Clinical effects of human macrophage inflammatory protein-1 alpha MIP-1 alpha (LD78) administration to humans: a phase I study in cancer patients and normal healthy volunteers with the genetically engineered variant, BB-10010.

BB-10010 is a genetically engineered variant of human macrophage inflammatory protein-1 alpha (hMIP-1 alpha) with improved pharmaceutical formulation properties. Although initially described as a pro-inflammatory cytokine, it is now recognised that hMIP-1 alpha has additional effects on haemopoietic stem cell cycling and on human immunodeficiency virus uptake by macrophages. In view of the potential clinical utility of the molecule, we have embarked on a clinical trials programme to evaluate the safety, tolerability and haematological effects of BB-10010. We now report the results of two phase I clinical studies in which 49 subjects (9 patients with advanced breast carcinoma and 40 normal healthy volunteers) received escalating doses of BB-10010, from 0.1 to 300 micrograms/kg using the subcutaneous (s.c.) or intravenous route (i.v.) of administration. Treatment was associated with a dose-related increase in monocyte count which peaked at 200% of steady-state levels and was preceded by an acute, short-lived, monocytopenia, 50-100% of baseline. no measurable effects were noted on other leucocyte subsets or on circulating progenitor cell numbers. In all cases, BB-10010 was extremely well tolerated with no significant toxicity observed at any dose level and a maximum tolerated dose was not defined. Pharmacokinetic analysis revealed that serum concentrations of BB-10010 were detectable using doses of > or = 10 micrograms/kg i.v. or > or = 30 micrograms/kg s.c., and that a single s.c. injection resulted in sustained plasma levels over a 24 h period. These preliminary studies have confirmed the safety and tolerability of BB-10010 using a dose range up to 300 micrograms/kg. Further clinical studies are ongoing to determine the biological effects and to investigate the potential myeloprotective properties using a variable dose range and schedule of BB-10010 in combination with cytotoxic chemotherapy.

Galanin-induced membrane depolarization of neonatal rat cultured dorsal root ganglion cells.

In this study we examined the effects of galanin on membrane currents recorded from neonatal rat cultured dorsal root ganglion neurones using the whole-cell patch-clamp technique. When neurones were voltage-clamped at -60 mV, galanin (1-300 nM) evoked an inward current associated with an increase in input conductance. These effects were observed in 21 of the 33 dorsal root ganglion neurones studied and were not attenuated by the galanin receptor antagonist galantide. Galanin fragments, galanin-(1-16) and galanin-(21-29) (300 nM) also elicited an inward current at -60 mV. The inward current induced by galanin was not linearly related to membrane potential indicating that the membrane current response was the result of more than one ionic event.