host immune responses to hypervirulent Sarcocystis singaporensis, and natural selection for intermediate virulence.

Parasite virulence (pathogenicity depending on inoculum size) and host immune reactions were examined for the apicomplexan protozoan Sarcocystis singaporensis. This parasite is endemic in southeastern Asia and multiplies as a proliferation (merozoite) and transmission stage (bradyzoite) in rats. Virulence in wild brown rats of parasites freshly isolated in the wild (wild-type) was surprisingly constant within the endemic area and showed an intermediate level. In contrast, serially passaged parasites either became avirulent or virulence increased markedly (hypervirulence). Production of transmission stages was maximal for the wild-type whereas numbers were significantly reduced for hypervirulent and avirulent (shown in a previous study) parasites. Analyses of B and T cell immunity revealed that immune responses of WKY rats to the transmission stage were significantly higher for hypervirulent than for wild-type parasites. These results suggest that it is the immune system of the host that is not only responsible for reduction of transmission stages in individual rats, but also could act as a selective force that maintains intermediate virulence at the population level because reduction of muscle stages challenges transmission of S. singaporensis to the definitive host. Collectively, the presented data support evolutionary theory, which predicts intermediate rates of parasite growth in nature and an 'arms race' between host immunity and parasite proliferation.

A comparison of the pharmacokinetics and tolerability of the novel antimigraine compound zolmitriptan in adolescents and adults.

This open-label, parallel-group study assessed pharmacokinetics and tolerability of zolmitriptan, a 5-HT1B/1D agonist for the acute treatment of migraine, and its active metabolite, 183C91, in adolescents compared with adults. Twenty-one healthy adolescent and 18 healthy adult volunteers (with and without history of migraine) received a single 5-mg dose of zolmitriptan. Mean ages were 14.5 years (range 12-17) for adolescents (13 girls, 8 boys) and 39.1 years (range 18-65) for adults (12 women, 6 men). The area under the curve (AUC) and highest observed plasma concentration (Cmax) of zolmitriptan were similar in both age groups; the half-life was 3.01 hours in adolescents versus 3.75 hours in adults. The AUC and Cmax of 183C91, however, were 36% and 39% higher in adolescents, respectively; the half-life was similar in both age groups. Adverse events were similar in both groups in terms of nature, intensity, and frequency. Exposure to zolmitriptan was not significantly different in adolescents compared with adults, but a shorter half-life in adolescents suggests faster elimination in this age group. Exposure to 183C91 was higher in adolescents, suggesting that formation of the metabolite is at least one of the elimination routes of zolmitriptan that occurs at a faster rate in adolescents.

Depression. Management techniques in primary care.

Depression is a commonly encountered problem in primary medical care. In cases of mild reactive depression, supportive psychotherapy by the primary care physician may be sufficient treatment. Referral for specialized psychotherapy (interpersonal, cognitive, or behavioral therapy) should be considered when psychological risk factors are thought to play an important role in the patient's depression. According to recent clinical trials, specialized psychotherapy is as effective in treating depression as standard tricyclic anti-depressant therapy and can be used as an alternative to medication. When used in conjunction with medication, psychotherapy may enhance compliance and therapeutic efficacy.

Safety and pharmacokinetics of single doses of (+)-calanolide a, a novel, naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy, human immunodeficiency virus-negative human subjects.

(+)-Calanolide A is a novel, naturally occurring, nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase first isolated from a tropical tree (Calophyllum lanigerum) in the Malaysian rain forest. Previous studies have demonstrated that (+)-calanolide A has specific activity against the reverse transcriptase of HIV-1 and a favorable safety profile in animals. In addition, (+)-calanolide A exhibits a unique HIV-1 resistance profile in vitro. The safety and pharmacokinetics of (+)-calanolide A was examined in four successive single-dose cohorts (200, 400, 600, and 800 mg) in healthy, HIV-negative volunteers. In this initial phase I study, the toxicity of (+)-calanolide A was minimal in the 47 subjects treated. Dizziness, taste perversion, headache, eructation, and nausea were the most frequently reported adverse events. These events were not all judged to be related to study medication nor were they dose related. While 51% of subjects reported mild and transient dizziness, in many cases this appeared to be temporally related to phlebotomy. Calculation of the terminal-phase half-life (t(1/2)) was precluded by intrasubject variability in the 200-, 400-, and 600-mg dose cohorts but was approximately 20 h for the 800-mg dose group. (+)-Calanolide A was rapidly absorbed following administration, with time to maximum concentration of drug in plasma (T(max)) values occurring between 2.4 and 5.2 h postdosing depending on the dose. Plasma levels of (+)-calanolide A at all dosing levels were quite variable; however, both the mean concentration in plasma (C(max)), and the area under the plasma concentration-time curve increased proportionately in relation to the dose. Although raw plasma drug levels were higher in women than in men, when doses were normalized for body mass, the pharmacokinetic profiles were virtually identical with those observed for males. In general, levels of (+)-calanolide A in human plasma were higher than would have been predicted from animal studies, yet the safety profile remained benign. In conclusion, this study demonstrated the safety and favorable pharmacokinetic profile of single doses of (+)-calanolide A in healthy, HIV-negative individuals.