Subjective ratings of sleepiness--the underlying circadian mechanisms

Previous field and laboratory studies have revealed that there is a diurnal variation in subjective sleepiness that is different in form to that of objective sleepiness and many measures of performance efficiency. The worst subjective sleepiness occurs at the trough in the circadian temperature rhythm, the least subjective sleepiness about 7 h before the peak in temperature. A series of forced desynchronization experiments, in which the endogenous circadian oscillator controlling the temperature rhythm ran at a different period to the sleep/wake cycle, revealed that these findings can be explained by postulating subjective sleepiness to be under the control of both factors, with minimum sleepiness occurring at the peak in temperature in terms of the temperature cycle and about 6 h after waking in terms of the sleep/wake cycle.     

Mexiletine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias

As a member of the class Ib antiarrhythmic drugs mexiletine's primary mechanism of action is blocking fast sodium channels, reducing the phase 0 maximal upstroke velocity of the action potential. It increases the ratio of effective refractory period to action potential duration, but has little effect on conductivity. Unlike quinidine it does not prolong QRS and QT (QTc) intervals. In the dosage range 600 to 900 mg daily mexiletine effectively suppresses premature ventricular contractions (PVCs) in 25% to 79% of patients, with or without underlying cardiac disease. In comparative studies the response rate was comparable to that with quinidine or disopyramide. However, the use of antiarrhythmic therapy in patients with asymptomatic arrhythmias is controversial. More importantly, mexiletine abolishes spontaneous or inducible ventricular tachycardia or fibrillation in the short term in 20% to 50% of patients with refractory arrhythmias. Arrhythmia suppression is maintained in 57% to over 80% of these early therapeutic successes in the long term, with mexiletine alone or in combination with another antiarrhythmic drug. As with other antiarrhythmic drugs, there is no substantial evidence that administration of mexiletine after acute myocardial infarction improves long term prognosis. Although the incidence of adverse effects associated with mexiletine is high, the majority are minor gastrointestinal or neurological effects which can be adequately controlled through dosage adjustment. Furthermore, mexiletine has minimal effects on haemodynamic variables, or on cardiac function in patients with or without pre-existing deterioration of left ventricular function, and it appears to have a low proarrhythmic potential. Thus, while the therapeutic efficacy of mexiletine for the prevention or suppression of symptomatic ventricular arrhythmias may be no greater than that of other antiarrhythmic drugs, and less than that of some (e.g. amiodarone), it is effective in a significant proportion of patients refractory to other treatments and can be administered without causing adverse haemodynamic effects to patients with complicating factors such as acute myocardial infarction or congestive heart failure.     

Inhaled pentamidine. An overview of its pharmacological properties and a review of its therapeutic use in Pneumocystis carinii pneumonia

Pentamidine is an aromatic diamidine derivative which has become one of the standard therapies for Pneumocystis carinii pneumonia (PCP), particularly in patients with acquired immunodeficiency syndrome (AIDS). However, with parenteral administration of the drug there is a high risk of toxicity. Inhaled pentamidine produces much higher concentrations of drug on the bronchoalveolar surface with minimal systemic absorption. It has been used successfully for the treatment of PCP in AIDS patients, but its most valuable contribution has been as prophylaxis in AIDS patients at high risk of developing PCP. In prospective controlled studies there has been greater than 80% reduction in relapse rate with pentamidine. The reduction in relapse rate among patients who have experienced one previous episode of PCP has been 50 to 100% compared with historical control groups, over a follow-up period averaging about 6 months. Significant systemic adverse effects to inhaled pentamidine are rare. Respiratory effects associated with inhalation are common but usually controllable without treatment discontinuation. The ideal particle size for even distribution of pentamidine throughout the lung is considered to be 1 to 2 microns. Jet nebulisers such as the 'Respirgard II' system produce a mass median aerodynamic diameter (MMAD) of particles in this range. Ultrasonic nebulisers produce larger particles. The implication from this difference is that while ultrasonic nebulisers may have poorer alveolar distribution and the incidence of local side effects (common with all formulations) may be higher, total drug delivery may be more efficient allowing effective PCP prophylaxis with lower dosages (120 mg vs 300 mg monthly). However, there are no data available comparing the efficacies and tolerabilities of the different formulations of inhaled pentamidine. Nevertheless, inhaled pentamidine would seem poised to become routine prophylaxis in patients with AIDS or AIDS-related complex at risk of developing PCP.     

Postoperative Cognitive Dysfunction in Middle-aged Patients

Background: Postoperative cognitive dysfunction (POCD) after noncardiac surgery is strongly associated with increasing age in elderly patients; middle-aged patients (aged 40-60 yr) may be expected to have a lower incidence, although subjective complaints are frequent.

Methods: The authors compared the changes in neuropsychological test results at 1 week and 3 months in patients aged 40-60 yr, using a battery of neuropsychological tests, with those of age-matched control subjects using Z-score analysis. They assessed risk factors and associations of POCD with measures of subjective cognitive function, depression, and activities of daily living.

Results: At 7 days, cognitive dysfunction as defined was present in 19.2% (confidence interval [CI], 15.7-23.1) of the patients and in 4.0% (CI, 1.6-8.0) of control subjects (P < 0.001). After 3 months, the incidence was 6.2% (CI, 4.1-8.9) in patients and 4.1% (CI, 1.7-8.4) in control subjects (not significant). POCD at 7 days was associated with supplementary epidural analgesia and reported avoidance of alcohol consumption. At 3 months, 29% of patients had subjective symptoms of POCD, and this finding was associated with depression. Early POCD was associated with reports of lower activity scores at 3 months.