How many sputum samples should be examined during follow-up of tuberculosis patients in Myanmar: two or one?

Setting: Ten selected microscopy centres in Sagaing Region, Myanmar, functioning under an external quality assurance system with no reported major errors. Objective: To assess the pattern of serial sputum results (NN, both smear-negative; NP, first smear-negative and second smear-positive; PN, first smear-positive and second smear-negative; and PP, both smear-positive) among follow-up sputum microscopy examinations of tuberculosis (TB) patients (end of intensive phase, mid-continuation phase and end of treatment) conducted from 1 November 2017 to 15 April 2018. Design: Cross-sectional study using secondary data (laboratory registers). Results: Of 2001 examinations, 94 (4.7%) were smear-positive: 66 PP (3.3%), 12 PN (0.6%) and 16 NP (0.8%); 75% of NP results were scanty. The proportion of NP results was 0.8% (95%CI 0.5-1.3), i.e., 125 smears (95%CI 77-200) were required to detect one additional smear-positive result in the second sample. Of the 16 NP results (15 patients), 14 were tested using Xpert® MTB/RIF and none had rifampicin resistance. During the continuation phase of treatment, 13 became smear-negative, one remained smear-positive and one had unknown follow-up smear status. Conclusion: The benefit of the second sputum sample for monitoring anti-tuberculosis treatment was negligible. Given the favourable resource implications (reduced laboratory workload and costs), we recommend changing the policy from two sputum smears to one during follow-up sputum examinations of TB patients.

Contexte : Dix centres de microscopie sélectionnés de la région de Sagaing, Myanmar, fonctionnant avec un système d'assurance de qualité externe sans erreurs majeures rapportées.Objectif : Evaluer les profils de séries de résultats de crachats (NN, deux frottis négatifs ; NP, premier frottis négatif et deuxième frottis positif ; PN, premier frottis positif et deuxième frottis négatif ; et PP, deux frottis positifs) parmi les examens de suivi de microscopie de crachats de patients TB (à la fin de la phase intensive, au milieu de la phase de continuation et à la fin du traitement) réalisés du 1e novembre 2017 au 15 avril 2018.Schéma : Etude transversale grâce à des données secondaires (registres de laboratoire).Résultats : Sur 2001 examens, 94 (4,7%) ont eu un frottis positif : 66 (3,3%) PP ; 12 (0,6%) PN ; 16 (0,8%) NP ; 75% des NP avaient de rares bacilles. La proportion de NP a été de 0,8% (IC95% 0,5­1,3), impliquant qu'il a fallu 125 frottis (IC95% 77­200) pour détecter un frottis positif supplémentaire dans un deuxième échantillon. Sur les 16 NP (15 patients), 14 ont été testés par Xpert® MTB/RIF et aucun n'a eu de résistance à la rifampicine. Lors de la continuation du traitement, 13 sont devenus à frottis négatif, un patient est resté à frottis positif et un autre a eu un frottis de suivi « indéterminé ¼.Conclusion : Le bénéfice du deuxième échantillon de crachats pour le suivi du traitement antituberculeux a été négligeable. Devant les implications favorables en termes de ressources (charge de travail et coûts réduits pour le laboratoire), nous recommandons de modifier la politique de deux frottis de crachats à un seul lors du suivi de patients TB par examens des crachats.

Marco de Referencia: Diez centros de microscopia escogidos en la región de Sagaing de Birmania, que funcionan con un sistema externo de garantía de la calidad y no notifican errores importantes.Objetivos: Evaluar el perfil de los resultados seriados del esputo (NN, ambas baciloscopias negativas; NP, primera baciloscopia negativa y segunda positiva; PN, primera baciloscopia positiva y segunda negativa; y PP, ambas baciloscopias positivas) en las baciloscopias de esputo de seguimiento de los pacientes con tuberculosis (TB) (al final de la fase intensiva, en medio de la fase de continuación y al final del tratamiento), realizadas del 1° de noviembre del 2017 al 15 de abril del 2018.Métodom: Fue este un estudio transversal que utilizó datos secundarios (los registros de laboratorio).Resultados: De las 2001 baciloscopias realizadas, 94 (4,7%) fueron positivas, a saber: 66 (3,3%) PP; 12 (0,6%) PN; 16 (0,8%) NP; 75% de los resultados NP se notificaron como 'escasos bacilos'. La proporción de resultados NP fue 0,8% (IC95% 0,5­1,3), lo cual indica que se precisaron 125 baciloscopias a fin de detectar una baciloscopia positiva adicional en la segunda muestra (IC95% 77­200). De los 16 casos NP (15 pacientes), 14 se examinaron mediante la prueba Xpert® MTB/RIF y ninguno exhibió resistencia a rifampicina. Durante la fase de continuación del tratamiento, en 13 casos la baciloscopia se hizo negativa, uno permaneció positivo y en otro caso el resultado de la baciloscopia de seguimiento era 'desconocido'.Conclusión: La utilidad de una segunda muestra de esputo en la supervisión del tratamiento antituberculoso fue insignificante. Teniendo en cuenta sus repercusiones económicas favorables (disminución de la carga de trabajo y los costos de laboratorio), se recomienda cambiar la norma de practicar dos muestras de esputo por una sola muestra, durante las baciloscopias de seguimiento de los pacientes con TB.

Effects and interaction, of cariporide and preconditioning on cardiac arrhythmias and infarction in rat in vivo.

1. Although Na+-H+ exchange (NHE) inhibitors are reported to protect the myocardium against ischaemic injury, NHE activation has also been proposed as a potential mechanism of ischaemic preconditioning-induced protection. This study was performed to test any modifiable effect of cariporide, an NHE inhibitor, on cardioprotective effects of preconditioning. 2. Anaesthetized rats were subjected to 30 min of coronary artery occlusion and 150 min of reperfusion. The preconditioning (PC) was induced by 3 min of ischaemia and 10 min of reperfusion (1PC) or three episodes of 3 min ischaemia and 5 min reperfusion (3PC). Cariporide (0.3 mg kg(-1)) an NHE inhibitor, was administered 30 min (cari(30)) or 45 min (cari(45)) before coronary ligation (n=8-11 for each group). 3. Ventricular arrhythmias during 30 min ischaemia and infarct size (measured by triphenyltetrazolium (TTC) and expressed as a per cent area at risk (%AAR)) were determined. Cari(30) reduced ventricular fibrillation (VF) incidence and infarct size (from 45 to 0% and 34+/-4 to 9+/-2%; each P<0.05), whereas cari(45) did not. Likewise, 3PC reduced these variables (to 0% and 10+/-2%; P<0.05 in each case) whereas 1PC did not. Moreover, subthreshold preconditioning (1PC) and cariporide (cari(45)), when combined, reduced VF incidence and infarct size (to 0% and 15+3%; each P<0.05 ). 4. In conclusion, changes in NHE activity do not seem to be responsible for the cardioprotective action of ischaemic preconditioning. Protective effects of NHE inhibition and subthreshold preconditioning appear to act additively.

MS-551 and KCB-328, two class III drugs aggravated adrenaline-induced arrhythmias.

We investigated the proarrhythmic effects of MS-551 and KCB-328, class III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 microg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrenaline injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhythmic ratio (as calculated by dividing the number of ventricular premature contraction by the number of the total heart rate) and the severity of arrhythmia were observed. MS-551 infusion, 1 mg/kg/30 min, decreased the heart rate (HR) by 16% (P<0.01) and prolonged the QTc interval by 20% (P<0.01). During the 30 min of MS-551 infusion, arrhythmias occurred in three out of seven dogs (torsades de pointes (TdP) type VT in one dog). After these arrhythmias disappeared, MS-551 decreased the latent interval of the adrenaline arrhythmias produced by the inducing dose (30+/-2 s compared with 43+/-3 s of the control interval, P < 0.05), increased the arrhythmic ratio (P<0.05) and induced arrhythmias by non-inducing adrenaline doses (P<0.05). Effect of a new class III drug KCB-328 infusion, 0.3 mg/kg/30 min, was compared witih MS-551 using the same model. KCB-328 decreased the HR by 21% (P<0.01) and prolonged the QTc interval by 25% (P<0.01). During the 30 min of infusion, arrhythmias occurred in five out of seven dogs (TdP in two dogs). KCB-328 also decreased the latent interval of the adrenaline arrhythmias produced by the inducing doses (31+/-3 s compared with 49+/-7 s of the control period, P<0.05), but did not significantly alter the arrhythmic ratio. Adrenaline induced TdP only after MS-551 or KCB-328 was administered, i.e. after MS-551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. To examine the direct arrhythmogenic effect of MS-551 and whether an adrenergic mechanism plays some role on this arrhythmogenesis, a bolus injection of MS-551, 3 mg/kg, was injected either without pre-treatment or after pre-treatment with propranolol 0.3 mg/kg. MS-551 induced arrhythmias in five out of seven dogs (TdP in one dog). Also in the propranolol pre-treated dogs, MS-551 induced arrhythmias in five out of seven dogs (TdP in 1 dog). In conclusion, these observations indicate that MS-551 and KCB-328 induced arrhythmias and intensified proarrhythmic effects of adrenaline, MS-551 being stronger than KCB-328 at the same QTc prolonging doses. The direct arrhythmogenic effect of MS-551 was not influenced by beta-blocker treatment.

Antiarrhythmic effects of cariporide, a novel Na+-H+ exchange inhibitor, on reperfusion ventricular arrhythmias in rat hearts.

Cariporide (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate: HOE642) is a novel Na+-H+ exchange subtype 1 inhibitor and has antiarrhythmic effects on ischemia/reperfusion arrhythmias without apparent cardiovascular effects in dogs and rats when given before coronary occlusion. The aim of this study was to determine the minimum effective dose and to examine the dose related effects of cariporide when it was administered before and during coronary occlusion as well as simultaneously with reperfusion. In the pre-treatment group, cariporide dose-dependently reduced the ventricular tachycardia duration from 140 to 36 (P < 0.01), 59 (P < 0.05) and 23 s (P < 0.01) with 0.03, 0.1 and 1 mg/kg, respectively, and reduced the incidence of reperfusion-induced ventricular tachycardia from 100 to 50 and 58% (P < 0.01), ventricular fibrillation from 83 to 8 and 0% (P < 0.01), and mortality from 75 to 8 and 8% (P < 0.01) with 0.1 and 1 mg/kg, respectively. In the post-treatment group, cariporide dose-dependently reduced the ventricular tachycardia duration from 92 to 37, 40, 42 (P < 0.05) and 24 s (P < 0.01) with 0.03, 0.1, 0.3 and 1 mg/kg, respectively, and the incidence of ventricular tachycardia from 100 to 53% (P < 0.01) by 1 mg/kg, and ventricular fibrillation from 87 to 33, 7 and 7% (P < 0.01), and the mortality from 73 to 27 (P < 0.05), 0 and 7% (P < 0.01) with 0.1, 0.3 and 1 mg/kg, respectively. In the group with simultaneous injection, both doses of cariporide (1 and 3 mg/kg) reduced the incidence of ventricular fibrillation from 83 to 42% (P < 0.05). The heart rate, blood pressure and QT interval did not change after drug treatment.

Antiarrhythmic effects of HOE642, a novel Na(+)-H+ exchange inhibitor, on ventricular arrhythmias in animal hearts.

HOE642 (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate), a novel Na(+)-H+ exchange subtype 1 inhibitor, was investigated for its possible antiarrhythmic effects on coronary artery ligation/reperfusion and ouabain-induced arrhythmias in the canine heart which may occur after intracellular Ca2+ overload. Also, the effects of HOE642 on coronary artery ligation/reperfusion of the left coronary artery were tested in rat hearts. HOE642 (1 mg/kg) significantly suppressed the occurrence of fatal ventricular fibrillation during coronary artery ligation and after reperfusion in dogs (2 out of 8 dogs in the treated group compared to 7 out of 8 dogs in the control group, P < 0.05), but did not suppress ventricular premature contractions and ventricular tachycardia during ischemia in the canine hearts. HOE642 at the same dose markedly reduced the total duration and the incidence of reperfusion-induced ventricular tachycardia, and the incidence and mortality of reperfusion-induced ventricular fibrillation in rats (ventricular tachycardia duration, 159 +/- 12 s to 21 +/- 8 s, P < 0.01; ventricular tachycardia, 100% to 69%; ventricular fibrillation, 89% to 0%, P < 0.01; mortality, 89% to 11%, P < 0.01). The heart rate, blood pressure, QT interval and ST segment did not change in the canine and rat hearts. HOE642 slightly decreased the arrhythmic ratio of the ouabain-induced arrhythmia only at two time points (28 and 35 min after injection) in the canine hearts. In conclusion, HOE642 has obvious antifibrillatory effects on ischemia/reperfusion arrhythmias and, in addition, has a weak suppressing effect on the ouabain-induced arrhythmia.

QT-prolonging class I drug, disopyramide, does not aggravate but suppresses adrenaline-induced arrhythmias. Comparison with cibenzoline and pilsicainide.

We investigated the effects of class I antiarrhythmic drugs on corrected QT (QTc) interval and adrenaline-induced arrhythmias in halothane-anaesthetized, closed-chest dogs. For this purpose, we plotted a dose-response curve for adrenaline by calculating the arrhythmic ratio, which is the number of ventricular ectopic beats induced by adrenaline divided by the total heart rate, and observed the changes in the arrhythmic ratio-adrenaline dose relation before and after administration of class I drugs. Disopyramide and cibenzoline decreased the arrhythmic ratio induced by adrenaline. Disopyramide prolonged the QTc interval by 20% (P<0.01), but cibenzoline did not. Pilsicainide prolonged the QTc interval (12%), but this drug did not change the arrhythmic ratio. These results indicate that in contrast to the class III drugs which we have reported earlier, i.e. 1, 3-dimethyl-6-2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)-propylamino]eth ylamino-2,4 (1H,3H)-pyrimidinedione hydrochloride (MS-551), 1-(2-amino-4-methanesulfonamidophenoxy)2-[N-(3, 4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride (KCB-328) and E-1-[(5-(4-chlorophenyl)-2-furanyl)methylene]amino-3-[4-(4-methyl-1 -piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride (azimilide), class I drugs do not aggravate adrenaline-induced arrhythmias even though some drugs prolong the QTc interval.

Antiarrhythmic effects of an aconitine-like compound, TJN-505, on canine arrhythmia models.

We examined the effects of an aconitine-like compound, TJN-505 (1alpha-16beta-dimethoxy-20-ethyl-14alpha-(4-methox ybenzoyloxy)-aconitan-8,13-diol hydrochloride), on canine arrhythmias provoked by digitalis, two-stage coronary ligation, adrenaline, programmed electrical stimulation, or aconitine. TJN-505 (2-2.5 mg/kg i.v.) suppressed digitalis-, two-stage coronary ligation- and adrenaline-induced ventricular arrhythmias. The antiarrhythmic plasma concentrations (IC50) of TJN-505 for these arrhythmia models were 1.26, 0.94 and 1.31 microg/ml, respectively. TJN-505 (2 mg/kg i.v. followed by the infusion of 0.1 mg/kg per min) prolonged PR, QRS, QTc and JTc intervals and the ventricular effective refractory period and reduced the incidence of programmed electrical stimulation-induced arrhythmias in dogs with 7-day-old myocardial infarction (P < 0.05). TJN-505 (2 mg/kg i.v.) also suppressed the aconitine-induced atrial arrhythmias. In conclusion, TJN-505 suppressed various canine ventricular and atrial arrhythmias and seems to act as a blocker of multiple channels.

Effects of an antiarrhythmic drug A-2545 on canine ventricular arrhythmia models; comparison with mexiletine and flecainide.

We investigated effects of a new Na+ channel blocking antiarrhythmic drug, A-2545, N-3 (2,2,5,5-tetramethyl-3-pyrroline-3-carboxamido)-propyl-phthalimide-hydro chloride, on various canine ventricular automaticity arrhythmias induced by two-stage coronary ligation, digitalis and adrenaline, and compared them with those of mexiletine. A-2545 showed antiarrhythmic effects, significantly decreasing the arrhythmic ratio of 24-h and 48-h coronary ligation-, digitalis- and adrenaline-induced automaticity arrhythmias. The antiarrhythmic plasma concentrations (IC50) of A-2545, 2 mg kg(-1) 10 min(-1), i.v., for 24-h and 48-h coronary ligation-, digitalis- and adrenaline-induced arrhythmias were 1.8, 1.3, 5.8 and 3.7 microg ml(-1), respectively, and that calculated for oral A-2545 (25 mg kg(-1)) in 24-h coronary ligation-induced arrhythmia was 1.8 microg ml(-1). A-2545 is specifically potent in suppressing coronary ligation-induced arrhythmias, i.e., decreasing the arrhythmic ratio nearly to zero by oral administration, and among the intravenously given experiments A-2545 was effective at lower concentrations than other arrhythmia models; A-2545, 2 mg kg(-1) 10 min(-1), was equipotent to 5 mg kg(-1) 10 min(-1) mexiletine in suppressing 24-h coronary ligation-induced arrhythmia, indicating that A-2545 is more potent than mexiletine. In order to determine whether A-2545 has arrhythmogenic effects, we used programmed electrical stimulation (PES)-induced reentry arrhythmias in dogs with old myocardial infarction and compared effects of A-2545 and flecainide. A-2545, 2 and 5 mg kg(-1) 10 min(-1), significantly suppressed the PES-induced arrhythmias in all six dogs without aggravating them. These arrhythmias were not markedly suppressed by flecainide either with 1 or 3 mg kg(-1) 1O min(-1); moreover even in one out of six dogs aggravation of arrhythmia was noted after 1 mg kg(-1) 10 min(-1). In conclusion, A-2545 suppressed various canine ventricular arrhythmias, and the antiarrhythmic effect of A-2545 was more potent than that of mexiletine, and A-2545 did not show arrhythmogenic effects compared to flecainide.

Promotion of insecticide-treated mosquito nets in Myanmar.

A simple health promotion message administered by village midwives raised bednet usage to over 60% in trial hamlets in north Shan State, Myanmar. Treatment of the nets in the study villages produced a reduction in malaria cases. Most villagers were prepared to buy their nets at market prices and were willing to pay for the cost of re-treatment of nets, but very poor, members of the Wa ethnic group required a half-price subsidy for them to afford them. The use of insecticide treated bednets was felt to be appropriate for undeveloped and remote areas of the country where malaria control was difficult.

Cariporide, a highly selective Na+/H+ exchange inhibitor, suppresses the reperfusion-induced lethal arrhythmias and "overshoot" phenomenon of creatine phosphate in situ rat heart.

The effects of a highly selective Na+/H+ exchange inhibitor cariporide on the reperfused in situ heart were assessed. Male Sprague-Dawley (SD) rats weighing 200-300 g were anesthetized with pentobarbital sodium (60 mg/kg, i.p.) and divided into four groups; sham-operated (n = 6), vehicle (n = 15), 0.1 mg/kg (n = 15), and 1.0 mg/kg (n = 15) groups. The left coronary artery was ligated for 5 min and then released with ECG and blood pressure monitoring. Cariporide was intravenously given as a bolus 2 min before the reperfusion. The heart was rapidly excised and frozen 3 min after the onset of ventricular fibrillation, otherwise 10 min after the reperfusion. The adenosine triphosphate (ATP), creatine phosphate (CP), and glycogen contents were measured in the reperfused ischemic myocardium by using an enzymatic fluorometric assay technique. The incidence of the lethal ventricular fibrillation was 53% in the vehicle, 27% in the low-dose and 7% in the high-dose group. The concentrations (mean+/-SEM) of ATP, CP (nmol/mg protein), and glycogen (nmol as glucose/mg protein) were 74+/-4, 255+/-19, and 164+/-21 in the sham, 23+/-4, 763+/-70, and 61+/-7 in the vehicle, 27+/-4, 180+/-16, and 104+/-14 in the low-dose, and 32+/-4, 178+/-24, and 108+/-8 in the high-dose groups, respectively, indicating that cariporide significantly blunted CP overshoot as well as glycogenolysis during reperfusion. Thus cariporide can be expected to depress arrhythmogenesis and protect the metabolic status of the heart.

Scanning electron microscope appearances of normal human amnion and umbilical cord at term.

The surface morphology of normal term amnion was studied by scanning electron microscopy. Four patterns were observed. Two of the patterns showed distinctive minority populations of cells. In one, there were cells surrounded by intracellular channels; in the other, there were large flat cells. The microvilli in all four patterns showed variable morphology in different samples. Possible functional implications of the findings are discussed.

Scanning electron microscopic appearances in the amnion in polyhydramnios and oligohydramnios.

The appearances of the amnion from two patients with polyhydramnios and two patients with oligohydramnios are described. In polyhydramnios the amnion showed a normal incidence of all the four patterns found in normal amnion at term and no abnormal features were noted. In oligohydramnios, two of four normal patterns predominated and intercellular canals were sparse.

[Antiarrhythmic effects of DHA-As on ventricular arrhythmias in rat and dog hearts].

DHA-Ascorbic acid (DHA-As), a new derivative of docosahexaenoic acid (DHA) was tested for its possible antiarrhythmic effects on coronary artery ligation/reperfusion arrhythmias in rat hearts, and adrenaline-induced arrhythmias in canine hearts. DHA-As (3 mg/kg i.v.) did not change the total duration of VT, and tended to suppress the incidence of VT, VF and mortality of reperfusion in rat hearts. The heart rate, QT90 and systolic blood pressure did not change, and the diastolic blood pressure was decreased by DHA-As in the rat hearts. DHA-As significantly decreased the arrhythmic ratio only at two time points (14 and 15 min after injection), and also decreased the heart rate and mean blood pressure in canine hearts. In conclusion, DHA-As tended to suppress the reperfusion-induced arrhythmias in rat hearts. However, the change was not statistically significant. In addition, DHA-As has a weak suppressing effect on adrenaline-induced arrhythmia.

Slowing Na+ channel inactivation prolongs QT interval and aggravates adrenaline-induced arrhythmias.

We investigated the effects of prolonged repolarization induced by slowed inactivation of Na+ channel on adrenaline-induced arrhythmias in halothane anesthetized, closed-chest dogs. We used sea anemone toxins (ATX-II and Anthopleurin-A) to prolong ventricular repolarization and examined their effects on adrenaline arrhythmias. Sea anemone toxins prolonged the QTc- and JTc-intervals (P<0.01), but did not affect the PQ interval, QRS duration, heart rate and mean blood pressure. Although sea anemone toxins did not induce any arrhythmias by themselves, under the treatment with these toxins, arrhythmias were induced by non-arrhythmia-inducing doses of adrenaline in four dogs out of seven and the control arrhythmias induced by adrenaline were aggravated. These results indicate that, similar to the inhibition of K+ channels by class III drugs, which we have already reported, slowing Na+ channel inactivation with QTc prolongation also aggravates adrenaline-induced arrhythmias.

Effects of magnesium sulfate on the canine cardiovascular system complicating astemizole overdose.

Polymorphic ventricular arrhythmias induced by astemizole overdose have been reported to be successfully managed with intravenous magnesium sulfate. This study was designed to assess the effects of magnesium sulfate on the cardiovascular system, complicating astemizole overdose, the better to understand the therapeutic utility and undesirable effects of magnesium sulfate. Beagle dogs were anesthetized with halothane inhalation (n = 6). Monophasic action potential of the right ventricle, electrocardiogram, and systemic and left ventricular pressure were continuously monitored. Cardiac output was measured by a thermodilution method. Effective refractory period of the right ventricle was assessed by programmed electrical stimulation. An intentionally high dose of astemizole (3 mg/kg, i.v.) prolonged the repolarization and refractory period, while it decreased the sinus automaticity, ventricular contraction, and conduction. A canine antiarrhythmic dose of magnesium sulfate (100 mg/kg, i.v.) was additionally injected 1 h after i.v. astemizole. Magnesium sulfate increased the atrioventricular conduction time, electrical vulnerability, and preload of the left ventricle, while it decreased the blood pressure and cardiac output, besides the effects similar to those observed after i.v. astemizole. The plasma concentration of astemizole was at least 10 times higher than its therapeutic concentration during the experimental period. Magnesium sulfate could be expected to act as a calcium channel blocker during astemizole overdose; however, it may not antagonize the proarrhythmic effects of astemizole.

Effects of sphingosine 1-phosphate, a naturally occurring biologically active lysophospholipid, on the rat cardiovascular system.

Recent studies have indicated that sphingosine 1-phosphate (Sph-1-P) is released into the blood flow from activated platelets upon stimulation to exhibit a wide spectrum of biological functions. The purpose of the present study was to assess the acute cardiovascular effects of circulating Sph-1-P in the in vivo rat model. Intravenous administration of Sph-1-P decreased the heart rate, ventricular contraction and blood pressure, while it hardly affected the atrioventricular and intraventricular conduction. Sph-1-P did not affect the adenylate cyclase activities of the membrane preparations made from the right atrium and left ventricle. These results suggest that functional receptors like lysophospholipid receptor Edg-1, which can inhibit adenylate cyclase via Gi protein, are lacking in the rat heart. Moreover, these observations will provide a clue to better understand the various types of Sph-1-P-related pathophysiological processes.

Effects of HNS-32, a novel antiarrhythmic drug, on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats.

HNS-32 (N1,N1-dimethyl-N2-(2-pyridylmethyl)-5-isopropyl-3, 8-dimethylazulene-1-carboxamidine: CAS 186086-10-2) is a newly synthesized compound, and possesses antiarrhythmic properties with vasodilator action in dog hearts. The aim of this study was to investigate the dose-dependent effects of HNS-32 on ischemia- and/or reperfusion-induced ventricular arrhythmias in anesthetized rats in vivo and compared with those of mexiletine. Saline or drugs were administered intravenously 5 min prior to coronary artery occlusion. On the ischemia-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of total number of premature ventricular complexes (PVC) from 2091+/-225 to 656+/-116 and 286+/-69 beats/30 min (p < 0.05), the ventricular tachycardia (VT) duration from 183+/-33 to 28+/-9 and 4+/-2 sec (p < 0.05), the incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), and the incidence of ventricular fibrillation (VF) from 50 to 0 and 0% (p < 0.05) with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 936+/-159 beats/30 min (p < 0.05), 39+/-22 sec (p < 0.05), 90% (n.s.) and 10% (n.s.), respectively. HNS-32 completely suppressed the late reperfusion-induced arrhythmias, however mexiletine did not affect them. On the early reperfusion-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of VT duration from 126+/-34 to 37+/-12 and 3+/-2 sec (p < 0.05), incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), incidence of VF from 100 to 10 and 0% (p < 0.05), and mortality rate from 90 to 0 and 0% (p < 0.05), with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 16+/-9 sec (p < 0.05), 80 (n.s.), 50 (p < 0.05), and 10% (p < 0.05), respectively. HNS-32 significantly reduced the heart rate in a dose-dependent manner, from 399+/-14 to 350+/-8 and 299+/-10 beats/min (p < 0.05) with 3 and 5 mg/kg, respectively. The antiarrhythmic effects of HNS-32 were more potent than that of the similar dose of mexiletine against occlusion-induced and reperfusion-induced arrhythmias in in vivo rats.

Effects of nonsedating antihistamine, astemizole, on the in situ canine heart assessed by cardiohemodynamic and monophasic action potential monitoring.

The possible mechanisms of cardiac adverse effects of astemizole were studied using a halothane-anesthetized in vivo canine model under the cardiohemodynamic and monophasic action potential monitoring. A dose of 0.3 mg/kg of iv astemizole (n = 7), which is close to the recommended dose for clinical use, showed a bradycardic effect and a reversed use-dependent lengthening of repolarization. The increase in the repolarization was greater than in the effective refractory period. These effects persisted even when the plasma drug concentration became undetectable. Additional administration of 3.0 mg/kg of iv astemizole (n = 7) decreased the mean blood pressure, suppressed the cardiac contraction and conduction, and induced early after depolarization-like potential in addition to the qualitatively similar effects compared to those observed by the lower dose. The decrease of the plasma concentration of astemizole followed the pattern predicted by the two-compartment theory of pharmacokinetics, but the drug concentration in the cardiac muscle was estimated to be more than 100 times greater than that in plasma. Our study emphasizes that each cardiac consequence of astemizole overdose may be related to proarrhythmic effects and the monitoring of plasma drug concentration will be less helpful in predicting the cardiac adverse effects of astemizole. The results provide some insights into the clinical cardiotoxicity of astemizole. Drugs or interventions inducing positive chronotropic, inotropic, and dromotropic effects can become good candidates for the treatment of astemizole intoxication, which may attenuate the cardiac effects of astemizole including the lengthening of repolarization.