Biomedical subjects

S B Howell

Publications and source records attributed to S B Howell.

257 records · Page 15Linked to original sources

PubMedDate not supplied

Clinical applications of a novel sustained-release injectable drug delivery system: DepoFoam technology.

The therapeutic effectiveness of drugs is often limited by the inability to sustain therapeutic levels at the target site. Encapsulation of drugs in multivesicular lipid-based particles for sustained release is a novel approach to improving the pharmacokinetics of drug therapy. This paper reviews the preclinical and clinical literature on the applications and potential therapeutic benefits of DepoFoam technology, a novel sustained-release, injectable drug delivery system. DepoFoam formulations of drugs, including anticancer agents (cytarabine, methotrexate, bleomycin, recombinant interferon alfa, 5-fluorouridine-5'-monophosphate, and others), anti-infective agents (dideoxycytidine, 2'-norcyclic guanosine monophosphate, cidofovir, tobramycin, gentamicin, amikacin), analgesics (morphine, bupivacaine), and macromolecules (insulin, interleukin-2), delivered intrathecally, subcutaneously, intraperitoneally, or intralesionally, provide sustained therapeutic levels of drug at the intended target site and reduce systemic exposure and toxicity. Pharmacokinetic studies have demonstrated that DepoFoam particle encapsulation effectively extends the half-life of drugs, thus prolonging the duration of therapeutic drug concentrations in local tissues or in body spaces into which the encapsulated drug is injected. In the case of cell-cycle phase-specific chemotherapeutic agents, such formulations can improve efficacy and therapeutic ratio. DepoFoam is a promising drug delivery system for sustained release of hydrophilic injectable drugs that has a wide range of potential applications in oncology, infectious disease, analgesia, and other therapeutic areas.

Analgesics, Opioid↗

PubMedDate not supplied

Comparison of lipid content, surface membrane fluidity, and temperature dependence of cis-diamminedichloroplatinum(II) accumulation in sensitive and resistant human ovarian carcinoma cells.

We conducted studies to determine whether the cisplatin (DDP)-resistant human ovarian carcinoma cell line designated 2008/DDP has membrane changes which could slow the passive diffusion of the drug into cells, thereby accounting for the observed reduction in DDP accumulation in 2008/DDP cells compared to the sensitive parental 2008 cells. To this end, we compared three indicators of membrane lipid composition and fluidity in the resistant and sensitive cells. In a comparison of major membrane lipid classes, the resistant line had a 17% increase in phosphatidyl choline, and an 11% increase in phosphatidyl ethanolamine relative to the sensitive line. There were no differences in the other major phospholipids or in the free cholesterol content of the cell lines. Secondly, results of fluorescence polarization measurements on whole cells of each line using the plasma membrane specific probe trimethylammonium diphenylhexatriene revealed no difference between the cell lines at both 28 degrees C and 37 degrees C. Finally, an examination of the temperature-dependence of DDP accumulation over 1 h produced Arrhenius plots of similar shape in 2008 and 2008/DDP cells. Both plots were linear from 40 degrees C down to a break point between 4 degrees C and 12 degrees C. The Q10's for DDP accumulation from 30 degrees C to 40 degrees C were greater than 2 in each cell line and were not significantly different. Results of these 3 comparisons point to substantial similarity in the bulk membrane lipid composition and fluidity of the two cell lines. We conclude that decreased DDP accumulation in our resistant cells is not due to membrane changes that would be expected to retard passive diffusion of the drug into the cells.

Biological Transport↗

PubMedDate not supplied

Multivesicular liposomes containing cytarabine entrapped in the presence of hydrochloric acid for intracavitary chemotherapy.

For a full exploitation of the 1000-fold ip pharmacokinetic advantage obtained when cytarabine is administered ip, the drug exposure must be prolonged because the drug is a cell cycle phase-specific agent. Multivesicular liposomes made from nontoxic components were studied as biodegradable, slow-release microcapsules for intracavitary therapy. No attempt was made to increase efficacy by fusing liposomal membrane with that of tumor cells or by selective targeting of liposomes to cancer cells other than simple administration into a cavity. The presence of HCl with cytarabine at the time of encapsulation was found to decrease the leakage rate in human plasma dramatically. After ip administration of encapsulated cytarabine to mice, the total intracavitary drug concentration initially increased tenfold in 15 hours, then fell to the original concentration at 87 hours. The total amount of the drug in the peritoneal cavity decreased with a 21-hour half-life. All mice treated 24 hours after ip inoculation with 1 X 10(6) L1210 cells were cured when 32 mg/kg or 16 mg/kg of cytarabine in liposomes was given ip every 4 days for a total of three doses. Multivesicular liposomes do prolong intracavitary exposure to cytarabine and are efficacious in this model system.

Animals↗

PubMedDate not supplied

Effect of sodium thiosulfate on cis-dichlorodiammineplatinum(II) toxicity and antitumor activity in L1210 leukemia.

Concurrent administration of sodium thiosulfate reduced the toxicity of cis-dichlorodiammineplatinum(II) (DDP) in a dose-related manner in mice. Sodium thiosulfate protected mice against an otherwise lethal dose of DDP (20 mg/kg), and reduced DDP-induced weight loss. Sodium thiosulfate (800 mg/kg) injected within 1 hour before or 1/2 hour after DDP blocked nephrotoxicity as measured by a rise in BUN, an increase in kidney weight, and medullary hemorrhage. In culture, sodium thiosulfate markedly reduced the toxicity of DDP to mouse colony-forming units. Concurrent injection of sodium thiosulfate partially reduced the antitumor activity of DDP. The therapeutic dose range of DDP was expanded, but the maximum increase in lifespan of mice bearing L1210 leukemia was reduced by 40%. Sodium thiosulfate offers the possibility of systemic protection against the cytotoxicity of regionally administered DDP in man.

Animals↗

PubMedDate not supplied

In vivo modulation of cisplatin cytotoxicity by the cholecystokinin antagonist MK-329 in human pancreatic cancer xenografts.

We have previously reported that the cholecystokinin antagonist MK-329 (also known as L-364,718 or devazepide) synergistically enhances sensitivity to cisplatin (DDP) in MIA-PaCa2 human pancreatic cancer cells in tissue culture. In this study, we examined the ability of MK-329 to modulate DDP sensitivity in vivo using MIA-PaCa2 pancreatic cancer xenografts growing subcutaneously in athymic nude mice. Twenty-four hours after tumor inoculation, mice received either DDP intraperitoneally, MK-329 subcutaneously, both DDP and MK-329 or drug vehicles alone. Both DDP and MK-329 alone caused a reduction in the rate of tumor growth. The combination of DDP and MK-329 resulted in enhanced tumor growth delay compared to DDP or MK-329 treated mice. Although MK-329 alone was not nephrotoxic, the addition of MK-329 to DDP treatment resulted in a significant increase in weight loss and nephrotoxicity compared to mice treated with DDP alone; this was reflected by an increase in the plasma BUN levels. Although we believe that the enhanced anti-tumor effect of DDP/MK-329 combination therapy may be independent MK-329's capability to block CCK receptors, the role of CCK receptor blockade in potentiating DDP-induced nephrotoxicity less clear.

Animals↗