Oral absorption of clarithromycin in acute illness and during convalescence in patients with community-acquired pneumonia.

STUDY OBJECTIVE: To compare the extent of oral clarithromycin absorption in patients during an illness and in health. DESIGN: Sequential two-phase prospective study including an acutely ill pneumonia phase (PP) and a subsequent convalescent phase (CP). STUDY POPULATION: Patients >/= 18 years old with radiographically confirmed community-acquired pneumonia (CAP) who were admitted to the hospital. METHODS: During both study phases, patients received one single 500-mg dose of oral clarithromycin. Serial blood samples were drawn over a 24-h period in order to characterize the plasma concentration-time curves. Area under the curve from zero to 24 h (AUC(0-24)), maximum plasma concentration (Cmax), and time to maximum concentration (Tmax) were determined for both clarithromycin and its metabolite, 14-hydroxyclarithromycin, and compared between the two phases. RESULTS: Twelve patients completed both phases of the study. For clarithromycin, there was a significant increase AUC(0-24) (47.37 +/- 8.51 microg/h/mL vs 36.22 +/- 6.09 microg/h/mL) in favor of the PP. There were no significant differences detected with respect to Cmax (4.32 +/- 0.63 microg/mL vs 3.57 +/- 0.46 microg/mL), or Tmax (3.50 +/- 0.50 h vs 2.83 +/- 0.59 h) between PP and CP. For 14-hydroxyclarithromycin, the AUC(0-24) and Cmax were significantly higher (5.84 +/- 1.08 microg/h/mL vs 8.84 +/- 1.92 microg/h/mL; 0.42 +/- 0.08 microg/mL vs 0.76 +/- 0.23 microg/mL) in the CP as compared to the PP. Tmax remained unchanged. CONCLUSION: The extent of absorption of oral clarithromycin was not diminished during an acute illness with CAP.

Successful anticoagulation with dalteparin in a patient with mechanical heart valves.

BACKGROUND: Standard thromboprophylaxis of patients with mechanical heart valves is achieved using warfarin. In certain patients this may be very difficult; thus, alternative pharmacotherapy must be used. OBJECTIVE: To report a case of a patient who successfully used dalteparin, a low-molecular-weight heparin, for anticoagulation. CASE SUMMARY: A 58-year-old white woman with mechanical aortic and mitral heart valves initially received warfarin for anticoagulation. Thromboprophylaxis was very challenging. Her international normalized ratios (INRs) were erratic and occasionally responded paradoxically to changes in dose. Finally, she experienced a left hemispheric stroke when her INR was extremely subtherapeutic. Subsequently, despite best efforts, her INR again was subtherapeutic; warfarin was discontinued and dalteparin was initiated with daily self-administered subcutaneous injections of 16 000 units. No complications have arisen since initiation of the new pharmacotherapy approximately 18 months ago. DISCUSSION: The use of low-molecular-weight heparin for the treatment and prevention of venous thromboembolism is well described. There are few reports of its use for thromboprophylaxis of patients with mechanical heart valves. Our patient has been managed successfully with dalteparin. CONCLUSIONS: Dalteparin was effectively and safely used for the thromboprophylaxis of a patient with mechanical heart valves whose anticoagulation was previously difficult to manage with warfarin. Dalteparin deserves further study in patients who are unable to tolerate warfarin.

Propranolol for the prevention of postoperative arrhythmias in general thoracic surgery.

BACKGROUND: Prevention of postoperative arrhythmias in patients undergoing general thoracic surgery is desirable to prevent morbidity. METHODS: A randomized, double-blind, placebo controlled trial of propranolol (10 mg every 6 hours) for 5 days was undertaken in patients undergoing major thoracic operations to determine whether arrhythmias requiring treatment could be reduced. Secondary outcomes included overall arrhythmia rate, adverse events, and length of stay. Arrhythmias were assessed by 72-hour Holter monitoring. Patients with a history of heart failure, asthma, advanced heart block, preexisting arrhythmias, sensitivity to propranolol, or use of antiarrhythmic drugs were excluded. RESULTS: Using the intention-to-treat principle there was a 70% relative risk reduction from 20% to 6% in the rate of treated arrhythmias with propranolol (p = 0.071, 95% confidence interval 0.6% to 27.2%). Overall arrhythmias were common but usually benign. Adverse effects were common, although generally mild with hypotension and bradycardia being reported more often in the propranolol group. Length of stay was not different. CONCLUSIONS: There was a trend to a reduction in the risk of perioperative arrhythmias with propranolol. Moreover, propranolol was well tolerated showing a slight increase in minor adverse events.

Myoclonus due to chlorambucil in two adults with lymphoma.

OBJECTIVE: To report myoclonus due to chlorambucil therapy in two adults with lymphoma, and to review the literature of chlorambucil neurotoxicity in adults. CASE SUMMARIES: Case 1: An 81-year-old man with lymphoma being treated with chlorambucil developed jerking movements and stiffness that persisted for 3 days and intensified at night. The dosage of chlorambucil was decreased with a subsequent decrease in symptomatology. Resolution of the myoclonus occurred with discontinuation of the chlorambucil. Rechallenge evoked a return of tremors the next day that later became constant and again resolved on discontinuation of chlorambucil. Case 2: A 75-year-old woman with lymphoma being treated with chlorambucil developed jerking movements in her limbs, particularly in her arms and right hip. The symptoms were so severe they prevented the patient from leaving her house. All symptoms resolved within 2-3 days after the cycle was completed and did not return. She was diagnosed as having had chlorambucil-induced myoclonus. DATA SOURCES: Searches were performed on MEDLINE, CancerLit, and Science Citation Index Review to identify reports and articles discussing chlorambucil-induced neurotoxicity, particularly myoclonus. DISCUSSION: Chlorambucil-induced myoclonus has been described in overdose situations and in the treatment of nephrotic syndrome in children. Three cases of reversible myoclonic activity associated with high-dose chlorambucil in adults have also been described. In each case, the myoclonus resolved following discontinuation of the drug. Only one other conclusive case of low-dose chlorambucil-induced myoclonus in an adult has been described. The two cases presented here are unique in that the myoclonus occurred in adults receiving low-dose chlorambucil who had no myoclonus before or after treatment with the drug. CONCLUSIONS: From the cases reviewed, it appears that chlorambucil may induce myoclonus in adults receiving therapeutic dosages of chlorambucil. The neurologic status of patients receiving chlorambucil should be followed closely during treatment. If myoclonus develops, drug-induced myoclonus should be considered, as well as discontinuation of the drug.

The clinical effects and cost-avoidance of a change in perioperative bronchodilator use.

The clinical effects and financial impact of a change in prescribing habits from routine to occasional use of perioperative bronchodilators, following the presentation of drug information, were assessed retrospectively by comparing the outcomes of patients admitted for major thoracic surgery. Eighteen of 24 (75%) patients in Period A (prior to change) received salbutamol bronchodilator therapy versus 10 of 17 (59%) in Period B (following the change) (p = .448). Of the patients who did receive salbutamol aerosols, the mean dose in grams per patient was greater in Period A than in Period B (6.85 +/- 5.96 vs. 2.64 +/- 4.44 respectively p < 0.05). Two patients from Period A and one from Period B were receiving digoxin prior to admission. In the remaining patients, 5 of 22 (23%) in Period A and 1 of 16 (6%) in Period B developed atrial fibrillation requiring digoxin (p = .36). The proportion of patients with obstructive airways disease (OAD) who developed an arrhythmia was not different between the two groups. However, in those patients without OAD an arrhythmia was reported in 9 of 16 patients (56%) receiving salbutamol, versus only 1 of 11 (9%) of those not receiving it (p = 0.032). The number of days patients were hospitalized during Period A and Period B were 10.2 +/- 4.97 and 9.4 +/- 3.68 respectively (p = 0.85). A potential average cost-avoidance of $68.46 per patient could be realized with this new practice. We conclude that a change in prescribing habits had no adverse clinical outcome and resulted in a considerable cost-avoidance.

The impact of formulary reservations on drug utilization: a controlled trial.

A controlled trial was conducted in two teaching hospitals (A and B), with similar case mixes to determine the impact of reservations, which were educational in nature, on the utilization of oral ciprofloxacin. Over a two-month period the health records of all the patients who received the drug were reviewed, and information on utilization and demographics of patients receiving the drug was recorded. As well, the number of admissions to the two hospitals over this period were compared. If culture and sensitivity (C & S) results were available, appropriateness was assessed in accordance with criteria for use established at site A; in the absence of C & S information, consensus by two microbiologists was used. Over the two-month period a total of 136 patients received ciprofloxacin at the two institutions. At site A, which had reservations, the number of patients who continued to receive ciprofloxacin upon admission was significantly decreased relative to site B, which did not have reservations (14% vs. 36% respectively, p = .029). As well, when assessed by total number of admissions to the institutions, the number of patients receiving ciprofloxacin at site A was less than site B (1.5% vs. 2.6% respectively, p = .003)). While the utilization was decreased at site A vs. site B, the proportion of patients with therapy deemed to be appropriate was not different between the two sites. Educationally based reservations are an effective formulary tool for optimizing drug utilization.

Observations and effects of educational consults on allopurinol prescribing.

Allopurinol has been used in the management of hyperuricemic states for several years. Despite its efficacy for these indications, recent concerns have been raised regarding the unnecessary morbidity and mortality occasionally associated with its inappropriate use. In an effort to assess the utilization of allopurinol, a concurrent drug utilization review was undertaken. Fifty patients who were prescribed allopurinol were entered into the study and underwent health record review and patient interview, to determine appropriateness of therapy and the need for educational intervention. A number of inconsistencies with regard to established guidelines were identified. As well, 11 of 50 patients (22%) required intervention because of either lack of indication or excessive dose. Fifty-five percent of the educational interventions, performed by the pharmacist, were accepted as written. The current utilization of allopurinol at our facility differs substantially from guidelines developed for optimal utilization of allopurinol. Further, a pharmacy based intervention program can improve prescribing practices of allopurinol.

Impact of a pharmacist on the educational value of pharmaceutical industry film showings.

A controlled trial was performed to assess the impact of drug information provided by a pharmacist on the educational value to physicians of pharmaceutical manufacturers' film showings. The trial consisted of two teams of physicians who attended pharmaceutical manufacturers' films and who afterward answered multiple choice questions on the drug being promoted. In one group, the liaison pharmacist, who had no knowledge of the content of the questionnaire, presented information on the drug being featured prior to the film showing while the control group did not have a pharmacist presentation. Out of a perfect score of five, there was a higher test score in the group of physicians who attended the pharmacist presentation/film showing (n = 75) than in the group which only attended the film (n = 65) (3.3 +/- 1.1 versus 2.8 +/- 1.2, respectively (p = 0.017)). While there was no difference in the scores obtained by the clerks, interns and residents (3.2 +/- 1.1, 3.3 +/- 0.9, 3.4 +/- 1.2 respectively) when a pharmacist was present, in his or her absence the scores for clerks, interns and residents were 2.5 +/- 1.3, 2.8 +/- 1.0, 3.6 +/- 1.2 respectively with residents scoring higher than clerks (p = 0.047). A pharmacist can enhance the educational value of a pharmaceutical manufacturer's film showing.

Physician assessment of pharmacists' interventions--a method of estimating cost avoidance and determining quality assurance.

The impact and quality of select pharmacists' interventions were assessed by four physicians with pharmacology experience. Each physician was sent 30 interventions and asked to indicate if the intervention by the pharmacist was of a positive nature and would prevent morbidity and/or mortality. They were also questioned regarding effect of the intervention on hospital stay. Each physician received 15 interventions which were, and 15 interventions which were not assessed by three other physicians. Of the 15 interventions assessed by all four physicians there was favourable agreement among the physicians with respect to the impact of the intervention with 86.7 percent (52 of 60) of the judgements indicating that the pharmacists' intervention had a positive effect on therapy. There was less agreement with regard to whether hospital stay would, and the extent to which it would, have been prolonged. Using consensus it was estimated that eight of 15 interventions would have prolonged stays approximately 3.7 days each. The use of physicians was helpful in assessing the impact of pharmacists' interventions.

Ethanol enhances the hemodynamic effects of felodipine.

The acute hemodynamic and pharmacokinetic interactions between the vasodilating/diuretic drugs ethanol and felodipine, a 1,4-dihydropyridine calcium entry blocker, were assessed in 10 patients with untreated borderline hypertension. A non-intoxicating dose of ethanol or placebo was administered in a randomized, crossover, double-blind manner followed by felodipine 5 mg. Maximum hemodynamic effects occurred at four hours. Felodipine plus ethanol decreased mean (+/- SE) supine total peripheral resistance (13 +/- 2 vs 17 +/- 2 mmHg/L/min, p = 0.05) and diastolic blood pressure (68 +/- 3 vs 75 +/- 2 mmHg, p less than 0.05) associated with increased heart rate (72 +/- 3 vs 67 +/- 2 bpm, p less than 0.05) and cardiac index (3.7 +/- 0.4 vs 3.0 +/- 0.3 L/min/m2, p less than 0.05) more than felodipine alone. Greater differences were apparent in standing blood pressure. Co-administration of ethanol decreased standing systolic (113 +/- 8 vs 126 +/- 5 mmHg, p less than 0.01) and diastolic (69 +/- 5 vs 82 +/- 3 mmHg, p less than 0.01) blood pressure to a greater degree, but heart rate was not altered (87 +/- 6 vs 84 +/- 3 bpm). Substantial four hour diuresis occurred with both treatments (807 +/- 126 vs 806 +/- 169 ml). Adverse effects were frequent but most often occurred with felodipine plus ethanol (17 vs 11) as a result of postural lightheadedness (5 vs 1) related to hypotension. Felodipine bioavailability was not influenced by ethanol. However felodipine plasma concentrations greatly exceeded the expected concentrations, possibly due to a pharmacokinetic interaction with the grapefruit juice vehicle. Ethanol can enhance felodipine hemodynamics to produce clinically relevant adverse effects.

The comparative efficacy of cimetidine and ranitidine in controlling gastric pH in critically ill patients.

The comparative efficacy of intravenous cimetidine and ranitidine in controlling gastric pH in 100 intensive care unit patients was assessed in a double blind, prospective, randomized study. The total number of gastric pH determinations and the number of pH determinations with pH less than five were recorded. Patients received either cimetidine or ranitidine via continuous infusion, with dosage adjustments for patients with renal insufficiency. Antacids were administered each time the gastric pH was less than five. There was no difference overall in the number of patients who had at least one gastric pH determination less than pH 5. There was however, a larger proportion of patients with greater than or equal to 10, greater than or equal to 15, greater than or equal to 20 and greater than or equal to 25 per cent of gastric pH determination less than pH 5 in the cimetidine group than in the ranitidine group. This difference was statistically significant for greater than or equal to 25 per cent. The drugs were well tolerated. Ranitidine was as effective as cimetidine and possibly more so in controlling gastric pH.

Pharmacokinetics of high-dose pentobarbital in severe head trauma.

High-dose pentobarbital infusion has been advocated as an effective adjunct in controlling persistent intracranial hypertension after severe head trauma in patients refractory to conventional therapy. Pentobarbital disposition was assessed in 10 adults with severe nonpenetrating head injury after an intravenous loading dose of sodium pentobarbital, 10 mg/kg, infused over 1 hour, followed by a continuous infusion at 0.5 to 3.0 mg/kg/hr provided the cerebral perfusion pressure remained greater than 50 torr. Pharmacokinetic parameters of volume of distribution at steady state (Vss), total body clearance (CL), and t1/2 for the patients with trauma were statistically compared with similar estimates reported for seven adult subjects without head injury. On discontinuation of the pentobarbital infusion, serum concentrations in the patients followed a monoexponential decline with a mean (+/- SD) t1/2 and Vss that were significantly less than values reported for the control subjects (15.6 +/- 3.9 vs. 22.3 +/- 4.0 hours and 44.0 +/- 11.7 vs. 63.4 +/- 15.2 L, respectively). However, there was no significant difference between the mean pentobarbital CL of the patients (2.0 +/- 0.7 L/hr) and the subjects (2.0 +/- 0.4 L/hr). To our knowledge this is the first report on the disposition, elimination, and intrasubject variability of high-dose pentobarbital infusion in adult patients with head trauma.

The use of halothane in the treatment of status asthmaticus.

The case is presented of a 39-year-old male in status asthmaticus who failed to respond to conventional therapy, including positive pressure ventilation, and who required halothane anesthesia. The urgent need to reduce his elevated airway pressure and his risk of barotrauma prompted this action. The patient's response was prompt with marked reductions in airway pressure. Discontinuing halothane resulted in rises in airway pressure, necessitating reinstitution of halothane on several occasions. The mechanism of the bronchodilating action of halothane, as well as potential interactions with other pharmacotherapy and precautions for its use, are described.

Stability of ranitidine hydrochloride in total parenteral nutrient solution.

The stability of ranitidine hydrochloride was studied in a standard total parenteral nutrition (TPN) solution. The Canadian formulation of ranitidine hydrochloride (25 mg/mL) was added in 100-, 200-, and 300-mg doses to approximately 1200 mL of a TPN solution and allowed to stand at room temperature (23 degrees C) for seven days. During this time, samples were drawn at least once a day, and the ranitidine concentration was determined by high-performance liquid chromatography. The ranitidine concentration declined at roughly the same rate regardless of the initial concentration. During the study period, each of the three different concentrations declined to less than 70% of the initial concentration. Approximately 10% of the initial concentration was lost in 48 hours. Ranitidine hydrochloride admixtures were stable for up to 48 hours at room temperature in this standard TPN solution.