The Use of Amiodarone in Children

Our use of amiodarone in 200 patients during an 8-year period confirms our previous experience which indicated that the drug was close lo being the ideal antiarrhythmic agent in children's arrhythmias. Its absence of cardiac toxicily, its powerful antiarrhythmic properties, its depressive effect on the AVnodal conduction, combined with its beta-inhibitory effect makes it effective and harmless in practically all forms of alrial, junctional and ventricular arrhythmias, whatever the reentrant or automatic mechanism of the arrhythmia. The metabolism is much faster in children than in adults, making the drug active in a few hours, with a lesser prolonged duration of act ion. Though there is practically no limitation forits use on a short- or mean-term basis, the long-term use must be limited to truly refractory arrhythmias, a situation which is rarely encountered, In such cases, combining amiodarone with conventional therapy allows a decrease in the maintenance dosage and a lower incidence of extracardiac side effects.     

Amiodaron effects on atrioventricular conduction

AIM: To assess short- and long-term effects of amiodaron on atrioventricular conduction (AVC) of the heart. MATERIAL AND METHODS: Amiodaron was given to 477 patients (mean age 48.7 +/- 0.7 years) with various arrhythmias caused, as a rule by coronary heart disease. A mean saturation dose was 809.4 +/- 13.4 mg/day, a mean maintanence dose--263.5 +/- 5.4 mg/day. Mean follow-up 20.85 +/- 1.2 months. The frequency of AVC disorders was estimated at regular Holter monitoring. RESULTS: In saturation, atrioventricular block of the first degree arose in 17.2% patients, of the second and third degree--only in one patient. AVC disorders disappeared at reduction of amiodaron dose. Only in one patient the drug was discontinued because of recurrent block of the third degree and bradycardia. CONCLUSION: In saturation, ECG records lengthening of P-R intervals by 18.9%, on the average. Maintenance therapy increases the length of P-R interval by 8.1%, on the average.     

Pericardial effusion in patients with schizophrenia: are they on clozapine?

Clozapine is used in the treatment of resistant schizophrenia. It is used as a reserve drug mainly because of its adverse effect profile affecting gastrointestinal, haematological and cardiorespiratory systems. Cardiac side effects are uncommon but could be potentially life threatening, hence early recognition and active monitoring are essential to prevent serious cardiac side effects. A case of pericarditis with pericardial effusion is described in a patient who was recently started on clozapine which disappeared within 1 week after discontinuation of clozapine.     

Microporous membrane drug delivery system for indomethacin.

Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of rheumatoid arthritis for more than a decade. The high incidence and severity of side effects, which are dose-related and associated with long-term administration, have limited its use. This has led to the search for new delivery systems which can overcome the side effects by controlling the drug release. In this study, Indomethacin Extended Release Formulation was developed by pelletization using the method of extrusion/spheronization. The drug containing pellets were further coated to achieve the required release profile as per USP. Coating systems developed on the principle of microporous membrane drug delivery using soluble salt gave the best results.     

Intraspinal drug therapy

Intraspinal drug delivery provides agents directly to their site of action. These sites, receptors within the spinal cord, are bound to a greater degree when drugs are administered intraspinally. The purpose for drug therapy, the acute or chronic nature of delivery, and the drug administration system affect the choice of epidural versus intrathecal route of delivery. Pharmacologic properties, such as solubility, pH, and pKa, aid in dictating the drug chosen for administration. Intraspinal opiates and anesthetics have been used extensively since the 1970s in postoperative, postpartum, and cancer populations. Various delivery systems are in use, including external catheters and implanted ports and pumps. Nursing care includes titration of doses, prevention and management of side effects, and maintenance of delivery systems. Intrathecal baclofen is a new treatment for severe spasticity for patients with multiple sclerosis or spinal cord injury. Candidates include patients who experience persistent spasticity unrelieved by antispasmodics or who experience unacceptable side effects to those oral drugs. Nurses assess spasticity, titrate the intrathecal baclofen to obtain an acceptable degree of spasticity, and manage side effects associated with intrathecal baclofen. A long-term benefit of intraspinal drug delivery, potentially providing benefit to many patients, is the identification of experimental agents that do not cross the blood-brain barrier but prove effective when delivered intraspinally. Pharmacologists and others then might undertake the costly modifications necessary to improve the solubility of the drug. The analogue then might be given orally. "The feasibility of an operation is not an indication for its performance." These words, attributed to the late Lord Cohen, also apply to intraspinal drug delivery. As with any therapy, the simplest and least invasive course should be taken. If, for example, the patient experiences good relief without side effects when given oral opiates or baclofen, there is no good rationale for inserting an intraspinal catheter. The potential for increased morbidity and the escalated expense make this an illogical choice. There are, however, many patients who cannot tolerate oral opiates or baclofen but obtain significant benefit from intraspinal drug delivery. Those who benefit should not be denied this therapy. Much research is necessary as this modality develops. Nurses who comprehend the science of intraspinal drug delivery, as well as the art of patient management, can contribute to this advancing field.     

The role of Ca++-sensitizers for the treatment of heart failure

For increasing myocardial contractility in patients with cardiac failure, catecholamines, phosphodiesterase-III (PDE) inhibitors, and calcium sensitizers are available. Improving myocardial performance with catecholamines and PDE inhibitors leads to increased intracellular calcium concentration as an unavoidable side effect. An increase in intracellular calcium can induce harmful arrhythmias and increases the energetic demands of the myocardium. Long-term trials with PDE inhibitors have raised concerns about the safety of positive inotropic treatment for cardiac failure. Calcium sensitizers are a new class of inotropic drugs. They improve myocardial performance by directly acting on contractile proteins without increasing intracellular calcium load. Thus, they avoid the undesired effects of an increased intracellular calcium load. Calcium sensitizers may enhance myocardial performance without increasing myocardial oxygen consumption and without provoking fatal arrhythmias. Two calcium sensitizers are available for the treatment of cardiac failure in men. Pimobendan is a drug with positive inotropic effects that additionally inhibits the production of proinflammatory cytokines. However, it exerts a significant inhibition of PDE at clinically relevant doses. Levosimendan is a calcium sensitizer with no major inhibition of PDE at clinically relevant doses. It opens ATP-dependent potassium channels and thus has vasodilating and cardioprotective effects. The most important studies of the long-term treatment of stable cardiac failure with pimobendan and on the short-term treatment of unstable cardiac failure with levosimendan are presented.     

AF-DX 116, a cardioselective muscarinic antagonist in humans: pharmacodynamic and pharmacokinetic properties

Effects of AF-DX 116, a cardioselective antagonist, on M cholinergic receptors (M-ChR) were studied in healthy volunteers. Occupancy of M-ChR subtypes by drug present in plasma samples (radioreceptor assay) was compared with these effects. After an intravenous dose of AF-DX 116 saturating greater than 90% of cardiac M2-ChR, an increase in heart rate by 25 beats/min was observed. This cardiac receptor occupancy and effect wore off with a parallel time course within 10 hours. No inhibition of salivary flow was observed, coinciding with a lack of M3-ChR blockade in the radioreceptor assay. Beta-adrenergic receptor blockade by propranolol did not affect either of the effects. No indication for active metabolites or stereoselective drug metabolism was found comparing HPLC and receptor assay for drug concentrations in plasma. We conclude that AF-DX 116 may be a useful drug for the treatment of bradycardia. Its lack of troublesome side effects is the result of its selectivity for cardiac M-ChR.     

Amitriptyline treatment of agitation associated with anoxic encephalopathy

A 43-year-old man exhibited agitation and nondirected aggression related to anoxic encephalopathy after a myocardial infarction. These symptoms abated upon treatment with amitriptyline, only to return upon its inadvertent discontinuation. The drug was well tolerated, in contrast to neuroleptics, which are frequently associated with serious side effects in this population. Although further experience is needed, amitriptyline may be an effective treatment option in agitation associated with anoxic encephalopathy.     

Safety of long-term therapy with a combination of various anti-arrhythmia agents

Safety and the effectiveness of combined therapy of arrhythmia was studied in 27 patients in prolonged (up to 4 months) administration of a combination of medicinal agents specially chosen during pharmacodynamic investigation. The obtained anti-arrhythmic effect was stable and there were no new side effects in prolonged administration of combinations of ethmozine with chinidin, ritmilen, obsidan, cordaron (amiodaron) and of allapinin with chinidin, ritmilen (disopyramide) and obsidan (propronalol). Tolerance to drugs was adequate and the ECG parameters remained unaffected.     

Rationale for an oral thrombin inhibitor from a pharmacological point of view

Direct thrombin inhibitors are in focus of interest for hereditary or acquired thrombophilic indications. Besides thrombosis prophylaxis in surgery, life-threatening cardiac diseases and stroke are of special interest for this new drug class. For long-term prophylaxis of genetically caused thrombophilia the only drug class currently available are the orally active dicoumarol derivatives. Their application is a time and cost intensive procedure and associated with side effects, too. Active site-directed inhibitors block the catalytic triad of the active centre of thrombin responsible for hydrolytic cleavage. Inhibitor ratios (K(j)) are in the nanomolar or picomolar range. As these substances are eliminated via liver or kidneys with an elimination half-life of 0.3-2 hours, parenteral administration should be used for acute therapy and prophylaxis. For long-term prophylaxis, orally absorbable derivatives of these direct thrombin inhibitors are available with absorption rates of 10-30%. They are converted into their parent substance in blood. Therapeutical range is relatively large so that an oral long-term prophylaxis using standard dose is possible without monitoring. The first representative of this new drug class, Ximelagatran, an orally absorbable variant of Melagatran, is currently undergoing phase III trials for different indications. Using oral administration of two partial doses per day, a good compliance is expected.     

Guanabenz and methyldopa on hypertension and cardiac performance.

In previous placebo-controlled studies, guanabenz was shown to be a safe and effective antihypertensive drug without acute effects on cardiac function. In view of its therapeutic advantages, a double-blind comparison of guanabenz with methyldopa was performed in a group of 36 patients over 6 mo. Both drugs produced statistically and clinically significant decreases in blood pressure with similar side effects. No laboratory or electrocardiographic abnormalities were found other than positive Coombs' tests which developed in 3 patients during methyldopa therapy. Cardiac performance in 26 of the patients, as measured by noninvasive techniques, showed no significant changes from either drug except for a progressive and statistically significant increase in systolic time interval (QS2) and the ratio of the pre-ejection period to left ventricular ejection time (PEP/LVET) during methyldopa therapy. For an additional 6 mo, continued efficacy and safety were shown under open conditions in those patients who had received guanabenz. The study suggests that guanabenz may be an important new antihypertensive drug because of effectiveness, absence of adverse cardiac effects, and paucity of side effects.     

Photodynamic therapy

Photodynamic therapy (PDT) is a photochemical process that uses?a photosensitizer drug activated by laser light to produce mucosal ablation. Porfimer sodium PDT has proved long-term efficacy and durability in the treatment of Barrett's esophagus and high-grade dysplasia and early esophageal adenocarcinoma. Its use has been limited by serious side effects including prolonged cutaneous photosensitivity and stricture formation. Other photosensitizers with a better safety profile have been used mostly in Europe with limited experience. The future of PDT lies on a better understanding of dosimetry, tissue properties, and host genetic factors.     

Opioids in the treatment of chronic pain: legal framework and therapeutic indications and limitations

The most important message that physicians must communicate to persons with chronic pain is that, currently, no medication exists that will take away more than 30% of the pain they experience. Chronic pain is a chronic disease and, like diabetes or hypertension, requires chronic concessions and lifestyle modifications. In controlled trials of short duration and small sample size with highly selected patients, patients sustaining moderate-to-severe pain still experience moderate pain even on opioid medication. Adverse drug effects are predictable and common, and, in fact, long-term compliance with opioids is low owing to side effects. Screening for substance abuse by history taking, observing behavior, obtaining old medical records,and using UDS in patients before initiating opioid therapy is important to identify patients with comorbid addictive disease who require coincident or antecedent treatment. Familiarity with federal and state controlled substance legislation and state health care provider and pain treatment acts is a mundane but essential educational endeavor for all physicians prescribing opioids. If physicians educate their patients with chronic pain about the limited efficacy of the medications, patients' expectations for drug treatment can be more realistic.     

Similia similibus obscurantur: the pharmacological clinical activity bias I. A prototype model to correct a disease-drug interaction leading to misestimations of drug-attributable side effects

Summary— Drugs have side effects that manifest as signs or symptoms which are sometimes undistinguishable from signs or symptoms of active disease. The conventional approximation of the rate of side effects of drugs is by subtracting the rate of signs and symptoms in the placebo group from that in the drug group. This measures net side effects and is adequate in studies with healthy volunteers, in which no interaction between drug and disease exists. For ethical and practical reasons, however, volunteer studies cannot be large and the frequency of non-rare side effects must be estimated in large-scale clinical trials. In the latter, biasing drug disease interactions may occur. We report on such a hitherto undescribed interaction: the pharmacological clinical activity bias. If one is interested in estimating not the net, but the direct or intrinsic, ie, drug-attributable side effects, the conventional approximation is biased whenever, in clinical trials, both of two conditions apply. The first is that the variable on the scale of which a sign or symptom is recorded as a putative side effect, is also in the absence of drug affected by uncontrolled disease. The second is that the drug has pharmacological clinical activity (A) on that sign or symptom, thus reducing the contribution of disease (D) to what is measured. In this case the drug affects the variable under study both directly, through its intrinsic side effect, and indirectly, through its clinical activity, and the rate of attributable side effects differs from the rate of net side effects as calculated by the conventional approximation. We present a simple deterministic model, which assumes that disease remains stable if untreated, additivity of the relative contributions of drug, placebo and disease to the total rate of the sign or symptom, and no other interaction between intrinsic properties of the drug and active disease than pharmacological clinical activity. This theoretical model quantifies the bias as D₀(A_d - A_p), in which D₀ is the baseline frequency of the sign or symptom in the studied patients, and A_d and A_p are the intrinsic clinical activities of drug and placebo, respectively, on the sign or symptom under study. The model confirms that the conventional approximation of drug side effects is unbiased only in healthy volunteers or with drugs devoid of clinical activity. Without correction by such a model, any clinical activity of the drug or manifestation of active disease will cause the conventional approximation of side effects to be biased. This may manifest as artifacts such as attribution of a side effect when there is none, and as under- or overestimation, pseudo- tachyphylaxis, or pseudo-delayedness of attributable side effects.     

Fluoxetine: prescribing guidelines for the newest antidepressant

Fluoxetine is an antidepressant drug with a unique chemical configuration which enhances serotoninergic transmission by inhibiting serotonin uptake. The chronic presence of serotonin in the synaptic cleft reduces postsynaptic receptors, a postulated explanation for its antidepressant efficacy. Comparative studies show that the therapeutic effectiveness of fluoxetine is equal to that of imipramine, amitriptyline, and doxepin. A 20 mg morning dose alleviates most depressions. The long half-life of one to three days for the parent compound and seven to 15 days for the active metabolite, desmethylfluoxetine, is largely unaffected by age or renal impairment. Nausea, nervousness, insomnia, and headache are the most common side effects. Therapeutic doses do not affect cardiac conduction or cause orthostasis. A primary benefit of this drug is its significant relative safety in overdoses as compared to other antidepressants.     

Sildenafil for primary and secondary pulmonary hypertension

BACKGROUND: Sildenafil is a selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, an enzyme that is abundant in both lung and penile tissues. Sildenafil is widely used to dilate penile arteries, suggesting that it may also dilate pulmonary arteries in patients with pulmonary hypertension. However, the long-term hemodynamic effects and safety of the drug in pulmonary hypertension are not known. METHODS: One patient with primary pulmonary hypertension and another with secondary pulmonary hypertension caused by collagen disease were given 50 mg oral sildenafil during cardiac catheterization for assessment of the acute hemodynamic effects of the drug. The patients were then given maintenance treatment with 25 mg oral sildenafil twice a day. Long-term hemodynamic effects were evaluated by repeated cardiac catheterization after 3 months, with the last oral dose given 15 hours before the procedure. The acute hemodynamic effects of sildenafil after the long-term treatment were studied during the same cardiac catheterization. RESULTS: Sildenafil did not affect aortic pressure, but it significantly decreased pulmonary artery pressure and increased cardiac index, thereby reducing pulmonary vascular resistance. Long-term maintenance therapy with 25 mg oral sildenafil twice a day remarkably improved the clinical condition of the patients, without causing any adverse effects; New York Heart Association functional classification returned to class II (from class III). The acute efficacy of sildenafil was well preserved after the long-term treatment; there was no tolerance. CONCLUSIONS: The data strongly suggest that sildenafil can be used as a valuable pulmonary vasodilator in patients with pulmonary hypertension, with good long-term hemodynamic effects and safety. The results necessitate larger trials to confirm these observations in a larger cohort of patients.     

Antiarrhythmic drugs for atrial fibrillation: focus on dronedarone

Patients with atrial fibrillation have an increased risk of stroke and heart failure, as well as impairment of their quality of life. Most trials have primarily focused on the prevention of stroke and heart failure, and the improvement of symptoms in these patients. More recently, a rate-control strategy has been reported to be a noninferior strategy compared with a rhythm-control strategy in atrial fibrillation patients. Many different classes of antiarrhythmic drugs have been used for rhythm control, with inconsistent results and adverse effects on mortality and morbidity. Of the available antiarrhythmic drugs, amiodarone is the single most effective drug in the prevention of atrial fibrillation recurrences and maintaining sinus rhythm; however, it is vastly limited by its various systemic side effects, especially those observed with long-term use. However, recent trial data from a new antiarrhythmic agent, dronedarone, suggest that this drug may be a safe alternative to amiodarone; however, its long-term efficacy and safety still require exploration.     

The Electrophysiologic Basis for the Use of Amiodarone for Treatment of Cardiac Arrhythmias

The electrophysioiogic basis for the use of amiodarone in the treatment of cardiac arrhythmias is outlined, with reference to studies in isolated cardiac tissues, whole animal, and human studies. Amiodarone appears fo have the distinctive property of directly prolonging action potential duration (and hence refractory periods) in nearly all cardiac tissues. Independenf of ifs effects on refrac-toryperiods, conduction may also be impaired in the His-Purkinje system, possibly due to depression of phase of the action potential. Sinus node and atrial automaticity, as well as that arising from diseased Purkinje fibers, may be depressed, Normal ventricular escape pacemakers appearrelatively unaffected, however. A nonspecific anti-andrenergic action may contribute to its observed effects. These electrophysiological effects are more obvious and predictable after several weeks of oral treatment than after intravenous administration, suggesting a time-dependent mechanism of action. The drug appears well suited to the prevention of enhanced automaficity in the ventricle and reentry throughout the heart. and its frequent clinical success in a broad spectrum of cardiac arrhythmias attests lo this. Unwanted side effects include sinus node depression, His-Purkinje conduction delay or block, and ventricular arrhythmias enhanced by QT prolongation. However, the frequency of clinically significant examples of unwanted arrhythmic effects appears to be acceptably low.     

The electrophysiologic basis for the use of amiodarone for treatment of cardiac arrhythmias

The electrophysiologic basis for the use of amiodarone in the treatment of cardiac arrhythmias is outlined, with reference to studies in isolated cardiac tissues, whole animal, and human studies. Amiodarone appears to have the distinctive property of directly prolonging action potential duration (and hence refractory periods) in nearly all cardiac tissues. Independent of its effects on refractory periods, conduction may also be impaired in the His-Purkinje system, possibly due to depression of phase 0 of the action potential. Sinus node and atrial automaticity, as well as that arising from diseased Purkinje fibers, may be depressed. Normal ventricular escape pacemakers appear relatively unaffected, however. A nonspecific anti-adrenergic action may contribute to its observed effects. These electrophysiological effects are more obvious and predictable after several weeks of oral treatment than after intravenous administration, suggesting a time-dependent mechanism of action. The drug appears well suited to the prevention of enhanced automaticity in the ventricle and re-entry throughout the heart, and its frequent clinical success in a broad spectrum of cardiac arrhythmias attests to this. Unwanted side effects include sinus node depression, His-Purkinje conduction delay or block, and ventricular arrhythmias enhanced by QT prolongation. However, the frequency of clinically significant examples of unwanted arrhythmic effects appears to be acceptably low.     

Saw palmetto for prostate disorders

Saw palmetto is an herbal product used in the treatment of symptoms related to benign prostatic hyperplasia. The active component is found in the fruit of the American dwarf palm tree. Studies have demonstrated the effectiveness of saw palmetto in reducing symptoms associated with benign prostatic hyperplasia. Saw palmetto appears to have efficacy similar to that of medications like finasteride, but it is better tolerated and less expensive. There are no known drug interactions with saw palmetto, and reported side effects are minor and rare. No data on its long-term usage are available. The herbal product also has been used to treat chronic prostatitis, but currently there is no evidence of its efficacy.