Intermittent dosing of alendronate.

OBJECTIVE: To review data describing use of intermittent dosing of alendronate. DATA SOURCES: A comprehensive literature search was conducted using MEDLINE (1966-May 2001) and EMBASE (1974-May 2001) databases to identify all information regarding intermittent dosing of alendronate. DATA SYNTHESIS: A small number of clinical studies have evaluated the use of intermittent alendronate dosing in an attempt to improve patient compliance and adverse events. CONCLUSIONS: Evidence from more controlled clinical trials and postmarketing data are needed to demonstrate the therapeutic efficacy and tolerability of intermittent alendronate dosing. The definitive role of intermittent dosing in patients with postmenopausal osteoporosis remains to be determined.     

Platelet transfusion therapy.

Platelet transfusions are of unquestionably proven benefit for the correction of thrombocytopenia or functional platelet disorders, and they have allowed for more intensive antineoplastic therapy. With the advent of blood component therapy most modern blood banks now have the capabilities for supplying at least limited quantities of platelets. Refinements in procurement methods will inevitably lead to a greater supply of platelets and the establishment of larger transfusion programs. These programs will need to incorporate facilities for platelet storage, recruitment of suitable donors, selection of special donors for refractory patients, and methods for quality control. As antineoplastic therapy becomes more aggressive, such transfusion programs will become an integral part of the operation of cancer treatment centers.     

Platelet storage media.

Platelet additive solutions (PASs) can be used as a substitute for plasma for the storage of platelet concentrates (PCs) in order to recover plasma for other purposes, to avoid transfusion of large volumes of plasma to patients, to improve storage conditions, and to make possible photochemical treatment for viral inactivation of PCs. The effects on platelet metabolism associated with different factors and compounds in PAS are only partly known. Available studies suggest that: (1) The presence of glucose in the platelet storage medium during the entire storage period is necessary for platelet metabolism. (2) Acetate is used as a substrate for platelet metabolism reducing production of lactate by platelets. By formation of bicarbonate, it maintains stable pH levels during storage. (3) The fall in pH can be rapid in PAS-containing media, due to the very limited buffering capacity of PAS compared with that of plasma. (4) Platelets stored in PAS at a citrate concentration of 8 mmol/l produce only half the quantity of lactate as that of platelets at 14-26 mmol/l of citrate. (5) Free fatty acids from plasma can be used as substrate for platelet metabolism and are supposed to be made available by the hydrolysis of plasma triglycerides. (6) For apheresis PCs with ACD anticoagulant, the presence of phosphate in PAS seems to be a critical factor to avoid low adenine nucleotide levels during storage. The results of available studies suggest that PAS for storing platelets has a great potential for wide use in transfusion medicine. A number of interesting questions regarding the effects of different compounds in PAS are still to be answered. It is expected that answers to these questions will be provided over the next few years.     

Platelet specific alloantigens.

The ability of platelets to aggregate and to form a platelet plug is central to the maintenance of normal hemostasis. When platelets have normal function, the severity of bleeding is related to the degree of thrombocytopenia. In patients with normal platelet production, the most common cause of thrombocytopenia is due to immune mechanisms that results in platelet injury and removal from the circulation. These mechanisms involve the binding of platelet-associated immunoglobulins and are classified as immune. Immune thrombocytopenias can be caused by autoantibodies (autoimmune thrombocytopenia), alloantibodies (isoimmune thrombocytopenia), or drug-induced immune complexes and conditions secondary to autoimmune disorders such as systemic lupus erythematosus. In this paper the focus is on alloimmune thrombocytopenias resulting from the formation of alloantibodies to platelet specific antigens. The clinical importance of the platelet alloantigens is due to their ability to elicit alloantibody production. Alloantigens, also referred to as isoantigens, are substances that induce the production of alloantibodies when they are infused into individuals of the same species who lack the specific alloantigen.     

Plasmin-Induced Platelet Aggregation and Platelet Release Reaction. EFFECTS ON HEMOSTASIS

Trypsin-activated pig plasmin and human plasmin activated by streptokinase (SK) caused aggregation of a suspension of washed platelets from human, rabbit, or pig blood. The platelet aggregation was reversible, but it was accompanied by a significant release of adenine nucleotides, serotonin, and platelet fibrinogen. Platelet fibrinogen was eventually digested. The effect of plasmin on platelets was inhibited by soybean trypsin inhibitor, epsilon aminocaproic acid, Persantin, prostaglandin E(1), and phenylbutazone. Short treatment of platelets with plasmin enhanced their sensitivity to ADP; however, this sensitivity was lost during longer incubation with plasmin. This enzyme also made platelets less sensitive to collagen and thrombin.Injecting SK into rabbits (10,000 U/kg body weight) caused a transitory drop of platelet count. These platelets lost part of their serotonin and fibrinogen. The administration of Persantin or of epsilon aminocaproic acid to rabbits before the injection of SK protected platelets from the loss of serotonin. Pretreatment with Persantin also resulted in partial protection of platelet fibrinogen in rabbits injected with SK. Platelets obtained from rabbits that had received both Persantin and SK were much more reactive with collagen than platelets obtained from rabbits injected with SK alone. Rabbits pretreated with Persantin did not show prolongation of the primary bleeding time that occurred after SK injection to control rabbits. It is suggested that plasmin generated after SK injection causes platelet release reaction in vivo. This may contribute to the hemostatic defect occurring during thrombolytic therapy or during systemic activation of fibrinolysis due to the other factors.     

Practical computer-assisted dosing for aminoglycoside antibiotics.

In principle, computer-assisted individualization of antibiotic dosing offers the prospect of better patient outcomes through improved dosing precision. In practice, however, the expertise in pharmacokinetics required to operate these programs has precluded their use by most physicians and pharmacists. We developed a computer program for individualization of dosing of aminoglycoside antibiotics under conditions in which access to experts in pharmacokinetics is impractical. The program is accurate, yet it requires less effort for data collection than previous drug dosing programs did. The program generates advice on a broad spectrum of topics, including dose adjustment, interpretation of measured drug concentrations in blood, and recommendations for monitoring drug concentrations. We tested its performance by prospectively comparing it with a clinical pharmacokinetic consultation service in a series of 78 consecutive patients. There were no differences in accuracy or bias in the prediction of drug concentrations. The rate of agreement between the program's dosing recommendations and those of the consultation service was 67 percent. This rate of agreement is typical of interexpert variation. In a stratified set of 24 of the 41 instances with significant disagreement regarding the recommended dose, experts ranked the program's recommendations as highly as those of the consultation service (95% confidence interval for difference in rank, -0.30 less than chi less than 0.47). The results suggest that expert systems can be coupled with pharmacokinetic dosing programs to deliver high-quality clinical recommendations for administration of antimicrobial agents.     

Accuracy in equianalgesic dosing. conversion dilemmas

The clinical benefit and increased application of opioid rotation has focused attention on efficacy differences between opioids and their respective equianalgesic dose ratios. Understanding the differences between the opioids is critical to understanding their equianalgesic dose ratios and for adjusting therapy following rotation to a new analgesic. The purpose of this article is to describe controversies regarding the relative potencies of these agents as presented in current equianalgesic charts and to provide pharmacologic information to assist the clinician with opioid rotation.     

Effect of once-daily dosing vs. multiple daily dosing of tobramycin on enzyme markers of nephrotoxicity

OBJECTIVE: To determine the incidence of nephrotoxicity of once-daily dosing (ODD) and multiple daily dosing (MDD) regimens of tobramycin in critically ill patients. DESIGN: Randomized, prospective clinical trial. SETTING:: Adult intensive care units at two university hospitals. PATIENTS: Fifty-eight critically ill patients with a suspected or documented aerobic Gram-negative infection. INTERVENTIONS: Patients were randomized to receive tobramycin by ODD (7 mg/kg) or MDD. Baseline urine aliquots and 24-hr urine collections were collected on days 3, 7, and 11 during therapy and on days 3, 7, and 11 following discontinuation of therapy for measurement of alanine aminopeptidase (AAP), N-acetyl-beta-d-glucosaminidase (NAG), and creatinine. MEASUREMENTS AND MAIN RESULTS: Fifty-four patients were evaluable (ODD n = 25; MDD n = 29). The groups were similar with regard to demographic and clinical variables. The tobramycin dose was higher in the ODD group compared with the MDD group (425 +/- 122.5 mg vs. 312.8 +/- 116.6 mg, p <.001). Patients in the MDD group received a mean of 3.89 +/- 1.14 mg.kg(-1)day(-1) at intervals of 11.92 +/- 3.12 hrs. In the ODD group, patients had a higher measured creatinine clearance at the end of therapy compared with MDD group (70 +/- 18.6 vs. 64.8 +/- 17.5 mL/min, p =.047). Fewer patients in the ODD group developed nephrotoxicity than the MDD group (5 vs. 12, p =.142). Although there were increases in urinary enzymes in both treatment groups (AAP, 8.7 +/- 2.9 vs. 5.2 +/- 2.1 units/24 hrs, p <.01 MDD vs. ODD; NAG, 14.7 +/- 4.9 vs. 6.8 +/- 3.1, p <.01 MDD vs. ODD), the increases in the ODD group were significantly lower than in the MDD group. CONCLUSIONS:: The ODD tobramycin regimen appeared to be less nephrotoxic than the MDD regimen despite significantly higher doses. Tobramycin administered by ODD may be the preferred dosing method in selected critically ill medical patients to reduce the incidence and extent of renal damage.     

Donepezil overdose: a tenfold dosing error.

OBJECTIVE: To report toxicity resulting from donepezil administration following a tenfold dosing error. CASE SUMMARY: A 79-year-old white nursing home patient with a history of Alzheimer disease and hypertension was inadvertently given 50 mg of donepezil instead of her usual 5-mg dose. She presented to the emergency department with nausea, vomiting, and persistent bradycardia (HR in the 40s). Routine laboratory studies were all within normal limits. Basilar rales were noted five hours after arrival. She was treated with atropine 0.2 mg as needed for bradycardia (HR <50 beats/min); a total of 3.0 mg was administered over 18 hours. Each bolus kept her HR >60 beats/min for one-half to two hours. No further vomiting or evidence of pulmonary edema occurred after her initial episodes. She returned to baseline by day 2 (HR in the 70s) and was returned to the nursing home. DISCUSSION: Donepezil is a centrally acting, reversible cholinesterase inhibitor that is used in the treatment of Alzheimer disease. Donepezil is highly specific for neural acetylcholinesterases, preferentially binding acetylcholinesterase by greater than three orders of magnitude over butyrylcholinesterases. This specificity minimizes peripheral adverse effects at therapeutic doses. Our patient mainly experienced bradycardia and had minimal secretory effects compared with what is usually seen with nonspecific cholinesterase inhibition. Medication errors like the one that produced this overdose are a common but preventable cause of morbidity in healthcare facilities. CONCLUSIONS: A tenfold dosing error caused donepezil toxicity. The main effect of this overdose was bradycardia, which responded to atropine therapy.