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Biomedical subjects

J W Karanian

Publications and source records attributed to J W Karanian.

At least 19 recordsLinked to original sources
PubMed1999

The US Food and Drug Administration investigational device exemptions (IDE) and clinical investigation of cardiovascular devices: information for the investigator.

The conduct of a clinical investigation of a medical device to determine the safety and effectiveness of the device is covered by the investigational device exemptions (IDE) regulation. The purpose of IDE regulation is "to encourage, to the extent consistent with the protection of public health and safety and with ethical standards, the discovery and development of useful devices intended for human use, and to that end to maintain optimum freedom for scientific investigators in their pursuit of this purpose" (Federal Food, Drug, and Cosmetic Act). Conducting a clinical investigation may require an approved IDE application. The US Food and Drug Administration encourages early interaction with the agency through the pre-IDE process during the development of a device or technology and during the preparation of an IDE application. This facilitates approval of the IDE application and progression into the clinical investigation. This paper reviews the terminology and applicability of the IDE regulation and the type of study that requires an IDE application to the Food and Drug Administration. The pre-IDE process and the development of an IDE application for a significant risk study of a cardiovascular device are discussed.

Cardiology↗
PubMed1999

The US Food and Drug Administration investigational device exemptions and clinical investigation of cardiovascular devices: information for the investigator.

The conduct of a clinical investigation of a medical device to determine the safety and effectiveness of the device is covered by the investigational device exemptions (IDE) regulation. The purpose of IDE regulation is "to encourage, to the extent consistent with the protection of public health and safety and with ethical standards, the discovery and development of useful devices intended for human use, and to that end to maintain optimum freedom for scientific investigators in their pursuit of this purpose." Conducting a clinical investigation may require an approved IDE application. The US Food and Drug Administration encourages early interaction with the agency through the pre-IDE approval process during the development of a device or technology and during the preparation of an IDE application. This facilitates approval of the IDE application and progression into the clinical investigation. This paper reviews the terminology and applicability of the IDE regulation and the type of study that requires an IDE application to the Food and Drug Administration. The pre-IDE approval process and the development of an IDE application for a significant risk study of a cardiovascular device are discussed.

Cardiology↗
PubMed1996

The structure-activity relationship of lipoxygenase products of long-chain polyunsaturated fatty acids: effects on human platelet aggregation.

The effect of hydroperoxy and hydroxy derivatives of various fatty acids on human platelet aggregation was determined to delineate potencies and structure-activity function. In this regard, the 22-carbon n-3 fatty acids are the most potent inhibitors in comparison to the n-6 lipoxygenase derivatives. Submicromolar levels of the docosapentaenoic (22:5) and especially docosahexaenoic (22:6) n-3 hydroperoxy and hydroxy derivatives specifically antagonize the platelet aggregating effect to arachidonic acid (AA, 20:4n-6) but not that of ADP or collagen. Chain length (22-C > 20-C), double-bond position (n-3 > n-6), and double-bond number (6 > 5 > 4) influence the degree of inhibition of AA-induced aggregation of human platelets. Moreover, significant differences in potency were associated with specific structural aspects of 22:6n-3 lipoxygenase derivatives of 22:6n-3 as follows: functional group (OOH > OH) and positional isomer (14-OOH, 14-OH, 20-OOH > 11-OOH, 17-OOH > 10-OOH > 11-OH, 8-OOH, 7-OOH > 4-OOH).

Arachidonic Acid↗
PubMed1996

Effect of gender and sex steroids on the contractile response of canine coronary and renal blood vessels.

The effect of gender, gonadal steroids, and antiandrogen/antiestrogen-treatment on the isotonic response of isolated preparations of the left anterior descending coronary artery (LAD), left circumflex coronary artery, and renal artery and vein of sexually mature dogs was investigated. The maximum isotonic response of the coronary and renal vasculature to the thromboxane A2 (TXA2)-mimetic U46619 was significantly greater, and the EC50 value was significantly lower in males as compared with females. Moreover, similar gender differences in the contractile response of the coronary vasculature to norepinephrine were observed. Pretreatment of male dogs with the antiandrogens flutamide or cyproterone acetate reduced the maximum contractile response of the LAD to the TXA2-mimetic. Pretreatment of female dogs with testosterone resulted in an increase in both the maximum contractile response and EC50 value to U46619. Antiestrogen treatment of female dogs with tamoxifen was associated with an increase in the maximum contractile response of the LAD to U46619. Estrogen pretreatment of male dogs decreased both the maximum contractile response and the EC50 value to U46619. Therefore, there is a sex difference in LAD and LCX contractile responses to both U46619 and norepinephrine. These results suggest that smooth muscle reactivity of dog coronary artery to the TXA2-mimetic U46619 may be susceptible to regulation by both androgens and estrogens. The observed gender differences in the catecholamine response may be similarly altered by changes in the hormonal milieu.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Hydroxylated 22-carbon fatty acids in platelet and vascular smooth muscle function: interference with TXA2/PGH2 receptors.

Sub-micromolar levels of the lipoxygenase products of n-3 fatty acids specifically antagonize both the contractile effects of thromboxane (U46619) and its platelet aggregating effect. In addition, OH-22:6n3 inhibits thromboxane-induced decreases in cerebral blood flow of the rat. Analysis of binding parameters indicates these derivatives induce a marked decrease in the affinity of the TXA2/PGH2 receptor for thromboxane with a mild change in the number of receptor sites. The 22-carbon n-3 hydroxy fatty acids are the most potent biological antagonists of thromboxane in comparison to the n-6 hydroxy fatty acids and their parent fatty acids. Dietary permutations modify the hydroxy fatty acid profile and correlate with changes in thromboxane-mediated responses.

Animals↗
PubMed1995

Time- and voltage-dependent block of delayed rectifier potassium channels by docosahexaenoic acid.

Docosahexaenoic acid (22:6n3) acts at an extracellular site to produce a voltage- and time-dependent block of the delayed rectifier current (IK) similar to that classically described for intracellularly applied quaternary ammonia compounds. In dissociated cells from the pineal gland, some long-chain polyunsaturated fatty acids reduced both late sustained (IK) (for 22:6n3, IC50 = 2.5 +/- 0.3 microM) and early transient (IA) (IC50 = 2.0 +/- 0.1 microM) components of potassium current when applied extracellularly, whereas the monounsaturate oleic acid had minimal efficacy. From comparisons of other related fatty acids, it was determined that there is a structural requirement for polyunsaturation to block IK. In contrast, chain-elongated 22-carbon polyunsaturates acted similarly to their precursor 20-carbon fatty acids (arachidonic acid and eicosapentanoic acid). Block of IK by 22:6n3 was accompanied by a dose-dependent acceleration of the current decay in both whole-cell and outside-out membrane patches, and 22:6n3 increased the macroscopic inactivation rate of IA. The combined "eicosanoid" inhibitor eicosatetraenoic acid, when included in the patch pipette, did not antagonize the action of 22:6n3. Instead, eicosatetraenoic acid produced a direct block of IK when applied extracellularly at high concentrations (25 microM). Analyses of voltage- and time-dependent block by 22:6n3 support the hypothesis that certain fatty acids directly interact with and preferentially block the open state of some potassium channels. We also describe an interaction between fatty acid block and zinc; 22:6n3 failed to block either IA or IK in the presence of zinc or cadmium, whereas extracellular calcium did not affect the response. These studies suggest a possible biological function for 22:6n3 in the nervous system, which may underlie its essential role during neural development.

Animals↗
PubMed1994

Lipoxygenase stimulating effects of hydroxylated docosahexaenoates produced by human platelets.

Human platelet suspensions are capable of lipoxygenating docosahexaenoic acid (22:6n3) to an 11(S)-OH-, 14(S)-OH- or 17(S)-OH-22:6n3. The structure and stereochemical purity of these derivatives were confirmed by GC/MS and chiral phase LC analysis. The purified OH-22:6n3 positional isomers which are formed by human platelets were capable of inducing a concentration-dependent contractile response in the guinea-pig lung parenchymal strip at sub-micromolar concentrations. OH-22:6n3 may act in part through stimulation of leukotriene (LT) production as an increase in peptidyl-LT levels (LTC4, LTD4 and LTE4) occurred during the OH-22:6n3-induced contraction in this preparation. Both specific lipoxygenase inhibitors (caffeic acid, 20 uM and NDGA, 50 uM) and a LT receptor antagonist (FPL55712, 20 uM) significantly inhibited the contractile response. Moreover, the OH-22:6n3 positional isomers induced a concentration-dependent increase in LTB4 and LTC4 production in the guinea-pig chopped lung preparation. Other hydroxylated fatty acids and parent fatty acids which were tested (12-OH-20:4n6, 5-OH-20:4n6, 12-OH-20:5n3, 20:5n3 and 22:6n3) did not significantly contract this airway smooth muscle preparation or alter LT production. The hydroxylated 22:6n3 metabolites may modulate airway smooth muscle function in part through the release of peptidyl-LTs from the guinea-pig lung.

Animals↗
PubMed1994

Inhibitory effects of n-6 and n-3 hydroxy fatty acids on thromboxane (U46619)-induced smooth muscle contraction.

Mammalian platelets are capable of enzymatically producing a number of n-6 and n-3 hydroxy fatty acids. Human platelet suspensions produce two major docosahexaenoic acid (22:6n3) metabolites, namely, 11-OH and 14-OH-22:6n3. The hydroxy fatty acids which were formed by human platelets and purified by high performance liquid chromatography specifically antagonize the contractile effects of a thromboxane mimetic, U46619, in airway, visceral and, especially, in the vascular smooth muscle preparations studied. The efficacy of OH-22:6n3 (IC25 = 1.1 microM) was compared to other n-6 and n-3 hydroxy fatty acids in the rat aortic ring preparation. The OH-22:6n3 was significantly more potent with the exception of OH-22:5n3. The rank order of their potency was 14-OH-22:5n3 > or = 14-OH-22:6n3 > 17-OH-22:6n3 > or = 11-OH-22:6n3 > or = 11-OH-22:5n3 > 12-OH-20:5n3 > or = 12-OH-20:4n6 > or = 14-OH-22:5n6 > 13-OH-18:2n6 > 14-OH-22:5n5. Antagonism of thromboxane effects may be an important aspect of the biological function of 22-carbon n-3 hydroxylated fatty acids in platelet-vascular smooth muscle cell interactions.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Ethanol inhalation and dietary n-6, n-3, and n-9 fatty acids in the rat: effect on platelet and aortic fatty acid composition.

The effects of 18-carbon n-6, n-3, and n-9 fatty acid diets and ethanol exposure on the fatty acyl composition of platelets and vascular tissue were examined. An experimental design was devised to control the dietary content of 18-carbon fatty acids. The levels of 18:3n6, 18:3n3 and 18:1n9 were varied by a formulation of dietary oils which contained similar proportions of 18:2n6. Male Sprague-Dawley rats were fed a purified diet containing 11% by weight of either borage oil (BOR) rich in 18:3n6, linseed/safflower oil (LSO) rich in 18:3n3, or sesame oil (SES) rich in 18:1n9 for 7 weeks and exposed to ethanol vapors by means of inhalation for the final 6 days of the dietary regimen. Moderate blood ethanol levels of 118 +/- 6.6 mg/dl were obtained. Total lipids were extracted from platelets and aortae, and the fatty acid distributions were analyzed by gas chromatography. BOR feeding resulted in increases in the proportion of n-6 fatty acids (18:3n6, 20:3n6, 20:4n6) in platelets and aorta. Animals fed the LSO diet had increased levels of n-3 fatty acids (18:3n3, 20:5n3, 22:6n3). The SES-based diet resulted in an increase in 18:1n9 in both aorta and platelets. Following ethanol exposure alone, the most marked change in the fatty acid profile was a decrease in 20:4n6 in the platelet. This effect was not observed in rats supplemented with BOR. No significant changes were observed in the aortic fatty acid content at this level of ethanol exposure. The results suggested that, in the rat, a diet enriched with BOR effectively prevented ethanol-induced alterations in platelet fatty acid composition.

Administration, Inhalation↗
PubMed1991

Prolonged ethanol inhalation decreases gamma-aminobutyric acidA receptor alpha subunit mRNAs in the rat cerebral cortex.

Ethanol administration to rats by ethanol vapor inhalation (14 days) results in a 40-50% reduction in the level of gamma-aminobutyric acidA (GABAA) receptor alpha 1 subunit mRNAs [4.4 and 4.8 kilobases (kb)] in the cerebral cortex. The level of alpha 2 subunit mRNA (8.0 kb) was also reduced by 29%, whereas there was no effect of prolonged ethanol exposure on the level of alpha 3 subunit mRNA (3.1 kb). Ethanol exposure did not alter the steady state levels of cerebral cortical glutamic acid decarboxylase or beta-actin mRNAs. Moreover, no alterations in the levels of total RNA, poly(A)+ RNA, or rRNA were observed, suggesting that the ethanol-induced reductions in GABAA receptor alpha 1 and alpha 2 subunit mRNAs were not the result of a generalized effect of ethanol administration on transcription or mRNA turnover. These ethanol-induced reductions in GABAA receptor alpha subunit mRNAs may underlie alterations in GABAA receptor function or number observed following prolonged ethanol exposure in rats.

Administration, Inhalation↗
PubMed1990

Docosahexaenoic acid (22:6n3)-induced relaxation of the rat aorta.

Dietary consumption of fish and fish oil supplements, containing eicosapentaenoic acid and docosahexaenoic acid, has been associated with favorable alterations in the cardiovascular system, such as, a reduction in blood pressure. Therefore, the effects of docosahexaenoic acid (22:6n3) on isometric tension of rat aortic smooth muscle were investigated. A concentration-dependent (1-127 microM) relaxation (6-30%) was induced by 22:6n3 in non-precontracted vessels. Docosaehexaenoic acid, concentration dependently (1-44 microM) reversed contractions of rat aortic rings induced by phenylephrine (7-43%) and by U44069 (8-52%). These results indicate that the relaxant effects produced by 22:6n3 in the rat aorta are concentration-dependent and not specific to the contractile agonist.

Animals↗
PubMed1990

Stereochemical analysis of hydroxylated docosahexaenoates produced by human platelets and rat brain homogenate.

The stereochemical configuration of hydroxylated products of docosahexaenoic acid (22:6w3) formed by human platelets and rat brain homogenate were characterized for the first time. Chiral phase HPLC was employed along with autooxidized 22:6w3 as reference material. The 14- and 11-hydroxy 22:6w3 (HDHE) products produced by human platelets were in the S configuration. Rat brain homogenate produced all of the ten possible positional isomers when incubated with 22:6w3. Their retention behavior on the reversed and chiral phase HPLC columns and GC/MS/EI analysis indicated that they were 20-, 17-, 16-, 14-, 13-, 11-, 10-, 8-, 7- and 4-HDHE. However, stereochemical analysis revealed that each positional isomer was a racemic mixture, suggesting that these were not formed by lipoxygenation but mainly by peroxidation process.

Animals↗
PubMed1990

Formation of 15-lipoxygenase product from docosahexaenoic acid (22:6w3) by human platelets.

The metabolism of docosahexaenoic acid (22:6w3) by 15-lipoxygenase activity of washed human platelets was investigated. Platelets produced 17-hydroxydocosahexaenoic acid (HDHE) when incubated with 22:6w3. Similarly, 15-hydroxyeicosatetraenoic acid (HETE) and 13- and 9-hydroxyoctadecadienoic acids (HODD) were produced when incubated with 20:4w6 and 18:2w6, respectively. However, these products were observed only as minor components in the platelet incubation mixture. Control studies with carefully purified platelets and mononuclear cells indicated that these products were formed by the platelets. Chiral phase HPLC analysis indicated that these compounds were mainly in the S configuration with the exception of the 9-HODD, thus, confirming that a lipoxygenase is responsible for their production. The 9-HODD produced by platelets was a racemic mixture.

Arachidonate 15-Lipoxygenase↗
PubMed1989

Prostaglandins in cerebrospinal fluid of healthy human volunteers, abstinent alcoholics and rhesus monkeys.

A sensitive and selective assay for measuring prostaglandins in cerebrospinal fluid has been developed, based on the selected-ion-monitoring, electron-capture negative ionization GC/MS detection for the MO-PFB-TMS derivatives of prostaglandins E2, E1, F2 alpha, F1 alpha, and 6-keto-F1 alpha. Improvements over previously published assay procedures have been made, and the new assay has been applied to measurement of prostaglandin concentrations in lumbar CSF of healthy human volunteers, abstinent alcoholic patients, in cisternal CSF of Rhesus monkeys, and continuously sampled lumbar CSF of awake Rhesus monkeys. Results indicated that the concentrations of PGE2, PGE1, PGF1 alpha, and 6-keto-PGF1 alpha were below 15 pg/mL CSF in lumbar CSF of healthy humans and abstinent alcoholics, and in cisternal CSF of Rhesus monkeys. In contrast, continuously sampled lumbar CSF of awake Rhesus monkeys contained more than 200 pg/mL of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha, probably present as a result of local production.

Alcoholism↗
PubMed1988

Effects of long-term ethanol inhalation on the immune and hematopoietic systems of the rat.

An inhalation method of ethanol administration was used to study the effects of 14 days of ethanol administration on the immune and hematopoietic systems of the rat. A decrease in cellularity was found in the spleen, thymus, and bone marrow of ethanol-treated rats. Although the red blood cell count, white blood cell count, and hemoglobin concentration were not significantly different between treatment and control groups, treatment with ethanol altered the relative proportion of lymphocytes and polymorphonuclear leukocytes in the peripheral blood. The granulocyte-macrophage progenitor cells in the bone marrow were unaffected by ethanol treatment, but a significant decline in the number of erythroid progenitor cells was noted in ethanol-treated rats. Splenic lymphocytes, although fewer in number in the ethanol-treated rats, showed no significant difference in ability to proliferate when stimulated by nonspecific mitogens.

Administration, Inhalation↗
PubMed1988

GC/MS assay of prostaglandins in cerebrospinal fluid from humans and monkeys.

The objective of this project has been to develop a sensitive and specific assay for prostaglandins in human cerebrospinal fluid (CSF) from patients with alcoholism and appropriate controls using gas chromatography/mass spectrometry. This study was initiated because numerous literature reports strongly suggest that a relationship exists between ethanol's central nervous system effects and the central production of prostaglandins. In both human and animal studies, administration of prostaglandin synthesis inhibitors prior to administration of ethanol attenuated central nervous system effects of ethanol. Samples from alcoholics after a three week period of abstinence and normals contained none of the measured prostaglandins (PGE2, PGE1, PGF1a, PGF2a, 6-keto-PGF1a) at a concentration more than twice the limit of quantification (3 pg/mL CSF). Comparison of GC/MS and radioimmunoassay methods provided further validation for these results. Literature reports of much higher levels of prostaglandins in normal controls, i.e., tens to hundreds of pg/mL CSF, appear to be incorrect. Examination of monkey CSF provided a positive control, since several of the prostaglandins were easily quantifiable in these samples.

6-Ketoprostaglandin F1 alpha↗