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Survival, proliferation, and functions of porcine hepatocytes encapsulated in coated alginate beads: a step toward a reliable bioartificial liver.

Orthotopic liver transplantation is the most effective treatment for fulminant hepatic failure. As an alternative treatment, an efficient extracorporeal bioartificial liver should contain a large yield of functional hepatocytes with an immunoprotective barrier, for providing temporary adequate metabolic support to allow spontaneous liver regeneration or for acting as a bridge toward transplantation. Survival, proliferation, and functions of porcine hepatocytes were evaluated in primary cultures and after embedding in alginate beads, which were subsequently coated with a membrane made by a transacylation reaction between propylene glycol alginate and human serum albumin. Disruption of total pig livers by collagenase perfusion/recirculation allowed the obtention of up to 10(11) hepatocytes with a viability greater than 95%. Hepatocytes in conventional cultures or embedded in coated alginate beads survived for about 10 days, secreted proteins, particularly albumin, and maintained several phase I and II enzymatic activities, namely ethoxyresorufin-O-deethylase, oxidation of nifedipine to pyridine, phenacetin deethylation to paracetamol, glucuroconjugation of paracetamol, and N-acetylation of procainamide. Typical features of mitosis and [3H]thymidine incorporation indicated that porcine hepatocytes proliferated in both conventional cultures and alginate beads. The efficacy of the membrane surrounding alginate beads for protecting cells from immunoglobulins was tested by embedding HLA-typed human lymphocytes, which were subsequently incubated with specific anti-HLA immunoglobulin G and complement. These data show that large yields of porcine hepatocytes that are embedded in coated alginate beads remain functional and are isolated from large molecular weight molecules, such as immunoglobulins. This system represents a promising tool for the design of an extracorporeal bioartificial liver, containing xenogeneic hepatocytes, to treat acute liver disease in humans.

Acetaminophen↗

Alkylating benzamides with melanoma cytotoxicity.

Radioiodinated N-(2-(diethylamino)ethyl)benzamides have recently been discovered as selective agents for melanotic melanoma and are used for scintigraphic imaging in nuclear medicine. Owing to the high binding capacity, benzamide derivatives conjugated with alkylating cytostatics were synthesized and tested for their potential for targeted drug delivery. Conjugates of chlorambucil with procainamide (1), diethylaminoethylamine (2) and 2-pyrrolidin-1-yl-ethylamine (3), as well as 4-(bis(2-chloroethyl)amino)- (6,7) and 4-(N,N-diethyltriazeno)-substituted (8-10) benzamides, were synthesized. Cell uptake studies with B16 melanoma cells revealed high uptake of radioiodinated 1 and 2, while radiolabelled chlorambucil was found to lack this characteristic. These results were confirmed by biodistribution studies in a mouse melanoma model. Viability measurements revealed that all chlorambucil-benzamide derivatives showed higher toxicity against B16 melanoma and SK-MEL-28 cells than did the parent chlorambucil itself, and that the triazene derivatives were more potent than dacarbazine, which is currently used as a standard cytostatic drug in melanoma therapy. Of all the compounds tested in this series, the triazenes 9 and 10 showed the most promising targeting effect. The toxicity of these compounds against hepatoma cells (MH3924A) and, to a lesser extent, against mouse fibroblast (NIH 3T3) and cervix carcinoma (HeLa) cells was also enhanced, but they were not as toxic as dacarbazine (HeLa). These findings support the concept of a selective, benzamide-mediated in vivo delivery of cytostatics in melanoma cells, leading to enhanced efficacy.

Animals↗

Strategies for reversing shock-resistant ventricular fibrillation.

PURPOSE OF REVIEW: Shock-resistant ventricular fibrillation is defined as ventricular fibrillation persisting after three defibrillation attempts. In approximately 10 to 25% of all cardiac arrests, shock-resistant ventricular fibrillation develops, and 87 to 98% of these patients die. RECENT FINDINGS: In the treatment of shock-resistant ventricular fibrillation, defibrillation using biphasic waveforms is considered as an intervention of choice. Intravenous amiodarone is also acceptable, safe, and useful, based on evidence from two randomized clinical trials. Intravenous vasopressin is acceptable and probably safe and useful, but the evidence supporting this recommendation is coming from a small, randomized clinical trial. Procainamide is acceptable but not recommended. In the presence of acute myocardial infarction and recurrent ventricular fibrillation, if all other therapies fail, beta-blockers can be considered. Magnesium, lidocaine, and bretylium are not recommended in the treatment of shock-resistant ventricular fibrillation. SUMMARY: Biphasic defibrillation and intravenous amiodarone are useful in shock-resistant ventricular fibrillation.

Adrenergic beta-Antagonists↗

Local anaesthetic effect of antiarrhythmic drugs and human sperm immobilization: mechanism and application of the interrelationship.

Sperm immobilizing activity of three class I antiarrhythmic drugs, quinidine, procainamide, mexiletine, one adrenoceptor blocking drug, labetalol and one calcium channel blocking drug, diltiazem was measured with a trans-membrane migration method. All these drugs immobilized human sperm. Local anaesthetic effect is the underlying mechanism for these drugs to inhibit sperm motility. Sperm immobilization could be a screening test for the local anaesthetic effect of antiarrhythmic drugs.

Anesthetics, Local↗

Acetylcholinesterase in Dendrobaena veneta (Oligochaeta: Opisthopora) is present with forms sensitive and insensitive to phosphatidylinositol phospholipase C. Biochemical characterization and histochemical localization in the nervous system.

Three distinct acetylcholinesterases were detected in the annelid oligochaete Dendrobaena veneta. Two enzymes (alpha, beta), copurified from a Triton-X-100-soluble extract of whole animals by affinity (edrophonium-Sepharose) chromatography, were separately eluted from a Sephadex G-200 column. Gel-filtration chromatography, sedimentation analysis and SDS/PAGE showed the alpha and beta forms to be a globular dimer (110 kDa, 7.0 S) and a hydrophilic monomer (58 kDa, 5.0 S) respectively, both weakly linked to the cell membrane. The third form (gamma), also purified to homogeneity by slower filtration through an edrophonium-Sepharose matrix, proved to be an amphiphilic globular dimer (133 kDa, 7.0 S) with a phosphatidylinositol anchor giving cell membrane insertion, detergent (Triton X-100, Brij 96) interaction and self-aggregation. The alpha acetylcholinesterase showed a fairly low substrate specificity: the beta form hydrolyzed propionylthiocholine at the highest rate and was inactive on butyrylthiocholine; the gamma acetylcholinesterase, showing a marked active-site specificity with differently sized substrates, was likely functional in cholinergic synapses. Studies with inhibitors showed incomplete inhibition of all three acetylcholinesterase by 1 mM eserine and different sensitivity for edrophonium or procainamide. The alpha and beta forms, sensitive to 1,5-bis(4-allyldimethylammoniumphenyl)-pentan-3-one dibromide, were unaffected by tetra(monoisopropyl)-pyrophosphortetramide, while both these agents inhibited the gamma enzyme. All three forms showed excess-substrate inhibition by acetylthiocholine. Enzyme activity was histochemically localized in the nerve ring and its minor branches. Monomeric acetylcholinesterase (beta) is likely the only form present in the ganglionic glial framework.

Acetylcholinesterase↗

Differential blockade of octopamine and dopamine receptors by analogues of clozapine and metoclopramide.

1. Sulpiride, but not procainamide, antagonizes the excitatory effects of (+/-)-octopamine receptors in the Tapes ventricle. Neither compound attenuates dopamine excitation. 2. Clozapine will attenuate the effects of (+/-)-octopamine and (-)-alpha-methyl octopamine at the octopamine receptor but not the excitatory effect of dopamine at dopamine receptors. 3. Clozapine is more potent than its 2-positional isomer HF 2046 in attenuating octopamine excitation. However, HF 2046, unlike clozapine, will attenuate the excitatory effects of dopamine. 4. These data indicate that replacement of the 8-chloro substituent in the clozapine nucleus with a 2-chloro substituent decreases the ability of the compound to blockaed octopamine receptors. However, the 2-chloro-substituted compound (HF 2046) now has the added ability to blockade excitatory dopamine receptors. 5. The greater potency of clozapine than HF 2046 as an octopamine antagonist suggests that it is the 8-chloro-substituted aromatic ring of clozapine which overlaps the aromatic site usually occupied by the octopamine aromatic ring.

Animals↗

A comparison of tests for antifibrillatory action.

THE OBJECT OF THE EXPERIMENTS WAS TWOFOLD: first, to choose the most satisfactory test for antifibrillatory action; secondly, to place several drugs with reputed antifibrillatory activity in an order of potency as a preliminary to investigating their mode of action. Measurements were made on isolated rabbit atria at 34 degrees C of (1) the maximum driving frequency the atria would follow, (2) conduction velocity, (3) contractions, and of the threshold for the production of (4) extrasystoles, (5) flutter and (6) fibrillation. Log dose-response curves were plotted for quinidine, papaverine, procaine, dibenamine and procaine amide. The maximum frequency test and fibrillation threshold test gave similar results with all the drugs, and the results gave the order quinidine 1.0, procaine 0.53, Dibenamine 0.47, papaverine 0.43 and procainamide 0.26. Thresholds for extrasystoles and flutter were much more variable. The regressions relating changes in conduction velocity and contraction to log dose were different from those for maximum driving frequency and fibrillation threshold for procaine, papaverine and dibenamine, but the regressions for quinidine and procaine amide were nearly parallel in all tests. Serpajmaline contained a substance with antifibrillatory activity as great as that of quinidine and with no greater depressant action on contractions.

Animals↗

An unusual mechanism of initiation of circus movement tachycardia in a patient with concealed Wolff-Parkinson-White syndrome.

Infranodal conduction delay is an uncommon mechanism of initiation of circus movement tachycardia in the Wolff-Parkinson-White syndrome. A patient with a concealed left free wall atrioventricular accessory pathway who underwent electrophysiological study is presented. During atrial extrastimulus testing, a pattern of alternating bundle branch block was observed and was most marked after the administration of intravenous procainamide. Conversion from right bundle branch block to left bundle branch block was reproducibly associated with the initiation of circus movement tachycardia utilizing the normal conducting system antegradely and the accessory pathway retrogradely. Initiation of tachycardia was critically related to the increase in the HV interval associated with left bundle branch block. Of interest, conduction in the right bundle branch became progressively slower as the prematurity of the atrial extrastimulus increased, whereas conduction time through the left bundle branch remained fixed prior to block. Implications of these findings are discussed. To our knowledge, this is the first report of alternating bundle branch block during atrial extrastimulus testing as a mode of initiation of circus movement tachycardia in the Wolff-Parkinson-White syndrome.

Adult↗

Suppression of incessant ventricular tachycardia in hypertrophic cardiomyopathy associated with improvement of severe left ventricular dysfunction.

A 32-year-old black man presented with a history of palpitations since childhood and two syncopal episodes. He was found to have incessant ventricular tachycardia, impaired left ventricular contraction (ejection fraction 9%), and nonobstructive hypertrophic cardiomyopathy. Procainamide abolished the arrhythmia and the ejection fraction rose to 22% in sinus rhythm. Later treatment was switched to amiodarone, which suppressed the ventricular tachycardia but necessitated pacemaker implantation. He has remained well during the subsequent 2 years. Left ventricular ejection fraction has increased to 47% measured in paced rhythm. The improvement in left ventricular function has been attributed to suppression of the incessant ventricular tachycardia.

Adult↗

Efficacy of type 1C antiarrhythmic agents for treatment of resistant atrial fibrillation.

In order to determine the efficacy of type 1C agents (flecainide, encainide, propafenone) in patients with atrial fibrillation who have failed to maintain sinus rhythm with type 1A agents (quinidine, procainamide, disopyramide), 147 patients, that were admitted into the John Dempsey Hospital with new or recurrent atrial fibrillation between 1987-1991, were studied retrospectively. Out of the total, 29 patients converted spontaneously to sinus rhythm, 14 patients were left in atrial fibrillation, and 104 patients were given a type 1A antiarrhythmic. Sixty-five of these patients remained in sinus rhythm (54% converted on drug alone, 46% required electrical cardioversion) for at least 6 months. Of the remaining 39 patients, 28 were given a type 1C antiarrhythmic; 13 were successfully converted (61% chemical, 39% electrical) to and remained in sinus rhythm for at least 6 months; the remaining 15 either failed to convert or reverted to atrial fibrillation. New onset atrial fibrillation had a significantly lower incidence of congestive heart failure (10%) than recurrent atrial fibrillation (33%; P < 0.01). No differences in digoxin, beta blocker use, or other clinical characteristics were seen either between type 1A or type 1C successes or failures. Similarly, echocardiographic dimensions did not predict success or failure with either class of agent. In conclusion, type 1C antiarrhythmics for suppression of recurrent atrial fibrillation represent a reasonable therapeutic alternative for suppression of atrial fibrillation in patients who have failed type 1A agents. Prognostic factors predicting success or failure remain undetermined.

Aged↗

Combined transesophageal left atrial pacing and antiarrhythmic therapy in the treatment of atrial flutter.

In order to terminate atrial flutter (AF) overdrive transesophageal left atrial pacing (TELAP) was performed in 760 patients with paroxysmal AF. There were 315 women and 415 men (mean age 59 years). In 260 patients, TELAP was used in an outpatient setting. Approximately half of the patients (51%) had coronary artery disease and/or arterial hypertension, and 23% of the patients had no structural heart disease. The duration of AF ranged between 1 hour and 1 month. TELAP was performed in 312 patients without any antiarrhythmic drug (AAD) administration (group I) and in 448 patients after administration of AAD (procainamide and/or amiodarone) in conventional doses (group II). TELAP resulted in immediate return of sinus rhythm in 85 patients (27%) of group I and in 222 patients (50%) of group II (P < 0.001). TELAP converted AF to atrial fibrillation (AFIB) in 185 of group I and in 214 (48%) of the group II patients (P < 0.01). In addition, within 1-2 days after TELAP AFIB converted to sinus rhythm spontaneously or after AAD in 87 patients of group I (28%) and in 84 (19%) of the group II patients (P < 0.01). In general sinus rhythm was restored in 172 (55%) of the group I and in 306 (68%) of the group II patients (P < 0.005). AF was converted to AFIB in 98 (31%) of the group I and in 130 (29%) of the patients in group II patients (NS). TELAP was ineffective in 42 (13.5%) of the group I and in 12 (3%) of the group II patients (P < 0.001). TELAP was an effective noninvasive method for the treatment of recent onset AF. Our experience showed that after TELAP, sinus rhythm was restored in most of the patients with paroxysmal AF within 1-2 days. In some patients TELAP converted AF to AFIB, making it easier to control the heart rate with AAD. Treatment with AAD before TELAP increased its effectiveness.

Ambulatory Care↗

Supernormality with cycle length-dependent intra-His alternans: a new cause of group beating.

This article describes a patient with baseline infranodal conduction disease. Following the administration of intravenous procainamide, the patient developed group beating. Careful electrophysiological evaluation revealed that the group beating was due to alternating intra-His conduction times. Systematic analysis of paced and spontaneous events provides strong evidence that the alternans results from supernormality within the His bundle.

Anti-Arrhythmia Agents↗

The use of the block cycle length as a safe and efficient means of interrupting sustained ventricular tachycardia and its pharmacological modification.

In nine patients who had inducible monomorphic sustained ventricular tachycardia (VT), rapid pacing was performed in 11 episodes of morphologically distinct VT at progressively shorter cycle lengths and VT was interrupted at a critical cycle length. The VT interrupting critical cycle length was defined as the block cycle length (BCL) and the effect of Class I antiarrhythmic drugs were examined. Both the VT cycle length (VTCL) and the BCL were prolonged after administration of either drug. The overall mean ratio of the BCL to the VTCL was unchanged after procainamide administration, but increased after the use of mexiletine. The ratio, however, varied in individual VTs and the BCL after treatment with Class I antiarrhythmic drugs could not be predicted from the ratio baseline value, although the ratio was always > 60% and the hazard of VT acceleration might be avoided if the BCL is used.

Administration, Oral↗

Atrial ejection force in patients with atrial fibrillation: comparison between DC shock and pharmacological cardioversion.

It is well known that the restoration of sinus rhythm is not always associated with the return of effective atrial contraction. Atrial ejection force (AEF) is a noninvasive Doppler derived parameter that measures the strength of the atrial contraction. The aim of the present study was to use pulsed-Doppler echocardiography to determine if different modalities of cardioversion influence the delay in the return of effective atrial contraction after cardioversion. DC shock and pharmacological therapy were compared. Sixty-eight patients were randomly cardioverted, either using DC shock or i.v. procainamide. The patients who were restored to a sinus rhythm had a complete Doppler echocardiographic examination within 1 hour after the restoration, after 24 hours, after 1 month, and after 3 months. AEF was measured and compared in the two groups of patients and within the same group. AEF was greater immediately and at 24 hours after cardioversion in patients who underwent pharmacological therapy compared to patients treated with DC shock (peak A wave, 60 +/- 9 vs 31 +/- 8 msec, P < 0.001; AEF 11.3 +/- 3 vs 5 +/- 2.9 dynes, P < 0.001). In both groups, AEF increases over time. In conclusion, AEF is a noninvasive parameter that can be easily measured after cardioversion and can give accurate information about the recovery of left atrial mechanical function. This finding may have important implications for guiding the anticoagulant therapy after cardioversion.

Anti-Arrhythmia Agents↗

Adenosine induced atrial fibrillation precipitating polymorphic ventricular tachycardia.

An 86-year-old female developed supraventricular tachycardia 36 hours after a myocardial infarction (MI). She developed atrial fibrillation and polymorphic ventricular tachycardia (PVT) following administration of 12 mg of adenosine. The PVT caused hemodynamic instability with no response to cardioversion, but termination with procainamide. The heart is vulnerable to hemodynamically unstable, possibly lethal, PVT early after MI under some circumstances. This vulnerability may be exposed following administration of adenosine. Extra caution is warranted when using adenosine in the post-MI period.

Adenosine↗

Association of drug therapy with survival in cardiac arrest: limited role of advanced cardiac life support drugs.

OBJECTIVE: To generate hypotheses regarding the association of standard Advanced Cardiac Life Support (ACLS) drugs with human cardiac arrest survival. METHODS: This observational cohort study was conducted over a two-year period in the wards, intensive care units, and EDs of two tertiary care hospitals. Included werc adult patients who suffered cardiac arrest either inside or outside the hospital and who required epinephrine according to standard ACLS guidelines. Six standard ACLS drugs (given while CPR was in progress) were assessed for association with survival from resuscitation to one hour and to hospital discharge by univariate and multivariate logistic regression analyses. RESULTS: In the 529 patients studied, initial cardiac rhythm had no impact on the association between drug administration and survival. The time of drug administration (quartile of ACLS period) was associated with resuscitation for atropine (p < 0.05) and lidocaine (p < 0.01). The odds ratios (95% CIs) for successful resuscitation, after multivariate adjustment for potential confounders, were: a respiratory initiating cause, 3.7 (2.1 -6.4); each 5-minute increase in CPR-ACLS interval, 0.5 (0.4-0.7); each 5-minute duration of ACLS. 0.9 (()1.8- 1.0; atropine, 1.2 (1.0-1.3); bretylium. (0.4 (0.1-1.1); calcium 0.8 (0.2-2.4); lidocaine, 0.9 (0.7-1.1); procainamide. 21.0 (5.2-84.0) d sodium bicarbonate 1.2 (1.0-1.6). All other potential confounding variables entered into the model were not significantly associated with resuscitation. CONCLUSION: Initiating cause of arrest, time to ACLS, and duration of ACLS were important correlates of survival. Other than procainaimide, standard ACLS drugs had relatively little association with survival, but timing of administration may be an important factor. Further research using definitive large randomized controlled trials is warranted to assess the role of drug therapy in improving cardiac arrest survival.

Adult↗

Metabolites of cardiac antiarrhythmic drugs: their clinical role.

Most antiarrhythmic drugs are extensively metabolized, and the accumulation of the metabolites of several of these drugs has been documented. In some cases, the steady-state plasma concentrations of metabolites are considerably greater than is the concentration of the parent drug. Several of these metabolites have been evaluated in animal models for antiarrhythmic activity and their potencies have been defined relative to the activity of their parent compound. Evaluations of activity are generally conducted in animal arrhythmia models, and very few metabolites of antiarrhythmic drugs have been evaluated directly in patients. However, from knowledge of antiarrhythmic activity in animals and the degree to which a metabolite accumulates in the plasma of patients, one can make qualitative judgments about its therapeutic role. Such judgments, however, need to be recognized as tenuous. Quantitative judgments require further information regarding the relationship between the parent drug and metabolite when present simultaneously in the myocardium. One must consider whether the effects of the parent drug and metabolite are additive, synergistic, or even antagonistic. The latter case is most possible with drug-metabolite pairs where the metabolite accumulates substantially, but does not have significant antiarrhythmic potency. Other considerations include noncardiac effects of the metabolites. As in the case of the mono-desethyl metabolite of lidocaine, the significance of its accumulation relates more to central nervous system side effects than to direct cardiac actions. The role of active metabolites also much be considered in regard to differences in the disposition kinetics between the parent drug and metabolite. The most obvious situation where this is important is in designing clinical drug evaluation protocols. As illustrated by the metabolites of encainide and lorcainide, the time course of accumulation and disappearance of the metabolites may be much longer than that of the parent drug. Clinical evaluations at steady state must take into account the time required to achieve steady-state concentrations of the metabolites as well. Similarly, after discontinuation of drug administration, the time required before washout is complete may be totally dependent on the kinetics of the metabolite, and not the parent drug. Variability in metabolic activity also needs to be considered. It has been shown with procainamide and encainide that genetic factors can influence the rate of production of active metabolites and consequently influence the clinical efficacy of these drugs. Another consideration that deserves attention is the question of drug interactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Amiodarone↗

Rapid assessment of rate and antiarrhythmic drug effect on the myocardium using asymmetric biphasic pulse stimulation.

An asymmetric biphasic pulse which stimulates the heart and neutralizes the poststimulation polarization at the electrode-myocardial interface permitting the recording of the evoked endocardial response (EER) up to approximately 1 ms poststimulation with the same electrode used for stimulation is described. Using this mode of cardiac stimulation in 20 dogs the effects on the EER of increasing heart rate and antiarrhythmic drugs, procainamide (PA) and N-acetylprocainamide (NAPA), were studied. EERs were recorded during bipolar and unipolar pacing rates of 120, 150, and 200/min before and during a five step PA or NAPA infusion which resulted in progressively increasing PA and NAPA plasma concentrations (Cps), 1.7-32.5 mg/l for PA and 8.1-116.1 mg/l for NAPA. The effects of progressively increasing heart rates were: The T wave amplitude and QS area increased with increases in rate; during pacing at 120, 150, and 200/min, the T wave amplitudes were 7.6 +/- 2.3, 8.2 +/- 2.1, and 9.8 +/- 2.5 mV and the QS areas were 905 +/- 204, 995 +/- 199, and 1101 +/- 231 mVms. The QT interval and QST area decreased with increases in rate; during pacing at 120, 150, and 200/min, the QT intervals were 265 +/- 61, 249 +/- 57, and 226 +/- 52 ms and the QST areas were 288 +/- 198, 221 +/- 154, and 154 +/- 52 mVms. The effects of the antiarrhythmic drugs, PA and NAPA, on the EER were: PA prolonged both the QS duration and QT interval at low Cp (type Ia antiarrhythmic drug property); at a therapeutic PA Cp of 15.0 +/- 0.2 mg/l and a heart rate of 120/min the percent increase of the QS duration was 12 +/- 4% (P = 0.001) and that of the QT interval was 20 +/- 6% (P less than 0.001). The prolongation of the QS duration by PA was rate dependent, the faster the rate the greater the prolongation. NAPA prolonged the QT interval at low Cp, while the QS duration was not significantly effected at low or therapeutic Cps (type III antiarrhythmic drug property); at a therapeutic NAPA Cp of 15.9 +/- 1.6 mg/l and a heart rate of 120/min the percent increase of the QS duration was 1 +/- 1% (NS) and that of the QT interval was 13 +/- 9% (P = 0.018). Our results show that the use of an asymmetric biphasic pulse allows for pacing and recording of an EER, QS and T waves, with a single electrode.(ABSTRACT TRUNCATED AT 400 WORDS)

Acecainide↗