Genetically-determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.

1. Quinidine is a potent inhibitor of the genetically-determined debrisoquine 4-hydroxylation. Oxidation reactions of several other drugs, including the 5-hydroxylation of the new antiarrhythmic drug propafenone, depend on the isozyme responsible for debrisoquine 4-hydroxylation. 2. The effect of quinidine on the debrisoquine phenotype-dependent 5-hydroxylation and the pharmacological activity of propafenone was studied in seven 'extensive' metabolizers and two 'poor' metabolizers of the drug receiving propafenone for the treatment of ventricular arrhythmias. 3. In patients with the extensive metabolizer phenotype, quinidine increased mean steady-state plasma propafenone concentrations more than two fold, from 408 +/- 351 (mean +/- s.d.) to 1096 +/- 644 ng ml-1 (P less than 0.001), decreased 5-hydroxypropafenone concentrations from 242 +/- 196 to 125 +/- 97 ng ml-1 (P less than 0.02) and reduced propafenone oral clearance by 58 +/- 23%. 4. Despite these changes in plasma concentrations, electrocardiographic intervals and arrhythmia frequency were unaltered by quinidine coadministration, indicating that 5-hydroxypropafenone contributes to the pharmacologic effects of propafenone therapy in extensive metabolizers. 5. In contrasts, plasma concentrations of propafenone and 5-hydroxypropafenone remained unchanged in the two patients with the poor metabolizer phenotype. 6. Biotransformation of substrates for the debrisoquine pathway can be markedly perturbed by even low doses of quinidine; interindividual variability in drug interactions may have a genetic component.     

Cholelithiasis: a serious complication after total gastrectomy

To establish the incidence of cholelithiasis after total gastrectomy, patients operated on between 1979 and 1985 were reviewed. The study group consisted of 30 patients, all free of gallstones at the time of their gastrectomy. The median age of the patients was 56 years, the average follow-up 40 months. Cholelithiasis developed in 47 per cent of patients (14/30) and always within 2 years of total gastrectomy. The incidence of cholelithiasis was not related significantly to the sex or age of the patients. Morbidity from cholelithiasis was not negligible. Three of the fourteen patients presenting with gallstones required medical treatment in hospital and later came to cholecystectomy because of specific biliary symptoms. Cholelithiasis appears to be a significant complication after total gastrectomy. It may be related to the vagotomy which is performed at the time of gastrectomy.     

Demystified. Human endogenous retroviruses.

Human endogenous retroviruses (HERVs) are a family of viruses within our genome with similarities to present day exogenous retroviruses. HERVs have been inherited by successive generations and it is possible that some have conferred biological benefits. However, several HERVs have been implicated in certain cancers and autoimmune diseases. This article demystifies these retroviruses by providing an insight into HERVs, their means of classification, and a synopsis of HERVs implicated in cancer and autoimmunity. Furthermore, the biological roles of HERVs are explored.     

Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibers. Relationship to potassium and cycle length

Marked QT prolongation with induction of polymorphous ventricular tachycardia ("Torsades de Pointes") is a well-described phenomenon during quinidine therapy, frequently occurring at low plasma quinidine concentrations, low serum potassium, and slow heart rates. We have therefore assessed the dose-electrophysiological effects of quinidine as a function of extracellular potassium and cycle length in canine Purkinje fibers, using standard microelectrode techniques. Quinidine (1 microM) prolonged action potential at 90% repolarization, while leaving phase zero upstroke slope (Vmax) unchanged at a cycle length 300-8000 msec; at 10 microM, Vmax depression became evident. Increases in the action potential at 90% repolarization were most marked at long cycle lengths and low extracellular potassium (in contrast to Vmax depression) and were partially reversed by tetrodotoxin (1 microM). The relationship between log of cycle length and action potential at 90% repolarization was linear (for cycle length 300-8000 msec) in the absence of quinidine. Quinidine increased the slope of this relationship in a concentration-related fashion, whereas increasing extracellular potassium shifted the curve rightward (without changing slope), regardless of the presence or absence of quinidine. Action potentials were also measured following pauses of 5-60 seconds. In the absence of quinidine, the action potential depolarization returned to its baseline value in a monoexponential fashion (time constant 36.0 +/- 4.9 sec, mean +/- SE, n = 10). In the presence of 1 microM quinidine, this return was better fit as a biexponential process (time constants 4.2 +/- 1.2 and 40.7 +/- 6.2 seconds, n = 14). At slow stimulation rates (cycle length greater than 4000 msec) in low extracellular potassium (2.7 mM), quinidine produced early afterdepolarizations in 7/14 (50%) of fibers at 1 microM and 14/18 (78%) at 10 microM. Early afterdepolarizations were eliminated by increasing stimulation rates, raising the extracellular the extracellular potassium concentration to 5 mM, or adding tetrodotoxin. These data suggest that prolongation by quinidine of action potentials at 90% repolarization is multifactorial, with both a "tonic" prolonging effect and a prominent frequency-dependent action potential shortening effect. At long cycle lengths and low extracellular potassium, low quinidine concentrations consistently produced early after-depolarizations. The parallels between this form of triggered activity and clinical arrhythmias induced by quinidine suggest that early afterdepolarizations may play a role in quinidine-induced Torsades de Pointes.     

Chronic and acute effects of thiazolidinediones BM13.1258 and BM15.2054 on rat skeletal muscle glucose metabolism

1 New thiazolidinediones BM13.1258 and BM15.2054 were studied with regard to their PPARgamma-agonistic activities and to their acute and chronic effects on glucose metabolism in soleus muscle strips from lean and genetically obese rats. 2 Both BM13.1258 and BM15.2054 revealed to be potent PPARgamma-activators in transient transfection assays in vitro. 3 In insulin-resistant obese rats, but not in lean rats, 10 days of oral treatment with either compound increased the stimulatory effect of insulin on muscle glycogen synthesis to a similar extent (insulin-induced increment in micromol glucose incorporated into glycogen g-1 h-1: control, +1.19+/-0.28; BM13.1258, +2.50+/-0.20; BM15.2054, +2.55+/-0.46; P<0.05 vs control each). 4 In parallel to insulin sensitization, mean glucose oxidation increased insulin-independently in response to BM13.1258 (to 191 and 183% of control in the absence and presence of insulin, respectively; P<0.01 each), which was hardly seen in response to BM15.2054 (to 137 and 124% of control, respectively; ns). 5 Comparable effects on PPARgamma activation and on amelioration of insulin resistance by BM13.1258 and BM15.2054 were therefore opposed by different effects on glucose oxidation. 6 In contrast to chronic oral treatment, acute exposure of muscles to BM13.1258 or BM15.2054 in vitro elicited a distinct catabolic response of glucose metabolism in specimens from both lean and obese rats. 7 The results provide evidence that BM13.1258 and BM15.2054 can affect muscle glucose metabolism via more than one mechanism of action. 8 Further efforts are required to clarify, to what extent other mechanisms besides insulin sensitization via the activation of PPARgamma are involved in the antidiabetic actions of thiazolidinediones.     

Endocrine patterns in patients with benign and malignant prostatic diseases

BACKGROUND: The known importance of the endocrine system, particularly of steroid hormones, for development of the prostate gland and the fact that steroid hormones act as immunmodulators prompted us to compare hypophyseal, adrenal, and gonadal hormones, including cortisol, in patients with benign and malignant prostatic diseases. METHODS: Patients with newly diagnosed, untreated prostate cancer (PC) (n = 75) and, as a control population, those with untreated lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) (n = 159) entered this prospective study. In all patients, the following parameters were obtained by serum analysis: prostate-specific antigen (PSA), human luteinizing hormone (hLH), human follicle-stimulating hormone (hFSH), testosterone, estradiol (E2), cortisol, and dehydroepiandrosterone-sulphate (DHEA-S). Serum samples were collected of fasting patients between 7. 30-10.00 AM. RESULTS: Age was comparable in both groups (PC: 65.6 +/- 7.6 years (mean +/- standard deviation) vs. controls: 64.9 +/- 8. 1 years; P = 0.56). HFSH (PC: 6.6 +/- 3.9 mIU/ml; controls: 8.4 +/- 6.4 mIU/ml; P = 0.04), hLH (PC: 5.3 +/- 4.8mIU/ml; controls: 7.6 +/- 6.2 mIU/ml; P = 0.009), and estradiol (PC: 25.8 +/- 12.7 pg/ml; controls: 32.6 +/- 12.6 pg/ml; P = 0.0003) were significantly lower in PC patients than controls. Cortisol (PC: 16.7 +/- 4.2 microg/dl; controls: 13.5 +/- 4.3 microg/dl; P < 0.0001) was significantly higher in cases. The difference for cortisol and estradiol concentrations between PC patients and controls held true in all life-decades. Serum concentrations for DHEA-S and testosterone were comparable between PC and control patients. In PC patients, none of the endocrine parameters correlated to serum PSA or clinical/pathological stage. CONCLUSIONS: Patients with newly diagnosed, untreated PC yielded significantly higher cortisol and lower estradiol serum concentrations than controls. The known effect of cortisol on the immune status warrants further studies.     

Real-time clinical note monitoring to detect conditions for rapid follow-up: A case study of clinical trial enrollment in drug-induced torsades de pointes and Stevens-Johnson syndrome

Identifying acute events as they occur is challenging in large hospital systems. Here, we describe an automated method to detect 2 rare adverse drug events (ADEs), drug-induced torsades de pointes and Stevens-Johnson syndrome and toxic epidermal necrolysis, in near real time for participant recruitment into prospective clinical studies. A text processing system searched clinical notes from the electronic health record (EHR) for relevant keywords and alerted study personnel via email of potential patients for chart review or in-person evaluation. Between 2016 and 2018, the automated recruitment system resulted in capture of 138 true cases of drug-induced rare events, improving recall from 43% to 93%. Our focused electronic alert system maintained 2-year enrollment, including across an EHR migration from a bespoke system to Epic. Real-time monitoring of EHR notes may accelerate research for certain conditions less amenable to conventional study recruitment paradigms.