Background and objectives: This report summarizes the first phase 1 trial treating patients with microalbuminuric diabetic kidney disease (DKD) using FG-3019, a human monoclonal antibody to connective tissue growth factor (CTGF). CTGF is critically involved in processes of progressive fibrosis, including DKD. This phase 1, open-label, dose-escalation trial evaluated safety, pharmacokinetics, and possible therapeutic effects of FG-3019 on albuminuria, proteinuria, and tubular proteins.Design, setting, participants, and measurements: Microalbuminuric subjects (n ‫؍‬ 24) with type 2 (79%) or type 1 (21%) diabetes received 3 or 10 mg/kg FG-3019 dosed intravenously every 14 days for four doses. Albuminuria and safety follow-up were to days 62 and 365, respectively.Results: No infusion was interrupted for symptoms, although 5 of 24 subjects had mild infusion-day adverse events thought to be possibly drug-related. No subject developed anti-FG-3019 antibodies. FG-3019 clearance was lower at 10 mg/kg than at 3 mg/kg, suggesting a saturable elimination pathway. Although this study was not designed for efficacy testing, it was notable that urinary albumin/creatinine ratio (ACR) decreased significantly from mean pretreatment ACR of 48 mg/g to mean post-treatment (day 56) ACR of 20 mg/g (P ‫؍‬ 0.027) without evidence for a dose-response relationship.Conclusions: Treatment of microalbuminuric DKD subjects using FG-3019 was well tolerated and associated with a decrease in albuminuria. The data demonstrate a saturable pathway for drug elimination, minimal infusion adverse events, and no significant drug-attributable adverse effects over the year of follow-up. Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study.

SUMMARY Uridine 5-triphosphate (UTP) induced long-lasting contractions of isolated human brain arteries; contractions without decrement were observed for periods of up to 20-24 hours at which time the tissues were relaxed in a dose-dependent manner by theophylline. In some vessels, rhythmic oscillations accompanied the prolonged elevation in tension. In canine middle cerebral arteries, UTP produced dose-related contractions within the dose range of 1.7 X 10 6 to 1.7 X 10*M; these responses were unaffected by methysergide 2.8 X 10 'M, phenoxybenzamine 2.9 X 10 5 M or indomethacin 9.8 X 10"M, suggesting that the UTP mechanism of action is probably independent of tryptaminergic or alpha adrenergic receptor activation, or of prostaglandin biosynthesis. The ability of UTP to produce prolonged contraction of cerebral vessels, thus, provides an in vitro preparation in which it is possible to study some of the basic mechanisms that are associated with cerebral vasospasm.SEVERAL CHEMICALS are known to induce doserelated contractile effects in isolated cerebral blood vessels of various animal species;1 ' 2 -3 the analysis of these effects has been centered on the magnitude of the contractions and their relationship to dose size, with relatively little attention to the time-course or duration of the responses. The study of this latter parameter may provide information of importance to the genesis of cerebral vasospasm. Thus, it has been recently reported that in vitro exposure of bovine cerebral arteries to blood is associated with arterial contraction lasting for 10 hours, a finding which has been related to the pathogenesis of the first part of the biphasic cerebral vasospasm. 4 Longitudinal stretch of the rabbit basilar artery has been observed to induce constrictions for more than 72 hours suggesting that injury to the artery wall is an important element in the genesis of vasospasm. 6The present study deals with the time-course of, and possible mechanisms underlying, the contractile responses of isolated human and canine cerebral arteries to uridine 5'-triphosphate (UTP). UTP is a nucleotide reported to be present in platelets along with other nucleotides, 6 and its ability to act on cerebral blood vessels has not been explored before. The UTP-induced contractions of the human arteries last for up to 24 hours and are reversed by pharmacological agents. The significance of this observation to the problem of cerebral vasospasm is undefined at this time, but it suggests that some vasoactive agents have the potential to elicit well-sustained contractions of cerebral vessels. A preliminary report of this work has been presented elsewhere. Methods Human Cerebral ArteriesHuman cerebral arteries were obtained during autopsy of patients who had died 5 to 10 hours before. The cause of death was variable and unrelated to the ability of the vessels to develop tension in response to UTP. The arteries were placed in Krebs-Henseleit solution and cylindrical segments (5 mm in length and approximately 500 /xm in outside diameter) were ...

5-Hydroxytryptamine (5-HT), norepinephrine (NE), histamine (H) and potassium (K⁺) chloride induce dose-dependent changes in tension of the isolated middle cerebral artery of the goat. Vasopressin produces highly variable responses followed by tachyphylaxis; angiotensin II is ineffective over a wide dose range. The order of potencies of these vasoactive agents is 5-HT > NE > H > K⁺. With regard to their ability to induce maximal contractile responses, the order is: H > 5-HT, K⁺ > NE. Lysergic acid diethylamide (LSD) antagonizes the actions of 5-HT in a manner which progresses from surmountability to unsurmountability of the blockade depending on the concentration of LSD. The blockade exerted by LSD is reversed by washing. Phentolamine and diphenhydramine competitively antagonize the actions of NE and H, respectively. The potency of phentolamine and diphenhydramine in the cerebral arteries of the goat is similar to that determined in different tissues obtained from a variety of animal species. It is concluded that the cerebral arteries of the goat possess receptors for biogenic amines, the most effective of which is 5-HT; receptors for vasoactive peptides are ill defined.

The catecholamine and nucleotide content of chromaffin granules from bovine adrenal medulla was analyzed both qualitatively and quantitatively. Nucleotides were examined by separation on anion exchange high pressure liquid chromatography and ultraviolet absorption, as well as by anion exchange thin-layer chromatography and luciferin-luciferase light emission analysis. Catecholamines were quantified via automated continuous-flow analysis using fluorescence. We found the average catecholamine/ATP ratio to be 8.2:1 with an SD of 1.98 and an SE of 0.50 for 16 separate glands. Relative percentages of epinephrine and norepinephrine were found to be 79.8 and 20.2, respectively. The granules contained 80.9% ATP, 12.3% GTP, and 6.8% UTP, as well as detectable amounts of ADP, AMP, GDP, and UDP. If we accept the catecholamine/ATP ratio of 4:1 proposed by Hillarp earlier, then those catecholamines constituting the remainder of our ratio of 8.2:1 should represent a nucleotide-unassociated pool. In view of recent evidence of a direct agonistic function of nucleotides, we propose that the granule-associated nucleotides may act locally as coagonists with certain biogenic amines, and may additionally provide a circulating pool of purines and pyrimidines for use by the heart and lungs.

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