Dose responsive effects of subcutaneous pentosan polysulfate injection in mucopolysaccharidosis type VI rats and comparison to oral treatment

Frohbergh M, Ge Y, Meng F, Karabul N, Solyom A, Lai A, Iatridis J, Schuchman EH, Simonaro CM · PLoS One

Weekly injection matched or beat daily oral dosing on the shared endpoints and reached several the oral route did not: urine glycosaminoglycans fell in every treated group and fell further on injection than on oral, tissue glycosaminoglycans in liver, spleen and kidney fell only in the injected groups, and rotarod endurance was better on injection than on oral at 30, 35 and 40 rpm. The articular-cartilage and growth-plate findings are descriptive histology of representative sections rather than a measured endpoint — reduced vacuole size and better chondrocyte orientation at 2 and 4 mg/kg, little to none at 1 mg/kg, and no gain in femur length. The optimum was 2 mg/kg subcutaneously, the same per-kilogram dose used in the human injection trials, with 4 mg/kg performing worse than 2 mg/kg on the rotarod. Liver enzymes and clotting factors, monitored weekly across the six months, stayed at baseline.

Population

One-month-old mucopolysaccharidosis type VI rats treated for 6 months

Intervention

Weekly subcutaneous PPS at human-equivalent 1, 2 and 4 mg/kg

Comparator

Daily oral PPS at human-equivalent 4 mg/kg

Limitations

Six female rats per group across six groups, in a genetic storage disease rather than osteoarthritis. The cartilage and growth-plate results are read off micrographs with no quantification and no statistical test, and the paper's figure legend and its body text name different tissues as showing a dose response. The premise that injected PPS is more bioavailable than oral is sourced to a personal communication from the manufacturer; the biodistribution work done here followed a fluorescent label, and the authors say they cannot tell whether the signal is bioactive drug or a degradation product. The drug was supplied by bene pharmaChem, two of whose staff are acknowledged for advice and consultation, while the declared competing interest is an unrelated patent.