Disopyramide Concentrations Research Articles

Effect of disopyramide on bacterial diversity in drinking water

Disopyramide was detected in drinking water by LC-MS/MS and the microbial diversity was investigated by PCR and high-throughput sequencing. The results showed that bacteria community structure in drinking water changed a lot when added different concentrations of disopyramide. The results of Shannon index showed that the total number and abundance of bacterial community species in drinking water samples decreased significantly after the addition of disopyramide. However, the number and abundance of community structure did not change with the concentration of disopyramide. Disopyramide inhibits the activity of bacterial community in drinking water and also can reduce the bacterial community diversity in drinking water.

Disopyramide and Mianserin Intoxication: A Unique Fatal Case – Review of the Literature

Lethal occurrence is exceptional after disopyramide or mianserin poisoning. A case of intentional lethal intoxication with these drugs was reported, as well as a review of the literature. Pre- and postmortem blood concentrations of disopyramide or mianserin were assessed in a woman who died from acute cardiac failure after ingestion. The premortem blood concentration of disopyramide alone was considered lethal, and a toxic premortem concentration of mianserin was observed that may have increased cardiovascular failure induced by disopyramide because the metabolism of both drugs is mediated via cytochrome P450. Moreover, it was shown that the postmortem redistribution of disopyramide was limited, as pre- and postmortem concentrations were 48 and 65 mg/L, respectively. As regards mianserin, redistribution was observed after death with pre- and portmortem concentrations at 0.23 and 0.79 mg/L, respectively. This case illustrates that if postmortem blood concentration of disopyramide is known, the premortem concentration can be deduced.

Effects of Serum Concentrations of Disopyramide and Its Metabolite Mono-N-dealkyldisopyramide on the Anticholinergic Side Effects Associated with Disopyramide

The aim of this study was to evaluate the relationship between the anticholinergic side effects associated with disopyramide (DP) and serum DP or mono-N-dealkyldisopyramide (MND) concentrations and the safety range of DP or MND for prevention of anticholinergic side effects in 141 inpatients. The serum DP and MND concentrations were determined by high-performance liquid chromatography. No correlation was observed between creatinine clearance (Ccr) and the ratio of the serum concentration to the dose (C/D) of DP, but a significant inverse correlation was observed between Ccr and the C/D of MND. It was observed that the ratio of MND concentration to DP concentration in the group, whose Ccr was below 20 ml/min, was higher than that of the other groups. Although no significant difference was observed in the DP concentration between the patients without (Group 1) or with (Group 2) anticholinergic side effects, significant differences were observed in the MND concentration, Ccr, and the ratio of MND/DP. The DP concentrations of both Groups 1 and 2 were distributed from 0.13 to about 5 microg/ml. On the other hand, although the MND concentrations of Group 1 were below about 1 microg/ml, the MND concentrations of Group 2 were above about 1 microg/ml. These results suggest that not only DP concentration but also MND concentration should be monitored in patients whose renal function is decreased to prevent anticholinergic side effects associated with DP, and that when serum MND concentration was over approximately 1 microg/ml, the dose should be decreased or discontinued.

Extractive-spectrophotometric determination of disopyramide and irbesartan in their pharmaceutical formulation

Picric acid, bromocresol green, bromothymol blue, cobalt thiocyanate and molybdenum(V) thiocyanate have been tested as spectrophotometric reagents for the determination of disopyramide and irbesartan. Reaction conditions have been optimized to obtain coloured comoplexes of higher sensitivity and longer stability. The absorbance of ion-pair complexes formed were found to increases linearity with increases in concentrations of disopyramide and irbesartan which were corroborated by correction coefficient values. The developed methods have been successfully applied for the determination of disopyramide and irbesartan in bulk drugs and pharmaceutical formulations. The common excipients and additives did not interfere in their determination. The results obtained by the proposed methods have been statistically compared by means of student t-test and by the variance ratio F-test. The validity was assessed by applying the standard addition technique. The results were compared statistically with the official or reference methods showing a good agreement with high precision and accuracy.

Population pharmacokinetic investigation of disopyramide by mixed effect modelling using routine clinical pharmacokinetic data in Japanese patients

To estimate the population pharmacokinetic parameters of disopyramide using non-linear mixed effects modelling. A total of 148 serum levels from 109 patients (61 males and 48 females) receiving disopyramide were collected. The final pharmacokinetic model was Cl (L/h)=3.75.TBW0.567.AGE-0.374.Conc(-0.719).1.48(DOSE>or=5), Vd (L/kg)=4.13 and k(a) (h-1)=0.363, where Cl is total body clearance, Vd is apparent volume of distribution, k(a) is absorption rate constant, TBW is total bodyweight (kg), AGE is age (years), Conc is the concentration of disopyramide (microg/mL), and DOSE>or=5=1 for patient received 5 mg/kg/day of disopyramide dosage or over and 0 otherwise. Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target disopyramide concentrations and the desired therapeutic effect.

Atrial Pacing Failure Following Termination of Atrial Fibrillation by Acute Administration of Disopyramide Phosphate

Atrial pacing failure occurred after termination of atrial fibrillation by acute administration of disopyramide phosphate in a 71-year-old woman implanted with an AAI pacemaker for sick sinus syndrome. The atrial pacing threshold showed an 810% increase; however, the serum concentration of disopyramide corresponded to therapeutic level. Infusion of the same dose of disopyramide phosphate used during the period of atrial pacing rhythm did not increase the atrial pacing threshold. In the present patient, we supposed that atrial pacing failure did not occur by the effect of disopyramide alone, but rather was a reciprocal action in response to atrial fibrillation.

Pilsicainide in breast milk from a mother: comparison with disopyramide and propafenone

Pilsicainide in breast milk from a mother: comparison with disopyramide and propafenone

個別薬物療法のための血しょう中蛋白非結合型Ｄｉｓｏｐｙｒａｍｉｄｅ濃度測定の有用性

The unbound concentration of disopyramide (DP) in plasma was studied to determine whether or not it is a useful index to assess the effectiveness of DP in anti-arrhythmic therapy. In 20 arrhythmic patients administered DP (Rythmodan®, 100-600 mg/day), there was no correlation between the dose and total or unbound plasma concentration of DP. The values of unbound fraction (fp) of DP in plasma widely varied from 0.25 to 0.57. The fp values were not correlated with the albumin concentration in plasma, but did correlate with the concentration of α1-acid glycoprotein. We further examined the relationship between the total or unbound plasma concentrations of DP and it's effectiveness in 16 of the 20 patients (4 patients had side effects). There was significant difference in the plasma concentrations of DP between the effective group and the ineffective group.However, as the range of the concentration for the two groups overlapped in 75%. the total concentration cannot be used to define the effectiveness. On the other hand, the unbound concentration of DP was greater than 0.8μg/mL in the effective group, whereas it was lower than 0.8μg/mL in the ineffective group.There was no correlation between the unbound concentration of mono-N-dealkyldisopyramide (MND) and the effectiveness. The range of the unbound plasma concentration of MND was 0.1-1.0μg/mL, and no patient developed side effects such as tachycardia or constipation due to the anticholinergic effect. In conciusion, an unbound concentration of DP in plasma of over 0.8μg/mL can be used as an index of the effectiveness of anti-arrhythmic therapy in therapeutic drug monitoring.

Role of biantennary glycans and genetic variants of human alpha1-acid glycoprotein in enantioselective binding of basic drugs as studied by high performance frontal analysis/capillary electrophoresis.

To establish a clear understanding of the role of biantennary branching glycans and genetic variants of alpha1-acid glycoprotein (AGP) in enantioselective bindings of basic drug. Human native AGP was separated using concanavalin A affinity chromatography into two subfractions, the unretained fraction (UR-AGP, defect of biantennary glycan) and the retained fraction (R-AGP, possessing biantennary glycan(s)). Imminodiacetate-copper (II) affinity chromatography was used to separate human native AGP into A variant and a mixture of F1 and S variants (F1*S variants). The mixed solutions of the (R)- or (S)-isomer of the model drugs (15 microM disopyramide (DP) or 30 microM verapamil (VER)) and 40 microM of respective AGP species were subjected to high-performance frontal analysis/capillary electrophoresis (HPFA/CE) to determine the unbound drug concentrations. The unbound concentrations (Cu) of DP in UR-AGP solutions were lower than those in R-AGP solutions, whereas there was no significant difference in the enantiomeric ratios (Cu(R)/Cu(S)) of DP between UR- and R-AGP solutions. In case of genetic variant, the Cu(R)/Cu(S) values of DP in F1*S and A solutions were 1.07 and 2.37, respectively. On the other hand, the enantiomeric ratio of VER in F1*S and A variant solutions were 0.900 and 0.871, respectively. The biantennary glycan structures are related to binding affinity of DP to AGP, but not responsible for the enantioselectivity. Genetic variants give significant effect on the enantioselectivity in DP binding, but not in VER binding.

Bioavailability assessment of disopyramide using pharmacokinetic-pharmacodynamic (PK-PD) modeling in the rat.

The relationship between the serum concentration and the pharmacological effect of disopyramide was investigated quantitatively to estimate the extent of its oral bioavailability (EBA(p.o.) and to evaluate the drug interaction with miconazole, a CYP3A4 inhibitor. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was used to describe the relationship between the serum concentrations and changes in QT interval (pharmacological data) of disopyramide after intra-vascular infusion for 15 min (i.v. short-term infusion) to rats. A two-compartment model was applied to the pharmacokinetics of disopyramide. The pharmacological data after short-term infusion were well explained using a PK-PD link model. To validate the present PK-PD model. disopyramide was administered intra-vascularly in separate experiments, and the doses were predicted only from the pharmacological data. The model predicted doses were identical to the actual doses, regardless of the dosing rates. This result indicates that the PK-PD model used in the present study is appropriate, and that the relationship between the serum concentrations and changes in QT intervals is independent of the dosing (input) rate. When miconazole was co-administered orally 1 h before disopyramide infusion, the serum disopyramide concentrations were significantly higher than that following disopyramide alone. The raised serum concentrations under miconazole co-administration were well explained by nonlinear elimination clearance. The pharmacological effects of disopyramide under miconazole co-administration, were also greater than those following disopyramide alone. The results of the PK-PD analysis indicated that the enhanced pharmacological response under miconazole co-administration was simply caused by a pharmacokinetic change. The EBA(p.o.) values estimated from the pharmacological effects predicted the observed values reasonably well. In conclusion, we demonstrated following: (1) the pharmacological effect after intra-vascular administration of disopyramide is related quantitatively to the serum concentrations using a PK-PD model; (2) miconazole affects only the elimination clearance of disopyramide to enhance the pharmacological effect; (3) the EBA of disopyramide can estimated reasonably only well from the pharmacological data using the PK-PD model; (4) there is no dosing-rate-dependent or dosing-route-dependent pharmacological effect of disopyramide.

服薬指導における症例報告 その２ ピルメノールにより肝障害を引き起こしたと疑われた一症例およびその検討

A 56-year-old woman inpatient that had been administrated warfarin, digoxin, verapamil and disopyramide after undergoing surgery for a mitral and aortic valve replacement associated with artrial fibrillation received a 300mg daily dose of disopyramide therapy before and after the operation. Although the serum disopyramide concentration was within the normal therapeutic range, dry mouth appeared as a side effect. Disopyramide was thus changed to pirmenol. The trough level of pirmenol was 2.1μg/mL at seven days after starting pirmenol therapy at the dose of 300 mg/day, and the dose was there after decreased to 200mg/day. About two weeks after pirmenol therapy was started, liver injury was observed. At approximately 30 days after pirmenol administration was stopped, the liver function returned to a normal level.On the other hand, according to recent reports pirmenol was suggested to show a high level in the liver. The reported levels of pirmenol were also similar to for amiodarone and aprindine, which are both well known to induce side effect in the liver. Therefore, one of the reasons that pimenol induced liver injury may be due to its high levels in the liver.

Disopyramide decreases the fasting serum glucose level in man.

The effect of disopyramide, a class Ia antiarrhythmic drug, on the serum glucose level was evaluated in 6 consecutive in-patients. A 19-hour starvation test was repeated with oral administration of sustained-release disopyramide (150 mg) 0 and 12 hours after starting the test. Serum glucose levels during the starvation test decreased with disopyramide administration from a mean value of 96.5 +/- 1.8 to 85.9 +/- 1.4 mg/dl (24 samples, p < 0.05). The average reduction of the serum glucose level by disopyramide in each patient was 9.7 +/- 2.2 mg/dl. The decrease in the serum glucose level was not related to the serum concentration of disopyramide or serum creatinine levels. The decrease in the serum glucose level was larger in older patients (r = 0.75) and in light patients under 45 kg. These results suggested that disopyramide reduced the fasting serum glucose levels even in normal ranges as a common side effect of the drug, and that not only the occurrence of severe hypoglycemia but also the decrease in glucose levels were influenced by multiple factors including age and body weight.

Pirmenol inhibits muscarinic acetylcholine receptor-operated K + current in the guinea pig heart

We examined the effects of pirmenol and disopyramide on the muscarinic acetylcholine receptor-operated K + current ( I K.ACh) in atrial cells and on experimental atrial fibrillation in isolated guinea-pig hearts. In isolated atrial myocytes, both pirmenol and disopyramide concentration dependently inhibited the I K.ACh induced by carbachol or intracellular loading of GTP γS. Their inhibitory effects on the carbachol-induced current were more potent than those on GTP γS-induced current, suggesting that these drugs inhibit I K.ACh mainly by blocking muscarinic receptors. In Langendorff-perfused hearts these drugs reversed the carbachol-induced decreases in effective refractory periods and atrial fibrillation threshold. These drugs may be useful for the prevention of vagally induced atrial fibrillation.

Determination of free disopyramide in blood serum in situ using a disopyramide-sensitive membrane electrode

Free disopyramide levels in blood serum, the monitoring of which is especially effective for antiarrhythmic therapy, were determined in situ using a disopyramide-sensitive membrane electrode. Sodium tetrakis[3,5-bis(2-methoxyhexafluoro-2-propyl)phenyl]borate was incorporated as the ion-exchanger and 2-fluoro-2′-nitrodiphenyl ether as the solvent mediator in a poly(vinyl chloride) membrane matrix to form the electrode. The lower limit of the detection for free disopyramide in serum was 0.8 μM. The free disopyramide concentrations measured by the ion-selective electrode agreed well with those determined by an established fluorescence polarization immunoassay that requires an additional ultrafiltration procedure to remove disopyramide bound to serum protein.

Inhibition of ATP-sensitive K + channels of mouse skeletal muscle by disopyramide

Single ATP-sensitive K + channels (K ATP channels) were studied in inside-out membrane patches excised from mouse skeletal muscle. The class Ia antiarrhythmic, disopyramide (5–100 μM), applied to the cytoplasmic membrane surface inhibited K ATP channels at −40 and +40 mV. Channel inhibition by disopyramide started slowly and reached an almost stationary level within 1 min. Recovery from channel inhibition by disopyramide was incomplete. At pH 7.4, the disopyramide concentrations producing 50% channel inhibition were 8.1 μM at −40 mV and 7.1 μM at +40 mV. The Hill coefficients of the concentration-response curves were close to unity at both potentials. Raising the internal pH from 7.4 to 8.0 had no significant effect on the actions of disopyramide, but lowering the pH to 6.5 greatly potentiated the inhibition of K ATP channels by the antiarrhythmic. Thus the open probabilities of K ATP channels at −40 mV and in the presence of disopyramide (20 μM) were smaller by a factor of 18 at pH 6.5 than at pH 7.4. The results suggest that disopyramide interacts with K ATP channels through the lipid phase of the membrane and that lowering the intracellular pH increases the affinity of K ATP channels to disopyramide. Thus disopyramide at therapeutic concentrations (6–15 μM) affects muscular K ATP channels, in particular at reduced intracellular pH values that occur under ischaemic conditions and during fatiguing exercise.

Nomogram for estimating plasma unbound disopyramide concentrations in patients with varying plasma alpha 1-acid glycoprotein concentrations.

Since plasma protein binding of disopyramide (DP)--a class IA antiarrhythmic widely used in the prevention and treatment of various types of cardiac arrhythmias--is not only saturable within the therapeutic range but also altered under various pathophysiological conditions, the interpretation of total DP concentrations, Ctotal, measured during routine therapeutic drug monitoring (TDM) is often complicated. To circumvent this problem, we attempted to establish a comprehensive nomogram that allows estimation of unbound DP concentrations (Cu) based upon Ctotal of the drug and plasma concentration of alpha 1-acid glycoprotein (AAG), a major DP-binding protein. The nomogram was formulated with use of the in vitro binding data retrieved from 103 subjects categorized into 10 different groups each with a different mean concentration of AAG (range: 0.14-1.54 g/L). Data analysis, using a binding model assuming one specific binding site and nonspecific binding(s), revealed that alterations in plasma DP binding are attributable mainly to those in the capacity, Bmax, rather than affinity, ka, constant of the specific binding site. In addition, plasma AAG concentration correlated significantly (r = 0.90, p < 0.001) with the Bmax value over the range 0.09-2.28 g/L. For this reason, we substituted Bmax calculated by the regression equation as a function of AAG and the overall mean ka and nonspecific binding parameter values for the respective individual variables of the binding model, so that Cu of each plasma sample was estimated from the corresponding data on Ctotal and plasma AAG levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Quinidine but Not Disopyramide Prolongs Cardiac Purkinje Fiber Action Potentials After a Pause

Prolongation of the cardiac action potential (AP), leading eventually to early afterdepolarizations (EADs), is believed to underlie drug-induced long QT syndromes and torsade de pointes. Episodes of torsade de pointes frequently occur after a prolonged pause. We studied the effects of quinidine and disopyramide on AP duration (APD) in canine cardiac Purkinje fibers after pauses of 2,000-10,000 ms. Standard intracellular microelectrode techniques were used to record APs from canine Purkinje fibers at an interstimulus interval (ISI) of 1,000 ms. Pauses of 2,000-10,000 ms were introduced into the basic drive cycle in the presence and absence of subtherapeutic and therapeutic concentrations of quinidine and disopyramide. We observed a biphasic response in APD to quinidine and disopyramide at ISI = 1,000 ms. Quinidine but not disopyramide produced a marked dose- and time-dependent additional prolongation of APD immediately after the pauses. This effect was highly statistically significant. We conclude that disopyramide and quinidine have qualitatively different effects on APD after a pause and that this observation may cast some light on the apparently greater frequency of torsade de pointes occurring with quinidine than with disopyramide. Possible mechanisms include differential drug effects on outward potassium or inward sodium channels.

Effects of disopyramide and flecainide on the kinetics of inward rectifier potassium channels in rabbit heart muscle.

1. Standard patch-clamp techniques were used to study the interaction of therapeutic concentrations of flecainide and disopyramide with single inwardly-rectifying potassium channels in cell-attached membrane patches from rabbit ventricular myocytes. 2. Under drug-free conditions, the potassium channels had a conductance of 31 +/- 2 pS (n = 13), a mean open time of 230 +/- 6 ms (n = 11) recorded at the resting cell potential, and an open probability of 0.66 +/- 0.20 (n = 39). The resting potential of the cells studied was -68.5 +/- 3.6 mV (n = 32). 3. Disopyramide did not reduce the open probability of the channel when the cell was voltage-clamped at the resting cell potential. However, disopyramide increased the mean open time of the channel, recorded at the resting cell potential, by 15% at 5 microM and by 29% at 20 microM. The action potential prolonging actions of disopyramide in therapeutic concentrations appear not to be due to blocking the inward rectifier K+ channel. 4. Flecainide (3.0 microM, but not at 0.5 microM) decreased the open probability without changing the conductance of the channel, at 3 microM (51.0 +/- 7.2%, n = 6, P = 0.03) at the resting cell potential. Flecainide increased the mean open time of the channel, recorded at the resting cell potential, by 12% at 3.0 microM. 5. We propose that flecainide stabilized the inward rectifier K+ channel in an inactivated state, without plugging the conducting pore. In addition, it appeared to bind to an open conformation of the channel,since some of the reduction in open probability could be accounted for by the lengthening of the mean open time. The changes in open-state kinetics suggest that this binding may be in the region of the activation gate.

Altered Alpha-1-acid Glycoprotein Concentration and Free Fraction of Disopyramide in Patients with Heart Disease.

Alpha-1-acid glycoprotein (AAG) concentration and protein binding of disopyramide (DSP) in serum were measured in patients with heart disease. An increase in AAG (121±45mg/dl, mean±SD) was fbund in padents with heart failure as compared with healthy controls (73±14) and with cardiac patients without heart failure (78±12). The free fraction of DSP (0.35±0.12) was decreased in patients with heart failure as compared with control (0.56±0.11) and with patients without heart failure (0.47±0.15). The values of the heart failure patients returned to the level of cardiac patients with out heart failure (89±23 mg/dl and 0.48±0.07) with recovery from the decompensated stage. These findings suggest that the free concentration of DSP should be monitored frequently in cardiac patients, especially in patients with congestive heart failure.

ジソピラミド服用入院患者における徐放剤と非徐放剤との血中濃度のバラツキの比較

The variation in serum disopyramide concentration at early morning (6: 00) in inpatients administered 300mg per day of sustained-release disopyramide tablet (Rthmodan R, preparation A) or the same dose of non sustained-release disopyramide capsule (Rthmodan, preparation B) was studied. Twenty-one inpatients, whose mean age was 68.4 ±10.2 (SD) yr and mean body weight was 52.0±7.6kg, received preparation A (q 12 hr at 7: 00 & 19: 00). Nineteen inpatients, whose mean age was 68.3±12.9 yr and body weight was 54.0±11.3kg, received preparation B (tid at 7: 00, 12: 00 & 19: 00). No differences were observed in the mean ratio of serum disopyramide concentration at 6: 00 to dose between inpatients receiving preparations A and B, although a signficant difference was observed in its variation. When the intra-individual variability in inpatients monitored more than three times was compared, the CV was 4.93±1.74%(SD) in inpatients receiving preparation A versus 21.8±7.8% in inpatients received preparation B. Therefore, this suggests that the variation in serum disopyramide concentration in inpatients receiving preparation A was significantly decreased over that of preparation B.