Methadone maintenance,QTc and torsade de pointes: Who needs an electrocardiogram and what is the prevalence of QTc prolongation?

Introduction and Aims. High‐dose methadone has been associated with rate‐corrected QT (QTc) prolongation and ‘torsade de pointes’. The Medicines and Healthcare products Regulatory Agency (MHRA) advise electrocardiograms (ECGs) for patients on methadone with heart/liver disease, electrolyte abnormalities, concomitant QT prolonging medications/CYP3A4 inhibitors or prescribed methadone >100 mg daily. The percentage of patients fulfilling MHRA criteria for ECG monitoring and prevalence of QT prolongation in patients who had an ECG was assessed. Design and Methods. A cross‐sectional study of opioid‐dependent patients prescribed opioid maintenance that completed a screening questionnaire prior to referral for an ECG. MHRA criteria were assessed in the referred group. The automated QTc score was analysed with methadone dose, substance use and QT risk factors. Results. Of 155 patients screened; 57.4% (n = 89) fulfilled MHRA criteria for ECG monitoring (75.5% (n = 117) if cocaine included as QT prolonging drug). Eighty‐three (53.5%) had ECGs; 19.3% (n = 16) prescribed QT prolonging medication, 22.9% (n = 19) prescribed >100 mg methadone and 47% (n = 39) used cocaine. Mean QTc interval was 429.0 ms (SD 26.4, 351–489). Eighteen per cent exceeded QTc gender‐specific thresholds (≥450 ms men and≥470 ms women). Linear regression found total daily methadone dose (β = 0.318, P = 0.003) and stimulant use (β = ?0.213, P = 0.043) predictive of QTc length. Discussion. Over half to three‐quarters of methadone maintenance patients fulfilled MHRA criteria for ECG monitoring, which has costly implications. QTc prolongation prevalence was 18.1% with no ‘clinically significant’ QTc prolongation >500 ms or torsade de pointes known to be present. Methadone dose and stimulant use were associated with longer QTc intervals. Further research on the clinical management of QTc prolongation with methadone is required.[Mayet S, Gossop M, Lintzeris N, Markides V, Strang J. Methadone maintenance, QTc and torsade de pointes: Who needs an electrocardiogram and what is the prevalence of QTc prolongation? Drug Alcohol Rev 2011;30:388–396]     

QTc interval prolongation by d-propoxyphene: what about other analgesics?

INTRODUCTION: d-Propoxyphene, which was previously available in many single-agent and combination products, was recently voluntarily withdrawn from the US market following an FDA recommendation based partly on the concern that the risk associated with QT prolongation exceeded the clinical benefit of the drug. The drug had previously been withdrawn from European markets. These recent actions prompt the question: what is known about QT prolongation and analgesic drugs? AREAS COVERED: A systematic search was conducted of 50 opioid and non-opioid analgesic drugs using PubMed, the FDA website, and the Internet. Search terms for opioids, NSAIDs, acetaminophen and other analgesics were used (including both generic and brand names), along with QTc, QTc prolongation, QTc interval, hERG, torsades de pointes (TdP), ventricular arrhythmias, and other relevant terms. EXPERT OPINION: There is a paucity of available information on the QT interval for most analgesics. Of those for which there is a lot of data, only methadone, oxycodone, and LAAM (levo--acetylmethadol) appear to have a known and accepted level of effect on the QT interval.     

QTc interval prolongation by d-propoxyphene: what about other analgesics?

Introduction: d-Propoxyphene, which was previously available in many single-agent and combination products, was recently voluntarily withdrawn from the US market following an FDA recommendation based partly on the concern that the risk associated with QT prolongation exceeded the clinical benefit of the drug. The drug had previously been withdrawn from European markets. These recent actions prompt the question: what is known about QT prolongation and analgesic drugs?

Areas covered: A systematic search was conducted of 50 opioid and non-opioid analgesic drugs using PubMed, the FDA website, and the Internet. Search terms for opioids, NSAIDs, acetaminophen and other analgesics were used (including both generic and brand names), along with QTc, QTc prolongation, QTc interval, hERG, torsades de pointes (TdP), ventricular arrhythmias, and other relevant terms.

Expert opinion: There is a paucity of available information on the QT interval for most analgesics. Of those for which there is a lot of data, only methadone, oxycodone, and LAAM (levo--acetylmethadol) appear to have a known and accepted level of effect on the QT interval.     

The role of concentration?effect relationships in the assessment of QTc interval prolongation

Population pharmacokinetic and pharmacokinetic−pharmacodynamic (PKPD) modelling has been widely used in clinical research. Yet, its application in the evaluation of cardiovascular safety remains limited, particularly in the evaluation of pro-arrhythmic effects. Here we discuss the advantages of disadvantages of population PKPD modelling and simulation, a paradigm built around the knowledge of the concentration−effect relationship as the basis for decision making in drug development and its utility as a guide to drug safety. A wide-ranging review of the literature was performed on the experimental protocols currently used to characterize the potential for QT interval prolongation, both pre-clinically and clinically. Focus was given to the role of modelling and simulation for design optimization and subsequent analysis and interpretation of the data, discriminating drug from system specific properties. Cardiovascular safety remains one of the major sources of attrition in drug development with stringent regulatory requirements. However, despite the myriad of tests, data are not integrated systematically to ensure accurate translation of the observed drug effects in clinically relevant conditions. The thorough QT study addresses a critical regulatory question but does not necessarily reflect knowledge of the underlying pharmacology and has limitations in its ability to address fundamental clinical questions. It is also prone to issues of multiplicity. Population approaches offer a paradigm for the evaluation of drug safety built around the knowledge of the concentration−effect relationship. It enables quantitative assessment of the probability of QT_c interval prolongation in patients, providing better guidance to regulatory labelling and understanding of benefit/risk in specific populations.     

Pharmacologic treatment of constipation: what is new?

Constipation is a common gastrointestinal disease affecting 2-27% of the population in Western hemisphere. Approximately in half of patients the diagnosis of functional constipation is made after having ruled out secondary causes. Treatment of chronic functional constipation primarily addresses education on toilet habits, dietary advice, and patient reassurance. Further therapies are guided according to functional subtype slow-transit constipation, dyssynergic defecation, and constipation-predominant irritable bowel syndrome (IBS-C). Traditionally, the pharmacologic treatment of constipation uses primarily bulking agents and/or laxatives (osmotic or secretory). However, often these therapies do not provide the desired improvement, have a short-lived efficacy and/or are accompanied by side-effects such as bloating and abdominal cramps. Thus, there is a clinical need for new, more potent drugs particularly for patients who are not satisfactorily treated by conventional therapies. This review discusses recent developments in the pharmacologic treatment of chronic constipation including recently FDA-approved lubiprostone, emerging 5-HT receptors modifiers, investigational substances, and probiotics.     

Effects of mental and physical stress on plasma catecholamine levels before and afterβ-adrenoceptor blocker treatment

Summary In a study in mild hypertensives, the impact of mental and physical stress on plasma epinephrine (E), norepinephrine (NE), and on their ratio (NE/E) was evaluated. The effect of two-adrenoceptor blocking drugs, atenolol and bopindolol, on plasma catecholamine levels was also examined.Each stressful stimulus significantly increased the NE and E levels compared to rest. The increase was progressive from mental stress, through the handgrip test to the treadmill test. A slight decrease in the NE/E ratio was observed following mental stress and the handgrip test, while this ratio increased during the treadmill test.No significant impact of beta blocking treatment on catecholamine levels was observed under any test condition.     

Antiangiogenesis and radiotherapy: what is the role of combined modality treatment?

The formation of new blood vessels is a prerequisite for the growth of primary and metastatic tumour. Thus, strategies that aim at the inhibition of tumour angiogenesis have gained considerable interest in recent years. Furthermore, there is a need to identify the role of antiangiogenic agents in conjunction with conventional anticancer modalities like chemotherapy or radiotherapy. It is the objective of this review to summarise experimental data for different antiangiogenic agents used for combined modality experiments with radiotherapy. Promising data have been reported for a series of antiangiogenic agents for combined modality treatment with radiotherapy using tumour growth delay as the primary end-point. Yet, the results from different agents with various tumour lines are contradictory in part. Furthermore, enhancement of local tumour control, the main objective of curative radiotherapy, has so far been demonstrated for only two agents (DC101 and CA4DP), while experiments using TNP-470 even revealed a reduction of local tumour control when combined with irradiation. Finally, detailed studies investigating the modulation of normal tissue reactions for the combination of radiotherapy and inhibitors of angiogenesis are pending so far. Thus, experimental data currently available do not consistently support the beneficial effects of combined modality treatment with inhibitors of angiogenesis and radiotherapy. We therefore conclude that there is still a long way to go until we know which antiangiogenic agent will clinically be suitable for what tumour entity for combined treatment of radiotherapy and inhibitors of angiogenesis.     

Tamoxifen: is it safe? Comparison of activation and detoxication mechanisms in rodents and in humans

Tamoxifen, a non-steroidal antiestrogen, is the class representative of a group of drugs that include toremifene, droloxifene and idoxifene. Tamoxifen has been successfully used worldwide as adjuvant therapy in the treatment of women with breast cancer. However, such therapy results in a slightly increased risk of endometrial cancers. Lifetime exposure of rats to high doses of tamoxifen results in a high incidence of liver tumors. Tamoxifen itself is not genotoxic but is activated in the liver to alpha-hydroxytamoxifen. This is further conjugated to form the sulfate ester as the putative reactive intermediate. Studies with recombinant human CYPs show only CYP3A4 is able to catalyze the formation of alpha-hydroxytamoxifen and the irreversible binding of [(14)C]tamoxifen to DNA. CYP3A4 and CYP2D6 convert tamoxifen to N-desmethyltamoxifen. The formation 4-hydroxytamoxifen is catalyzed by CYP2D6 and at a much lower level by CYP2C19. In women, detoxication of alpha-hydroxytamoxifen via a stable glucuronide occurs at a rate in the order of 100 fold higher than in rats whereas rates of sulfation are 3 fold lower than in rats. These factors, together with the low dose of tamoxifen used therapeutically in women, indicates a minimum risk of liver cancers. Results from (32)P-postlabeling and accelerator mass spectrometry suggest that low levels of uterine DNA binding does occur but this is probably too low to play a role in uterine tumor development and it is more likely to be the estrogen agonist action of this class of drug that is the most important factor in tumor development in humans.     

When should clozapine be initiated in schizophrenia?: Some arguments for and against earlier use of clozapine

Clozapine is one of the original atypical antipsychotics. It was withdrawn from the market in 1974 because of haematological safety concerns, but since 1989 has enjoyed a renaissance for the management of treatment-resistant schizophrenia under systems where case registration allows regular haematological monitoring. Clozapine continues to show enduring superiority across many aspects of the clinical pharmacology of the treatment of schizophrenia, e.g. it has specific anti-suicidal properties and recent broader trials have shown continuing superiority in wide groups of patients. This article considers some of the arguments for unshackling clozapine from its current license for schizophrenia (its superiority overall in treatment-resistant schizophrenia, its potential for use in first-episode patients, and its anti-suicidal potential), and tries to synthesise these into some of the national guidelines available for the treatment of schizophrenia.     

Valproic-acid-induced thrombocytopenia and hepatotoxicity: discontinuation of treatment?

We report the case of a 4-year-old boy with long-term sodium valproate (valproic acid; VPA) therapy who suddenly developed clinically relevant thrombocytopenia and signs of hepatotoxicity. Reduction of the VPA dosage led to clinical and laboratory parameter improvement, while discontinuation of therapy was not necessary. The current practice of the management of VPA-induced side effects is discussed in view of the current recommendations from the literature.     

Personal review: is profound acid inhibition safe?

Inhibitors of gastric acid secretion, particular proton pump inhibitors, are effective drugs in the treatment and prophylaxis of acid-related diseases. Proton pump inhibitors are therefore prescribed widely, often for minor complaints. Gastric acidity kills swallowed microorganisms, and acid secretion must be of biological importance because it is maintained in phylogenesis. Acid secretion is controlled by feedback mechanisms, mainly via gastrin. A decrease in acidity always causes an increase in plasma gastrin. The trophic effect of gastrin leads to hyperplasia and neoplasia of the enterochromaffin-like (ECL) cell. ECL cell derived tumours in man were previously regarded as rare, and also as rather benign. It is now clear that the ECL cell gives rise to a significant proportion of gastric carcinomas. Moreover, ECL cell carcinoids secondary to hypergastrinaemia may develop into highly malignant tumours. Treatment with a proton pump inhibitor is followed by rebound acid hypersecretion and decreased efficiency of H2-blockers, thus such treatment may induce a type of physical dependence. It is therefore reasonable to be cautious and not to treat younger (< 50 years) patients for long periods of time with profound inhibitors of gastric acid secretion. Chromogranin A in the blood is a sensitive marker of the ECL cell mass, and it could be used to survey patients on long-term proton pump inhibitors.     

Drug hybridization strategies: before or after lead identification?

The molecular hybridization approach is one of the most valuable structural modification tools useful for the discovery of ligands and prototypes presenting either optimized affinity for one bioreceptor or the ability to modulate more than one bioreceptor associated with the target disease. The growing efforts to discover hybrid drugs resulting from the combination of pharmacophoric moieties of different known lead compounds have brought a new hope for the treatment of multifactorial diseases in recent years. This editorial describes possible ways of exploring molecular hybridization strategies to plan new effective dual or symbiotic drug candidates.     

Monitoring clozapine: are fingerprick blood and plasma clozapine levels equivalent to arm venipuncture blood and plasma levels?

The objective of this pilot study was to determine whether fingerprick blood and plasma clozapine levels were equivalent to arm venipuncture blood and plasma levels for the purpose of therapeutic monitoring. A convenient sample of 10 outpatients from the Elgin Program of Assertive Community Treatment Team (PACT) participated in the study. Blood samples were obtained simultaneously from both the arm and finger in patients at steady state to measure clozapine levels. Each site provided a blood and plasma clozapine level, and they were compared. Clozapine levels from arm and finger sites were found to be equivalent in both blood and plasma. Although plasma clozapine levels were consistently greater than those in whole blood by a mean value of 27%, the plasma therapeutic threshold level (350-400 micro g/L) was considered an adequate target for monitoring. A fingerprick blood sample of 50 micro L was sufficient to measure clozapine levels accurately at steady state. We therefore concluded that fingerprick blood testing is as effective as the traditional arm venipuncture method in obtaining accurate clozapine levels. This procedure may provide certain benefits for the seriously mentally ill.     

Surgical approach to ulcerative colitis: when is the best timing after medical treatment?

Ulcerative colitis (UC) is a chronic inflammatory condition of the mucosa affecting the rectum and extending up the colon in a continuous manner. Its etiology is unknown, but is most probably the result of the interaction of genetic and environmental factors. Approximately 30% of UC patients will need to undergo surgery at some point during their lifetime, despite progresses made in medical therapies. Indications for surgery include acute severe colitis with its complications, steroid-or antiTNF-refractory colitis (or growth impairment in children), and the onset of colorectal dysplasia/cancer. Recently, the introduction of biologic agents has provided a rationale for prolonging medical therapy before considering surgery in the treatment of active, moderate to severe colitis. When surgery becomes indicated, especially in the urgent setting, it usually involves dealing with immunosuppressive medications, possibly impacting the onset of post-operative septic complications. In both acute and chronic settings, patients should be informed about the medical and surgical options and their respective prognoses; the crucial decision regarding the timing for surgery should be shared by both gastroenterologists and colorectal surgeons. The aim of the present review is to highlight surgical indications and options for UC patients as well as the evidence about surgical complications following medical therapies, in order to aid clinicians in determining the best timing for surgery.