Dextropropoxyphene induced hepatotoxicity mimicking biliary tract disease.

Three patients are described with recurrent jaundice, upper abdominal pain and rigors attributable to dextropropoxyphene hepatotoxicity. The diagnosis was established in each patient by rechallenge; post challenge hepatic histology is reported in two. Twelve previous patients with probable dextropropoxyphene hepatic toxicity have been described and are reviewed. In 10 of the 15 patients, a clinical diagnosis of gall stone disease was made. Liver function tests are usually hepatitic shortly after challenge, but more cholestatic after a few days. No fatalities have been described, but as dextropropoxyphene is widely available in many different analgesic preparations possible toxicity should be considered in patients with relapsing jaundice mimicking biliary disease, in whom gall stones have been excluded.     

Oxidation of tricyclic antidepressant drugs, debrisoquine and 7-ethoxyresorufin, by human liver preparations

Data obtained from human studies in vivo show that the dispositions of the tricyclic antidepressant drugs desmethylimipramine (DMI) and nortriptyline are related to the debrisoquine hydroxylation phenotype. To obtain insight into the enzymic mechanisms behind this, the metabolism of debrisoquine and antidepressant drugs by human liver preparations have been studied. The 2-hydroxylation of DMI in vitro correlates with the 4-hydroxylation of debrisoquine among various livers (rs = 0.90). Debrisoquine inhibits DMI hydroxylation competitively, and DMI inhibits debrisoquine hydroxylation, suggesting that DMI hydroxylation is catalysed by the debrisoquine hydroxylase in human liver. By monitoring the hydroxylation of DMI in various fractions during separation and purification of cytochrome P-450 from human liver microsomes we have purified a cytochrome P-450 which efficiently hydroxylates this drug. The apparently electrophoretically homogeneous enzyme had a molecular weight of 51,500 and hydroxylated DMI and debrisoquine at rates of up to 0.95 and 0.45 nmol/min . nmol P-450, respectively. This is probably the major debrisoquine hydroxylating cytochrome P-450 in man. Nortriptyline 10-hydroxylation correlates strongly (r = 0.96) with debrisoquine hydroxylation in human liver microsomes. Nortriptyline inhibits DMI-hydroxylation competitively, and the drug also inhibits the 4-hydroxylation of debrisoquine. Thus it is probable that nortriptyline is hydroxylated by debrisoquine hydroxylase. Imipramine N-demethylation did not correlate significantly (P greater than 0.1) with debrisoquine hydroxylation among microsomes from nine livers. However, if a liver from a subject, which was a poor metabolizer of debrisoquine in vivo, was included, a correlation was obtained (r = 0.79, P less than 0.01, N = 10). Imipramine demethylation also correlated with DMI-hydroxylation only if the 'poor metabolizer' liver was included (r = 0.75, P less than 0.05, N = 10). Debrisoquine inhibited imipramine demethylation competitively. The data indicate that imipramine can interact with debrisoquine- and DMI-hydroxylase, but it is uncertain if this enzyme plays an important quantitative role in its demethylation. Ethoxyresorufin O-deethylation correlated with DMI hydroxylation (r = 0.80) in human liver preparations, and DMI inhibited the former reaction in what is probably a mixed competitive-non-competitive inhibition. Liver preparations from a subject who was a poor oxidizer of debrisoquine both in vivo and in vitro had unusually low capacity to metabolize ethoxyresorufin. Thus ethoxyresorufin, at least partly, seems to interact with an enzyme that can metabolize DMI in human liver.(ABSTRACT TRUNCATED AT 400 WORDS)     

Arachidonic acid products and the thoracic accumulation of neutrophils and platelets following i.v. antigen challenge of sensitised guinea-pig

The 5-lipoxygenase inhibitors, AA861 and phenidone, have been shown to inhibit the formation and release of leukotrienes C4, D4 and B4 from isolated perfused sensitised guinea pigs lungs when challenged through either the pulmonary system or the airways. The same drugs inhibit the thoracic neutrophil, but not platelet, accumulation observed following i.v. antigen challenge of sensitised guinea pigs. Indomethacin, a cyclooxygenase inhibitor, at doses which inhibited an arachidonic acid-induced thoracic platelet accumulation, had no effect on the platelet response following antigen challenge. Indomethacin did affect, however, the neutrophil response to antigen challenge presumably through mechanisms unrelated to cyclooxygenase inhibition. These observations suggest a role for lipoxygenase products, possibly LTB4, but not cyclooxygenase products in the neutrophil response to i.v. antigen challenge.     

Altered motor control patterns in whiplash and chronic neck pain

Background  

Persistent whiplash associated disorders (WAD) have been associated with alterations in kinesthetic sense and motor control. The evidence is however inconclusive, particularly for differences between WAD patients and patients with chronic non-traumatic neck pain. The aim of this study was to investigate motor control deficits in WAD compared to chronic non-traumatic neck pain and healthy controls in relation to cervical range of motion (ROM), conjunct motion, joint position error and ROM-variability.     

Physician response to screening for hypercholesterolaemia in a coronary care unit

Abstract Hypercholesterolaemia is a known risk factor for coronary artery disease. This study describes a retrospective analysis of 176 patients admitted to the Coronary Care Unit (CCU) in a six month period with an admission fasting serum cholesterol of greater than 5.5 millimoles per litre (mmols/L). The patient records were examined at least six months after hospital discharge to determine what action, if any, was instituted in response to their hypercholesterolaemia. One hundred and thirty-four (76%) patients had a discharge diagnosis of myocardial ischaemia or infarction. Of the 176 patients, 73 were referred to a dietitian, 31 were given dietary advice by a medical officer, 13 were commenced on lipid-lowering drugs with nine continuing lipid-lowering drugs and only 13 patients were referred to this hospital's lipid clinic. Sixty-nine (39%) received no response to their hypercholesterolaemia. It is likely that our experience is not unique and greater attention to CCU measured lipid results and risk factor modification should be instituted by physicians. (Aust NZ J Med 1991; 21: 401–404.)     

Binding of the novel ligand [4,5-3H-Leu10]substance P to high-affinity NK-1 receptors on guinea pig lung membranes: modulation by GTP analogs and sulfhydryl modifying agents.

A novel ligand, [4,5-3H-Leu10]substance P ([3H]SP), with high specific activity (137 Ci/mmole) was utilized to investigate the properties of NK (neurokinin)-1 receptors on guinea pig lung membranes (GPLM) and compared them to NK-1 receptors on rat submaxillary glands (RSGM). In the presence of a neutral endopeptidase inhibitor, thiorphan (100 microM), [3H]SP bound with high specificity (greater than 95%), rapidly (k1 = 0.116 nM-1 x min-1) and in a reversible (k-1 = 0.012 min-1) manner to a single class of high-affinity (Kd = 0.16 nM) and saturable (Bmax = 256 fmol/mg protein) receptors. High specific binding with higher density (5-fold) was also detected in RSGM, albeit with a lower affinity (Kd = 1.36 nM). Guanyl-5'-yl-imidodiphosphate and guanosine-5'-O-3-thiotriphosphate inhibited binding to GPLM (and RSGM) in a concentration-related manner. In GPLM, this effect was mediated by a reduction in affinity, mainly via enhancement of ligand dissociation rates and appearance of a lower affinity state (Kd = 3.4 nM). Preincubation of GPLM with sulfhydryl modifying agents (p-chloromercuriphenyl sulfonic acid and N-ethylmaleimide) reduced receptor density and affinity in a time- and concentration-dependent manner. Competition experiments with tachykinins and analogs illustrated a rank order of potency of: SP greater than or equal to [Sar9,Met(O2)11]SP greater than SP-methyl ester greater than or equal to physalaemin greater than SP(6-11) much greater than kassinin greater than neurokinin A = eledoisin much greater than neurokinin B greater than Nle10-NKA(4-10), clearly demonstrating that these receptors are of NK-1 type. Moreover, analysis of over 30 peptide and non-peptide hormones and antagonists demonstrated exquisite selectivity (greater than 10,000-fold) towards NK-1-selective agonists (vs. other ligands. A highly significant (P less than .005) linear correlation (r = 0.924) exists between agonist affinities in GPLM and RSGM. Combined, the data suggest that [3H]SP labels a nearly homogeneous population of high-affinity, G-protein coupled NK-1 receptors on GPLM and RSGM, with very high degree of selectivity.     

Delayed ectopic pregnancies after sterilization

Female sterilization as an interval, postabortal or postpartum procedure, is one of the most widely employed contraceptive techniques on a global basis. The short-term complications of sterilization, which include intra- and extrauterine pregnancies, are well researched and documented. The figures for long-term complications, including ectopic pregnancy, are much less reliable as the follow-up rates diminish as time passes after sterilization. Three cases of tubal pregnancy that occurred long after interval sterilization are presented as a warning against the assumption that long-term complications cannot occur.     

Human immunodeficiency virus type 1-infected blood donors: epidemiologic, laboratory, and donation characteristics. The HIV Blood Donor Study Group

Transmission of human immunodeficiency virus type 1 (HIV-1) by homologous blood transfusion in the United States (US) is minimized by the deferral of potential donors who are at risk for HIV-1 infection and by the screening of all donations for HIV-1 antibody. HIV-1-seropositive donors at 20 blood centers were studied for information to be used in evaluating the safety of the US blood supply and making recommendations to increase that safety. From June 1988 to August 1989, 829 (0.04%) of 2,192,000 donors were found to be seropositive; 512 were interviewed. Of 388 seropositive men, 56 percent had had sex with men, 10 percent had used drugs intravenously, 8 percent had had sex with intravenous drug users, and 27 percent had no identified risk. Of 124 seropositive women, 58 percent had had sex with men at risk for HIV (81% of whom used drugs intravenously), 5 percent had used drugs intravenously, and 41 percent had no identified risk. Racial and ethnic minorities made up 68 percent of seropositive donors (black, 38%; Hispanic, 30%) and approximately 14 percent of all donors. The 157 persons with no identified risk had demographic characteristics and serologic test results for syphilis and hepatitis B that were more similar to those of HIV-1-seropositive donors with recognized risk than to those of seronegative donors. Three health care worker-blood donors (from an estimated 93,100 health care worker-donors) had infection that was probably acquired occupationally.(ABSTRACT TRUNCATED AT 250 WORDS)