Tramadol as a Voltage-Gated Sodium Channel Blocker ofPeripheral Sodium Channels Na v 1.7 and Na v 1.5

Tramadol is an opioid analog used to treat chronic and acute pain. Intradermal injections of tramadol at hundreds of millimoles have been shown to produce a local anesthetic effect. We used the whole-cell patch-clamp technique in this study to investigate whether tramadol blocks the sodium current in HEK293 cells, which stably express the pain threshold sodium channel Na v1.7 or the cardiac sodium channel Na v1.5. The half-maximal inhibitory concentration of tramadol was 0.73 mM for Na v1.7 and 0.43 mM for Na v1.5 at a holding potential of –100 mV. The blocking effects of tramadol were completely reversible. Tramadol shifted the steady-state inactivation curves of Na v1.7 and Na v1.5 toward hyperpolarization. Tramadol also slowed the recovery rate from the inactivation of Na v1.7 and Na v1.5 and induced stronger use-dependent inhibition. Because the mean plasma concentration of tramadol upon oral administration is lower than its mean blocking concentration of sodium channels in this study, it is unlikely that tramadol in plasma will have an analgesic effect by blocking Na v1.7 or show cardiotoxicity by blocking Na v1.5. However, tramadol could act as a local anesthetic when used at a concentration of several hundred millimoles by intradermal injection and as an antiarrhythmic when injected intravenously at a similar dose, as does lidocaine.

Open channel block of Kv1.4 potassium channels by aripiprazole

Aripiprazole is a quinolinone derivative approved as an atypical antipsychotic drug for the treatment of schizophrenia and bipolar disorder. It acts as with partial agonist activities at the dopamine D2 receptors. Although it is known to be relatively safe for patients with cardiac ailments, less is known about the effect of aripiprazole on voltage-gated ion channels such as transient A-type K+ channels, which are important for the repolarization of cardiac and neuronal action potentials. Here, we investigated the effects of aripiprazole on Kv1.4 currents expressed in HEK293 cells using a whole-cell patch-clamp technique. Aripiprazole blocked Kv1.4 channels in a concentration-dependent manner with an IC50 value of 4.4 μM and a Hill coefficient of 2.5. Aripiprazole also accelerated the activation (time-to-peak) and inactivation kinetics. Aripiprazole induced a voltage-dependent (δ = 0.17) inhibition, which was use-dependent with successive pulses on Kv1.4 currents without altering the time course of recovery from inactivation. Dehydroaripiprazole, an active metabolite of aripiprazole, inhibited Kv1.4 with an IC50 value of 6.3 μM (p < 0.05 compared with aripiprazole) with a Hill coefficient of 2.0. Furthermore, aripiprazole inhibited Kv4.3 currents to a similar extent in a concentration-dependent manner with an IC50 value of 4.9 μM and a Hill coefficient of 2.3. Thus, our results indicate that aripiprazole blocked Kv1.4 by preferentially binding to the open state of the channels.

Open channel block of Kv1.4 potassium channels by aripiprazole

Aripiprazole is a quinolinone derivative approved as an atypical antipsychotic drug for the treatment of schizophrenia and bipolar disorder. It acts as with partial agonist activities at the dopamine D2 receptors. Although it is known to be relatively safe for patients with cardiac ailments, less is known about the effect of aripiprazole on voltage-gated ion channels such as transient A-type K+ channels, which are important for the repolarization of cardiac and neuronal action potentials. Here, we investigated the effects of aripiprazole on Kv1.4 currents expressed in HEK293 cells using a whole-cell patch-clamp technique. Aripiprazole blocked Kv1.4 channels in a concentration-dependent manner with an IC50 value of 4.4 μM and a Hill coefficient of 2.5. Aripiprazole also accelerated the activation (time-to-peak) and inactivation kinetics. Aripiprazole induced a voltage-dependent (δ = 0.17) inhibition, which was use-dependent with successive pulses on Kv1.4 currents without altering the time course of recovery from inactivation. Dehydroaripiprazole, an active metabolite of aripiprazole, inhibited Kv1.4 with an IC50 value of 6.3 μM (p < 0.05 compared with aripiprazole) with a Hill coefficient of 2.0. Furthermore, aripiprazole inhibited Kv4.3 currents to a similar extent in a concentration-dependent manner with an IC50 value of 4.9 μM and a Hill coefficient of 2.3. Thus, our results indicate that aripiprazole blocked Kv1.4 by preferentially binding to the open state of the channels.

Acepromazine inhibits hERG potassium ion channels expressed in human embryonic kidney 293 cells

The effects of acepromazine on human ether-à-go-go-related gene (hERG) potassium channels were investigated using whole-cell voltage-clamp technique in human embryonic kidney (HEK293) cells transfected with hERG. The hERG currents were recorded with or without acepromazine, and the steady-state and peak tail currents were analyzed for the evaluating the drug effects. Acepromazine inhibited the hERG currents in a concentration-dependent manner with an IC₅₀ value of 1.5 µM and Hill coefficient of 1.1. Acepromazine blocked hERG currents in a voltage-dependent manner between –40 and +10 mV. Before and after application of acepromazine, the half activation potentials of hERG currents changed to hyperpolarizing direction. Acepromazine blocked both the steady-state hERG currents by depolarizing pulse and the peak tail currents by repolarizing pulse; however, the extent of blocking by acepromazine in the repolarizing pulse was more profound than that in the depolarizing pulse, indicating that acepromazine has a high affinity for the open state of the channels, with a relatively lower affinity for the closed state of hERG channels. A fast application of acepromazine during the tail currents inhibited the open state of hERG channels in a concentration-dependent. The steady-state inactivation of hERG currents shifted to the hyperpolarized direction by acepromazine. These results suggest that acepromazine inhibits the hERG channels probably by an open- and inactivated-channel blocking mechanism. Regarding to the fact that the hERG channels are the potential target of drug-induced long QT syndrome, our results suggest that acepromazine can possibly induce a cardiac arrhythmia through the inhibition of hERG channels.

Intravenous Anti-D immunoglobulin treatment of adult chronic immune thrombocytopenic purpura (ITP) / 대한내과학회지

BACKGROUND/AIMS: Immune thrombocytopenic purpura (ITP) is an autoimmune disease that is mediated by anti-platelet antibodies. Based on the pathogenesis of ITP we evaluated the efficacy of intravenous anti-D immunoglobulin for adult chronic ITP. METHODS: Fourteen patients (4 without splenectomy and 10 with splenectomy) with refractory chronic ITP were treated with 50-70 microgram/kg of intravenous anti-D immunoglobulin only once. Treatment effects were evaluated by measuring the platelet counts and hemoglobin levels. RESULTS: Five patients (36%) showed a response; improvement in the platelet count lasted for on average 7 days (range: 2~24 days). There were no serious adverse effects. CONCLUSION: Anti-D immunoglobulin, which is associated with an Fc receptor blockade, appeared to be safe and effective for the treatment of adults with chronic ITP. Further studies are needed to confirm these findings and define further potentially effective treatment protocols with intravenous anti-D immunoglobulin.

A case of pyomyositis due to Mycobacterium tuberculosis / 소아과

Pyomyositis is a primary bacterial infection of the skeletal muscles. Although infection can affect any skeletal muscle, the large muscle groups such as the quadriceps or gluteal muscles are most often the focus of this disease, and most commonly the inflammation is focal, involving a single muscle. The mechanism of pyomyositis is poorly understood. The local mechanical trauma at the time of an incidental bacteremia is frequently postulated as a mechanism that could explain the high incidence of the disease in tropical areas and its male preponderance. Staphylococcus aureus is the most common organism responsible for pyomyositis. Mycobacterium tuberculosis primarily affects the lungs, and the prevalence of active pulmonary tuberculosis co-existing with musculoskeletal tuberculosis has been about 30 percent. We report here on a case of an otherwise healthy 17-month-old girl, who had tuberculous pyomyositis at the upper arm after the hepatitis A vaccination with no evidence of any coexistent active tuberculosis.

A Study of Epileptiform Discharges in Children with Chronic Recurrent Headaches / 대한소아신경학회지

PURPOSE: This study was undertaken to determine the incidence and the meaning of epileptiform discharges accompanied by chronic recurrent headaches. METHODS: We selected 449 cases of children who visited Dong-A University Hospital because of recurrent headaches from January 1999 to July 2005. The headaches were classified by the criteria established by the International Headache Research Committee in 2004. The electroencephalography was performed in 336 cases and 36 cases who showed epileptiform discharges were selected. We studied the characteristics of epileptiform discharges, MRI findings and the relationship with epilepsy. RESULTS: The incidence of interictal epileptiform discharges(ILEDs) of the patients with chronic headaches was 10.7%, which was higher than that in a normal population. In the location of ILEDs, focal areas(9.2%) were more common than general areas(1.5%). The incidence of the ILEDs was different according to the types of headaches(P<0.01). The focal ILEDs were concentrated at the central temporal areas. The most common type of ILEDs was frequent epileptiform discharges(63.9%). For the wave forms of ILEDs, focal spike activities were 83.3%, and bursts of slow waves mixed with spikes were 13.9%. Among the 36 cases that showed the ILEDs, 2 cases were associated with epilepsy and another 2 with AV malformation on the MRI images. CONCLUSION: The ILEDs of the patients with chronic recurrent headaches mainly occurred in the central temporal areas as focal spike wave forms, which shows a benign course. Because a few cases can accompany epilepsy and brain abnormalities, close observation and follow-up tests are needed.

Comparison of total parenteral nutrition-associated cholestasis according to amino acid mixtures in very low birth weight infants / 소아과

PURPOSE: The purpose of this study was to evaluate the effect of amino acid mixtures on incidence and severity of total parenteral nutrition associated-cholestasis(PNAC) in very low birth weight infants. METHODS: Retrospective review of 63 very low birth weight infants(birth weight < or =1,500 g) who received total parenteral nutrition(TPN) in our neonatal intensive care unit from January 2000 to December 2004 was performed. Patients were divided into 2 groups : Group I(n=32, Jan 2000-Jun 2002) and Group II(n=31, Jul 2002-Dec 2004), where infants in Group II received taurine and glutamic acid-rich amino acid mixtures. PNAC was defined as serum direct bilirubin(DB) level greater than 2.0 mg/dL. The incidence and severity of PNAC were compared between these groups. RESULTS: The incidence of PNAC was significantly lower in Group II than in Group I(21.9% vs 6.5%, P<0.148). Maximum and mean DB levels were also significantly lower in Group II(P<0.05). CONCLUSION: The incidence and severity of PNAC in very low birth weight infants may be reduced with different composition of amino acid mixtures in TPN. Further prospective randomized controlled studies are needed to determine an ideal composition of acid mixtures to prevent the development of PNAC.

Effectiveness of Cognitive Training based on Virtual Reality for the Elderly

OBJECTIVE: Virtual reality (VR) has been thought to have great usability to enhance cognitive functions. This study was designed to evaluate the efficacy of a VR program which was developed to improve cognition of the elderly. METHOD: After developing a VR program, we set special input units and a large projection type monitor for the elderly. The VR program simulated 17 different house-hold tasks. Thirty elderly persons including 9 mild-dementia and 21 none-dementia were involved and were randomly divided into two groups. Fifteen were belonged to the training group and the other 15 belonged to the control group. The training group subjects underwent this VR program for 4 weeks by 3 times a week. Cognitive function change was assess by neuropsychological test scores before and after training period. RESULTS: In the training group, scores in attention and immediate and delayed auditory memory tests were improved after training. However the control group didn't show any changes. And most subjects of the training group enjoyed this program. CONCLUSION: VR based cognitive training is a useful method to enhance cognitive functions for the elderly.

Inhibition by Norfluoxetine, the Major Metabolite of Fluoxetine, of Voltage-Gated K+ Channels in Primary Cultured Rat Hippocampal Neurons / 대한마취과학회지

BACKGROUND: Fluoxetine (Prozac), a selective serotonin reuptake inhibitor, has been shown to be effective in the treatment of depression. We investigated the effects of norfluoxetine, the major active metabolite of fluoxetine, on voltage-gated K+ currents in primary cultured hippocampal neurons, and determined the potency and modes of actions of norfluoxetine. METHODS: Voltage-gated K+ currents were studied in primary cultured rat hippocampal neurons using the whole-cell configuration of the patch-clamp technique. Electrophysiological recordings were done in hippocampal neurons between 5-10 days in culture. Transient A-type K+ currents (KA) and delayed-rectifier K+ (KDR) currents were isolated from whole-cell K+ currents using a pulse protocol. RESULTS: Norfluoxetine accelerated the decay rate of whole-cell K+ currents, and thus decreased the current amplitude at the end of a pulse in a concentration-dependent manner. Norfluoxetine inhibited KA and KDR currents in a concentration-dependent manner with IC50's of 0.93 and 0.70micro M, respectively. Norfluoxetine also reduced the areas of KA currents and the steady-state KDR current over the range of test potentials, and the reduction was voltage-dependent (greater increase at more positive potentials). From the onset of the fractional block of KA currents by norfluoxetine during the initial 40 ms of a clamp step, we calculated k1 = 53.26/micro M.s for the association rate constant, and k2 = 70.24/s for the dissociation rate constant. The resulting apparent KD was 1.32micro M, which is similar to the IC50 value obtained from the concentration-response curve. CONCLUSIONS: Our results indicate that norfluoxetine, the major metabolite of fluoxetine, at therapeutic levels, produces a concentration- and voltage-dependent inhibition of KA and KDR currents in primary cultured hippocampal neurons. These effects could perturb the neuronal excitability in the hippocampus, and may contribute to the therapeutic antidepressant action of fluoxetine.