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.

Monitoring disopyramide, lidocaine, and quinidine by micellar liquid chromatography.

A micellar liquid chromatography (MLC) method using a C18 column was developed to determine three antiarrhythmic drugs--disopyramide, lidocaine, and quinidine--that are most usually monitored in serum samples. After the application of an interpretative strategy for optimization of sodium dodecyl sulfate (SDS) and modifier concentrations in order to ensure the minimum analysis time, maximum sensitivity, and good resolution, the optimum chromatographic conditions for the determination of the three antiarrhythmics were flow rate, 1 mL/min; injection volume, 20 microL; separation temperature, 25 degrees C; mobile phase, 150 mmol/L SDS-7% (v/v) butanol-phosphate buffer, 10 mmol/L, pH 7-0.9% (w/v) NaCl; and detection at 214 nm. The calibration curves for the drugs were linear (r2 > 0.999). The intraday and interday precisions were lower than 3.9% (CV). Recoveries were 100 +/- 0.6% when the method was applied to both serum samples spiked with the antiarrhythmics (n = 10) and real serum samples. In all cases, the results were similar to those obtained using the reference method (fluorescence polarization immunoassay) usually used in the Spanish hospital. The proposed method is useful for hospital monitoring of the antiarrhythmics by direct injection into the chromatograph.

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.

Stability-indicating methods for the determination of disopyramide phosphate.

Four methods were developed for the determination of intact disopyramide phosphate in the presence of its degradation product. In the first and second methods, third-derivative spectrophotometry and first derivative of the ratio spectra were used. For the third-derivative spectrophotometric method, the peak amplitude was measured at 272 nm, while for the derivative ratio spectrophotometric method, disopyramide phosphate was determined by measuring the peak amplitude at 248 and 273 nm. Both methods were used for the determination of disopyramide phosphate in the concentration range 12.5-87.5 microg/mL, with corresponding mean recovery 100.8 +/- 0.7% for the first method and 99.9 +/- 0.7% and 99.6 +/- 0.7% for the second method at 248 and 273 nm, respectively. In the third method, an ion selective electrode (ISE) was fabricated using phosphotungstic acid as an anionic exchanger, PVC as the polymer matrix, and dibutylsebacate as a plasticizer. The ISE was used for the determination of disopyramide phosphate in pure powder form in the concentration range 10(-2)-10(-5) M. The slope was found to be 58.5 (mV/decade), and the average recovery was 99.9 +/- 1.6%. The fourth method depended on the quantitative densitometric determination of the drug in concentration range of 0.25-2.5 microg/spot using silica gel 60 F245 plates and ethyl acetate-chloroform-ammonium hydroxide (85 + 10 + 5, v/v/v) as the mobile phase, with corresponding mean accuracy of 100.3 +/- 1.1%. The 4 proposed methods were found to be specific for disopyramide phosphate in presence of up to 80% of its degradation product for the spectrophotometric methods, 90% of its degradation for the densitometric method, and 40% for the ISE method. The 4 proposed procedures were successfully applied for the determination of disopyramide phosphate in Norpace capsules. Statistical comparison between the results obtained by these methods and the official method of the drug was done, and no significant differences were found.

Isotachophoretic determination of bisoprolol, clonidine, disopyramide and tolazoline in human fluids.

Separation and determination of bisoprolol, clonidine, disopyramide and tolazoline in control serum and in human urine was investigated by capillary isotachophoresis. The drugs were separated by using the cationic electrolyte system. viz., sodium acetate buffer (pH 4.64) (c1 = 10 mM)-beta-alanine. The compounds were almost totally isolated from serum by solid-phase extraction using a Sep-Pak C18 cartridge. The recovery of compounds varied from 87 to 99%. The linear calibration range was studied to apply the method to real human fluids. The limit of determination of the drugs was 40.0 micrograms/ml serum. The limit of determination by direct sampling for bisoprolol is 3 micrograms/ml urine.

Quantitative determination of disopyramide, verapamil and flecainide enantiomers in rat plasma and tissues by high-performance liquid chromatography.

Enantiomers of disopyramide (DP), flecainide (FLC) and verapamil (VP) were extracted from rat plasma and tissues (brain, lung, heart, liver, kidney and muscle), followed by quantitative determination using enantioselective high-performance liquid chromatography with chiral stationary-phase columns. The recoveries of S-(+)- and R-(-)-DP from tissues were higher than 69%, and the within- and between-day coefficients of variation were very low (0.5 - 5.7%). The lower limits of detection in each tissue were less than 289 ng/g tissue. The recoveries of S-(+)- and R-(-)-FLC from tissues were higher than 88%, and the within- and between-day coefficients of variation were 1.2-6.0%. The lower limits of detection in each tissue were less than 37 ng/g tissue. The recoveries of S-(-)- and R-(+)-VP from tissues were higher than 80%, and the within- and between-day coefficients of variation were 0.5-6.2%. The lower limits of detection in each tissue were less than 51 ng/g tissue. The analytical methods established in this study will be suitable for determining the concentrations of the enantiomers of these anti-arrhythmic agents in rat plasma and tissues.

Chromatographic (TLC) analysis of diltiazem in pharmaceutical form in presence of other antiarrhythmics.

Diltiazem was identified by TLC method on silica gel by ascending technique, in presence of five another antiarrhythmic drugs (disopyramide, flecainide, lidocaine, lorcainide, procainamide). Suitable conditions for separation of diltiazem were established using ethanol-benzene-dioxane-ammonia (2:20:16:3) as the mobile phase. When using acidified iodoplatinate solution or Dragendorff reagent as indicators, the amount of diltiazem as small as 100 ng can be identified. The TLC method is simple and sensitive and it was used to identify diltiazem in tablets.

Disopyramide analysis using REMEDi: comparison with EMIT and conventional high performance liquid chromatographic methods.

REMEDi (Rapid EMErgency Drug identification; Bio-Rad) is an automated high performance liquid chromatographic (HPLC) system designed to detect, identify and measure a range of basic and neutral drugs in 0.5-1.0 mL of urine or plasma/serum. We have evaluated REMEDi in the analysis of the antiarrhythmic drug disopyramide in patient samples. The specimens were also analysed by a conventional HPLC method, based on solvent extraction and UV detection (254 nm), and by EMIT. There were good correlations between the results obtained with each method (r = 0.91 or greater). REMEDi gave a lower mean result than EMIT [means +/- SD (mg/L): REMEDi 2.64 +/- 1.10, EMIT 3.14 +/- 1.51; t = 4.0, p less than 0.01; n = 25], but there were no other significant differences in mean results. The principal disopyramide metabolite, mono-N-desalkyldisopyramide, did not interfere in any method. Clearly REMEDi can be used for therapeutic drug monitoring of disopyramide provided enough sample is available.

Simultaneous determination of disopyramide and its mono-N-dealkylated metabolite enantiomers in human plasma and urine by enantioselective high-performance liquid chromatography.

Enantiomers of disopyramide (DP) and its mono-N-dealkylated metabolite (MND) were determined in human plasma and urine by enantioselective high-performance liquid chromatography using a chiral stationary-phase column. This method was precise and sensitive: the mean recoveries from plasma at a concentration of 0.5 microgram/ml were 101.1% for (+)-DP, 98.0% for (-)-DP, 94.4% for (+)-MND and 82.9% for (-)-MND; the within- and between-day coefficients of variation at the same concentration were 4.4 and 3.3% for (+)-DP, 4.7 and 4.1% for (-)-DP, 6.5 and 4.1% for (+)-MND and 7.8 and 2.4% for (-)-MND for plasma; the lower detection limits were 40 ng/ml for (+)-DP, 80 ng/ml for (-)-DP, 100 ng/ml for (-)-MND and 200 ng/ml for (+)-MND, for 0.5 ml of plasma and 0.2 ml of urine. The ultrafiltration technique was used for determination of the unbound concentration of DP enantiomers in plasma. A preliminary study of the determination of DP and MND enantiomers in plasma and urine samples from a healthy subject given racemic DP demonstrated the clinical applicability of the present method for therapeutic monitoring and pharmacokinetic studies.

Simultaneous determination of disopyramide and mono-N-dealkyldisopyramide enantiomers in plasma and urine by use of a chiral cellulose-derivative column.

This assay allows simultaneous determination of the enantiomers of both disopyramide and its active metabolite, mono-N-dealkyldisopyramide, in 1 mL of plasma or 0.1 mL of urine within approximately 35 min by HPLC with a chiral cellulose-derivative column and ultraviolet detection. Recoveries for the analytes and the internal standard (racemic verapamil) with an extraction from alkalinized plasma or urine into diethyl ether were greater than 90%. Intra- and interassay CVs for disopyramide enantiomers were less than 5.5% at 2.5 mg/L in plasma and less than 6.5% at 25 mg/L in urine; for mono-N-dealkyldisopyramide enantiomers they were less than 6.3% and less than 8.9%, respectively. Intra- and interassay relative errors for determining these analytes in plasma and urine at 2.5 and 25 mg/L, respectively, ranged from -5.9% to +2.5%. The calibration curves for the respective analytes were linear (r = 0.995 or greater, P less than 0.01) from 0.025 to 5.0 mg/L in plasma and from 0.5 to 10 mg/L in urine. The lower detection limits (signal-to-noise ratio of 3) for S(+)-disopyramide and the other analytes were 0.010 and 0.025 mg/L, respectively. We evaluated clinical applicability of this method by determining steady-state plasma concentrations and urinary excretions of the respective analytes in a pediatric patient being treated with racemic disopyramide.

Fatal disopyramide intoxication from suicidal/accidental overdose.

Disopyramide is an oral antiarrhythmic drug which reduces conduction velocity, prolongs duration of action potential and the effective refractory period, and exerts vagolytic properties. The drug is usually well absorbed orally. The principal use of the drug is to suppress ventricular extrasystoles with usual oral dosage of 100 to 200 mg every 6 h, until blood levels of 2 to 4 micrograms/mL are attained. The use of the drug for suicide is uncommon as it is a prescription drug. Two cases of fatal disopyramide intoxication seen at the Los Angeles County Medical Examiner's Office will be discussed followed by a review of the literature of fatal suicidal disopyramide overdose. Case 1 was a 31-year-old male pharmacist with known history of depression and no history of heart disease. His decomposed remains were found with a suicide note and with several disopyramide tablets. At autopsy the blood level for disopyramide was 146 micrograms/mL. Case 2 is a 40-year-old male with history of alcoholism and prior suicidal attempts who regularly took disopyramide to control ventricular arrhythmias. He apparently ingested 36 100-mg tablets of disopyramide before his final collapse. At autopsy his blood level of disopyramide was 63 micrograms/mL.

Saliva concentrations of disopyramide cannot substitute the drug's plasma concentrations.

For many drugs the salivary concentration corresponds to the free plasma drug concentration, which may be more closely related to drug activity or toxicity than the total plasma drug concentration. In this study a preliminary investigation was undertaken to determine the feasibility of monitoring saliva levels of disopyramide, an antiarrhythmic drug, for clinical and toxicological purposes. Single oral doses of this compound were administered to healthy volunteers. Stimulated mixed saliva and plasma levels were measured by the EMIT technique. The concentrations of disopyramide in the stimulated mixed saliva tended to be lower than those found in the corresponding plasma sample (fp 0.3-0.5), and the saliva-to-plasma concentration ratio increased with a decreasing salivary pH (pH 6.89, S/P = 0.25; pH 8.15, S/P = 0.08). The correlation between the saliva and the total plasma concentrations was significant but relatively poor, however. Consequently, mixed salivary disopyramide concentrations are a poor indicator of plasma concentrations, even if correction is made for pH change.

Total and free disopyramide by fluorescence polarization immunoassay and relationship between free fraction and alpha-1 acid glycoprotein.

Disopyramide is an antiarrhythmic drug with concentration dependent protein binding within the therapeutic range. We found good agreement between fluorescence polarization immunoassay (FPIA, Abbott TDX) and high performance liquid chromatography (HPLC) for total disopyramide among 27 admission patients' sera (FPIA = 1.12 (HPLC) -0.002, r = 0.982, SEE = 0.378 mg/l). Agreement between FPIA and HPLC for free disopyramide was similarly good (FPIA = 0.867 (HPLC) -0.003, r = 0.986, SEE = 0.09 mg/l, n = 27). Serum alpha 1 acid glycoprotein concentration (AAG) and free fraction (FF) percent of disopyramide correlated inversely (FF = -0.0112 (AAG) + 31.3 r = 0.707, SEE = 6.41 mg/l, n = 24), and the free disopyramide fraction varied greatly. For two pooled sera with 12 different disopyramide concentrations (range from 0.5-20.0 mg/l), the proportion of free fraction ranged from 6.5 to 73.2%. Overall, we found the free disopyramide fraction variable with each individual, total drug, and protein concentration. Therefore, free drug concentration should be monitored in disopyramide therapy, and FPIA is reliable for free as well as total drug assay.

Simultaneous determination of disopyramide and its mono-N-dealkyl metabolite in plasma and urine by high-performance liquid chromatography.

A high-performance liquid chromatographic procedure is described for the determination of disopyramide and its mono-N-dealkyl metabolite which offers simplicity of extraction with excellent selectivity, sensitivity and reproducibility. The drug and metabolite, following basic diethyl ether extraction and back-extraction with acetic acid, are injected into a reversed-phase high-performance liquid chromatographic column and the absorbance of the eluate measured at 254 nm. Detectability limits of 0.05 micrograms/ml were obtained with both compounds, and studies of the reproducibility, precision, recovery, stability during storage and effect of time in separating plasma from erythrocytes are described. Applications of this high-performance liquid chromatographic procedure to plasma samples from patients on disopyramide therapy and to plasma and urine from a healthy dog administered single doses are reported.

An HPLC method for the simultaneous quantitation of quinidine, procainamide, N-acetylprocainamide, and disopyramide.

A high performance liquid chromatographic method is reported, which incorporates three internal standards (I-cinchonidine, N-propylprocainamide, and para-chlorodisopyramide) for the simultaneous quantitation of four commonly prescribed antiarrhythmic drugs: quinidine, procainamide, N-acetylprocainamide, and disopyramide. Compounds were separated using combined ion-pairing and adsorption chromatography on a silica column. Inter-run variation was 5.9 CV% for all drugs.