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Biomedical subjects

F K Patterson

Publications and source records attributed to F K Patterson.

12 recordsLinked to original sources
PubMed1994

Reversal agent inhibition of the multidrug resistance pump in human leukemic lymphoblasts.

Multidrug resistant cancer cells of the MDR-1 phenotype utilize an ATP-dependent pump to excrete toxic drugs. Rhodamine 123 (R123) is a fluorescent substrate of the MDR pump. An assay for the ATP-dependent initial efflux of R123 from CEM/VLB100 human leukemic lymphoblasts has been developed. The MDR-1 cells were treated with a reversal agent and preloaded with 40.0 nM R123 in buffer at 30 degrees C that contained sodium azide and 2-deoxyglucose. The cells were rinsed with cold buffer and resuspended in L-glutamine/glucose solution at 23 degrees C. The cell suspension was passed through a filter and R123 in the filtrate was detected at 2-s intervals by fluorescence. Efflux of R123 was inhibited by the reversal agents amiodarone, cyclosporin A, Ro11-2933 (DMDP), quinidine, and the optical isomers of propranolol. The MDR pump is stereospecific for the (R)-diastereomer quinidine; however, the (S)-diastereomer quinine is a relatively weak inhibitor of the pump. Cyclosporin A was the most potent inhibitor tested against the efflux of R123 by the MDR pump.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Epoxide metabolite of quinine and inhibition of the multidrug resistance pump in human leukemic lymphoblasts.

Multidrug resistance (MDR) in neoplastic cells is usually due to decreased cellular retention of drugs such as vincristine or doxorubicin. An ATP-dependent drug efflux pump has been detected in MDR-1-phenotypic cells; inhibition of the MDR pump is probably the primary mechanism for reversal of MDR. Although quinine (SQ1) and quinidine are reversal agents and inhibitors of the MDR pump, the results from in vivo experiments and in vitro experiments with these diastereomers are contradictory. These observations suggest that an oxidized metabolite of SQ1 is a more potent inhibitor of the MDR pump than is the parent compound. The chemical synthesis of the epoxides of SQ1 and quinidine is reported. The epoxy compounds have been tested as inhibitors of the ATP-dependent MDR pump in human CEM/VLB100 cells. The procedure is based on preloading the cells with an inhibitor and a low concentration of a substrate, rhodamine 123 (R123). After several cold rinses, the cell suspension is passed through a filtration-flow apparatus and the R123 in the filtrate (determined by fluorescence measurements) reveals the initial efflux of R123 through the MDR pump. When tested as an inhibitor of the MDR pump, quinine-10,11-epoxide is approximately 8-fold more potent than SQ1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Inhibition of the multidrug resistance efflux pump.

An ATP-dependent efflux pump is found in the plasma membrane of certain multidrug resistant (MDR) cancer cells. Drug resistance is due to decreased intracellular drug levels that have been reduced to subcytotoxic concentrations. Inhibition of the MDR efflux pump with a reversal agent may 'trap' the cytotoxic drug inside the cell; thus, cellular drug resistance is reversed. Although many different lipophilic substances exhibit reversal activity, inhibition of the pump is stereospecific with respect to the chiral agent cinchonine. In this article, several methods for the estimation of reversal potency are reviewed. Furthermore, information on the transport characteristics of reversal agents is presented. The rate equations for ATP-dependent drug efflux, competitive inhibition of the MDR pump, and noncompetitive inhibition of the pump are derived. A method is presented that discriminates between competitive or noncompetitive inhibition of the pump. These studies show the potential contribution of fundamental inhibition studies to the design of clinical reversal protocols.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1985

Skin penetration and metabolism of topically applied chemicals in six mammalian species, including man: an in vitro study with benzo[a]pyrene and testosterone.

Percutaneous absorption of chemicals is generally considered a diffusional process, with the rate-limiting barrier being the nonviable stratum corneum. Because viable skin possesses enzyme activities, including those involved in the metabolism of xenobiotics, the extent to which cutaneous metabolism may influence the percutaneous fate of topically applied chemicals in the skin was examined in mammalian skin maintained as short-term organ cultures. Skin samples from mouse, rat, rabbit, guinea pig, marmoset, and man were examined. The results from studies with benzo[a]pyrene (BP) and testosterone showed that, in all species, metabolic viability was a major factor involved in the in vitro skin permeation of surface-applied chemicals. Permeation was accompanied by extensive cutaneous "first pass" metabolism; both parent compounds and a full spectrum of metabolites were found in the receptor fluid from viable skin preparations. However, in previously frozen nonviable skin preparations, essentially only unchanged parent compounds were detected in the receptor fluid. Permeation of BP and testosterone was highest in mouse skin, and significant species variations in the metabolite profiles were observed. Studies with mouse skin also demonstrated that induction of cutaneous drug-metabolizing enzymes can result in a two- to threefold increase in the in vitro permeation of topical BP, and a significant reduction in permeation was observed when KCN was added to the perfusion medium. These results indicate that diffusional and metabolic processes are intimately involved in the percutaneous fate of surface-applied chemicals. The relative importance of these processes is dependent upon the physicochemical properties of the compounds and the metabolic capabilities of the skin toward the compounds in question. Furthermore, these findings suggest that meaningful in vitro studies on skin absorption should consider both diffusion and cutaneous biotransformation of the applied compound.

Administration, Topical↗
PubMed1985

Practical hepatobiliary imaging using pretreatment with sincalide in 139 hepatobiliary studies.

Hepatobiliary studies were performed over a three-year period on 139 patients suspected of having cystic duct obstruction. Each patient was infused intravenously with sincalide, a C-terminal octapeptide of CCK, 15 minutes prior to the administration of the hepatobiliary imaging agent Tc-99m paraisopropyl iminodiacetic acid (PIPIDA). Analysis of the results demonstrated significant advantages in pretreating patients with sincalide in hepatobiliary studies in a small facility with a relatively large patient load. Most of our studies were completed within 2 hours without jeopardizing the sensitivity (97%) or accuracy (96%) of the test. The specificity (88%) was comparable to percentages reported by others. Most investigators have reported that chronic cholecystitis contributed to the majority of false-positive cases. In addition, inconsistency in the documentation of criteria for the determination of acute cholecystitis (surgical, radiologic, or histologic also could be a cause for such a discrepancy. Knowledge of some important variables may help improve the specificity of the test: an awareness of the following factors during scan interpretation: 1) the effectiveness of the sincalide pretreatment dose, 2) the patient's pretest status (fasting or nonfasting, postanalgesic medication or no analgesics), and 3) time limit for gallbladder visualization. With these variables in mind, the hepatobiliary imaging using pretreatment with sincalide is proven to be a practical procedure protocol with good sensitivity and accuracy as well as specificity.

Bile Duct Diseases↗
PubMed1982

Sudden death in a young adult with anomalous origin of the posterior circumflex artery.

Sudden unexpected death occurred in an apparently healthy young adult during physical exertion. At autopsy the posterior circumflex artery was found to emerge at an acute angle from the right aortic sinus and course behind the great vessels to reach the atrioventricular groove. There was an old superior posterolateral infarct, and fibrosis and acute hemorrhage in the region of the atrioventricular node.

Adult↗
PubMed1980

Dexamethasone-inhibited pertechnetate uptake in metastatic carcinoma of the cerebellum.

Two sodium pertechnetate Tc 99m brain scans, done within several days of each other, demonstrated inhibition of pertechnetate localization in a cerebellar lesion after dexamethasone therapy for cerebral edema. The lesion, a metastasis from a bronchogenic mucinous adenocarcinoma, was clearly present in the first scan, which was done before treatment.

Adenocarcinoma, Mucinous↗
PubMed1980

Delayed fatal outcome after possible Ru-Tuss overdose.

Death resulted from the delayed onset of the acute respiratory distress syndrome and disseminated intravascular coagulation with left ventricular mural thrombus formation and nonbacterial thrombotic endocarditis approximately five days after an alleged attempted suicide by the ingestion of ten to twelve prolonged-action Ru-Tuss tablets. Although these lesions are thought to be similar in pathogenesis, this combination has not been previously reported in association with a drug overdose. The delay in onset is also of interest because of its clinical implications.

Adult↗