Management of the pseudobulbar affect (PBA) in Kabuki syndrome combined dextromethorphan-fluoxetine treatment as an alternative to dextromethorphan/quinidine

A case report of a patient with pseudo bulbar affect previous treatments included haloperidol (10mg), Inosina pranobex (600mg), clozapine (600mg), olanzapine (20mg), carbamazepine (200mg), paroxetine (20mg), phenobarbital (100mg) and topiramate (50mg), all suspended at August 2016, with current use of quetiapine (700mg) Chlorpromazine (600mg) (+ 200mg on demand of aggression), clonazepam (4 mg), valproate 2500 mg, propranolol (40mg). that was successful treated with off label treatment (dextromethorphan plus quinidine). Previous Brief Psychiatric Rating Scale and Clinical Global Impression-Improvement was applied after and before treatment with dextromethorphan (20mg) plus fluoxetine (20 mg, further increased to 40 mg). Previous Brief Psychiatric Rating Scale BPRS score 56 points and Clinical Global Impression-Severity (CGI-S) Score was 6 (severely ill). The addition of dextromethorphan (20mg) and fluoxetine (20 mg, further increased to 40 mg), allowed clear improvement of pathological crying and outbursts, with BPRS decrease of 8 points and Clinical Global Impression-Improvement (CGI-I) 2 (much improved) ­ especially pertaining to PBA related symptoms and aggressive behavior. There were no noticeable side-effects. This case report shown an interesting clinical response. It's could be a great alternative in treatment of pseudobulbar affect symptoms. Even though an only case and a great clinical study be necessary. (AU)

Improved Bulbar Function in Amyotrophic Lateral Sclerosis after Nuedexta (Dextromethorphan and Quinidine) Treatment

Nuedexta (dextromethorphan and quinidine) is an Food and Drug Administration approved medication for pseudobulbar affect. Interestingly, this drug was recently reported to improve speech, swallowing, and the ability to handle oral secretions along with emotional lability in amyotrophic lateral sclerosis (ALS) patients with bulbar symptoms. We report a Korean ALS patient whose bulbar function improved after administering Nuedexta for 6 months, extending therapeutic choice of approach in treating ALS patients.

Arritmias ventriculares sustentadas: a tempestade chegou / Sustained ventricular arrhythmias: the storm has arrived

Um dos grandes desafios no atendimento dos pacientes nas unidades de emergência é o tratamento das arritmias ventriculares, principalmente, quando sustentadas e recorrentes, pois são de difícil tratamento e estão associadas à alta mortalidade. O principal mecanismo envolvido na sustentação das taquicardias ventriculares é o mecanismo de reentrada, devido às cicatrizes miocárdicas secundárias a diversas cardiopatias estruturais. A tempestade elétrica pode ser séria quando ocorre em portadores de desfibriladores automáticos, provocando múltiplos choques correspondentes fora do ambiente hospitalar. Nesses casos é necessária a internação hospitalar, onde medidas específicas e escalonadas de tratamento são realizadas, indo desde o manejo clínico até intervenções específicas, como programação de dispositivos eletrônicos, intervenções eletrofisiológicas ou cirúrgicas

One of the biggest challenges in the care of patients in emergency units is the treatment of ventricular arrhythmias, particularly when sustained and relapsing, as they are difficult to treat and are associated with high mortality. The main mechanism involved in the maintenance of ventricular tachycardias is the mechanism of reentry, due to myocardial scars secondary to various structural heart diseases. The electrical storm may be serious when it occurs in patients with automatic defibrillators, causing multiple corresponding shocks outside the hospital setting. In these cases, admission to hospital is necessary, where specific and stepwise treatment measures are performed, ranging from clinical management to specific interventions, such as programming of electronic devices, and electrophysiological or surgical interventions

Quinidine Trial in a Patient with Epilepsy of Infancy with Migrating Focal Seizure and KCNT1 Mutation / 대한소아신경학회지

Epilepsy of infancy with migrating focal seizure (MFEI) is an early-onset epileptic encephalopathy characterized by randomly migrating focal seizures and psychomotor deterioration. It is associated with mutations in a variety of genes, with potassium sodium-activated channel subfamily T member 1 (KCNT1) being an example. Previously reported KCNT1 mutations in MFEI are gain-of-function mutations. Therefore, quinidine therapy targeted at reduction of pathologically increased KCNT1 channel-mediated potassium conductance has been proposed as a target treatment for MEFI with KCNT1 mutation. The authors report a case involving a patient with MFEI and a missense mutation in KCNT1 (c.7129G>A; p.Phe346Leu) treated with quinidine therapy. Seizure activity was poorly responsive to quinidine.

Inhibitory effects of neferine on Nav1.5 channels expressed in HEK293 cells / 华中科技大学学报（医学）（英德文版）

Neferine, a bisbenzylisoquinoline alkaloid in Lotus Plumule, was proved to have a wide range of biological activities. In the present study, using whole-cell patch-clamp technique, we investigated the effects of neferine on Nav1.5 channels that are stably expressed in HEK 293 cells. We found that neferine potently and reversibly inhibited Nav1.5 currents in a concentration dependent manner with a half-maximal inhibition (IC50) being 26.15 μmol/L. The inhibitory effects of neferine on Nav1.5 currents were weaker than those of quinidine at the same concentration. The steady-state inactivation curve was significantly shifted towards hyperpolarizing direction in the presence of 30 μmol/L neferine, while the voltage-dependent activation was unaltered. Neferine prolonged the time to peak of activation, increased the inactivation time constants of Nav1.5 currents and markedly slowed the recovery from inactivation. The inhibitory effect of neferine could be potentiated in a frequency-dependent manner. These results suggested that neferine can block Nav1.5 channels under the open state and inactivating state and it is an open channel blocker of Nav1.5 channels.

Myometrial relaxation of mice via expression of two pore domain acid sensitive K⁺ (TASK-2) channels

Myometrial relaxation of mouse via expression of two-pore domain acid sensitive (TASK) channels was studied. In our previous report, we suggested that two-pore domain acid-sensing K⁺ channels (TASK-2) might be one of the candidates for the regulation of uterine circular smooth muscles in mice. In this study, we tried to show the mechanisms of relaxation via TASK-2 channels in marine myometrium. Isometric contraction measurements and patch clamp technique were used to verify TASK conductance in murine myometrium. Western blot and immunehistochemical study under confocal microscopy were used to investigate molecular identity of TASK channel. In this study, we showed that TEA and 4-AP insensitive non-inactivating outward K⁺ current (NIOK) may be responsible for the quiescence of murine pregnant longitudinal myometrium. The characteristics of NIOK coincided with two-pore domain acid-sensing K⁺ channels (TASK-2). NIOK in the presence of K⁺ channel blockers was inhibited further by TASK inhibitors such as quinidine, bupivacaine, lidocaine, and extracellular acidosis. Furthermore, oxytocin and estrogen inhibited NIOK in pregnant myometrium. When compared to non-pregnant myometrium, pregnant myometrium showed stronger inhibition of NIOK by quinidine and increased immunohistochemical expression of TASK-2. Finally, TASK-2 inhibitors induced strong myometrial contraction even in the presence of L-methionine, a known inhibitor of stretch-activated channels in the longitudinal myometrium of mouse. Activation of TASK-2 channels seems to play an essential role for relaxing uterus during pregnancy and it might be one of the alternatives for preventing preterm delivery.

Management of Aborted Sudden Cardiac Arrest with J Wave Syndrome

We report the case of a 19-year-old male who successfully recovered from sudden cardiac arrest. Careful evaluation did not reveal any electrical or structural abnormalities. He underwent implantable cardioverter defibrillator (ICD) implantation, with a diagnosis of idiopathic ventricular fibrillation (VF). Three months later, VF recurred and was successfully terminated by ICD shock. Electrocardiogram (ECG) revealed a slurred type J point elevation at the inferolateral leads with a horizontal/descending ST segment change, which was not present during the initial hospitalization. Cilostazol was prescribed to prevent further lethal ventricular arrhythmias. Subsequently, no arrhythmic events were reported, and the J wave disappeared at the follow-up ECG. However, recurrent VF episodes with an interval of 1–2 weeks occurred 1 year later, and were terminated by ICD shock. Simultaneous ECG revealed a J point elevation at the inferolateral leads. Cilostazol was replaced by quinidine. Subsequently, no arrhythmic event recurred for over 12 months. Serial follow-up ECG is needed to identify masked inherited primary arrhythmic syndromes in sudden cardiac arrest survivors diagnosed with idiopathic VF. Cilostazol and quinidine might be good therapeutic options to prevent further lethal events in cases where the J wave syndrome is present with recurrent ventricular arrhythmias.

The Use of Orphan Drugs for Infectious Disease: Current Status and Unmet Needs / 대한내과학회지

BACKGROUND/AIMS: The aim of this study was to investigate the inconveniences and potential improvements in the use of orphan drugs for the treatment of infectious diseases, as determined by a survey of medical professionals. METHODS: An email was sent twice to the members of the Korean Society for Chemotherapy, and an online survey was conducted. The data collected were analyzed in terms of the frequency of drug use and associated difficulties as well as the scope for improvement. RESULTS: A total of 77 medical professionals participated in this survey. Rabies vaccine (n = 52), rabies immunoglobulin (n = 47), and foscarnet injection (n = 43) were supplied mainly through the Korea Orphan Drug Center (KODC), while artesunate (n = 29), quinine sulfate capsule (n = 24), quinine dihydrochloride injection (n = 23), and quinidine gluconate injection (n = 21) were supplied mainly through the National Medical Center (NMC). Difficulties in obtaining orphan drugs through the KODC were related to the KODC drug retrieval system (n = 67, 95.7% of respondents), lack of supplies on holidays (n = 66, 94.3%), complicated application procedures and documents (n = 61, 87.1%), and shipping inconveniences (n = 61, 87.1%). With regard to the use of orphan drugs supplied through the NMC, 52 participants (98.1%) responded that a staff visit should be mandatory for obtaining the drugs. CONCLUSIONS: Antivirals and antimalarial drugs are major orphan drugs used for the treatment of rare infections. It is necessary to establish a more efficient system to ensure a stable supply of orphan drugs, including on holidays, to enhance the smart drug searching system, and to simplify related administrative procedures.

A pediatric case of Brugada syndrome diagnosed by fever-provoked ventricular tachycardia / 소아과

Brugada syndrome is a rare channelopathy associated with the SCN5A gene that causes fatal ventricular arrhythmias. This case of Brugada syndrome, in which ventricular tachycardia (VT) was provoked by high fever, is the first report in a Korean child. The boy had retinoblastoma of his left eye diagnosed at 16 months of age. After chemotherapy, he contracted a catheter-related infection with a high fever up to 41degrees C leading to monomorphic VT. This was characterized as having right bundle branch block morphology, superior axis deviation, and a heart rate of 212/min. Direct current cardioversion recovered the VT to sinus rhythm after a lack of response to amiodarone and lidocaine. A second attack of VT that was not controlled by cardioversion, however, responded to lidocaine. The baseline electrocardiogram showed a long PR interval and QRS duration, and the patient's grandfather had a history of Brugada syndrome. A mutation in SCN5A was identified in this patient, his father, and his grandfather. The patient was treated with quinidine and followed up for 1 year.

Interações medicamentosas em cardiologia: Fármacos antiárritmicos / Drugs interactions in cardiology: Antiarrhythmics drugs

As arritmias cardíacas são geradas por diferentes mecanismoseletrofisiológicos que atuam isoladamente ou interagem entresi para a formação e condução do impulso anormal. Com baseno conhecimento da eletrofisiologia celular e dos mecanismosgeradores de arritmias, diversos fármacos antiarrítmicos foramdesenvolvidos com objetivo de propiciar terapias cada vez maiseficazes e seguras. A necessidade de se agrupar os antiarrítmicos deacordo com seu mecanismo de ação e efeitos no impulsocardíaco, resultou na classificação de Vaughan- Williams que,apesar de amplamente difundida, não contempla algumasmedicações classicamente utilizadas como antiarrítmicos, taiscomo a adenosina e os digitálicos. Os antiarrítmicos são, emgeral, metabolizados pelo fígado por meio dos citocromos.Fármacos que interagem no mesmo sítio de ação em que sãometabolizados podem resultar em potencialização ou inibiçãodos efeitos antiarrítmicos. A redução ou o aumento do nívelsérico do antiarrítmico causado pelo fármaco utilizado concomitantemente,em decorrência da alteração na velocidade demetabolização, da redução na absorção ou somatório de efeitos,pode aumentar o potencial para efeitos colaterais deletérios eefeitos pró-arrítmicos e resultar em efeitos tóxicos potencialmentegraves. O objetivo deste capítulo é revisar os diversosmecanismos de interação medicamentosa que podem ocorrerenvolvendo as classes de antiarrítmicos...

Cardiac arrhythrnias are generated by different electrophysiologicalmechanisms that act alone or interact for the formation andconduction of the abnormal impulse. Based on the knowledge ofcellular electrophysiology and arrhythmia mechanisms, severalantiarrhythrnics were developed in order to provide therapiesincreasingly effective and safe. The need of grouping the antiarrhythmicagents according to their mechanism of action andeffects on cardiac impulse have led to the development of theVaughan- Williams c1assification. Although widespread used,this c1assification does not include some drugs c1assically usedas antiarrhythmics such as adenosine and digitalis.Antiarrhythmic agents are generaUy metabolized by the livervia the cytochrome. Drugs that interact at the same site of actionthat are metabolized may result in potentiation or inhibition ofantiarrhythmic effects. The reduction or increase in serum levelscaused by antiarrhythmic drug used concomitantly, due to thechange in the metabolism, reduction in absorption or summationeffects may increase the potential for deleterious side effects andproarrhythmic effects and result in potentiaUy serious toxic effects.The purpose of this chapter is to review the variousmechanisms of drug interactions that may occur involving theantiarrhythmic drugs...

Mechanism of Relaxation Via TASK-2 Channels in Uterine Circular Muscle of Mouse

Plasma pH can be altered during pregnancy and at labor. Membrane excitability of smooth muscle including uterine muscle is suppressed by the activation of K+ channels. Because contractility of uterine muscle is regulated by extracellular pH and humoral factors, K+ conductance could be connected to factors regulating uterine contractility during pregnancy. Here, we showed that TASK-2 inhibitors such as quinidine, lidocaine, and extracellular acidosis produced contraction in uterine circular muscle of mouse. Furthermore, contractility was significantly increased in pregnant uterine circular muscle than that of non-pregnant muscle. These patterns were not changed even in the presence of tetraetylammonium (TEA) and 4-aminopyridine (4-AP). Finally, TASK-2 inhibitors induced strong myometrial contraction even in the presence of L-methionine, a known inhibitor of stretchactivated channels in myometrium. When compared to non-pregnant myometrium, pregnant myometrium showed increased immunohistochemical expression of TASK-2. Therefore, TASK-2, seems to play a key role during regulation of myometrial contractility in the pregnancy and provides new insight into preventing preterm delivery.

Evaluation of P-glycoprotein mediated in vitro loperamide biliary excretion with sandwich-cultured rat hepatocytes model / 药学学报

An in vitro P-glycoprotein mediated drug biliary excretion model (B-Clear model) was developed and validated using sandwich-cultured rat hepatocytes (SCRH) and a model substrate rhodamine 123 (Rh123). SCRH formed functional bile canalicular networks after 5 days of culture. Rh123 (10 micromol x L(-1)) was then incubated with the SCRH in standard Ca+ Hanks buffer or Ca(2+)-free buffer. The cumulative cell uptake and canalicular efflux of Rh123 under Ca2+ and Ca(2+)-free conditions were measured with a LC-MS/MS method. The biliary excretion index (BEI) and instinct biliary clearance (CL(bile, int)) were calculated. To assess the effect of known P-gp inhibitors on the efflux of Rh123, cyclosporine A (CyA), tariquidar (TQD) or quinidine (QND) (10, 50 and 100 micromol x L(-1)) was pre-incubated separately with SCRH for 30 min, then co-incubated with Rh123. The BEI and CL(bile, int) of Rh123 obtained from the SCRH model were (17.8 +/- 1.3) % and (10.7 +/- 0.9) mL x min(-1) x kg(-1), respectively. All the three P-gp inhibitors showed a dose-dependent inhibition on the bile clearance of Rh123, indicating that the B-Clear model with SCRH was functional properly. The biliary excretion of loperamide (LPAD) and the role of P-gp were further investigated with this validated model. The BEI and CL(bile, int) for LPAD (20 micromol x L(-1)) were obtained after it was incubated with SCRH for 30 min, and found to be (12.9 +/- 1.2)% and (6.1 +/- 0.3) mL x min(-1) x kg(-1) respectively. The dose-dependent inhibition on LPAD biliary excretion by CyA, TQD or QND confirmed the major role of P-gp in LPAD canalicular efflux. The results suggested that the B-Clear model with SCRH would be a useful tool for evaluation of P-gp mediated efflux and drug-drug interaction.

Drug Interactions between Cardiovascular Agents and Psychotropic Drugs / 정신신체의학

There are numerous drug interactions related to many psychotropic and cardiovascular medications. Firstly, the principles in predicting drug interactions are discussed. Cytochrome P (CYP) 450 plays a significant role in the metabolism of these drugs that are substrates, inhibitors, or inducers of CYP450 enzymes. The two most significant enzymes are CYP2D6 and CYP3A4. The ability of psychotropic drugs to act as inhibitors for the enzymes may lead to altered efficacy or toxicity of co-administered cardiovascular agents as a substrate for the enzymes. The following is also a review of the known interactions between many commonly prescribed cardiovascular agents and psychotropic drugs. Most beta blockers are metabolized by CYP2D6, which may lead to drug toxicity when they use in combination with potent CYP2D6 inhibitors including bupropion, chlorpromazine, haloperidol, selective serotonin reuptake inhibitors, and quinidine. Concomitant administration of lithium with angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and diuretics may increase serum lithium concentrations and toxicity. Calcium channel blockers and cholesterol lowering agents are subject to interactions with potent inhibitors of CYP3A4, such as amiodarone, diltiazem, fluvoxamine, nefazodone, and verapamil. Prescribing antiarrhythmic drugs in conjunction with medications are known to prolong QT interval and/or inhibitors on a relevant CYP450 enzyme is generally not recommended, or needs watchful monitoring. Digoxin and warfarin also have warrant careful monitoring if co-administered with psychotropic drugs.

Atrial standstill treated with implantation of permanent pacemaker / 대한내과학회지

Persistent atrial standstill is an extremely rare arrhythmia that was first described by Chavez et al. Electrocardiographically, atrial standstill is characterized by bradycardia, the absence of a P wave, and a junctional narrow complex escape rhythm. Atrial standstill is usually classified into two types. The transient type is observed in drug intoxication, such as with digitalis or quinidine, and hyperkalemia. The persistent type is uncommon, often accompanied by syncopal attacks or brain embolism. We report a case of persistent atrial standstill in an 83-year-old man who was treated with implantation of a permanent pacemaker.

In vitro hepatic metabolism of cinchona antimalarials by hamster enzymes

Cinchona alkaloids [quinidine and cinchonine] were incubated with aldehyde oxidase and microsomal monooxygenases from hamster liver. Reversed-phase HPLC method was used to separate quinidine and cichonine from their metabolites. Characterisation of the metabolites arising from aldehyde oxidase by infrared and mass spectral analysis, exhibited that quinidine and cinchonine were oxidised to the corresponding 2'-quinolones. In vitro microsomal metabolites of quinidine were identified as 2'-quinidinone and O-desmethylquinidine. Incubation of cinchonine with microsomal enzymes showed that no metabolites were generated

Effect of chemosensitizers on minimum inhibitory concentrations of fluconazole in candida albicans

To evaluate the effect of chemosensitizers on the in vitro activity of fluconazole against Candida albicans strains. Using Clinical Laboratory Standard Institute method, antifungal activity of fluconazole was determined alone and in combination with 16 chemosensitizers that included verapamil, reserpine, quinine, quinidine, gemfibrozil, lansoprazole, tamoxifen, diltiazem, desipramine, nicardipine, cyclosporine, chlorpromazine, prochlorperazine, promethazine, thioridazine, and trifluoperazine. Further studies were done using double combinations of selected chemosensitizers with fluconazole [28 combinations]. For testing combinations, half of the minimum inhibitory concentration [MIC] of each agent was selected in order to avoid the effect of the drug alone. One reference strain [ATCC90028] and one clinical isolate of C. albicans were used for testing the in vitro activity. Broth dilution method was used to determine the MICs of fluconazole and chemosensitizers. Of the 16 chemosensitizers tested, 3 exhibited in vitro activity by increasing fluconazole susceptibility to 7-fold. The MICs of the reference strain and clinical isolate for fluconazole were 5.5 and 0.55 MU g/ml, respectively, and these were reduced to 0.76 MU g/ml by gemfibrozil, 0.83 MU g/ml by quinine, and 0.76 MU g/ml by chlorpromazine in the reference strain, with MIC reduction to 0.08 MU g/ml by all three chemosensitizers in the clinical isolate. Some double combinations reduced the MIC of fluconazole to 10- to 100-fold, even when the chemosensitizers were not effective alone. The most effective double combinations were those of chlorpromazine with either reserpine or nicardipine

A Case of Chloroquine-resistant Plasmodium vivax Malaria Imported from Indonesia / 감염과화학요법

Resistance of falciparum malaria to antimalarial agents is prevalent in many areas, whereas chloroquine-resistant vivax malaria has been reported mainly around New Guinea since 1989. Concomitant with the spread of chloroquine-resistant P. vivax and increase in number of international travelers, imported cases of chloroquine-resistant vivax malaria in travelers returning from these areas has been reported. We experienced a case of chloroquine resistance P. vivax infection imported from Mangole Island, Indonesia. Its origin is confirmed not to be indigenous by the gene encoding analysis for the polymorphic region of apical membrane antigen-1 in P. vivax. Gene sequencing of the P. vivax mdr1 gene revealed only one substitution located at the codon 1076 (F1076L). The case was managed with oral quinidine with successful outcomes.

A Case of Chloroquine-resistant Plasmodium vivax Malaria Imported from Indonesia / 감염과화학요법

Resistance of falciparum malaria to antimalarial agents is prevalent in many areas, whereas chloroquine-resistant vivax malaria has been reported mainly around New Guinea since 1989. Concomitant with the spread of chloroquine-resistant P. vivax and increase in number of international travelers, imported cases of chloroquine-resistant vivax malaria in travelers returning from these areas has been reported. We experienced a case of chloroquine resistance P. vivax infection imported from Mangole Island, Indonesia. Its origin is confirmed not to be indigenous by the gene encoding analysis for the polymorphic region of apical membrane antigen-1 in P. vivax. Gene sequencing of the P. vivax mdr1 gene revealed only one substitution located at the codon 1076 (F1076L). The case was managed with oral quinidine with successful outcomes.

Fibrilación auricular / Atrial fibrillation

Atrial fibrillation is an arrhythmia characterized by no-coordinated atrial contraction that results in an inefficient atrial systole. The clinical classification of atrial fibrillation includes: ocassional, paroxysmal, persistent, and permanent. Multiple mechanisms have been described and accounts for a single ECG manifestation. Treatment should be individualized and has to considered several aspects including age, associated heart disease, and symptoms. Treatment strategies are: rhythm control, rate control, and thromboprophylaxis.