Tissue disposition and pharmacokinetics of recombinant human nerve growth factor after acute and chronic subcutaneous administration in monkeys.

In this study, we have characterized the metabolism, tissue disposition, excretion routes, and plasma pharmacokinetics of recombinant human nerve growth factor after single and multiple s.c. administration in male cynomolgus monkeys. Unlabeled nerve growth factor (NGF; 2 mg/kg) was administered three times a week for 4 weeks and a full pharmacokinetic profile was obtained for doses 1 and 12. For the tissue distribution studies, 0.8 microg/kg of trace (125)I-labeled recombinant human nerve growth factor was dosed. Histological analysis of emulsion-microautoradiography indicated that specific (125)I-NGF labeling was confined to sections of nerves most frequently localized adjacent to large vessels in sections of kidney, spleen, liver, and salivary gland. A small percentage of large neurons within the sympathetic ganglia were intensely labeled, as well as large neurons within the dorsal root ganglia. We found an increased disposition of (125)I-NGF in parts of the peripheral nervous system (including sympathetic ganglia) from 8 to 24 h postdose. In contrast, radioactivity in most non-neuronal tissues declined. This suggests specific uptake in these target tissues known to express specific receptors for NGF. We also identified changes in pharmacokinetic parameters after single versus chronic s. c. administration. These studies demonstrated that s.c. administration of NGF at 0.8 microg/kg doses in monkeys is capable of accessing and localizing in the target tissues.

Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment.

PURPOSE: To determine the toxicity, pharmacokinetics, response rate, and response duration of intravenous (i.v.) administration of recombinant, humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) plus cisplatin (CDDP) in a phase II, open-label, multicenter clinical trial for patients with HER2/neu-overexpressing metastatic breast cancer. PATIENTS AND METHODS: The study population consisted of extensively pretreated advanced breast cancer patients with HER2/neu overexpression and disease progression during standard chemotherapy. Patients received a loading dose of rhuMAb HER2 (250 mg i.v.) on day 0, followed by weekly doses of 100 mg i.v. for 9 weeks. Patients received CDDP (75 mg/m2) on days 1, 29, and 57. RESULTS: Of 37 patients assessable for response, nine (24.3%) achieved a PR, nine (24.3%) had a minor response or stable disease, and disease progression occurred in 19 (51.3%). The median response duration was 5.3 months (range, 1.6-18). Grade III or IV toxicity was observed in 22 of 39 patients (56%). The toxicity profile reflected that expected from CDDP alone with the most common toxicities being cytopenias (n = 10), nausea/vomiting (n = 9), and asthenia (n = 5). Mean pharmacokinetic parameters of rhuMAb HER2 were unaltered by coadministration of CDDP. CONCLUSION: The use of rhuMAb HER2 in combination with CDDP in patients with HER2/neu-overexpressing metastatic breast cancer results in objective clinical response rates higher than those reported previously for CDDP alone, or rhuMAb HER2 alone. In addition, the combination results in no apparent increase in toxicity. Finally, the pharmacology of rhuMAb HER2 was unaffected by coadministration with CDDP.

Pharmacokinetics and pharmacodynamics of TP-9201, a gpIIbIIIa antagonist, administered in combination with recombinant tissue-type plasminogen activator, heparin, and aspirin in beagles.

The effect of heparin, aspirin, and recombinat tissue-type plasminogen activator (rt-PA) on TP-9201 pharmacokinetics and pharmacodynamics was investigated in beagles. Animals received TP-9201, an Arginine-Glycine-Aspartic acid (RGD)-containing synthetic peptide glycoprotein (gp)IIbIIIa antagonist as a bolus of 0.31 mg/kg, followed by a 4-h infusion of 0.5 mg/kg/h. rt-PA was administered as a modification of the weight-adjusted standard regimen. Heparin was administered as a bolus followed by an infusion producing a 1.5- to 2-fold increase in the activated prothromboplastin time (aPTT) above baseline values. Aspirin was administered orally, approximately 24 and 2 h before TP-9201. TP-9201 had a plasma clearance of 9.9 +/- 2 ml/min/kg and a volume of distribution that was larger than plasma volume. Administration of heparin and aspirin with TP-9201 did not affect the clearance of TP-9201, whereas rt-PA resulted in a faster clearance (p = 0.05). Whether the faster clearance is physiologic or a result of rt-PA interference in the TP-9201 assay is unclear. TP-9201 completely inhibited ADP-mediated platelet aggregation. After discontinuation of TP-9201, recovery of platelet aggregation had a half life (t1/2) of 2-3 h and was complete < or = 24 h. Coadministration of heparin did not interfere with TP-9201 pharmacodynamics, whereas aspirin and rt-PA slowed the recovery of platelet aggregation. The template bleeding time profile for the TP-9201-treated animals was similar to that of the aspirin-treated animals.

Pharmacokinetics and pharmacodynamics of TP-9201, a GPIIbIIIa antagonist, in rats and dogs.

Because activation of the glycoprotein IIbIIIa (GPIIbIIIa) on platelets represents the final common pathway of platelet aggregation, inhibition of fibrinogen binding to the GPIIbIIIa complex provides an excellent target for inhibiting platelet aggregation. Peptides containing the arginine-glycine-aspartic acid (RGD) sequence have been shown to inhibit the binding of fibrinogen to the GPIIbIIIa receptor on platelets competitively. We studied the pharmacokinetics of TP-9201, a synthetic cyclic peptide containing the RGD sequence, in rats and dogs after a 24-h intravenous (I.V.) infusion at three doses. The mean plasma clearance of TP-9201 after intravenous infusions of 30, 150, and 600 mg/kg/day in rats was 20.2, 18.7, and 18.5 ml/min/kg, respectively. In beagles, TP-9201 clearance was 9.0, 7.5, and 7.3 ml/min/kg, corresponding to infusions of 10, 75, and 600 mg/kg/day, respectively. The volume of distribution was larger than plasma volume, and the terminal half-life (t1/2) was short in both species studied ranging from 0.5 to 0.7 h in rats and from 2.5 to 2.6 h in dogs. The results suggest that TP-9201 follows linear pharmacokinetics over the dose range studied. Despite the multiple blood sampling procedure used in the study, there were no hemorrhagic complications. Pharmacodynamic assessment in beagles showed that TP-9201 produces a dose-dependent inhibition of ADP-mediated platelet aggregation. The estimated in vivo IC50 value and sigmoidicity were 124 and 3.5 ng/ml, respectively, suggesting that TP-9201 is a potent GPIIbIIIa antagonist with a steep concentration-effect relationship. TP-9201 is rapidly cleared from the circulation on termination of the intravenous infusion. There is a corresponding reversal of platelet inhibition as TP-9201 is cleared from the circulation.

Evaluation of the adult carrier state in juvenile tinea capitis caused by Trichophyton tonsurans.

The anthropophilic dermatophyte Trichophyton tonsurans is an occasional cause of scalp ringworm in adults. An asymptomatic adult carrier state also has been described. In this study the parents and/or grandparents of 50 children with proved T. tonsurans tinea capitis were evaluated. Cultures were obtained from the scalps of 46 asymptomatic adults; 14 of the cultures grew T. tonsurans. This population may provide a source for continued reinfection in children.

Elephantiasis nostras--a case report.

Elephantiasis nostras, the result of chronic lymphedema, is characterized by marked edema of the affected extremity with a thickened, verrucous, pebbly appearance of the skin. The pathogenesis is thought to be related to fibroblast proliferation following impaired lymphatic drainage, leading to fibrosis and further restriction of lymph drainage with progressive edema. A case report of a patient with massive chronic lymphedema of her feet is presented.