Benefit-risk profile of tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: pooled analysis across six clinical trials.

BACKGROUND: Although existing psoriasis treatments are effective and well tolerated in many patients, there is still a need for new effective targeted treatment options. Tofacitinib is an oral Janus kinase inhibitor that has been investigated in patients with moderate-to-severe chronic plaque psoriasis. OBJECTIVES: To consider the benefits and risks of tofacitinib in patients with moderate-to-severe psoriasis. METHODS: Data were pooled from one phase II, four phase III and one long-term extension study comprising 5204 patient-years of tofacitinib treatment. Efficacy end points included patients achieving Physician's Global Assessments of 'clear' or 'almost clear', ≥ 75% and ≥ 90% reduction in Psoriasis Area and Severity Index (coprimary end points) and improvements in Dermatology Life Quality Index score, Hospital Anxiety and Depression Scale depression score and Itch Severity Item score, at weeks 16 and 52. Safety data were summarized for 3 years of tofacitinib exposure. RESULTS: Tofacitinib 5 and 10 mg twice daily (BID) showed superiority over placebo for all efficacy end points at week 16, with response maintained for 52 weeks of continued treatment. Tofacitinib improved patients' quality of life and was well tolerated. Rates of safety events of interest (except herpes zoster) were similar to those in the published literature and healthcare databases for other systemic psoriasis therapies. Tofacitinib 10 mg BID demonstrated greater efficacy than 5 mg BID. CONCLUSIONS: Tofacitinib has a benefit-risk profile in moderate-to-severe psoriasis consistent with that of other systemic treatments.

Association between serum interleukin-17A and clinical response to tofacitinib and etanercept in moderate to severe psoriasis.

BACKGROUND: Psoriasis is a systemic inflammatory disease with a pathophysiology involving interleukin (IL)-17. Tofacitinib is an oral Janus kinase inhibitor. Etanercept is a tumour necrosis factor-α inhibitor used in the treatment of psoriasis. Neither agent inhibits IL-17 directly. AIM: To evaluate correlations between circulating IL-17A and clinical efficacy in patients with psoriasis treated with tofacitinib or etanercept. METHODS: Serum concentrations of IL-17A homodimer and IL-17A/F heterodimer were determined by immunoassays at weeks 0, 4 and 12 in patients with moderate to severe psoriasis treated with placebo (n = 60), tofacitinib 5 mg twice daily (n = 184), tofacitinib 10 mg twice daily (n = 190), or etanercept 50 mg subcutaneously twice weekly (n = 190). Disease severity was assessed using the Psoriasis Area and Severity Index (PASI) and clinical response was defined as patients achieving ≥ 75% improvement from baseline PASI (PASI75). RESULTS: Serum levels of IL-17A homodimer at week 0 showed moderate correlation with PASI, with a Spearman correlation coefficient of 0.43. Furthermore, serum levels of IL-17A homodimer showed a clear correlation with clinical response, with a decrease of 57.1% in patients achieving PASI75 at week 12, but only 15.9% decrease in nonresponders. PASI75 responders had lower median concentrations of IL-17A (range across treatments: 0.24-0.27 pg/mL) at week 12 vs. nonresponders (0.37-0.62 pg/mL), regardless of the treatment. Serum IL-17A/F heterodimer showed similar decreases at week 12 in responders and nonresponders. CONCLUSIONS: Baseline serum IL-17A correlates moderately with psoriasis severity. Reduction in circulating IL-17A is required for disease remission regardless of therapeutic agent.

Quantitative Evaluations of Time-Course and Treatment Effects of Systemic Agents for Psoriasis: A Model-Based Meta-Analysis.

Aggregate data model-based meta-analysis is a regression approach to compare the dose-response and/or time-course across different treatments using summary level data from the literature. Literature search and systematic review following the Cochrane approach yielded 912 sources for investigational and approved treatments for psoriasis. In addition, data for tofacitinib were obtained from an internal database. Tofacitinib is an oral Janus kinase inhibitor. Two mathematical models were developed for Psoriasis Area and Severity Index (PASI) response in moderate to severe psoriasis patients to quantify the time to maximum effect for PASI75 and to evaluate the dose-response relationship for PASI responders (PASI50, PASI75, PASI90, PASI100) at Week 12. Body weight exhibited an inverse effect on the placebo component of both models, suggesting that body weight affects the overall PASI response regardless of drug. This analysis provides a quantitative framework for efficacy comparisons across psoriasis treatments.

Evaluating Dosage Optimality for Tofacitinib, an Oral Janus Kinase Inhibitor, in Plaque Psoriasis, and the Influence of Body Weight.

Tofacitinib is an oral Janus kinase inhibitor. An integrated analysis was conducted to evaluate dosage optimality for tofacitinib in patients with moderate-to-severe plaque psoriasis and the impact of body weight on optimality in this patient population. Data were pooled from one phase IIb trial (2, 5, and 15 mg twice daily (b.i.d.)) and four phase III trials (5 and 10 mg b.i.d.). A longitudinal exposure-response model for Psoriasis Area and Severity Index (PASI) improvement (percent change from baseline) was established. Body weight influenced potency; heavier subjects require higher doses to achieve comparable benefit to lighter subjects. Disease severity, sex, and prior biologic usage were also predictive of response. The 10 and 5 mg doses were predicted to achieve 81% and 65%, respectively, of the maximum effect based on a 75% improvement in PASI. The greater efficacy of 10 mg over 5 mg was clinically meaningful.

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. OBJECTIVES: To determine the 16-week efficacy and safety of two oral tofacitinib doses vs. placebo in patients with moderate-to-severe chronic plaque psoriasis. METHODS: Patients in two similarly designed phase III studies (OPT Pivotal 1, NCT01276639, n = 901; OPT Pivotal 2, NCT01309737, n = 960) were initially randomized 2 : 2 : 1 to tofacitinib 10 or 5 mg or placebo, twice daily. Coprimary efficacy end points (week 16) included the proportion of patients achieving Physician's Global Assessment (PGA) of 'clear' or 'almost clear' (PGA response) and the proportion achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75). RESULTS: Across OPT Pivotal 1 and OPT Pivotal 2, 745 patients received tofacitinib 5 mg, 741 received tofacitinib 10 mg and 373 received placebo. At week 16, a greater proportion of patients achieved PGA responses with tofacitinib 5 and 10 mg twice daily vs. placebo (OPT Pivotal 1, 41·9% and 59·2% vs. 9·0%; OPT Pivotal 2, 46·0% and 59·1% vs. 10·9%; all P < 0·001). Higher PASI 75 rates were observed with tofacitinib vs. placebo (OPT Pivotal 1, 39·9%, 59·2% and 6·2%, respectively, for tofacitinib 5 and 10 mg twice daily and placebo; OPT Pivotal 2, 46·0%, 59·6% and 11·4%; all P < 0·001 vs. placebo). Adverse event (AE) rates appeared generally similar across groups; rates of serious AEs, infections, malignancies and discontinuations due to AEs were low. Twelve patients reported herpes zoster across the tofacitinib treatment groups in both studies vs. none in the respective placebo groups. The most common AE across groups was nasopharyngitis. CONCLUSIONS: Oral tofacitinib demonstrated significant efficacy vs. placebo during the initial 16 weeks of treatment in patients with moderate-to-severe psoriasis. Safety findings were consistent with prior studies.

Tofacitinib withdrawal and retreatment in moderate-to-severe chronic plaque psoriasis: a randomized controlled trial.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor being investigated for the treatment of moderate-to-severe plaque psoriasis. OBJECTIVES: To compare outcomes following tofacitinib withdrawal with outcomes of continuation. METHODS: In this phase 3 study (NCT01186744), patients received tofacitinib 5 mg (n = 331) or 10 mg (n = 335) twice daily for 24 weeks. The patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) score from baseline and Physician's Global Assessment (PGA) of 'clear' or 'almost clear' (PGA response) received a placebo (withdrawal) or the previous dose. At relapse (> 50% reduction in the PASI improvement during initial treatment) or week 40, the patients received the initial dose. RESULTS: Initial treatment: 33·5% and 55·2% achieved both PASI 75 and PGA responses with tofacitinib 5 and 10 mg twice daily, respectively, making them eligible for the treatment-withdrawal period. Withdrawal: 56·2%, 62·3%, 23·3% and 26·1% maintained PASI 75 responses with tofacitinib 5, 10 mg, placebo (5 mg) and placebo (10 mg) twice daily, respectively; 49·9%, 63·9%, 22·9% and 18·0% maintained PGA responses; and 92·3%, 93·0%, 32·8% and 42·9% did not relapse. Elevations in low-density lipoprotein-cholesterol levels following initial treatment (mean increase: 8·71 mg dL(-1) with 5 mg twice daily, 10·26 mg dL(-1) with 10 mg twice daily) were reversed upon withdrawal. Retreatment: 36·8% and 61·0% of patients who relapsed achieved PASI 75 responses with tofacitinib 5 or 10 mg after 16 weeks; 44·8% and 57·1% regained PGA responses. CONCLUSIONS: Patients who received continuous treatment maintained a response more effectively when compared with placebo recipients. Safety profiles were comparable in both the continuous treatment group and retreatment group. Of those patients who relapsed, up to 60% recaptured a response with tofacitinib.

Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment.

BACKGROUND: The Janus kinase (JAK) inhibitor, tofacitinib, has shown efficacy for the treatment of psoriasis in a phase IIb trial (A3921047; NCT00678210). OBJECTIVES: To report haematology data from the phase IIb trial, given the importance of JAK-dependent signalling in haematopoiesis. METHODS: Patients with moderate-to-severe chronic plaque psoriasis were randomized to receive tofacitinib 2, 5 or 15 mg, or placebo, twice daily over 12 weeks. Blood samples were collected at screening, baseline, weeks 2, 4, 8 and 12 during treatment, and weeks 14 and 16 during off-treatment follow-up. RESULTS: Baseline haematology was similar across patients receiving tofacitinib 2 mg (n = 49), 5 mg (n = 49) or 15 mg (n = 49), or placebo (n = 50). Tofacitinib conferred dose-dependent decreases in haemoglobin, haematocrit and red blood cell counts, while reticulocyte counts initially declined, before recovering by week 8, and exceeding baseline levels after treatment cessation. With regard to white blood cells, tofacitinib had no clear dose-dependent effects on basophils or monocytes, but appeared to be associated with transient or reversible dose-dependent decreases in neutrophil and eosinophil counts and transient increases in lymphocyte counts, which were primarily attributable to increases in B-cell counts. Natural killer cell counts declined with tofacitinib. CONCLUSIONS: Tofacitinib conferred tolerable, dose-dependent changes in haematological parameters during short-term administration in patients with psoriasis. The effects did not appear to be progressive, and were often transient or reversible.

Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study.

BACKGROUND: Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis. OBJECTIVES: This Phase 2b, 12-week, dose-ranging study (A3921047, NCT00678210) aimed to characterize the exposure-response, efficacy and safety of tofacitinib vs. placebo in patients with moderate-to-severe chronic plaque psoriasis. METHODS: One hundred and ninety-seven patients were randomized. The primary endpoint was the proportion of patients achieving a ≥ 75% reduction in the Psoriasis Area and Severity Index (PASI 75) score at week 12. RESULTS: At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25·0% (2 mg; P < 0·001), 40·8% (5 mg; P < 0·0001) and 66·7% (15 mg; P < 0·0001), compared with placebo (2·0%). Significant increases in the proportion of PASI 75 responses were seen by week 4 and were maintained at week 12. Exposure-response over the 0-15 mg tofacitinib twice-daily dose range was successfully characterized. PASI 50, PASI 90 and Physician's Global Assessment response rates were also higher for tofacitinib vs. placebo. The most frequently reported adverse events (AEs) were infections and infestations: 22·4% (2 mg twice daily), 20·4% (5 mg twice daily), 36·7% (15 mg twice daily) and 32·0% (placebo). Discontinuations due to AEs were 6·0%, 2·0%, 4·1% and 6·1% of patients in the placebo, and 2, 5 and 15 mg twice-daily tofacitinib groups, respectively. Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein and total cholesterol, and decreases in haemoglobin and neutrophils were observed. CONCLUSION: Short-term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis and is generally well tolerated.

Pharmacokinetic, pharmacodynamic, and safety profile of a new cholesteryl ester transfer protein inhibitor in healthy human subjects.

A new cholesteryl ester (CE) transfer protein (CETP) inhibitor (CP-800,569) was evaluated. Doses of 30-1,800 mg were administered once daily to healthy subjects for 14 days. Serum CP-800,569 levels increased, and CETP activity decreased, in a dose-related manner. Serum levels of high-density lipoprotein (HDL) increased (by a maximum of 156%), and those of low-density lipoprotein (LDL) decreased (by a maximum of 47%). CP-800,569 also had the effect of lowering postprandial triglyceride levels. Trough concentrations of apolipoprotein E (apoE) increased: the maximum increases were 89% for total plasma apoE and 280% for HDL apoE. By contrast, the postprandial increases in total plasma levels of apoE and non HDL apoE were either diminished by CP-800,569 or reversed to decreases. CP-800,569 was very well tolerated, with some nonserious gastrointestinal adverse events seen only with the 1,800-mg dose. No changes in blood pressure (BP) were observed. The possible effects of higher CP-800,569 doses on aldosterone and cortisol levels could not be excluded. The results of this study may be useful in CP-800,569 dose selection.

Obesity-related cardiovascular disease: implications of obstructive sleep apnea.

Obesity and obstructive sleep apnea (OSA) often coexist. OSA has been linked to cardiovascular disease. Thus, OSA may contribute to the cardiovascular consequences of obesity. In this review, we explore clinical and pathophysiological interactions between obesity, cardiovascular disease and OSA. We discuss the mechanisms whereby OSA may contribute to hypertension, atherosclerosis, insulin resistance and atrial fibrillation associated with obesity, and emphasize the potential implications for understanding why only a subgroup of obese patients develop cardiovascular disease. Identification of the OSA-dependent and OSA-independent pathways in the cardiovascular pathophysiology of obesity may hold clinical and therapeutic promise.

Event-free survival in patients after an acute coronary event with exercise-induced normalization of the T-wave.

BACKGROUND: Risk stratification of patients with unstable angina or non-Q-wave myocardial infarction (MI) is an unresolved clinical problem. The prognostic value of T-wave normalization (TWN) during exercise has not been studied in this group of patients. HYPOTHESIS: Event-free survival in clinically stable patients after an acute coronary event without ST-segment elevation can be predicted by the presence of exercise-induced TWN. METHODS: Sixty-five patients (43 men and 22 women, mean age 62+/-10 years) entered the study. The diagnosis of unstable angina and non-Q-wave MI was made in 40 and 25 patients, respectively. A treadmill exercise test was performed in all patients after clinical stabilization. The patients were divided into three groups: those with negative baseline T waves and exercise-induced TWN (Group 1); those with negative baseline T waves, but without TWN (Group 2); and those with positive baseline T waves (Group 3). The patients were followed up for 6 months. RESULTS: During follow-up, serious cardiovascular complications occurred in 15 (23%) patients. These included exacerbation of ischemic heart disease (14 patients) and acute MI (1 patient). Event-free survival was greater in patients in Group 1 (95%) than in those in Group 2 (68%, p < 0.034) or Group 3 (71%, NS). Among all patients studied, exercise-induced TWN was predictive of event-free survival with a sensitivity of 38% and a specificity of 93%. CONCLUSIONS: In clinically stable patients after an acute coronary event without ST-segment elevation, exercise-induced TWN is a specific but n ot sensitive predictor of event-free survival after 6 months.

Left ventricular hypertrophy increases transepicardial dispersion of repolarisation in hypertensive patients: a differential effect on QTpeak and QTend dispersion.

BACKGROUND: Ventricular arrhythmias in left ventricular hypertrophy (LVH) are related to regional electrical heterogeneity. The significance of noninvasive electrocardiographic indices of electrical heterogeneity in LVH has not been established. The aim of the study was to investigate changes in the Tpeak-Tend interval (an index of transmural dispersion of repolarisation) in addition to other traditional electrocardiographic indices of electrical dispersion in patients with hypertensive LVH. METHODS: Consecutive patients were screened for the presence of hypertensive echocardiographic LVH and compared with a control group. LVH was identified as left ventricular mass > 134 g m-2 in men and > 110 g m-2 in women. Twelve-lead ECGs were analysed in respect of various indices of electrical dispersion. RESULTS: Left ventricular mass was greater in the LVH than in the control group (174 +/- 39 vs. 101 +/- 18 g m-2, P < 0.0001). The Tpeak-Tend interval was not affected by LVH. The main effect of LVH was an increase in QTpeak dispersion (40 +/- 13 vs. 53 +/- 21 ms, P < 0.05), which resulted from an increase in the maximum QTpeak interval (337 +/- 24 vs. 358 +/- 30 ms, P < 0.04), without any change in the minimum QTpeak interval. There was a significant correlation between the left ventricular mass index and QTpeak dispersion (r = 0.40; P < 0.01). In contrast, LVH did not exert any effect on QTend dispersion (65 +/- 21 vs. 65 +/- 16 ms, ns), because LVH increased both the maximum QTend interval (430 +/- 30 vs. 449 +/- 28 ms, P < 0.05) and the minimum QTend interval (365 +/- 29 vs. 384 +/- 27 ms, P < 0.04). CONCLUSIONS: Hypertensive LVH exerts a differential effect on QTpeak and QTend interval dispersion. The most likely explanation is that these changes reflect a nonuniform prolongation of action potential duration across the epicardium, leading to an increase in transepicardial dispersion of repolarisation.

[Conduction disturbances and cardiac arrhythmias in myotonic dystrophy--diagnosis and clinical significance in adult populations]. / Zaburzenia przewodzenia i rytmu serca w dystrofii miotonicznej--diagnostyka i znaczenie kliniczne w doroslej populacji.

Myotonic dystrophy (DM) is the most frequent adult form of muscular dystrophy. The clinical presentation consists of both muscular and systemic involvement. One of the main causes of high mortality is sudden cardiac death due to tachyarrhythmias and conduction disturbances. The knowledge of cardiovascular complications is very important because of diagnostic and therapeutic possibilities. The main cardiological complications of DM are arrhythmias associated with the destruction of the conduction system. The main electrocardiographic changes (prolongation of the P-R interval, left anterior hemiblock, increased QRS duration) reflect destruction of the His-Purkinje system and may progress very rapidly, leading to death due to Stokes-Adams attacks. The most frequent tachyarrhythmias are atrial and ventricular extrasystoles, atrial flutter and fibrillation, as well as ventricular tachycardia, that can be a cause of sudden death. The mechanisms underlying ventricular arrhythmias are conduction disturbances, prolongation of the QT interval, impaired coronary reserve and autonomic function. A common type of tachycardia seen in patients with DM is that originating from the branches of the bundle of His (bundle-branch re-entry). Risk stratification (in respect of cardiological complications) is possible on the basis of electrophysiological studies, clinical symptoms and a family history. Invasive electrophysiological investigation and implantation of a pacemaker may be indicated in patients with electrocardiographic features of a significant disease of the conduction system. Multicentre clinical trials assessing the efficacy of this therapeutic strategy are underway.

Clinical characteristics of patients with increased urinary excretion of adrenaline in mild to moderate heart failure.

BACKGROUND: We have previously demonstrated that adrenaline (AD) is released into the circulation during acute myocardial infarction and is associated with a more severe clinical course. The role of elevated AD levels in congestive heart failure is not known. HYPOTHESIS: The study aimed to determine whether increased daily AD excretion is associated with more severe clinical symptoms and a more complicated clinical course in patients with exacerbation of congestive heart failure (CHF). METHODS: Urinary excretion of AD, noradrenaline, magnesium (Mg), and potassium (K), serum levels of aldosterone, K, and Mg, as well as the incidence of arrhythmias (24-h Holter) were assessed in 49 patients with CHF New York Heart Association (NYHA) class II-III. The patients were allocated to two groups, with normal (Group 1) and increased (Group 2) excretion of AD. RESULTS: Groups 1 and 2 did not differ in respect of age, etiology of CHF, or the medication used. Also, left ventricular ejection fraction was similar in the two groups. However, left ventricular end-diastolic dimension was greater in Group 2 (61+/-9 vs. 55+/-11 mm, p<0.05), as was the proportion of patients in NYHA class III (74 vs. 40%). Group 2 was also characterized by increased urinary excretion of Mg (60+/-24 vs. 43+/-16 mg/24 h, p < 0.007) and the presence of more complex and numerous ventricular arrhythmias (74 vs. 37% and 68 vs. 33% of patients, respectively). CONCLUSIONS: Urinary excretion of AD is increased only in a subgroup of patients with CHF. These patients are characterized by a more advanced NYHA class, increased end-diastolic left ventricular diameter, and increased urinary excretion of magnesium. It is likely that all these factors contribute to the presence of more complex and numerous ventricular arrhythmias in this subgroup of patients.

Extrasystolic beats affect transmural electrical dispersion during programmed electrical stimulation.

BACKGROUND: Experimental studies suggest that the electrocardiographic Tpeak-Tend (TpTe) interval reflects transmural dispersion of repolarization (TDR). The genesis and role of the TpTe interval in a clinical setting have not been established. This study aimed to assess the clinical usefulness of the TpTe interval as an index of TDR and a pro-arrhythmic marker. MATERIALS AND METHODS: Endocardial monophasic action potential (MAP) duration and electrocardiographic QTp, QTe and TpTe intervals were assessed in 13 patients undergoing an electrophysiological study. Surface electrocardiograms were recorded during right ventricular pacing (Basic Cycle Length = 600 ms) before and after single extrastimuli. RESULTS: Ventricular arrhythmia was induced in six patients. During ventricular pacing, MAP duration and QTp intervals shortened in response to extrastimuli applied at progressively shorter coupling intervals. In contrast, QTe intervals increased in response to premature stimulation and QTe dispersion increased at short coupling intervals. During sinus rhythm, the TpTe interval was greater in the inducible group in leads V3-V4. Premature stimulation increased the duration of TpTe intervals, suggesting an increase in TDR. The maximum TpTe interval was greater in the inducible than in the noninducible group, both during baseline ventricular drive pacing (163 +/- 22 vs. 130 +/- 27 ms, respectively, P < 0.03) and after application of shortly coupled extrastimuli (263 +/- 66 vs. 200 +/- 47 ms, respectively, P < 0.05). CONCLUSIONS: The TpTe interval of surface ECG is likely to represent TDR. TDR is increased by premature ventricular stimulation and the magnitude of the maximum TpTe interval (i.e. maximum TDR) during ventricular pacing is greater in patients with inducible arrhythmias.

Effects of glucose-insulin-potassium infusion on QT dispersion in patients with acute myocardial infarction.

BACKGROUND: Increased QT dispersion during acute myocardial infarction (AMI) has been associated with the occurrence of ventricular arrhythmias. Also, serum potassium levels have been shown to be relevant to the arrhythmic risk in this group of patients. The aim of the present study was to assess changes in QT dispersion during infusion of glucose-insulin-potassium (GIK) during AMI. METHODS: Patients from the Pol-GIK study were analyzed retrospectively. The patients were selected from the placebo (1000 mL of 0.89% NaCl) and the GIK (1000 mL of 10% dextrose, 20-32 units of insulin, 80 mEq K(+)) groups (18 and 24 patients, respectively). QT interval duration and dispersion (the difference between the longest and shortest QT intervals) were measured at baseline, 18-24 hours into placebo/GIK infusion and 24 hours after the end of infusion. RESULTS: In the placebo group, plasma potassium levels changed from 4.1 +/- 0.5 mmol/L at baseline to 4.6 +/- 0.8 mmol/L during infusion (P < 0.05) and 4.6 +/- 0.4 mmol/L after infusion, whereas in the GIK group the respective values were 4.0 +/- 0.4, 4.6 +/- 0.3 (P < 0.0001), and 4.5 +/- 0.5 mmol/L. QT interval duration was stable throughout the study and there was no difference between the groups. The two groups did not differ in respect to QT dispersion at any time point, the respective values were 79 +/- 28, 65 +/- 25, and 77 +/- 27 ms in the placebo group, and 61 +/- 35, 60 +/- 26, and 76 +/- 43 ms in the GIK group. The incidence of arrhythmias was also similar in both groups. CONCLUSIONS: GIK, at the dose used, is unlikely to affect heterogeneity of ventricular repolarization during AMI.

Isosorbide dinitrate inhibits platelet adhesion and aggregation in nonthrombolyzed patients with acute myocardial infarction.

BACKGROUND: Apart from their vasodilatatory properties, nitrates have been shown to inhibit platelet aggregation. The effects of nitrates on platelet adhesion have not been studied. Nonselected patients with acute myocardial infarction (AMI) have been suggested to gain no benefit from administration of nitrates. However, the importance of nitrates may be greater in a subgroup of nonthrombolyzed patients with AMI. HYPOTHESIS: Isosorbide dinitrate (ISDN) decreases platelet adhesion and aggregation in nonthrombolyzed patients with AMI. METHODS: Consecutive 48 men with AMI, not eligible for thrombolytic therapy because of late presentation (> 12 h), were prospectively randomized 2:1 to double-blind ISDN (mean dose 2.4 +/- 0.9 mg/h) (n = 33) or placebo (0.9% sodium chloride) (n = 15) infusion. All patients received aspirin. Blood samples were taken at baseline (no study medication) and 3 h into ISDN or placebo infusion. Platelet adhesion to collagen was measured in the ethylene diamine tetraacetic acid (EDTA)-platelet rich plasma by recording changes in light transmission with an optical aggregometer. Platelet aggregation was measured using the Born's method. RESULTS: Isosorbide dinitrate significantly decreased both platelet adhesion and aggregation. No effect was seen in the placebo group. CONCLUSIONS: In patients with AMI who do not receive thrombolytic therapy, ISDN effectively inhibits platelet adhesion and aggregation. These effects of nitrates may be of therapeutic and prognostic significance in this group of patients.

Effects of oral L-arginine supplementation on exercise-induced QT dispersion and exercise tolerance in stable angina pectoris.

We assessed the effects of L-arginine (an endogenous precursor of nitric oxide) on the magnitude of exercise-induced QT dispersion in patients with coronary artery disease. The study had a randomized double-blind cross-over design. Twenty-five patients with stable coronary artery disease underwent two separate exercise tests: after oral administration of L-arginine (6 g/24 h for 3 days) or placebo. Indications for cessation of exercise included: pulse limit, exhaustion, chest pain, ST segment depression >2 mm. We found that arginine significantly increased exercise duration from 604+/-146 to 647+/-159 s (P<0.03). However, it had no effect on the sum of exercise-induced ST segment depressions (1.9+/-2.3 and 2.4+/-3.3 on and off arginine, respectively, NS). Exercise shortened QT interval to a similar extent in patients treated with placebo or arginine. QT dispersion changed during exercise from 55+/-21 to 60+/-19 ms (NS) and from 60+/-21 to 53+/-17 ms (NS), respectively. We conclude that, in patients with coronary artery disease, oral supplementation of L-arginine does not affect exercise-induced changes in QT interval duration, QT dispersion or the magnitude of ST segment depression. However, it significantly increases exercise tolerance, most likely due to improved peripheral vasomotion. These results may be of clinical and therapeutic importance.

Regional electrophysiological effects of left ventricular hypertrophy in isolated rabbit hearts under normal and ischaemic conditions.

OBJECTIVES: Left ventricular hypertrophy (LVH) has been reported to produce differential electrophysiological effects in isolated epicardial and endocardial cells. This study aimed to examine regional electrophysiological effects of LVH in normal and ischaemic conditions in the whole heart. METHODS: LVH was secondary to perinephritis-induced hypertension. Monophasic action potential duration (MAPD(90)), effective refractory period (ERP) and conduction delay were measured in paced, isolated working rabbit hearts either at one right ventricular and two left ventricular sites (apical and basal epicardium) or at three left ventricular sites (apical and basal epicardium, apical endocardium). The hearts were subjected to 30 min of regional ischaemia and 15 min of reperfusion. RESULTS: In non-ischaemic conditions, LVH produced uniform prolongation of MAPD(90) and ERP in the left ventricular epicardium, but not in the endocardium. After coronary artery occlusion, LVH significantly increased ischaemia-induced transepicardial dispersion of repolarisation, but not refractoriness. LVH did not affect arrhythmogenesis in either non-ischaemic or ischaemic conditions. CONCLUSIONS: Differential effects of LVH on epicardial and endocardial electrophysiological parameters are also observed in the whole heart. In addition, the sensitivity of hypertrophied myocardium to ischaemia is increased and leads to an increase in ischaemia-induced dispersion of repolarisation. However, neither dispersion of refractoriness nor arrhythmogenesis are affected by LVH in non-ischaemic or ischaemic conditions in this experimental model.