Biomedical subjects

S Li

Publications and source records attributed to S Li.

At least 1,027 records · Page 57Linked to original sources

PubMed1997

Cellular basis of contractile derangements of hypertrophied feline ventricular myocytes.

The objective of this study was to further explore the cellular basis of the reduced rate and magnitude of contraction of feline left ventricular myocytes with severe hypertrophy induced by slow progressive pressure overload. A 3.0 mm internal diameter band was placed around the ascending aorta of 12 young (8-10 weeks old) cats, and sham operations were performed in 13 others. This caused no major pressure overload initially, but 15 weeks later there was a significant pressure gradient across the band (56+/-14 mmHg) and the heart weight to body weight ratio had increased from 4.2-7 gm/kg. Contraction rates and magnitudes of myocytes isolated from the hearts with hypertrophy (LVH) were significantly slower and smaller, respectively, than those from control (C) animals. Indo-1 fluorescence transients in LVH myocytes were significantly smaller in magnitude and longer in duration than in C, suggesting that contractile defects result from Ca2+ derangements. Elevation of bath Ca2+ increased the peak Indo-1 fluorescence and the rate and magnitude of contraction in all myocytes. At the bath Ca2+ which had maximal inotropic effects there were no differences in the peak Indo-1 fluorescence in LVH and C myocytes, but contraction magnitude remained significantly smaller in LVH. This suggests that there are Ca2+-independent contractile derangements in LVH. In support of this hypothesis, the relationship between contraction magnitude and the peak Indo-1 fluorescence (index of myofibrillar Ca2+ sensitivity) was significantly shifted in LVH myocytes, suggesting that myofibrillar Ca2+ sensitivity was reduced. There was also a significant shift of the terminal portions of hysteresis loops of cell length v indo-1 fluorescence ratio, providing additional support for this idea. Experiments with isoproterenol suggest that it can reduce myofibrillar Ca2+ sensitivity in C, but not LVH myocytes. The idea that increased internal resistance to shortening (internal load) is responsible for the contractile defects of LVH myocytes was examined by defining the relationship between the rate of relengthening and the magnitude of shortening. There was no significant difference in this relation between C and LVH myocytes. In addition, colchicine (which depolymerizes microtubular tubulin) had no significant effect on contraction magnitude in either C or LVH myocytes. These results suggest that the contractile properties of feline LVH myocytes result from changes in cellular Ca2+ regulation and myofibrillar Ca2+ sensitivity, but not from changes in the internal loading.

Actin Cytoskeleton↗

PubMed1997

Pharmacokinetics of ochratoxin A and its metabolites in rats.

Ochratoxin A (OA) is a mycotoxin that is produced on moist grain. It is commonly found in the blood of swine in western Canada and is a potent nephrotoxic, carcinogen, and immunosuppressive agent. The pharmacokinetic characteristics of six analogs of OA including OA, OB (OA without chloride), OC (OA ethyl ester), and some metabolites, such as O alpha (OA without phenylalanine), OA-OH (hydroxylated OA), and a newly discovered form of OA, OP-OA (lactone opened ring of OA), were investigated in rats after a single intravenous administration of the compounds. All of the ochratoxin analogs were distributed following a two compartment open model. The elimination half-lives of OA, OP-OA, O alpha, OA-OH, OB, and OC were 103+/-16, 50.5+/-2.8, 9.6+/-2.3, 6+/-0.9, 4.2+/-1.2, and 0.6+/-0.2 hr, respectively. Total body clearance of OA, OP-OA, O alpha, OA-OH, and OB via the bile, urine, and metabolic routes were 3.1, 3.6, 40, 65, and 43 ml/hr kg, respectively. OA, OB, and O alpha were mainly cleared in the urine (> or = 48%), OA-OH in the bile (41%), and OP-OA as metabolites (43%). Metabolism accounted for 43, 44, 33, and 29% of the total clearance of OA, O alpha, OA-OH, and OB, respectively. It is concluded that OA has a long half-life and is very slowly cleared from the body and that its metabolites are cleared at a much faster rate with much shorter half-lives. Procedures should be devised to enhance the conversion in the body of OA to O alpha, OA-OH, or other metabolites as this would shorten its half-life and therefore its toxicity.

Animals↗

PubMed1997

Superinduction of IL-2 gene expression by vomitoxin (deoxynivalenol) involves increased mRNA stability.

To better understand molecular mechanisms by which the trichothecene vomitoxin (VT) superinduces cytokine gene expression, we studied the posttranscriptional effects of this mycotoxin on interleukin-2 (IL-2) gene expression in murine EL-4 thymoma cells stimulated with phorbol 12-myristate 13-acetate and ionomycin (PMA + ION). Northern analysis revealed that doses of 50 to 500 ng/ml VT superinduced IL-2 mRNA expression in a dose- and time-dependent manner in a synchronous model where VT was added at onset of PMA + ION stimulation. In accordance with the mRNA levels, IL-2 production was significantly elevated in the presence of 50 to 250 ng/ml VT. Superinduction of IL-2 mRNA was also observed in a delayed synchronous model (VT added 20 hr after PMA + ION stimulation) and an asynchronous model (VT added 20 hr after PMA + ION stimulation and removal). To assess the effects of VT (500 ng/ml) on IL-2 mRNA half-life, three transcriptional inhibitors were used in the delayed synchronous model. Actinomycin D (ActD) had a pronounced stabilizing effect on IL-2 mRNA but not on mRNA for the housekeeping gene GAPDH. VT did not affect IL-2 mRNA levels in ActD-treated cells. Although 5,6-dichloro-beta-D-ribofuranosyl-benzimidazole (DRB) also had a stabilizing effect on IL-2 mRNA, IL-2 mRNA half-life t1/2 in VT-treated cells was three times that of control. In contrast, inclusion of cyclosporin A (CsA) into the cultures specifically arrested IL-2 transcription in EL-4 cells without any stabilizing effect. VT exposure in the presence of CsA markedly prolonged the half-life of IL-2 mRNA in a dose-dependent manner. The t1/2 for IL-2 mRNA in the control culture was 2.1 hr, whereas t1/2 was 3.1, 3.4, 4.2, and 10.5 hr in cultures containing 50, 100, 250, and 500 ng/ml VT, respectively. These results suggest that VT can superinduce IL-2 at both the mRNA and the protein level and that this superinduction can be explained, in part, by posttranscriptional mechanisms such as enhanced mRNA stability.

Animals↗

PubMed1997

A comparison of 99mTc-MIBI myocardial SPET with electron beam computed tomography in the assessment of coronary artery disease.

UNLABELLED: We compared technetium-99m methoxyisobutylisonitrile (MIBI) myocardial perfusion single-photon emission tomography (SPET) (MPS) and electron beam computed tomography (EBCT) in order to assess their respective value in the detection of coronary artery disease (CAD). 99mTc-MIBI SPET (stress-resting) and EBCT studies were performed in 51 patients with suspected CAD who underwent coronary angiography (CAG). CAG showed that of the 51 patients, 36 had coronary stenosis >/=50% while 15 had normal results. A moderate positive rank correlation was found between coronary calcification detected by EBCT and MPS score (rs=0.5283, P<0.01). The concordance between EBCT and MPS for the evaluation of CAD was 72.5% (37/51). The sensitivity of EBCT in detecting CAD in 51 patients was comparable to that of MPS (81% vs 94%, NS). However, the accuracy of EBCT was lower than that of MPS (78% vs 94%, P<0.025). As regards the detection of individual coronary artery disease, there was no significant difference in sensitivity between EBCT and MPS (65% vs 75%, NS); however, the specificity and accuracy of EBCT were lower than those of MPS (specificity: 77% vs 95%, P<0.005; accuracy 71% vs 85%, P<0.005). The sensitivity, specificity and accuracy of MPS in detecting single-vessel disease were higher than those of EBCT (sensitivity: 86% vs 42%, P<0.025; specificity: 96% vs 70%, P<0.025; accuracy: 93% vs 61%, P<0.005). However, no significant differences in the sensitivity, specificity and accuracy of MPS and EBCT were found in respect of multivessel disease. IN CONCLUSION: 99mTc-MIBI myocardial perfusion SPET and EBCT provide different information in the assessment of CAD. The sensitivity of EBCT for the detection of CAD is comparable with that of MPS; however, the specificity and accuracy of EBCT are lower than those of MPS. More reliable results will be obtained if both myocardial perfusion SPET and EBCT are performed.

Adult↗

PubMed1997

Dehydroepiandrosterone administration reverses the inhibitory influence of aging on gonadotrophin-releasing hormone gene expression in the male and female rat brain.

Dehydroepiandrosterone (DHEA) has been shown to exert a beneficial influence on some aging-associated deficits in rodents. It is well documented that in the rat, aging is associated with a decline in reproductive functions. In order to evaluate the effect of DHEA on GnRH gene expression in aged animals, we have studied the effect of 2.5-d administration of DHEA to young (50-54 d of age) and aged (18 mo of age) rats of both sexes. In the young males, DHEA induced an 18% reduction in the hybridization signal. In the aged animals, the mRNA levels were 10% lower than those observed in the young rats. DHEA completely restored the mRNA levels when compared to those detected in young male animals. In the young female, DHEA produced a 11% increase in GnRH mRNA, whereas, in the aged animals, hybridization signal was decreased by 28%. DHEA administration to aged females induced a 33% increase in the amount of mRNA, thus completely reversing the influence of aging. These results indicate that the decrease in GnRH gene expression which is likely involved in the loss of reproductive functions in aged rats can be totally reversed by a short term administration of DHEA which restored the GnRH neuronal activity. They also suggest that DHEA might play a role in the prevention and/or improvement of some deficits associated with aging through stimulation of GnRH biosynthesis.

Aging↗

PubMed1997

Mechanism of anti-beta-adrenoceptor antibody mediated myocardial damage in dilated cardiomyopathy.

Antibodies against beta(1)-adrenoceptor can be detected in serum of patients with dilated cardiomyopathy (DCM), which have beta-agonist-like activity, and induce a positive chronotropic effect on cardiac myocytes by its persistence at full strength. Effects of the antibodies against beta-adrenoceptor from sera of patients with DCM on myocardial cytotoxicity and cytoplasmic free Ca(2+)-concentration ([Ca2+]i) were observed in the cultured single layer SD rat ventricular cells by using the cytotoxicity assay and fluorescent Ca(2+)-indicator fura-2/AM. The positive sera of the anti-beta-adrenoceptor antibodies from patients with DCM markedly enhanced myocardial [Ca2+]i. Betaloc, a beta(1)-receptor blocker, might inhibit the increase of the antibody-mediated myocardial [Ca2+]i, and the sera from healthy donors had no effect on myocardial [Ca2+]i. Our results suggest that the anti-beta-adrenoceptor antibody might increase myocardial [Ca2+]i and result in myocardial damage. The antibodies might activate receptor-gating Ca(2+)-channel, thereby causing myocardial [Ca2+]i rise and calcium overload. Early use of betaloc is recommended in the treatment of dilated cardiomyopathy.

Adult↗

PubMed1997

Multiple respiratory gas monitoring causes changes of inspired oxygen concentration in closed anesthesia system.

Effect of multiple respiratory gas monitoring (MRGM) on inspired concentration of oxygen in circuit system during closed anesthesia was studied in 51 adult patients scheduled for abdominal surgery. Required flow rate of fresh oxygen (OFR), inspired oxygen concentration (FiO2) and oxygen saturation of pulse oximeter (SpO2) were measured continuously. Patients were equally divided into three groups at random, group C (no MRGN used), group M1 (using MRGM with its tail gas returned to circuit system), group M2 (using MRGM without tail gas returned). The results revealed that during 180 min of closed anesthesia, OFR required in group C and M1 were about 200-230 ml/min, and in group M2 it was about 400 ml/min. In group C FiO2 decreased by about 10% after 60 min of closed anesthesia (P < 0.01, 60 min vs 0 min) and then stayed stable at this level. In group M1, FiO2 decreased by 16% at 60 min and 34% at 180 min and the decrease was significantly greater than that in group C (P < 0.01). In group M2, FiO2 remained constant during closed anesthesia, which was much higher than those in group C and M1. The tail gas of Capnomac Ultima MRGM contained less oxygen than its sample gas drawn from circuit system simultaneously.

Adult↗

PubMed1997

Rearranged patterns of IgH and TcR gamma genes in patients with acute lymphoblastic leukemia.

The rearrangement of immunoglobulin heavy chain gene (IgH) and T cell receptor gamma gene (TcR gamma) was studied in 30 patients with acute lymphoblastic leukemia (ALL) by the polymerase chain reaction (PCR). 19 cases was found to have rearrangement of IgH gene, 12 of TcR gamma. Most of IgH rearrangement was characterized by one or two specific bands while some had more than two. Rearrangement of TcR gamma gene appeared as one specific band. A slight difference in number, size and lightness of bands was found among the patients. 4 different kinds of rearrangement were observed in the detection of IgH rearrangement in combination with TcR gamma gene. The rearranged patterns of IgH and TcR gamma gene as well as the clinical significance were discussed.

Adult↗

PubMed1997

Polymerase chain reaction determination of RhC, Rhc, and RhE blood types: an evaluation of accuracy and clinical utility.

OBJECTIVE: Polymerase chain reaction amplification of a portion of the RhC/c/E/e gene could lead to a rapid, accurate determination of fetal RhC/c/E status. The purpose of this study was to evaluate the accuracy of this technique by testing for the first time a large number of deoxyribonucleic acid samples derived from individuals whose RhC/c/E status was established by standard serologic methods. We also evaluated the potential clinical utility of polymerase chain reaction to ascertain fetal antigen status. STUDY DESIGN: Samples were obtained from Centre d'Etude du Polymorphisme Humain families used for studies of genetic variation (n = 655). Deoxyribonucleic acid was extracted by standard techniques. With few modifications, published primers and reaction conditions were used. Samples were digested with restriction enzymes yielding characteristic electrophoresis patterns for RhC/c/E. Clinical utility was assessed by review of all patients evaluated for erythrocyte sensitization. RESULTS: RhC-positive (n = 479), RhC-negative (n = 176), Rhc-positive (n = 524), Rhc-negative (n = 131), RhE-positive (n = 131) and RhE-negative (n = 524) samples were evaluated. The sensitivity of RhC/ c and E typing by polymerase chain reaction was 98.3%, 98.1%, and 96.9%, respectively. The specificity of polymerase chain reaction for identifying the RhC/c/E antigens was 91.5%, 94.7%, and 99.2%, respectively. CONCLUSIONS: Although it would appear that use of polymerase chain reaction to establish RhC/c/E type could aid in evaluation of RhC/c/E sensitization, we are concerned about the instances of antigen-positive individuals characterized as antigen negative. Further study is necessary to determine if this reflects a polymorphism, mutation, a data coding error, or a combination. The Centre d'Etude du Polymorphisme Humain database is known to contain such errors at a rate that may surpass the error rate of our testing. A second molecular technique could be used to achieve better accuracy in the ascertainment of Rh C/c/E type. On the basis of a review of our patient population, molecular deoxyribonucleic acid techniques now available could aid the management of erythrocyte sensitization in pregnancy in > 96% of cases.

Blood Grouping and Crossmatching↗

PubMed1997

Influence of cis double bonds in the sn-2 acyl chain of phosphatidylethanolamine on the gel-to-liquid crystalline phase transition.

We have semisynthesized 19 species of mixed-chain phosphatidylethanolamines (PEs) in which the sn-1 acyl chain is derived from saturated fatty acids with varying chain lengths and the sn-2 acyl chain has different chain lengths but contains 0, 1, and 2 cis double bond(s). The gel-to-liquid crystalline phase transition temperatures (Tm) of lipid bilayers prepared from these 19 mixed-chain PEs were determined calorimetrically. When the Tm values are compared with those of saturated and monounsaturated counterparts, a common Tm profile is observed in the plot of Tm versus the number of cis double bonds. Specifically, a marked stepwise decrease in Tm is detected as the number of cis double bonds in the sn-2 acyl chain of the mixed-chain PE is successively increased from 0 to 1 and then to 2. The large Tm-lowering effect of the acyl chain unsaturation can be attributed to the increase in Gibbs free energy of the gel-state bilayer as a result of weaker lateral chain-chain interactions. In addition, we have applied molecular mechanics calculations to simulate the molecular structure of dienoic mixed-chain C(X):C(Y:2 delta n,n+3)PE in the gel-state bilayer, thus enabling the three independent structural parameters (N, delta C, and LS) to be calculated in terms of X, Y, and n, which are intrinsic quantities of C(X):C(Y:2 delta n,n+3)PE. When the Tm values and the corresponding N and delta C values of all dienoic mixed-chain PEs under study are first codified and then analyzed statistically by multiple regressions, the dependence of Tm on the structural parameters can be described quantitatively by a simple and general equation. The physical meaning and the usefulness of this simple and general equation are explained.

Calorimetry, Differential Scanning↗

PubMed1997

The relationship between the vas volume and the anatomic size of the vas deferens.

The anatomic sizes of 210 vas segments from 107 volunteers of vasectomy were measured by computerized image graphic technique with microphotography. The mean equivalent-round, outer and inner diameters of the vas were 2.17 +/- 0.20 mm and 0.56 +/- 0.08 mm, respectively. The calculated thickness of vas wall was 0.81 +/- 0.21 mm. The maximal volumes of 124 vas segments (1 cm in length) were tested by injecting colored solution into vas lumen until vas rupture. The mean rupture volume of 1 cm vas lumen was 0.05 +/- 0.007 mL. A significant influence of the thickness of vas wall (p < 0.05) and body height (p < 0.05) on the rupture volume was noticed in stepwise regression analysis. A tunnel-like rupturing pattern was observed in morphological observation. The obtained rupture volume provides a security line in determining the injection volume of occlusive material or the size of the implanted contraceptive device.

Adult↗

PubMed1997

Role of adrenal and gonadal steroids in the response of GnRH gene expression to the endogenous benzodiazepine receptor ligand octadecaneuropeptide in the male rat brain.

We have recently demonstrated that the inhibitory influence of the endogenous benzodiazepine receptor ligand octadecaneuropeptide (ODN) on gonadotropin-releasing hormone (GnRH) gene expression could be prevented by specific inhibitors of 3 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase in adrenalectomized and castrated male rats, then suggesting an involvement of neurosteroids in the action of ODN on GnRH neurons. In order to study in detail the role of circulating steroids in the effect of ODN, we have evaluated the influence of adrenalectomy, castration and the combination of adrenalectomy and castration as well as the effect of dexamethasone administration in the response of GnRH gene expression to ODN in the male rat. The intracerebroventricular injection of ODN (4 h before sacrifice) produced a 36% decrease in the hybridization signal. Adrenalectomy induced a 21% decrease in GnRH mRNA levels. In the adrenalectomized rats, the injection of ODN increased by 11% the amounts of mRNA. As previously reported by our group, castration was found to enhance GnRH mRNA (15% over control values). In castrated animals, ODN produced an inhibitory effect in the hybridization signal which was of the same amplitude as that observed in sham-operated animals. Finally, the combination of adrenalectomy and castration resulted in a small but significant decrease in the hybridization signal, the values being intermediary between those observed after adrenalectomy and those obtained after castration. In these animals, ODN induced a 38% decrease in the amounts of GnRH mRNA. In animals that had been castrated and adrenalectomized, dexamethasone treatment during 4 days produced a 19% increase in hybridization signal. In these dexamethasone-treated animals, ODN produced the usual decrease (33%) in GnRH mRNA. These results demonstrate that gonadal hormones do not play a major role in the activation of the GABAA receptor complex by ODN. On the other hand, it clearly appears that glucocorticoids exert a tonic stimulatory influence on GnRH neuronal activity and are involved in the inhibitory effect of ODN. The mechanism of action of glucocorticoids, which seems complex since the influence of adrenalectomy on the ODN action can be prevented by orchidectomy, remains to be fully elucidated.

3-Hydroxysteroid Dehydrogenases↗

PubMed1997

Antigen presentation by autoreactive proteolipid protein peptide-specific T cell clones from chronic progressive multiple sclerosis patients: roles of co-stimulatory B7 molecules and IL-12.

To assess the role of T cell antigen (Ag) presentation in multiple sclerosis (MS), proteolipid protein (PLP) peptide reactive CD4+ T cell clones (TCCs) from MS patients and normal subjects were studied. TCCs derived from chronic progressive (CP) MS patients were able to proliferate and secret cytokines in response to PLP peptide stimulation in the absence of professional antigen presenting cells (APCs), suggesting that these T cells can simultaneously present and respond to Ags. However, they did not respond to total PLP protein, suggesting that PLP-peptide TCCs were unable to process and present the whole PLP molecule. The ability of the different TCCs to act as APCs in response to Ag stimulation did not correlate with expression of HLA-class II molecules. However, the degree of expression of B7-1 and B7-2 co-stimulatory molecules showed a significant correlation with APC capacity. Furthermore, a combination of anti-B7-1 and anti-B7-2 mAbs effectively inhibited proliferative responses as well as secretion of IL-10, IFN gamma and TGF beta induced by antigen presenting T cells. By contrast, IL-4 secretion was not affected. Finally, IL-12 significantly enhanced the efficiency of T cell Ag presentation by a pathway independent of Ag processing, suggesting that IL-12 might act as an additional co-stimulatory signal for T cell activation during T-T cell interactions. Together, these observations suggest that Ag presentation by T cells might amplify and perpetuate an autoimmune response previously initiated by professional APCs. These properties may account for progression of MS into a CP phase.

Adult↗

PubMed1997

Age-related decrease in the hypothalamic CRH mRNA expression is reduced by dehydroepiandrosterone (DHEA) treatment in male and female rats.

Aging is frequently associated with changes in physiological and cognitive processes. Among these changes, it has been shown that aging has a profound impact on the hypothalamo-pituitary-adrenocortical (HPA) axis. Since there is controversy about the influence of aging on the HPA axis, the first objective of the present study was to clarify the effects of aging on the HPA axis using the genetic expression of hypothalamic corticotropin-releasing hormone (CRH). Changes in the CRH mRNA expression were quantified in the hypothalamic paraventricular nucleus (PVN) using in situ hybridization, in young (50 days) and old (18 months) rats of both sexes. The second objective was to determine the effects of dehydroepiandrosterone (DHEA) treatment on the age-related changes in CRH mRNA in both sexes. In aged animals of both sexes, CRH mRNA levels in PVN were significantly reduced by 20%. DHEA treatment increased the CRH mRNA expression in young rats and reversed the decrease in the CRH mRNA expression in old rats. Young males were more sensitive to DHEA than young females (+15% vs. +9%) whereas in old animals females showed more striking changes than males (+38% vs. +24%). These findings clearly demonstrate that in old apparently healthy rats of both sexes aging process induced a significant decrease in basal CRH mRNA levels and that DHEA treatment which exerts a positive influence on CRH gene expression completely reversed the decrease of the CRH mRNA levels associated with aging.

Aging↗

PubMed1997

Effects of aging and melatonin administration on gonadotropin-releasing hormones (GnRH) gene expression in the male and female rat.

It is well documented that in the rat of both sexes aging is associated with a decline in reproductive functions. We have recently shown that melatonin exerts a positive influence on GnRH gene expression in the adult male rats. In order to evaluate the effect of aging as well as melatonin on GnRH mRNA levels, we have studied the effect of 2.5-day administration of melatonin to young (50-55 day of age) and aged (18 month of age) rats of both sexes. In the young males melatonin induced a 11% increase in the hybridization signal. In the aged males, the GnRH mRNA levels were 13% lower than those observed in the young animals. Melatonin administration to aged animals completely restored GnRH mRNA levels when compared to those observed in the young untreated male rats. In contrast, melatonin did not modify the hybridization signal in young female rats, while aging induced a 20% decrease in mRNA levels. Melatonin administration to aged female induced a 18% increase in GnRH mRNA levels, thus completely reversing the influence of aging. These results indicate that the decrease in GnRH gene expression which is likely involved in the decline of reproductive functions in aging can be totally reversed by a short term administration of melatonin, then suggesting that the pineal hormone may be involved in the decrease of GnRH neuronal activity during aging.

Aging↗

PubMed1997

Rapid measurement of the spatial resolution of colour flow scanners.

An acoustic grid for rapid measurement of the spatial resolution of colour velocity images is described. The grid is composed of alternate widths of acoustic window and acoustic attenuator. Attenuation is provided by the use of a layer of waterproof paper, which is wrapped in close contact with a tube of a flow phantom. The colour image consists of several closely spaced lines. When the grid line spacing is less than the spatial resolution, the colour lines cannot be separately visualised. The use of several grids of different spacing provides a measure of the spatial resolution. It is shown that the spatial resolution is dependent on the position of the focal zone.

Blood Flow Velocity↗

PubMed1997

Loss of analgesic effect of morphine due to coadministration of rifampin.

Methadone withdrawal symptoms have been reported in drug addicts treated with the tuberculostatic rifampin. Whereas this interaction can be explained by induction of phase I drug metabolism (CYP3A4), knowledge about induction of phase II metabolism (e.g., UDP-glucuronosyltransferases = UGTs) and its influence on drug effects in man, however, is very limited. The potent analgesic morphine is metabolized by more than one UGT to the active metabolite morphine-6-glucuronide and to morphine-3-glucuronide, which is devoid of analgesic activity. Thus, differential induction of UGTs involved in metabolism of morphine might lead to decreased or increased analgesic effects, depending on which UGT is preferentially induced. We therefore investigated the influence of the potent enzyme inducer rifampin on analgesic effects and pharmacokinetics of morphine, which is primarily eliminated by phase II metabolism. Ten healthy male volunteers participated in this double-blind, placebo-controlled study with double crossover design. Morphine (10 mg p.o.) and placebo were administered on two separate occasions before and near the end of 13 days of treatment with rifampin (600 mg/day). Blood samples were collected for 31 h. Morphine effects on pain sensation were determined using the cold pressor test. When morphine was given alone, the opioid elicited a significant increase in pain threshold and pain tolerance in comparison to placebo (P < or = 0.05). However, following administration of rifampin no analgesic effect of morphine was observed. In agreement, the area under the serum concentration-time curve (AUC) of morphine and the maximum serum concentration of morphine were considerably reduced during coadministration of rifampin (-27.7 +/- 19.3% and -40.7 +/- 27.1%; P < or = 0.01). Moreover, during treatment with rifampin a proportional reduction of AUCs of morphine-3-glucuronide (P < or = 0.01), morphine-6-glucuronide (P < or = 0.05) and morphine was observed. Since urinary recoveries of both morphine-3-glucuronide and morphine-6-glucuronide were also reduced during administration of rifampin, there is no evidence for a contribution of UGT induction to the observed interaction. In summary, a major drug interaction was observed between morphine and rifampin, which could not be attributed to induction of UGTs, but resulted in a complete loss of analgesic effects of the opioid.

Adult↗

PubMed1997

Smaller intravenous perfluorocarbon-containing microbubbles produce greater myocardial contrast with intermittent harmonic imaging and better delineation of risk area during acute myocardial ischemia.

The purpose of this article was to determine whether applying negative or positive pressure to perfluorocarbon-containing microbubbles before intravenous injection would improve the myocardial contrast when using newer imaging techniques such as harmonic and intermittent imaging. Perfluorocarbon-containing microbubbles were exposed to sustained negative or positive pressure before intravenous injection in 10 dogs. Microbubble size distribution and concentration were measured after each exposure. Peak myocardial videointensity with intermittent harmonic imaging with each sample was compared. Microbubbles exposed to -200 mm Hg pressure before intravenous injection produced both the highest concentration of microbubbles and greater numbers of microbubbles less than 4 microns. Peak myocardial videointensity did not correlate with microbubble concentration or size but did correlate with the absolute number of microbubbles < 4 microns (mean r value 0.76, range 0.61 to 0.90). Risk area was best visualized with perfluorocarbon-containing microbubble samples containing the smallest microbubbles. We conclude that the myocardial contrast observed with perfluorocarbon-containing microbubbles can be enhanced by applying negative pressure before injection. The mechanism for this improved contrast appears to be related to creation of smaller microbubbles.

Animals↗