ABSTRACT:Fifty-nine patients were treated in a prospective, randomized comparison of pentobarbital and mannitol for the control of intracranial hypertension resulting from head injury. Patients with elevated intracranial pressure (ICP) after evacuation of intracranial hematomas were randomized to one of two treatment groups; mannitol initially or pentobarbital initially, followed by the second drug as required by further elevation of ICP. Similarly, patients with raised ICP but without hematomas requiring evacuation were randomly assigned to two treatment groups in an identical paradigm.Those with ICP elevation and no hematoma treated with pentobarbital as initial therapy had a 77% mortality compared to a 41% mortality for those with mannitol as initial treatment. Patients with evacuated hematomas had mortalities of 40% and 43% (no significant difference) for pentobarbital and mannitol respectively. In both no-hematoma and hematoma streams pentobarbital was less effective than mannitol for control of raised ICP.Multivariate statistical analysis indicates that pentobarbital coma is not better than mannitol for the treatment of intracranial hypertension and may be harmful in no-hematoma patients with intracranial hypertension after head injury. RESUME: Au cours d'une 6tude prospective randomisee, 59 patients ont 6t6 trails par Pentobarbital et Mannitol pour controle de l'hypertension intracranienne secondaire a un traumatisme cranien. Les patients dont la pression intra-cranienne (PIC) 6tait 61ev6e apres Evacuation d'un hgmatome intra-cranien ont 6t6 ranges au hasard dans deux groupes respectifs de traitement: administration, initialement, soit de Mannitol, soit de Pentobarbital; addition, subs6quemment, de l'un ou l'autre agent, advenant une nouvelle Elevation de la PIC. De meme, des patients avec PIC elev6e, mais sans h6matome a Evacuer, ont €t& disbribuEs au hasard dans deux groupes de traitement selon le meme protocole.Le groupe avec pression intra-cranienne dlevee et sans hematome, qui fut traits initialement par Pentobarbital a eu un taux de mortality de 77%, contre 41% pour le groupe debutant le traitement par du Mannitol. Les patients porteurs d'hdmatomes ope>6s ont eu des morbidity de 40% et 43% (sans difference significative), selon qu'ils Staient trails respectivement par Pentobarbital ou Mannitol. Dans les deux groupes -avec et sans hematome -le Pentobarbital fut moins efficace que le Mannitol pour le controle de la PIC 61ev6e.L'analyse statistique multifactorielle indique que le coma par Pentobarbital n'est pas preferable au Mannitol dans le traitement de l'hypertension intra-cranienne et qu'il peut etre nefaste chez les patients sans h6matome porteurs d'une hypertension intracranienne secondaire a un traumatisme cranien.

A high rate of discontinuation of dabigatran, mainly due to GI symptoms, was observed. There does not appear to be any specific predictor of dabigatran tolerance. When prescribed according to guidelines, rates of serious adverse events associated with dabigatran appear to be low.

The influence of renal impairment on the pharmacokinetics of eplerenone following single and multiple dosing was evaluated. Subjects (n = 64) were stratified based on creatinine clearance values as follows: renal impairment (mild, moderate, severe), hemodialysis, and normal matches. Subjects received a single dose of eplerenone 100 mg on day 1 and then received 100 mg once daily on days 3 to 8. There were no statistically significant differences between any of the renal impairment groups and their matched-normal groups for area under the curve (AUC), C(max), or CL/F or CL/F/WT following either single or multiple dosing (P > or = .093). The inactive metabolite and inactive ring-opened form displayed greater AUCs in renal impairment. Hemodialysis removed approximately 10% of the eplerenone dose. Eplerenone 100 mg once daily was well tolerated in all groups. Considering that renal function had no significant effects on eplerenone CL/F and that eplerenone metabolites are inactive, no dose adjustment appears necessary in patients with renal dysfunction.

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Eplerenone pharmacokinetics were studied in subjects with varying degrees of renal function after single (100 mg) and multiple doses (100 mg daily for 5 days). This open‐label, parallel‐group study enrolled 32 renally impaired subjects and 32 normal matches. Subjects were stratified based on CLcr: normal CLcr80 mL/min; mild CLcr=50–80 mL/min, moderate CLcr=30‐49 mL/min, or severe impairment CLcr<30 mL/min; and hemodialysis. The pharmacokinetics of eplerenone and metabolites were determined from plasma and urinary results. Following single or multiple dosing, eplerenone AUC, Cmax, CL/F, and CL/F/WT were not statistically different (P>0.093) between renally impaired and normal subjects. Compared to normal subjects, eplerenone renal clearance was significantly decreased in subjects with moderate and severe impairment. Since <2% of eplerenone is excreted unchanged, decreases in renal clearance did not result in significant alterations in CL/F. Subjects with severe impairment displayed the greatest decrease (18%) in mean CL/F/WT as compared to normal matches. In subjects with end‐stage renal failure, approximately 10% of the dose was removed after 4 hours of hemodialysis. Eplerenone was well tolerated in all subjects. Dose adjustment based on pharmacokinetic alterations does not appear necessary in patients with renal impairment; rather, dose adjustment for eplerenone in renal failure, as with spironolactone, should be based on its potential effect on serum potassium values. Clinical Pharmacology & Therapeutics (2004) 75, P37–P37; doi:

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1. The electrocardiogram was recorded for 3 min during spontaneous respiration in 70 subjects aged 15-86 years who were in sinus rhythm. Using a signal-averaging approach, the presence of respiratory variation of P-P intervals was analysed by multiple regression against a cosine function (cosinor analysis). 2. By cosinor analysis the phase of respiration when the intervals were longest was determined, together with the amplitude of the variation of the intervals around their mean value. 3. Respiratory variation of P-P intervals (respiratory sinus arrhythmia) was demonstrated in 84% of subjects; its amplitude decreased with age and respiratory rate. On average, the duration of P-P intervals varied by 2.8% around the mean, and the maximum duration occurred around the time of end-expiration. 4. By cosinor analysis, and allowing for variation of heart rate, P-R intervals showed an independent respiratory variation in 39% of cases, and its average amplitude was 1.2% around the mean. 5. The respiratory variation of P-R and P-P intervals showed similar phase relationships to respiration, suggesting that during respiration there is parallel alteration of sinoatrial and atrioventricular node function.

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