No abstract

The intrathecal delivery of r-metHuBDNF in doses of up to 150 microg/day was well tolerated and appears feasible. The reversible CNS effects with higher dose indicate that BDNF can be delivered cranially against CSF flow. The small number of patients and the design of the study did not permit conclusions to be drawn about the efficacy of the treatment.

Receptor autoradiography with (−)‐[125 I]‐cyanopindolol (CYP) was used to study the distribution of β1 and β2‐adrenoceptor subtypes in the human internal mammary artery and saphenous vein. Images from X‐ray film and nuclear emulsion coated coverslips, exposed to [125 I]‐CYP labelled sections, showed a high density of β2‐adrenoceptors localized to the endothelium of the internal mammary artery and fewer β2‐adrenoceptors on the smooth muscle. The function of β‐adrenoceptors in ring preparations of the internal mammary artery was investigated in organ bath studies. (−)‐Isoprenaline produced concentration‐dependent relaxation of phenylephrine contracted rings. The potency and maximal effects of (−)‐isoprenaline were not influenced by the presence of the endothelium. Images of [125 I]‐CYP binding to the saphenous vein, from X‐ray film and nuclear emulsion coated coverslips, showed localization of β2‐adrenoceptors to the outer smooth muscle and not to the endothelium. Relaxation of mammary artery and saphenous vein to (−)‐isoprenaline is mediated via β2‐adrenoceptors located on the smooth muscle. Endothelial β2‐adrenoceptors, although present on the internal mammary artery, mediate other functions.

1(-)-Isoprenaline and the selective P1-adrenoceptor agonist R0363 were tested for their inotropic effects in left atrial (1i,) 3 The pKD values for (-)-isoprenaline were similar in the two tissues (left atria 6.4, uterus 6.0) whilst for R0363 the atrial value (7.8) was considerably greater than that for the uterus (6.0). The latter value is very similar to the pKB value determined from shifts in (-)-isoprenaline curves produced by R0363 in uterine preparations. 4 Graphical plots of the fraction of receptors occupied vs response were constructed. The relative efficacy of (-)-isoprenaline with respect to R0363 was calculated to be 25 in atrial and 2633 in uterine preparations.5 The selective Pf-adrenoceptor stimulant actions of R0363 are a reflection of both its greater affinity and efficacy for Pl-as opposed to P2-adrenoceptor sites. The potent actions of (-)-isoprenaline in both tissues are largely dependent on efficacy.

BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and non-human primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP. The single-dose no-observed-adverse-effect-levels (NOAELs) were 7 mg (28 mg/kg) in rats and 60 mg (20 mg/kg) in NHP, corresponding to peak concentration values of 89,400 ng/mL and 436,000 ng/mL and area-under-the-curve exposure values of 130,000 hr*ng/mL and 1,240,000 hr*ng/mL, respectively. Based on a human imaging dose of 3 mg, dose safety margins are > 100 for rat and monkey. BLZ-100 produced hypersensitivity reactions in canine imaging studies (lethargy, pruritus, swollen muzzle, etc.). The severity of the reactions was not dose-related. In a follow-up study in dogs, plasma histamine concentrations were increased 5 to 60 minutes after BLZ-100 injection; this coincided with signs of hypersensitivity, supporting the conclusion that the reactions were histamine-based. Hypersensitivity reactions were not observed in other species or in BLZ-100 human clinical studies conducted to date. The combined imaging, safety pharmacology, PK, and toxicology studies contributed to an extensive initial nonclinical profile for BLZ-100, supporting first-in-human clinical trials.