Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs.

Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene. A second gene, SMN2, produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1. Risdiplam (RG7916; RO7034067) is an orally administered, small-molecule SMN2 pre-mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n = 90), rats (n = 148), and monkeys (n = 24). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39 weeks. A parallel dose-dependent increase in SMN protein levels was seen in CNS and peripheral tissues in two SMA mouse models dosed with risdiplam. These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients' blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues.

Novel azo derivatives as prodrugs of 5-aminosalicylic acid and amino derivatives with potent platelet activating factor antagonist activity.

This paper describes the synthesis of a series of azo compounds able to deliver 5-aminosalicylic acid (5-ASA) and a potent platelet activating factor (PAF) antagonist in a colon-specific manner for the purpose of treating ulcerative colitis. We found it possible to add an amino group on the aromatic moiety of our reported 1-[(1-acyl-4-piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives or on British Biotech compounds BB-882 and BB-823 maintaining a high level of activity as PAF antagonist. A selected compound UR-12715 (49c) showed an IC(50) of 8 nM in the in vitro PAF-induced aggregation assay, and an ID(50) of 29 microg/kg in the in vivo PAF-induced hypotension test in normotensive rats. Through attachment of 49c to the 5-ASA via azo functionality we obtained UR-12746 (70). Pharmacokinetics experiments with [14C]-70 allow us to reach the following conclusions, critical in the design of these new prodrugs of 5-ASA. Neither the whole molecule 70 nor the carrier 49c were absorbed after oral administration of [14C]-70 in rat as was demonstrated by the absence of plasma levels of radioactivity and the high recovery of it in feces. Effective cleavage of azo bond (84%) by microflora in the colon is achieved. These facts ensure high topical concentrations of 5-ASA and 49c in the colon. Additionally, 70 exhibited a potent anticolitic effect in the trinitrobenzenesulfonic acid-induced colitis model in the rat. This profile suggests that UR-12746 (70) provides an attractive new approach to the treatment of ulcerative colitis.

O/W lipid emulsions for parenteral drug delivery. III. Lipophilicity necessary for incorporation in oil particles even after intravenous injection.

The potential usefulness of oil-in-water (O/W) lipid emulsions as injectable drug delivery systems was examined. Plasma concentrations of oil particles after intravenous injection of a standard lipid emulsion composed of soybean oil and egg yolk phosphatides were monitored based on the plasma concentrations of phospholipids and triglycerides, and the light scattering intensity of the plasma. Their time profiles were similar to each other, and the oil particle size decreased time-dependently. Pretreatment with dextran sulfate, a known reticuloendothelial system (RES) suppressor, resulted in marked reduction of the plasma clearance of the oil particles and of the time-dependent alteration of oil particle size, suggesting that oil particles were trapped by RES. The lipophilicity of the drug needed for its incorporation in the oil particles even after intravenous injection was found to be clog P > 8, where clog P is the calculated logarithm of the partition coefficient between n-octanol and water. In the case of sudan II (clog P = 5.4), the release from the oil particles was very quick after intravenous injection, resulting in slight alteration in biodistribution when compared with its micellar solution. In contrast, menatetrenone (clog P = 9.5) was selectively delivered to the liver, lungs and spleen, being consistent with the oil particles taken up by RES.

O/W lipid emulsions for parenteral drug delivery. I. Pharmacokinetics of the oil particles and incorporated sudan II.

The potential usefulness of oil in water (O/W) lipid emulsions as parenteral drug delivery system for lipophilic drugs was examined in tumor-bearing rats. A model lipophilic drug, sudan II (PCoct = 226000), was formulated in five lipid emulsions consisting of soybean oil and various surfactants. Compared with HCO-60 micellar and plasma solutions of sudan II, the blood concentration of sudan II was markedly elevated by administration as a lipid emulsion. However, the distribution of sudan II to the liver, lungs, spleen, and adipose tissue was not altered, and that to the brain, heart, kidneys, muscle, and tumor was slightly decreased. To understand these results, pharmacokinetic analysis was performed using a newly derived compartmental model, and moreover, the organ distribution clearance was analyzed. It was suggested that the oil particles deliver the incorporated drug selectively to the liver, lungs, and spleen, and the speed of delivery could be surpressed by using HCO-60. However, in the case of sudan II, its rapid release from the oil particles after i.v. injection prevented a drastic alteration in the distribution of sudan II. The simulation studies suggested that a considerable decrease in the release rate or an increase in partition coefficient (experimentally more than 10(8) would be required for delivery.

The role of topical agents in the healing of full-thickness wounds.

Eight topical agents in current use were studied for their effects on wound contraction and rate of reepithelialization of full-thickness excisions using a porcine animal model. The following agents were applied daily for a period of 27 days: scarlet red ointment, benzoyl peroxide lotion, bacitracin ointment, silver sulfadiazine cream, aloe vera gel, tretinoin cream, capsaicin cream, and mupirocin ointment. The rate of reepithelialization was significantly enhanced by treatment with capsaicin, bacitracin, silver sulfadiazine, and scarlet red, and was markedly retarded by treatment with tretinoin. Wound contraction was significantly retarded by mupirocin, bacitracin, and silver sulfadizine. Knowledge of the effects of topical agents on various aspects of healing allows the clinician to choose the most appropriate material to use in a given clinical situation to optimize the healing process and produce the best final result.