ABSTRACT
Biodegradable microspheres containing cyclosporin A (CyA, cyclosporine) were prepared using poly(L-lactic acid) (PLA) and poly(lactide-co-glycolide)(PLGA) by a solvent evaporation method. CyA was efficiently entrapped in PLA, PLGA(50/50) and PLGA(75/25) microspheres in a range of 81-85%. CyA released constantly from PLA microspheres without any lag time, whereas the drug from PLGA(50/50) and PLGA(75/25) microspheres was released after lag time of about 1 and 3 weeks, respectively. Addition of fatty acid esters enhanced the release rates of CyA from PLA microspheres. In-vivo study was performed using rats with adjuvant-induced arthritis. PLA microspheres with ethyl myristate sustained high blood levels of CyA compared with the microspheres with no additives over 4 weeks. In addition, the PLA microspheres improved the symptoms such as the decrease in body weight and the increase in paw swelling occurred by adjuvant-induced arthritis in rats. Consequently, the release rate of CyA from PLA microspheres can be improved by adding fatty acid esters and PLA microspheres with fatty acid esters seem to be a useful dosage form for autoimmune disease therapy.
Subject(s)
Cyclosporine/chemistry , Drug Delivery Systems , Fatty Acids/chemistry , Immunosuppressive Agents/chemistry , Lactic Acid/chemistry , Polymers/chemistry , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/pathology , Body Weight/drug effects , Cyclosporine/administration & dosage , Cyclosporine/therapeutic use , Hindlimb/pathology , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/therapeutic use , Male , Microspheres , Particle Size , Polyesters , Rats , Rats, WistarABSTRACT
The intracellular concentration of many steroids and xenobiotics is influenced by the membrane protein P-glycoprotein (Pgp). It has been inferred that the intracellular retention of many drugs that upregulate Pgp or modulate Pgp function might also be affected by Pgp. However, the ability of Pgp to influence the translocation of these drugs needs to be established to understand Pgp's influence upon their pharmacological effect. We utilized two approaches to determine the interaction of several agents with Pgp: (a) an in vitro system, LLC-PK1 cell lines and derivative LLC cell lines stably expressing on the apical membrane either mouse mdr1a or human MDR1 Pgp grown as polarized epithelium in transwell culture to measure translocation of radiolabeled drugs; and (b) an in vivo system, mdr1a nullizygous and wild-type animals, to compare the contribution of Pgp to in vivo distribution of radiolabeled drugs. In combination these complementary approaches identified erythromycin as a drug whose intracellular retention is influenced by Pgp, while the intracellular accumulation and tissue distribution of retinoic acid and benzo(a)pyrene were unaffected by Pgp.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , ATP Binding Cassette Transporter, Subfamily B , ATP-Binding Cassette Transporters/physiology , Benzo(a)pyrene/pharmacokinetics , Erythromycin/pharmacokinetics , Tretinoin/pharmacokinetics , Animals , Biological Transport/physiology , Cell Line , Gene Expression/genetics , Humans , Mice , Mice, Knockout , Transfection/genetics , Vinblastine/pharmacokineticsABSTRACT
Prophylactic effects of N-benzoyl-beta-alanine (betamipron, BP), one of a series of N-acyl amino acids, were examined against cisplatin-induced nephrotoxicity. Male Wistar rats were injected i.p. with 6 mg/kg of cisplatin combined with an i.p. BP dose given at various times and various doses. Rats were sacrificed 5 days after cisplatin injection to weigh the kidney and liver, and to determine blood urea nitrogen (BUN) and serum creatinine (serum Cr) levels. Preliminary results suggest that treatment with BP is an effective means of protection against cisplatin-induced nephrotoxicity. Combination with BP reduced the weight loss following treatment with cisplatin. The ratios of the kidney and liver weights to the body weight in the animals treated with cisplatin followed later with BP are significantly different (p < 0.05) from those in the animals that received only cisplatin. The BUN and serum Cr levels in the animals treated with cisplatin followed from -1 to 4 hr, and from -4 to 4 hr later with 250 mg/kg BP dose and followed 1 hr later with from 250 to 1000 mg/kg, and from 250 to 2000 mg/kg BP doses differed significantly (p < 0.05) from those in the animals that received only cisplatin. Histological analysis of the kidneys confirmed the protective effect of BP.
Subject(s)
Alanine/analogs & derivatives , Antineoplastic Agents/toxicity , Cisplatin/toxicity , Kidney/drug effects , Alanine/therapeutic use , Animals , Body Weight/drug effects , Drug Evaluation, Preclinical , Kidney/pathology , Liver/drug effects , Liver/pathology , Male , Organ Size/drug effects , Random Allocation , Rats , Rats, Wistar , Time FactorsABSTRACT
The BG-104, a Chinese herbal medicine, has been reported to restore decreased plasma superoxide scavenging activity. This report showed in vivo effect of BG-104 on two patients with hemophilia A infected with human immunodeficiency virus by infusions of the concentrated Factor VIII. Both patients, showed a peripheral CD4+ T-lymphocytopenia for more than half a year. BG-104 was administered daily and follow-up observations were continued for 3 years. The number of CD4+ T-lymphocytes remained relatively constant during BG-104 treatment without disease progression.