Nanoparticulate tablet dosage form of lisofylline-linoleic acid conjugate for type 1 diabetes: in situ single-pass intestinal perfusion (SPIP) studies and pharmacokinetics in rat.

Lisofylline (LSF) is an anti-inflammatory molecule with high aqueous solubility and rapid metabolic interconversion to its parent drug, pentoxifylline (PTX) resulting in very poor pharmacokinetic (PK) parameters, necessitating high dose and dosing frequency. In the present study, we resolved the physicochemical and pharmacokinetic limitations associated with LSF and designed its oral dosage form as a tablet for effective treatment in type 1 diabetes (T1D). Self-assembling polymeric micelles of LSF (lisofylline-linoleic acid polymeric micelles (LSF-LA PLM)) were optimized for scale-up (6 g batch size) and lyophilized followed by compression into tablets. Powder blend and tablets were evaluated as per USP. LSF-LA PLM tablet so formed was evaluated for in vitro release in simulated biological fluids (with enzymes) and for cell viability in MIN-6 cells. LSF-LA PLM in tablet formulation was further evaluated for intestinal permeability (in situ) along with LSF and LSF-LA self-assembled micelles (SM) as controls in a rat model using single-pass intestinal perfusion (SPIP) study. SPIP studies revealed 1.8-fold higher oral absorption of LSF-LA from LSF-LA PLM as compared to LSF-LA SM and ~5.9-fold higher than LSF (alone) solution. Pharmacokinetic studies of LSF-LA PLM tablet showed greater Cmax than LSF, LSF-LA, and LSF-LA PLM. Designed facile LSF-LA PLM tablet dosage form has potential for an immediate decrease in the postprandial glucose levels in patients of T1D.

Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes.

Lisofylline (LSF, 1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine) is an anti-inflammatory agent that protects beta-cells from Th1 cytokine-induced dysfunction and reduces the onset of Type 1 diabetes in non-obese diabetic (NOD) mice. Due to its low potency, poor oral bioavailability, and short half-life, the widespread clinical utility of LSF may be limited. Our goal has been to develop new agents based on the LSF structural motif that resolve the potency and pharmacokinetic liabilities of LSF. In this study, we have generated a focused library of LSF analogs that maintain the side chain (5-R-hydroxyhexyl) constant, while substituting a variety of nitrogen-containing heterocyclic substructures for the xanthine moiety of LSF. This library includes the xanthine-like (5-aza-7-deazaxanthine), as well as non-xanthine-like skeletons. The LSF analogs were evaluated in a pancreatic beta-cell line for the effects on apoptosis protection and insulin release. The metabolic stability of selected compounds was also tested.

Carbonyl group of aliphatic side chain of pentoxifylline does not play role for P-glycoprotein antagonizing effect of pentoxifylline.

Previously we have found that pentoxifylline (PTX), but not caffeine, theophylline, or 1-methyl-3-isobutylxanthine, affects sensitivity of L1210/VCR cells, a line with multidrug resistance mediated by P-glycoprotein (P-gp) to vincristine (VCR) and doxorubicine. Comparison of chemical structure of PTX with other above xanthines has revealed only one marked difference. PTX contains extended aliphatic chain containing reactive electrophilic carbonyl group in the position N1. The investigation of possibility that this group is crucial for PTX-induced MDR reversal represents the aim of the current paper. To prove this hypothesis, we used the new synthesized PTX derivative in which the carbonyl group is modified by a substance containing amino-group and the product of reaction is the respective Schiff base (SB). Successful reaction was observed when PTX reacted with 3,5-diaminobenzenesulfonyl acid (DABS). The product of reaction of DABS with carbonyl group of aliphatic part of PTX was proved using NMR and IR spectroscopy. We found that the resulting PTX derivative PTX-SB revealed higher cytotoxicity on both sensitive L1210 and multidrug resistant L1210/VCR cells than PTX. Moreover, PTX-SB exerts more pronounced MDR reversal effect on L1210/VCR cells than PTX. These results indicate that electrophilic carbonyl group on aliphatic chain located in position N1 of PTX is not essential for MDR reversal effects of PTX.

Pentoxifylline downregulares nitric oxide and tumor necrosis factor-a induced by mycobacterial lipoarabinomannan in a macrophage cell line

Pentoxifylline (PTX), a phosphodiesterase inhibitor, is known to downregulate tumor necrosis factor-alpha (TNF-alpha) secretion induced by lipopolysacchride (LPS) and gamma interferon (IFN-gamma). We have had limited success in treating leprosy reactions, including erythema nodosum leprosum (ENL), in which TNF-alpha has been identified as a major proinflammatory cytokine. PTX inhibited production of NO (IC50 approximately equal to 1.0 mg/ml) and TNF-alpha (IC50 approximately equal to 0.05 mg/ml) in a dose-dependent fashion. As little as 0.5 mg/ml of PTX decreased NO production and 0.01 mg/ml of PTX inhibited TNF-alpha production. Western blot analyses demonstrated that iNOS was suppressed by PTX. Northern blot analyses showed significant reduction of TNF-alpha mRNA. We conclude that PTX is an effective inhibitor of lipoarabinomannan (LAM)-induced TNF-alpha production at both the product and transcriptional levels in our macrophage cell line. PTX also showed moderate inhibition of NO at the product level as well as translation of iNOS.

Efectos de la pentoxifilina sobre la movilidad espermática en pacientes normo y oligoastenospérnicos y su relación con la fecundación in vitro

Objetivo: Determinar los efectos de la incubación de espermatozoides (spz) con Pentoxifilina (PF) sobre las características de movimiento de pacientes normo y oligoastenospérmicos y el resultado de su utilización en la fecundación in vitro (FIV) por oligoastenospermia severa. Material y Métodos: Sobre un total de 46 pacientes divididos en tres grupos: Grupo I(n=10) normospérmicos; Grupo 2a(n=14) oligoastenospermia moderada y Grupo 2b(n=22) oligoastenospermia severa se cuantificaron los parámetros de movimiento usando computer-assited sperm analysis (CASA). Una segunda parte del estudio consistió en la evaluación del resultado de fecundación in vitro(FIV) en 16 parejas del grupo 2b. Los resultados de FIV e inseminación subzonal (SUZI) con o sin PF fueron comparados. Preparación del Semen: El semen fue preparado con gradiente de percoll y dividido en dos partes, uno como control y la otra mitad fue incubada con pentoxifilina 1 mg/ml después de dos horas de capacitación. Luego de remover la PF del semen, fue analizado con CASA y tres horas después. Resultados: Se encontró un incremento significativo del desplazamiento lateral de la cabeza (ALH) solamente en el grupo 2b después de la utilización de la PF (Pmenor 0.05). En los otros dos grupos ningún efecto superior significativo de los parámetros de movimiento fue observado en comparación a una preparación solamente de percoll. Ningún aumento de la taza de fecundación fue observada cuando el semen tratado con PF fue usado comparado con el semen control. Conclusiones: Aunque la pentoxifilina puede mejorar los parámetros de movimiento en algunos pacientes con oligoastenospermia, dicho tratamiento no supera la capacidad fecundante cuando el semen ha sido previamente seleccionado con gradiente de percoll. Su utilidad en FIV por infertilidad masculina deberá ser evaluada en un grupo más amplio