Gaucher Disease: A Glance from a Medicinal Chemistry Perspective.

Rare diseases are particular pathological conditions affecting a limited number of people and few drugs are known to be effective as therapeutic treatment. Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, belongs to this class of disorders, and it is considered the most common among the Lysosomal Storage Diseases. The two main therapeutic approaches are the Enzyme Replacement Therapy (ERT) and the Substrate Reduction Therapy (SRT). ERT, consisting in replacing the defective enzyme by administering a recombinant enzyme, is effective in alleviating the visceral symptoms, hallmarks of the most common subtype of the disease whereas it has no effects when symptoms involve CNS, since the recombinant protein is unable to significantly cross the Blood Brain Barrier. The SRT strategy involves inhibiting glucosylceramide synthase (GCS), the enzyme responsible for the production of the associated storage molecule. The rational design of new inhibitors of GCS has been hampered by the lack of either the crystal structure of the enzyme or an in-silico model of the active site which could provide important information regarding the interactions of potential inhibitors with the target, but, despite this, interesting results have been obtained and are herein reviewed.

Human pharmacokinetics and rationale for once-weekly dosing of dalbavancin, a semi-synthetic glycopeptide.

The selection of a novel weekly dalbavancin dosage regimen was based on pharmacokinetic and pharmacodynamic data from humans and an animal model of infection. The results from the granuloma pouch model of infection suggested that dalbavancin concentrations >/=5 mg/L are necessary for extended in vivo activity. Serum bactericidal activity assessments demonstrated that dalbavancin serum concentrations of approximately 20 mg/L were bactericidal upon two-fold dilution. These data, coupled with simulations based on the pharmacokinetic profile derived from a clinical study in healthy volunteers, were used to design the weekly regimen studied in the initial efficacy trial. This efficacy study showed that a two-dose weekly regimen was well tolerated and associated with a higher clinical response rate than the comparator regimens. The data collectively support the further study of dalbavancin as a once-weekly regimen for the treatment of infections caused by Gram-positive bacteria.

Tolerability, pharmacokinetics, and serum bactericidal activity of intravenous dalbavancin in healthy volunteers.

Fifty-two healthy adult male and female volunteers were enrolled in this double-blind study to determine the maximum tolerated dose, characterize the pharmacokinetics, and obtain serum bactericidal activity (SBA) data for intravenous dalbavancin. Subjects were assigned to single- or multiple-dose groups and randomized to receive dalbavancin or placebo intravenously over 30 min. Doses started at 140 mg in the single-dose group and with a 300-mg loading dose (LD), followed by six daily 30-mg maintenance doses (MDs), in the multiple-dose cohort and escalated to a 1120-mg single dose and a 1000-mg LD and 100-mg MD regimen. Plasma, urine, and skin blister fluid aspirate drug concentrations were measured, and pharmacokinetic parameters were determined via noncompartmental methods. SBA against methicillin-resistant Staphylococcus aureus (MRSA) was determined at several time points. Adverse events and changes from the baseline for laboratory data, electrocardiograms, audiologic assessments, physical examinations, and vital signs were assessed. Concentrations increased in proportion to the dose. Steady-state concentrations were achieved by day 3 with the 10:1 LD-MD regimen. The half-life averaged 181 h, and the mean volume of distribution and clearance were 9.75 liters and 0.0473 liters/h, respectively. Mean values were similar in all groups and in males and females. The portion of the dose excreted renally averaged 33.5%. Bactericidal activity was demonstrated in serum at 7 days in all subjects receiving single doses of >or=500 mg. All doses were well tolerated. Dose-limiting toxicity was not encountered. No changes in auditory or vestibular function occurred. The long half-life and maintenance of SBA against MRSA for 1 week suggest that weekly dosing may be feasible.