Annals of Pharmacotherapy

Lipids and lipoproteins have been shown to bind and neutralize endotoxin and to improve outcomes in animal models of sepsis.

To provide safety and pharmacokinetic data for a protein-free, phospholipid-rich emulsion developed as an agent to neutralize endotoxin, and to study the changes in lipids and lipoproteins following emulsion administration.

Thirty healthy male volunteers (aged 18–45 y) were given an emulsion containing 92.5% soy phospholipid, 7.5% soy triglyceride, and 18 mM sodium cholate using a double-blind, placebo-controlled crossover protocol. Emulsion at 3 escalating doses (75, 150, 300 mg/kg) based on phospholipid content was administered by intravenous infusion over 2 hours in the low- and mid-dose groups and 6 hours in the high-dose group.

All subjects completed the protocol without significant toxicities. A slight dose-dependent increase in indirect bilirubin at the 24-hour time point was observed in the emulsion treatment period, with a maximum difference between placebo and emulsion of 0.9 mg/dL. Mean ± SD peak phospholipid levels were 316 ± 30, 533 ± 53, and 709 ± 86 mg/dL, and phospholipid half-lives were 5.4 ± 0.6, 5.4 ± 0.5, and 8.0 ± 0.8 hours for the low, mid, and high doses, respectively. Increases in total cholesterol, low-density lipoprotein cholesterol and apolipoprotein A-I and B levels were observed. High-density lipoprotein cholesterol decreased immediately following emulsion infusion, but rebounded to above placebo levels by 24 hours.

A unique phospholipid-rich emulsion was shown to have a favorable safety profile and to expand the blood lipid and lipoprotein pool without the use of human-derived blood products. Lipid levels expected to protect against the physiologic effects of bacterial endotoxin were achieved.

To assess current prescribing practices regarding concomitant use of antipsychotic medications and summarize the reasons clinicians may prescribe >1 scheduled agent.

The pharmacy identified patients at William R Sharpe Jr Hospital currently receiving antipsychotic therapy. All patients receiving ≥2 scheduled antipsychotic agents concomitantly were included in the study. Data regarding the demographics, current medication combinations used, history of therapeutic regimens tried, and prescriber rationale were prospectively evaluated for a 60-day period beginning December 13, 2000, and ending February 10, 2001. Prescriber rationale for using >1 antipsychotic simultaneously and other drug therapy regimens that had been tried were compared with chart documentation and published therapeutic guidelines for schizophrenia.

Over a 60-day surveillance period, 206 patients were placed on scheduled antipsychotic medications, with 85 (41%) receiving at least 2 agents. Responders to a prescriber questionnaire (59%) indicated the most common rationale for combination therapy was augmentation; the least likely rationale was cross-titration. Survey responses also indicated a belief that there was questionable therapeutic benefit in more than half of the patients being treated with multiple antipsychotic combinations. Additionally, chart documentation showed that the majority of these patients did not receive an adequate trial of monotherapy with other atypical or typical agents, or clozapine prior to the combination antipsychotic regimen. Fifty-one percent of medical records did not document the rationale for concomitant therapy.

Due to the lack of published data, the practice of using multiple antipsychotic agents is considered to be a gray area that requires the prescriber to be at a heightened level of awareness in assessing effectiveness and safety. Documentation of rationale, adverse effects, and response to the treatment regimen is essential in providing optimal care for the patient.

To determine whether a letter-based intervention program submitted to prescribers and pharmacists would improve drug therapy in users of high-dose β₂-agonists (HDBs). STUDY DESIGN: Retrospective drug utilization review.

The intervention group consisted of 135 asthmatic patients (identified through ICD-9-CM codes) in the Connecticut Medicaid Program who submitted >1 claim per month for short-acting β₂-agonists (over a 6-mo period). Patient-specific intervention packets were mailed to the patients' prescribers and pharmacists, and their use of long-term control agents and healthcare utilization was evaluated over 6 months. These variables were compared with a comparison group (n = 510) of asthmatics drawn from the same Medicaid program who were not considered to be high-dose users of short-acting β₂-agonists at baseline.

Prior to the intervention, the intervention group used fewer long-term asthma control agents as compared with the comparison group (58% vs. 96%; p < 0.001); there was no significant difference after the intervention program (65% vs. 71%; p = 0.169). The acquisition of spacers was greater in the intervention group than in the control group after the intervention (7% vs. 2%; p = 0.007). At the end of the 6-month intervention period, 46% of patients in the intervention group were no longer HDB users (p < 0.001). The higher frequency of prescriber office visits in the intervention group than the comparison group before the intervention (0.46 ± 0.82 vs. 0.25 ± 0.66; p < 0.001) was not evident after the intervention program (0.24 ± 0.63 vs. 0.18 ± 0.60; p = 0.283).

This intervention program had modest impact on improving the use of long-term control agents and reducing prescriber office visits.

To improve medication adherence by reducing self-reported adherence barriers, and to identify medication discrepancies by comparing physician-prescribed and patient-reported medical regimens.

Prospective, randomized, controlled trial.

A single academically affiliated community health center. Eligible patients had type 2 diabetes, had undergone laboratory testing in the year preceding the study, and had visited the clinic in the 6 months preceding the study.

A pharmacist administered detailed questionnaires, provided tailored education regarding medication use and help with appointment referrals, and created a summary of adherence barriers and medication discrepancies that was entered into the medical record and electronically forwarded to the primary care provider.

Changes in self-reported adherence rates and barriers were compared 3 months after the initial interview. Intervention patients with medication discrepancies at baseline were assessed for resolution of discrepancies at 3 months.

Rates of self-reported medication adherence were very high and did not improve further at 3 months (6.9 of 7 d, with all medicines taken as prescribed; p = 0.3). Medical regimen discrepancies were identified in 44% of intervention patients, involving 45 doses of medicines. At 3-month follow-up, 60% of discrepancies were resolved by corrections in the medical record, while only 7% reflected corrections by patients.

In this community cohort, patients reported few adherence barriers and very high medication adherence rates. Our patient-tailored intervention did not further reduce these barriers or improve self-reported adherence. The high prevalence of medication discrepancies appeared to mostly reflect inaccuracies in the medical record rather than patient errors.

To retrospectively evaluate clinical experiences with argatroban dosing, particularly incremental dosage adjustments, during a clinical trial of argatroban anticoagulation in heparin-induced thrombocytopenia (HIT).

Records of 304 patients with HIT administered argatroban during a prospective study were reviewed to determine each dose, incremental dosage adjustment, and duration of therapy. Dosing information (stratified by patient initial dose) and incremental adjustments (overall, and stratified by dose from which adjustment occurred) were summarized. The relationship between median incremental adjustments and adverse outcomes, including bleeding, was investigated.

Two hundred seventy-one (89%) patients received initial doses of 1.9–2.1 μg/kg/min (group B). Twenty-six (9%) patients were started at a lower dose. Group B's median (5–95th percentile) final dose was 1.6 (0.25–4.0) μg/kg/min. During a median of 6 days of argatroban therapy, patients underwent a median of 3.0 dosage adjustments using a median and mode incremental adjustment of 0.5 μg/kg/min (5–95th percentile, 0.1–2.0 μg/kg/min). Fifty-two (17%) patients required no dosage adjustment. Incremental adjustments decreased with decreasing current dose (e.g., median 0.25 μg/kg/min from doses of 0.26–0.75 μg/kg/min). Outcomes were similar between patients with no adjustment or with median incremental adjustments of ≤0.4, 0.41–0.75, or >0.75 μg/kg/min.

Based on this clinical experience, together with the established linear pharmacokinetics and pharmacodynamics of argatroban, appropriate dosage increments may be proposed for argatroban-treated patients with HIT. Incremental adjustments of 0.5 μg/kg/min are reasonable for most patients. Smaller adjustments (e.g., 0.25 μg/kg/min) should be used when modifying lower doses, such as those recommended for use in hepatically impaired patients.

To determine whether there is an association between a woman's exposure to direct-to-consumer (DTC) advertisements for 2 osteoporosis drugs and presentation for bone densitometry.

A matched case–control study was conducted between October and December 1998 at an academic primary care clinic in Seattle, WA. Seventeen women from the study population (aged ≥18 y, seen in the previous 2 y at the academic primary care clinic) presented for bone densitometry. All 51 women completed a self-administered questionnaire.

Women familiar with 1 of 2 osteoporosis drugs due to exposure to advertisements had 9 times the odds of densitometry (unadjusted OR 9.3, 95% CI 1.0 to 86). Multivariate analysis, including confounders such as education level and whether a woman had previously had 3 screening tests (mammography, Pap smear, serum cholesterol), revealed a significant and strong association between exposure to advertisements and densitometry (adjusted OR 29, 95% CI 1.6 to 511).

DTC marketing may increase health services utilization. Further independent evaluation of DTC marketing based on available observational evidence is feasible and warranted.

To evaluate and validate a 10-item self-administered questionnaire for use by elderly patients to identify who is at increased risk of potentially experiencing a medication-related problem (MRP).

Forty participants aged ≥60 years who took ≥2 prescription drugs regularly completed the questionnaire. Data collection was based on patient interviews, review of pharmacy or medical records, and drug regimen reviews (DRRs). Outcome measures included feasibility, inter-rater reliability, test–retest reliability, internal consistency, and validity of the questionnaire. DRR severity scores were determined for each participant based on published guidelines for appropriate use.

The questionnaire was easily administered to this group of older adults. Overall inter-rater reliability was high (r = 0.847). Nine of 10 individual questions matched well between the investigator and participants (κ 0.4–0.6 for 3 questions; >0.6 for 6 questions). Test–retest reliability was significant for all 10 questions (κ > 0.6). Internal consistency was acceptable (a = 0.69). DRR severity scores were correlated with questionnaire responses to determine validity. The number of yes answers correlated significantly with higher DRR severity scores (p < 0.001). Furthermore, 5 individual questions significantly correlated with DRR severity scores.

This study suggests that a self-administered questionnaire can be used in an older adult population to identify patients potentially at increased risk of MRPs. Clinicians in ambulatory care settings with similar patient populations can use a modified form of the questionnaire to screen for patients who should receive a medication review.

To describe the prevalence of potentially inappropriate medication use in community residential care (CRC) facilities at baseline, describe exposure to potentially inappropriate drugs during the 1-year follow-up, and examine characteristics associated with potentially inappropriate use.

A cohort study was conducted using 282 individuals aged ≥65 years entering a CRC facility in a 3-county area in the Puget Sound region of Washington State between April 1998 and December 1998 on Medicaid funding.

Use of potentially inappropriate medications as defined by explicit criteria (e.g., drugs that should generally be avoided in the elderly because potential risks outweigh any potential benefits).

Sixty-two (22%) residents took a total of 75 potentially inappropriate medications at baseline. The most common agents used at baseline were oxybutynin (3.5%) and amitriptyline (3.5%). The incidence of new use of potentially inappropriate medications was 0.1/100 person-days during the follow-up period. Potentially inappropriate use was related to self-reported fair or poor health (adjusted OR 1.42; 95% CI 1.05 to 1.92) and number of prescription drugs (adjusted OR 1.12; 95% CI 1.05 to 1.19). In the Cox proportional hazard model, no characteristics predicted new potentially inappropriate medication use during the follow-up.

Potentially inappropriate medication use is common among residents in CRC facilities. A comprehensive periodic review may be beneficial for reducing potentially inappropriate use, especially for patients taking multiple drugs.

Angiotensin-converting enzyme (ACE) inhibitor–induced acute pancreatitis has been described in various case reports and drug surveillance databases. At present, no epidemiologic studies examining the potential association between ACE inhibitors and acute pancreatitis have been identified.

To determine whether there is an association between ACE inhibitor use and pancreatic events (acute pancreatitis, pancreatic surgery).

A retrospective cohort of Ontario residents aged ≥66 years was created using population-based administrative databases from January 1, 1994, through March 31, 2000. We compared the incidence of pancreatic events among new users of ACE inhibitors (study group), warfarin (null baseline group), and dihydropyridine calcium-channel antagonists (DCCAs; disease control group) using multivariate Cox proportional hazard models.

The primary outcome measure was hospitalization with acute pancreatitis; the secondary outcome measure was incidence of pancreatic surgery.

For acute pancreatitis, the crude incidence rates per 10 000 person-years were 9.0 for the ACE inhibitor group (n = 174 824); 7.1 for the DCCA group (n = 73 719), and 7.6 for the warfarin group (n = 40 057). Relative to warfarin users, neither ACE inhibitor users (adjusted rate ratio [aRR] = 1.35; 95% CI 0.94 to 1.93) nor DCCA users (aRR = 1.09; 95% CI 0.72 to 1.62) were at significantly higher risk of hospitalization for acute pancreatitis. For pancreatic surgery in the same population, the crude incidence rates per 10 000 person-years were 10.5 for the ACE inhibitor group, 10.6 for the DCCA group, and 10.7 for the warfarin group. Relative to subjects taking warfarin, neither ACE inhibitor users (aRR = 1.09; 95% CI 0.80 to 4.49) nor DCCA users (aRR = 1.11; 95% CI 0.79 to 1.56) were at significantly higher risk for pancreatic surgery.

The use of ACE inhibitors does not appear to be associated with significant risk of acute pancreatitis among the elderly.

To investigate the cardiotoxicity of bupropion hydrochloride in deliberate self-poisoning.

A prospective study was conducted in a national poisons information center (PIC) of cases of adult deliberate self-poisoning with medical record follow-up of the patients. Fifty-nine cases of bupropion deliberate self-poisoning managed in the hospital, in which the New South Wales PIC was contacted for advice, were evaluated from November 2000 through July 2001. Clinical effects and electrocardiographic (ECG) parameters (QRS, QT, QTc) were the main outcome measures.

ECGs were available for 17 of the 59 patients for analysis, 9 patients (53%) were women, and median patient age was 28 years (interquartile range 22–37). The mean ± SD ingested bupropion dose was 3.8 ± 3.1 g. Tachycardia occurred in 13 patients (76%; 95% CI 50 to 93) and hypertension in 8 patients (47%). There were no reports of hypotension or arrhythmias. There was a significantly increased QTc of 461 ± 34 msec in the patients with bupropion overdose compared with previously developed controls; 13 of the 17 cases had a QTc >440 msec (76%; 95% CI 50 to 93). The uncorrected QT interval did not differ from that of controls.

A moderately prolonged QTc (>440 msec) is common in bupropion overdose. However, this may not be a result of intrinsic cardiac toxicity, but overcorrection of the QTc due to the tachycardia that occurs. It is important that the QTc is interpreted with caution in overdoses of agents that cause significant tachycardia (>100 beats/min).

To design, develop, and evaluate a simple, understandable medicine label and patient information leaflet (PIL) for nystatin suspension, and to assess the effect of incorporating pictograms on understanding in low-literate participants.

Patient information materials were designed and pretested in a pilot study (n = 20), and were subjected to the Fry's readability test. The final evaluation was conducted with 60 low-literate participants who had a maximum of 7 years of formal schooling and for whom English was their second language. Demographic data were collected. Participants were randomly allocated to a control (text-only information) or experimental (text + pictogram information) group, shown the medicine label and PIL, and asked to read them. A series of questions was asked about the instructions and an understanding level was calculated in each case. A second series of questions assessed patient acceptability of the materials. Differences in understanding were determined by χ² tests.

Both sets of these simple written materials were generally well understood. However, the presence of pictograms was shown to improve the comprehension of more complex information, resulting in significantly more participants in the experimental group obtaining a score for understanding >80% for both the medicine label and PIL. A clear preference for the materials incorporating pictograms was expressed.

The presence of pictograms had a positive effect in the acquisition and comprehension of drug information.

To report a case of autoimmune hemolytic anemia (AIHA) secondary to levofloxacin.

An 82-year-old white man was treated with levofloxacin 500 mg/d for cellulitis. Three days following completion of levofloxacin therapy, the patient presented to the emergency department with severe jaundice, dizziness, and loss of vision. He received packed red blood cells (PRBCs) and was discharged home. Two days later at the follow-up visit, he was diagnosed with AIHA secondary to levofloxacin. The patient was hospitalized and treated with a tapering dose of prednisone and additional PRBC infusion. He was discharged from the hospital in stable condition after 3 days. Repeated hematologic laboratory studies following discharge demonstrated that the hemolytic anemia had resolved.

Hemolytic anemia due to levofloxacin is an extremely rare, but potentially fatal, adverse drug event. An objective causality assessment revealed that the adverse reaction was probable. To our knowledge, this is the first published case of levofloxacin-induced AIHA. However, there are published case reports of hemolytic anemia with other fluoroquinolones including ciprofloxacin (n = 12) and temafloxacin (n = 95). Temafloxacin was withdrawn from the market in 1992 due to this adverse effect. The mechanism by which levofloxacin triggers hemolytic anemia is unknown. We believe that an immune-mediated reaction is most likely.

Levofloxacin-induced AIHA is a rare but serious complication of therapy. Immediate discontinuation of the offending medication and treatment of the hemolytic anemia are essential. Until more information is available, levofloxacin should not be prescribed for patients with previous reactions to any fluoroquinolone.

To describe a case of levofloxacin-induced partial Achilles tendon rupture; this occurred in the presence of known risk factors and acute renal failure.

A 79-year-old white man received levofloxacin for presumed pneumonia, developed acute renal failure in the setting of dehydration, and began having ankle pain on the 12th day of admission. Levofloxacin was discontinued, and magnetic resonance imaging revealed a 6-cm partial tear and degenerative changes.

The Naranjo probability scale indicates a possible association between levofloxacin and tendon rupture because the event occurred in the setting of known risk factors such as steroid use, renal failure, older age, and male gender.

Levofloxacin, like other fluoroquinolones, may cause Achilles tendon rupture, and this may be particularly likely with known risk factors.

To report a case of anaphylactoid reaction in an HIV-negative patient associated with the administration of intravenous ciprofloxacin.

A 79-year-old Armenian man developed an anaphylactoid reaction following a first-time exposure to intravenous ciprofloxacin. This reaction was characterized by severe hypotension, wheezing, tachypnea, tachycardia, and pruritus. The patient had complete recovery once ciprofloxacin treatment was terminated and supportive care was provided.

Fluoroquinolones are important therapeutic agents in the management of infectious diseases and are generally safe and well tolerated. Anaphylactoid and anaphylactic reactions have been documented as adverse effects of ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, and moxifloxacin. To date, >33 cases have been reported with ciprofloxacin, of which at least 10 occurred in HIV-positive patients. In Europe, 15 cases of anaphylactoid reactions to ofloxacin have been reported and, more recently, with moxifloxacin. Since anaphylactoid reactions are potentially life threatening, the administration of fluoroquinolones to patients who have experienced a prior reaction to any of these agents should be avoided, unless tolerance has been confirmed by oral challenge tests.

The anaphylactoid reaction in our patient was probably induced by ciprofloxacin as validated by the Naranjo probability scale. Although anaphylactoid/anaphylactic reactions are rare adverse effects of ciprofloxacin and other fluoroquinolones, clinicians should be aware of this potentially fatal event.

To report a case of dose-dependent angioedema secondary to the use of the angiotensin-receptor blocker (ARB) valsartan.

A 64-year-old Hispanic woman presented with swelling of the lips shortly after an increase in her valsartan dose for uncontrolled hypertension. Other potential causes were not identified. The angioedema subsequently resided after a dosage reduction and observation. Use of the Naranjo probability scale indicated a probable relationship between the angioedema and valsartan therapy in this patient.

Drug-induced angioedema is often associated with the use of angiotensin-converting enzyme (ACE) inhibitors and is probably secondary to their effects on bradykinin levels. ARBs are thought to produce few, if any, cases of angioedema if excess bradykinin levels are the root cause of angioedema secondary to ACE inhibitor use. Several potential ARB-induced cases of angioedema have been reported. The exact mechanism of angioedema induced by drugs in both of these classes is unknown. Animal data suggest that there may be a relationship between ARB use and increased tissue bradykinin levels secondary to stimulation of angiotensin II AT2 receptors.

This is the third reported case of valsartan-induced angioedema and the first thought to be dose dependent. Practitioners should be aware of this potential adverse effect of valsartan, although the underlying cause is still not known.

To report a case of decreased international normalized ratio (INR) in a patient receiving warfarin and bosentan.

A 35-year-old African American woman with a history of primary pulmonary hypertension managed with warfarin, diltiazem, and hydrochlorothiazide was initiated on bosentan therapy. The patient's INR had been stable and within therapeutic range (goal 2.0–3.0) for the previous 3 months with warfarin 27.5 mg/wk, but became subtherapeutic after 10 days of bosentan therapy. Addition of over-the-counter medications, herbal products, vitamins, or dietary changes was denied. The INR remained subtherapeutic for 5 weeks despite weekly warfarin dose increases. After these 5 weeks of dosage increases, the INR became supratherapeutic for 3 weeks, resulting in a subsequent dosage decrease. The resultant warfarin dose required to maintain a therapeutic INR was 45 mg/wk, a 63.6% dosage increase after the initiation of bosentan.

This case shows that a clinically significant interaction between bosentan and warfarin may exist. An objective causality assessment revealed that the interaction was probable. Although the possibility of this interaction has been noted, no previously documented occurrence of this interaction has been identified.

Bosentan may significantly decrease the anticoagulant properties of warfarin. The INR should be monitored more frequently when bosentan is initiated, adjusted, or discontinued in patients taking warfarin.

To report a case of rhabdomyolysis after concomitant use of simvastatin, a commonly used hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and fluconazole, an azole antifungal agent.

An 83-year-old white man with a history of congestive heart failure and hyperlipidemia presented to the hospital 1 week following the addition of fluconazole to a medication regimen that included simvastatin 40 mg once daily. The patient had severe muscle weakness and a markedly elevated serum creatine kinase activity, which resolved following discontinuation of simvastatin and fluconazole.

Rhabdomyolysis is a recognized adverse effect of HMG-CoA reductase inhibitors (statins), commonly caused by their interaction with other drugs, such as azole antifungals, that inhibit the cytochrome P450 isoenzyme family. An objective causality assessment revealed that the adverse drug event was probable. Although drug interactions have been described for combinations of other HMG-CoA reductase inhibitors and azole antifungals, rhabdomyolysis likely caused by the interaction between simvastatin and fluconazole has not yet been reported. This case reinforces the importance of being vigilant for drug interactions, particularly in connection with commonly prescribed medications such as statins.

Patients receiving statins who have cancer may receive azole antifungals and other drugs that inhibit CYP3A4 during treatment, predisposing them to toxicity. These patients should therefore be monitored closely for drug interactions.

To report a case of steroid-induced psychosis in a child that resolved with the treatment of promethazine, a phenothiazine derivative.

A 2-year-old white boy with a history of relapsed acute lymphoblastic leukemia underwent a bone marrow transplant and developed graft-versus-host disease, which was treated with methylprednisolone. Within 24 hours of initiation of the methylprednisolone, the patient developed symptoms associated with steroid-induced psychosis including mania, head-banging, and excessive crying. Because the corticosteroid could not be discontinued, promethazine, a phenothiazine derivative, was used to treat the psychotic symptoms. Symptoms resolved with use of promethazine.

A number of published reports describe the appearance of psychological symptoms with corticosteroid use. While the mechanism is unclear, the reaction is usually reversible with dose reduction or discontinuation of the corticosteroid. In cases where this cannot be done, typical treatment involves an antipsychotic medication. Most antipsychotic medications, such as the phenothiazine class, have not been evaluated in very young childen. Promethazine is a phenothiazine derivative that has been used in children for a number of nonpsychiatric indications.

Promethazine may be effective in treating steroid-induced psychosis in pediatric patients.

To report a case of thalidomide-induced sinus bradycardia in an elderly man.

A 72-year-old white man, with transfusion-dependent refractory anemia with ringed sideroblasts and hypertension treated with atenolol, was started on thalidomide 100 mg at bedtime. During the dose titration period (maximum dose 400 mg/d), his heart rate decreased from a baseline of 63 beats/min to as low as 44 beats/min with positive electrocardiogram findings of sinus bradycardia. After discontinuation of atenolol, the patient's heart rate increased to 68 beats/min, but symptoms of bradycardia persisted. Due to the patient's continued dizziness and lightheadedness, thalidomide was discontinued. In the 3 months following discontinuation of thalidomide, the patient's heart rate increased to an average of 74 beats/min.

Clinical trials and postmarketing surveillance suggest that the incidence of thalidomide-induced bradycardia is low. The mechanism of this effect is unknown. Concurrent medications affecting the heart rate may also increase the risk of thalidomide-induced bradycardia. Following titration of thalidomide to a maximum dose of 400 mg/d, our patient's heart rate decreased markedly, resulting in intermittent symptoms of lightheadedness and dizziness. He may have been at higher risk of thalidomide-induced bradycardia because of concurrent administration of atenolol. An objective causality assessment revealed that the adverse event was probable.

Despite the low incidence of thalidomide-induced bradycardia, it appears to be an important adverse effect, particularly in patients with comorbidities or concurrent medications that decrease heart rate. Therefore, providers should monitor these patients closely for signs and symptoms of bradycardia during the administration of thalidomide.

To report a patient with dapsone-induced sulfone syndrome.

A 42-year-old HIV-infected African American man developed fever, lymphadenopathy, exfoliative dermatitis, hepatitis, and methemoglobinemia 4 weeks after starting dapsone. Complete resolution of symptoms and laboratory abnormalities occurred with cessation of dapsone therapy.

Sulfone syndrome is not a well-known sequela of dapsone therapy. It is not dose-related, usually occurs in doses of 50–300 mg/d, all cases occur within 2 months of starting dapsone, all patients have fever, and most patients will develop rash and evidence of hepatic injury. The temporal relationship between dapsone therapy and onset of clinical symptoms and objective data led us to believe that dapsone caused sulfone syndrome in our patient. An objective causality assessment revealed that the adverse drug event was probable.

Although sulfone syndrome appears to be relatively uncommon, healthcare practitioners must be aware of the potentially fatal syndrome associated with dapsone use.

To review the information currently available on rasburicase for treatment and prevention of hyperuricemia.

MEDLINE (1966–August 2002) was searched for primary and review articles.

Studies evaluating rasburicase, including abstracts and proceedings, were considered for inclusion. English-language literature was evaluated for the pharmacology, pharmacodynamics, pharmacokinetics, therapeutic use, and adverse effects of rasburicase.

Rasburicase, a recombinant urate oxidase, has been shown to be effective in lowering uric acid and preventing uric acid accumulation in patients with hematologic malignancies who had hyperuricemia or who were at high risk for developing hyperuricemia. It has been approved for pediatric use in the US.

In addition to allopurinol, hydration, and urinary alkalinization, rasburicase is a new alternative for the treatment and prevention of hyperuricemia in patients with hematologic malignancies. Its rapid onset of action and the ability to lower preexisting elevated uric acid levels are the advantages of rasburicase compared with allopurinol. It may allow the patient to receive chemotherapy treatment without delay.

To describe the pharmacology, pharmacokinetics, efficacy, and safety of bosentan in the treatment of pulmonary arterial hypertension (PAH).

A MEDLINE and Current Contents search (1966–June 2002) of the English-language literature was conducted to identify published dose-ranging, pharmacokinetic, pivotal efficacy trials and review articles of bosentan and endothelin antagonists. Additional references were identified from the bibliographies of the retrieved articles.

Bosentan is the first orally active, nonpeptide endothelin receptor antagonist approved by the Food and Drug Administration for use in patients with World Health Organization (WHO) functional class III and IV PAH. Titrated to a dose of 125 mg twice daily, bosentan produces pulmonary vasodilation, improving cardiopulmonary hemodynamics leading to better outcomes for patients. It is metabolized primarily by the hepatic system via the cytochrome P450 enzyme pathway and eliminated by biliary excretion. Bosentan is an inducer of the isoenzymes CYP3A4 and 2C9. It possesses a unique pharmacokinetic profile with a terminal elimination half-life of approximately 5 hours, yet steady-state plasma concentrations are not achieved for 3–5 days as a result of enhanced drug clearance and autoinduction following multiple daily dosing. The major adverse effects of bosentan are the potential for birth defects and hepatotoxicity.

The use of bosentan in patients with WHO functional class III and IV PAH is associated with improved exercise tolerance, cardiopulmonary hemodynamics, and increased time to clinical worsening when compared with placebo. It offers significant advantage in ease of administration and quality of life compared with epoprostenol therapy, with similar efficacy.

To review the current evidence for use of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) in nontraditional lipid-related applications, including acute coronary syndromes, peripheral arterial disease, stroke, and renal disease, and to describe ongoing trials evaluating the role of statins in these conditions.

Clinical literature was identified by a MEDLINE search (1990–November 2002) using ≥1 of the following search terms: acute coronary syndrome(s), angina pectoris, atherosclerosis, atorvastatin, clinical trials, diabetes mellitus, end-stage renal disease, fluvastatin, lovastatin, myocardial infarction, peripheral arterial disease, pravastatin, simvastatin, statins, and stroke. Treatment guidelines issued by professional and governmental organizations, such as the American Diabetes Association, American Heart Association, National Cholesterol Education Program, National Kidney Foundation, and National Stroke Foundation, were reviewed.

Articles identified from the data sources were included if they pertained to the conditions described in the objectives and provided unique information concerning use of statins.

Substantial evidence exists for the use of statins in acute coronary syndromes. Meta-analyses of data from major clinical trials indicate that statins prevent first and recurrent stroke, and large-scale trials are underway to evaluate the efficacy of statins in this setting. Accumulating evidence suggests that statins may be beneficial in reducing the morbidity and mortality associated with peripheral arterial disease and end-stage renal disease, and results from ongoing trials may confirm these benefits. Statins may also have a future role in amelioration of other conditions associated with atherosclerosis, such as diabetes mellitus.

A large body of evidence supports the evaluation of statins in clinical settings beyond primary and secondary prevention of morbidity and mortality associated with coronary atherosclerosis.

To describe the development of guidelines for initial use of low-molecular-weight heparins (LMWHs) and other anticoagulants in acute-care hospitals that are part of a national group purchasing organization (GPO).

A systematic literature search (1970–December 2001) was conducted to identify evidence on the efficacy of various anticoagulants for initial therapy in deep-vein thrombosis and pulmonary embolism, and in treatment of acute coronary syndrome. A group consensus method was then used to develop guidelines. Guidelines were reviewed and revised by an internal expert panel as well as an external expert panel. Final guidelines were disseminated to GPO members and assistance was provided with implementation at the local level.

The final set of guidelines is described. The guidelines are organized based on recommended therapeutic options for each indication. For each option, consensus opinion is provided on the level of evidence that exists in the literature, comparisons of cost and convenience, and additional dosing information. The guidelines were disseminated along with supporting material to interested GPO member hospitals, and teleconferences were held to facilitate implementation at the local level. The guidelines were initially implemented at 18 hospitals across the country.

The process by which these guidelines were developed, plus the final set of guidelines, may be useful to hospitals and healthcare systems contemplating or engaged in a similar effort with this class of drugs.

To provide an overview of the role of amylin, as well as that of pramlintide, a synthetic analog of amylin, in maintaining glucose homeostasis; and discuss the pharmacology, pharmacokinetics, efficacy, adverse effects, and role of pramlintide in the control of postprandial hyperglycemia.

The data presented in this review were obtained from published literature, abstracts presented at scientific meetings, and information on file with the manufacturer. MEDLINE searches (1986–March 2003) using the search terms pramlintide and amylin were conducted to identify clinical trials and review articles. Additionally, the bibliographies of the identified articles were reviewed.

Clinical trials have demonstrated that amylin in combination with insulin controls postprandial glucose levels by decreasing food intake, slowing gastric emptying, and suppressing glucagon secretion. Clinical trials also showed significant decreases in mean plasma glucose levels and glycosylated hemoglobin, as well as the added benefits of weight loss and reduction in insulin doses. The most commonly reported adverse effects associated with pramlintide in clinical trials were gastrointestinal complaints and hypoglycemia, which occurred most frequently during initiation of therapy.

The administration of insulin alone often does not result in optimal metabolic control. The treatment of amylin deficiency, in addition to insulin deficiency, may be warranted in order to obtain glucose homeostasis. The role of pramlintide, an amylin analog, will become clearer as more clinical data become available.

To review the literature related to the treatment of alcohol dependence with acamprosate, a synthetic compound structurally similar to the naturally occurring amino acid, homotaurine.

Primary literature and review articles were identified by MEDLINE search (1966–June 2003). Abstracts from recent meetings were also reviewed.

Acamprosate has been marketed in 24 countries. Although the precise mechanism of acamprosate in the treatment of alcohol-dependent patients is unclear, it may restore the balance between inhibitory and excitatory neurotransmission in the central nervous system. European trials have shown consistent increases in abstinence rates compared with placebo when acamprosate use was paired with appropriate psychosocial and behavioral therapies. Decreased direct and indirect healthcare costs associated with acamprosate treatment have also been reported.

Acamprosate is a promising medication for the treatment of alcohol dependence in the US.

To review the etiology, diagnosis, and clinical presentation of Graves disease and provide an overview of the standard and adjunctive treatments. Specifically, antithyroid drugs, β-blockers, inorganic iodide, lithium, and radioactive iodine are discussed, focusing on current controversies.

Primary articles were identified through a MEDLINE search (1966–July 2000). Key word searches included β-blockers, Graves disease, inorganic iodide, lithium, methimazole, and propylthiouracil. Additional articles from these sources and endocrinology textbooks were also identified. We agreed to include articles that would highlight the most relevant points, as well as current areas of controversy.

Graves disease is the most common cause of hyperthyroidism. The 3 main treatment options for patients with Graves hyperthyroidism include antithyroid drugs, radioactive iodine, and surgery. Although the antithyroid drugs propylthiouracil (PTU) and methimazole (MMI) have similar efficacy, there are situations when 1 agent is preferred. MMI has a longer half-life than PTU, allowing once-daily dosing that can improve patient adherence to treatment. PTU has historically been the drug of choice for treating pregnant and breast-feeding women because of its limited transfer into the placenta and breast milk. Adjuvant therapies for Graves disease include β-blockers, inorganic iodide, and lithium. β-Blockers are used to decrease the symptoms of hyperthyroidism. Inorganic iodide is primarily used to prepare patients for thyroid surgery because of its ability to decrease the vascularity of the thyroid gland. Lithium, which acts in a manner similar to iodine, is not routinely used due to its transient effect and the risk of potentially serious adverse effects. In the US, radioiodine therapy has become the preferred treatment for adults with Graves disease. It is easy to administer, safe, effective, and more affordable than long-term treatment with antithyroid drugs. Hypothyroidism is an inevitable consequence of radioiodine therapy. Radioiodine is contraindicated in pregnant women because it can damage the fetal thyroid gland, resulting in fetal hypothyroidism. Bilateral subtotal thyroidectomy, which was once the only treatment available, is now performed only in special circumstances. In addition to the normal risks associated with surgery, laryngeal nerve damage, hypoparathyroidism, and hypothyroidism can occur following that procedure.

Despite extensive experience with medical management, controversy prevails regarding choosing among the various drugs for treatment of Graves disease. None of the treatment options, including antithyroid drugs, radioiodine, and surgery, is ideal. Each has risks and benefits, and selection should be tailored to the individual patient.

To demonstrate the usefulness of interrupted time series analysis in clinical trial design.

A safety data set of electrocardiographic (ECG) information was simulated from actual data that had been collected in a Phase I study. Simulated data on 18 healthy volunteers based on a study performed in a contract research facility were collected based on single doses of an experimental medication that may affect ECG parameters. Serial ECGs were collected before and during treatment with the experimental medication. Data from 7 real subjects receiving placebo were used to simulate the pretreatment phase of time series; data from 18 real subjects receiving active treatment were used to simulate the treatment phase of the time series. Visual inspection of data was performed, followed by tests for trend, seasonality, and autocorrelation by use of SAS.

There was no evidence of trend, seasonality, or autocorrelation. In 11 of 18 simulated individuals, statistically significant changes in QTc intervals were observed following treatment with the experimental medication. A significant time of day and treatment interaction was observed in 4 simulated patients.

Interrupted time series analysis techniques offer an additional tool for the study of clinical situations in which patients must act as their own controls and where serial data can be collected at evenly distributed intervals.

Statistical techniques have traditionally been underused in spontaneous reporting systems used for postmarketing surveillance of adverse drug events. Regulatory agencies, pharmaceutical companies, and drug monitoring centers have recently devoted considerable efforts to develop and implement computer-assisted automated signal detection methodologies that employ statistical theory to enhance screening efforts of expert clinical reviewers.

To provide a concise state-of-the-art review of the most commonly used automated signal detection procedures, including the underlying statistical concepts, performance characteristics, and outstanding limitations, and issues to be resolved.

Primary articles were identified by MEDLINE search (1965–December 2002) and through secondary sources.

All of the articles identified from the data sources were evaluated and all information deemed relevant was included in this review.

Commonly used methods of automated signal detection are self-contained and involve screening large databases of spontaneous adverse event reports in search of interestingly large disproportionalities or dependencies between significant variables, usually single drug–event pairs, based on an underlying model of statistical independence. The models vary according to the underlying model of statistical independence and whether additional mathematical modeling using Bayesian analysis is applied to the crude measures of disproportionality. There are many potential advantages and disadvantages of these methods, as well as significant unresolved issues related to the application of these techniques, including lack of comprehensive head-to-head comparisons in a single large transnational database, lack of prospective evaluations, and the lack of gold standard of signal detection.

Current methods of automated signal detection are nonclinical and only highlight deviations from independence without explaining whether these deviations are due to a causal linkage or numerous potential confounders. They therefore cannot replace expert clinical reviewers, but can help them to focus attention when confronted with the difficult task of screening huge numbers of drug–event combinations for potential signals. Important questions remain to be answered about the performance characteristics of these methods. Pharmacovigilance professionals should take the time to learn the underlying mathematical concepts in order to critically evaluate accumulating experience pertaining to the relative performance characteristics of these methods that are incompletely defined.

To evaluate the relationship between isotretinoin and psychiatric illness in adolescents and young adults.

Primary literature located via MEDLINE (1966–December 2002). Key terms were isotretinoin, depression, psychosis, suicide, and adolescents.

Information regarding depression was added to isotretinoin labeling in 1998 following a series of case reports and submitted to the MedWatch system.

Although a causal relationship may exist between isotretinoin and psychiatric illness in adolescents and young adults, this has not been demonstrated in the literature. Until evidence establishes a presence or lack of causality, prescribers should exercise caution when treating adolescents and young adults with isotretinoin.

To review the available literature regarding the use of melatonin in the treatment of tardive dyskinesia (TD).

Literature was identified through MEDLINE (1966–September 2002), PsycINFO (1967–September 2002), and references of relevant articles. Review articles, case reports/series, and animal and human studies were reviewed.

Melatonin has been investigated in TD based on its antioxidant properties. Animal studies and several human case series describe an association between melatonin and TD. Two recent, controlled studies evaluated the role of melatonin in the treatment of TD.

There is a paucity of data evaluating the use of melatonin in TD. Both of the controlled studies evaluating its use are limited by methodologic issues. Although the most recent trial did report a statistically significant improvement in TD with melatonin, these results are not considered to be clinically significant. There are inadequate data at the present time to support the use of melatonin in patients with TD.

To compare the different sterility standards and the cost issues involved when choosing an opioid product for intraspinal administration.

Literature accessed through MEDLINE and other Internet search engines (September 2002–April 2003) was evaluated. Key search terms included epidural/intrathecal, opioids, sterility, and compounding.

Intraspinal use is prevalent in the area of pain management. Product selection is of utmost importance when administering through the intraspinal route. An evaluation of guidelines on sterility and a cost comparison were conducted.

The preservative-free commercially available products that are indicated for intrathecal/epidural use are the best alternative due to proper outside testing and stringent quality assurance. The generic morphine preservative-free product may also be considered if proper steps are taken to ensure that the final product is diluted properly.

To evaluate drug use in 2 Dutch nursing homes (254 residents) by developing and evaluating prescribing indicators based on pharmacy prescription data.

We evaluated the prescribing of benzodiazepines, nonsteroidal antiinflammatory drugs (NSAIDs), ulcer-healing drugs, and diuretics. Prescribing indicators were used to identify prescribing that was potentially not in line with recommendations in national and regional prescribing guidelines. We used both descriptive indicators, such as the number and percentage of users, and indicators reflecting potentially suboptimal prescribing, such as use of drugs outside the regional drug formulary, use of >1 drug from the same drug class, and prescription of drug dosages above recommended values. When potentially suboptimal prescribing was found, we verified the findings by means of an interview with 1 of the prescribers.

The prescribing indicators we assessed were generally in agreement with national and regional guidelines. However, prescribing of NSAIDs without concomitant prescribing of gastroprotective drugs was found in a relatively high number of patients. After prescriber interview and patient chart review, it was found that some prescribing indicators, such as dosages above recommended values, were not always indicative for suboptimal prescribing.

This pilot study showed that prescribing indicators based solely on pharmacy prescription data can be a useful tool to evaluate drug prescribing. With some of these prescribing indicators, we identified cases of potentially suboptimal prescribing. However, with other indicators such as those based on drug dosages, we could not identify suboptimal prescribing, and clinical information from the prescriber was necessary to get insight into the appropriateness of prescribing.