Pharmacotherapy

Study Objective. To compare drug adherence rates among patients with gout, hypercholesterolemia, hypertension, hypothyroidism, osteoporosis, seizure disorders, and type 2 diabetes mellitus by using a standardized approach.

Design. Longitudinal study

Data Source. Health care claims data from 2001–2004.

Patients. A total of 706,032 adults aged 18 years or older with at least one of the seven medical conditions and with incident use of drug therapy for that condition.

Measurements and Main Results. Drug adherence was measured as the sum of the days' supply of drug therapy over the first year observed. Covariates were age, sex, geographic residence, type of health plan, and a comorbidity score calculated by using the Hierarchical Condition Categories risk adjuster. Bivariate statistics and stratification analyses were used to assess unadjusted means and frequency distributions. Sample sizes ranged from 4984 subjects for seizure disorders to 457,395 for hypertension. During the first year of drug therapy, 72.3% of individuals with hypertension achieved adherence rates of 80% or better compared with 68.4%, 65.4%, 60.8%, 54.6%, 51.2%, or 36.8% for those with hypothyroidism, type 2 diabetes, seizure disorders, hypercholesterolemia, osteoporosis, or gout, respectively. Age younger than 60 years was associated with lower adherence across all diseases except seizure disorders. Comorbidity burden and adherence varied by disease. As comorbidity increased, adherence among subjects with osteoporosis decreased, whereas adherence among those with hypertension, hypercholesterolemia, or gout increased. Add‐on drug therapies and previous experience with taking drugs for the condition increased adherence among subjects with hypertension, type 2 diabetes, hypothyroidism, or seizure disorders but not the other conditions.

Conclusion. This uniform comparison of drug adherence revealed modest variation across six of seven diseases, with the outlier condition being gout.

Cannabis, or marijuana, has been used for medicinal purposes for many years. Several types of cannabinoid medicines are available in the United States and Canada. Dronabinol (schedule III), nabilone (schedule II), and nabiximols (not U.S. Food and Drug Administration approved) are cannabis‐derived pharmaceuticals. Medical cannabis or medical marijuana, a leafy plant cultivated for the production of its leaves and flowering tops, is a schedule I drug, but patients obtain it through cannabis dispensaries and statewide programs. The effect that cannabinoid compounds have on the cannabinoid receptors (CB₁ and CB₂) found in the brain can create varying pharmacologic responses based on formulation and patient characteristics. The cannabinoid Δ⁹‐tetrahydrocannabinol has been determined to have the primary psychoactive effects; the effects of several other key cannabinoid compounds have yet to be fully elucidated. Dronabinol and nabilone are indicated for the treatment of nausea and vomiting associated with cancer chemotherapy and of anorexia associated with weight loss in patients with acquired immune deficiency syndrome. However, pain and muscle spasms are the most common reasons that medical cannabis is being recommended. Studies of medical cannabis show significant improvement in various types of pain and muscle spasticity. Reported adverse effects are typically not serious, with the most common being dizziness. Safety concerns regarding cannabis include the increased risk of developing schizophrenia with adolescent use, impairments in memory and cognition, accidental pediatric ingestions, and lack of safety packaging for medical cannabis formulations. This article will describe the pharmacology of cannabis, effects of various dosage formulations, therapeutics benefits and risks of cannabis for pain and muscle spasm, and safety concerns of medical cannabis use.

Study Objective. To determine the pharmacokinetics and pharmacodynamics of argatroban in healthy volunteers and patients with hepatic or renal dysfunction.

Design. Prospective, open‐label study (studies 1 and 3); prospective, open‐label, parallel‐group study (study 2).

Settings. Two research centers and an inpatient clinic.

Subjects. Study 1, healthy volunteers; study 2, healthy volunteers and volunteers with hepatic disease; study 3, volunteers with normal to severely impaired renal function assigned to one of four groups based on creatinine clearance.

Intervention. Study 1, argatroban 125‐μg/kg bolus followed by 4‐hour continuous infusion of 2.5 μg/kg/minute; study 2, 4‐hour infusion of 2.5 μg/kg/minute (1.25 μg/kg/minute in one patient with hepatic impairment); study 3, 5‐μg/kg/minute continuous infusion over 4 hours.

Measurements and Main Results. Blood samples were obtained to assess plasma argatroban concentration, plasma activated partial thromboplastin time (aPTT), and whole blood activated clotting time (ACT). Study 1: the pharmacokinetic profile was well described by a two‐compartment model with first‐order elimination; effect response and plasma argatroban concentrations were well correlated. Mean ± SD clearance, steady‐state volume of distribution, and half‐life values (40 healthy volunteers) were 4.7 ± 1.1 ml/minute/kg, 179.5 ± 33.0 ml/kg, and 46.2 ± 10.2 minutes, respectively. The only effect of age or gender was the approximately 20% lower clearance in elderly men versus elderly women, which did not translate to clinically or statistically significant differences in pharmacodynamic response. Study 2: in patients with hepatic impairment, area under the concentration versus time curve (AUC) from time zero (t₀) to last measurable concentration, AUC from t₀ to infinity, maximum concentration, and half‐life of argatroban were increased approximately 2‐to 3‐fold; clearance was one‐fourth that of healthy volunteers. For aPTT and ACT, AUC over time for mean effect and mean maximum effect was higher in these volunteers. Study 3: no significant differences were detected. All four groups had predictable response profiles over time.

Conclusion. Argatroban should be easy to monitor and control, with little potential for underdosing or overdosing, regardless of age, gender, or renal function. Dosing precautions are recommended, however, in patients with hepatic dysfunction.

Study Objective. To explore the clinical characteristics of hyperglycemia in patients treated with olanzapine.

Design. Retrospective, epidemiologic survey of spontaneously reported adverse events related to olanzapine therapy.

Setting. Government‐affiliated drug evaluation center.

Patients. Two hundred thirty‐seven patients with olanzapine‐associated diabetes or hyperglycemia.

Intervention. One hundred ninety‐six cases from January 1994‐May 15, 2001, were identified with the United States Food and Drug Administration's MedWatch Drug Surveillance System, and 41 cases published through May 15, 2001, were identified with MEDLINE or through meeting abstracts.

Measurements and Main Results. Of the 237 cases, 188 were new‐onset diabetes, 44 were exacerbations of preexistent disease, and 5 could not be classified. Mean patient age for newly diagnosed cases was 40.7 ± 12.9 years and male:female ratio was 1.8. Seventy‐three percent of all cases of hyperglycemia appeared within 6 months of start of olanzapine therapy. Eighty patients had metabolic acidosis or ketosis, 41 had glucose levels of 1000 mg/dl or greater, and 15 patients died. When olanzapine was discontinued or the dosage decreased, 78% of patients had improved glycemic control. Hyperglycemia recurred in 8 of 10 cases with rechallenge.

Conclusions. Number of reports, temporal relationship to start of olanzapine therapy, relatively young age, and improvement on drug withdrawal suggest that olanzapine may precipitate or unmask diabetes in susceptible patients.

Midazolam là một dẫn xuất của 1,4-benzodiazepin với cấu trúc hóa học độc đáo: tùy thuộc vào pH môi trường, thuốc có thể tạo ra muối dễ tan trong nước (pH < 4) hoặc tồn tại ở dạng vòng diazepin ưu béo (pH > 4). Tính chất này góp phần vào sự khởi phát nhanh chóng của tác dụng và sự dung nạp tốt tại vị trí cục bộ sau khi tiêm parenteral. Sau khi uống và tiêm parenteral, midazolam có tốc độ hấp thu nhanh và được bài tiết nhanh chóng, với thời gian bán thải chỉ khoảng 2 giờ. Có một mối quan hệ hợp lý giữa nồng độ trong huyết tương và tác dụng lâm sàng, điều này cho thấy một phản ứng nhanh nhưng ngắn. Như một thuốc an thần, midazolam chủ yếu được chỉ định cho bệnh nhân mất ngủ gặp khó khăn trong việc ngủ hoặc có mô hình giấc ngủ bất thường trong phần đầu của đêm. Không có hiệu ứng "nỡ người" rõ rệt vào sáng hôm sau. Trong gây mê, midazolam tỏ ra là một thuốc an thần, giảm lo âu và tiềm ẩn khả năng gây mê ngắn sau khi dùng thuốc qua đường uống và tiêm parenteral. Tuy nhiên, trong phẫu thuật nhỏ, sự khởi phát chậm, không dự đoán được và thời gian tác dụng thay đổi, so với thiopental, có thể cản trở việc sử dụng thường xuyên của thuốc này như một chất khởi phát, đặc biệt ở bệnh nhân trẻ, không có sự sẵn sàng mạnh mẽ. Trong phẫu thuật lớn, midazolam là một lựa chọn thay thế cho thiopental để khởi đầu gây mê dù thời gian khởi phát chậm, thay đổi. Các lợi điểm của midazolam bao gồm sự ổn định tim mạch tốt, ức chế hô hấp thoáng qua và nhẹ, tần suất kích ứng tĩnh mạch thấp, tạo ra amnesia trước và ngắn hơn so với các benzodiazepine khác.

Study Objective. To assess the risk of liver function test (LFT) abnormalities with the use of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) for the treatment of hyperlipidemia.

Design. Meta‐analysis of randomized, placebo‐controlled trials of statins used for the treatment of hyperlipidemia or for primary or secondary prevention of cardiovascular disease.

Setting. University research center.

Patients. A total of 49,275 patients from 13 trials.

Intervention. A literature search of published clinical trials was performed in MEDLINE (January 1966–March 2003) and the Cochrane Controlled Trials Registry (first quarter 2003). Studies also were identified from the references of the trials and of published systematic reviews.

Measurements and Main Results. For a trial to be included in the meta‐analysis, its duration of follow‐up had to be at least 48 weeks and the trial had to include at least 400 patients, with at least 200 treated with a statin. Trials conducted in transplant recipients were excluded. The proportion of patients having LFT abnormalities was low in both groups (statins 1.14% vs placebo 1.05%, odds ratio [OR] 1.26, 95% confidence interval [CI] 0.99–1.62, p=0.07). Only fluvastatin was associated with a significant increase in the odds of having LFT abnormalities (fluvastatin 1.13% vs placebo 0.29%, OR 3.54, 95% CI 1.1–11.6, p=0.04) compared with placebo, although this finding was based on only two trials.

Conclusions. Our results support previous observations that pravastatin, lovastatin, and simvastatin at low‐to‐moderate doses are not associated with a significant risk of LFT abnormalities. Additional data are required to determine whether other statins have a similar safety profile.

Ketorolac tromethamine is a new injectable nonnarcotic analgesic. In a parallel, double‐blind study, the analgesic efficacies of single intramuscular doses of ketorolac 10, 30 and 90 mg were compared with those of morphine sulfate 6 and 12 mg. Two hundred forty‐one patients were categorized according to type of surgical procedure and severity of pain. Pain intensity and pain relief were assessed for 6 hours by scoring standard verbal and visual analog scales. Patients receiving ketorolac 10, 30 or 90 mg or morphine (MS) 12 mg all had significantly better pain relief in almost all measurements performed than those receiving MS 6 mg (p < 0.05). Ketorolac 10 and 30 mg were as effective as morphine 12 mg during the entire 6‐hour observation period, and ketorolac 90 mg was more effective than morphine 12 mg during the entire 6 hours. Patients with pain related to major surgery (e.g., cholecystectomy and abdominal hysterectomy) were better able to distinguish analgesic potency of morphine than those having less traumatic procedures (e.g., tendon and ligament repairs)

Rivastigmine is a cholinesterase inhibitor (ChEI) with a structural formula different from that of currently available ChEIs. Tacrine and donepezil are classified as short‐acting or reversible agents since binding to acetylcholinesterase enzyme (AChE) is hydrolyzed within minutes. Rivastigmine is classified as an intermediate‐acting or pseudo‐irreversible agent due to its long inhibition on AChE of up to 10 hours. Preclinical biochemical studies indicated that rivastigmine has central nervous system selectivity over peripheral inhibition. It ameliorated memory impairment in rats with forebrain lesions. The drug is rapidly absorbed orally, with a bioavailability of 0.355 and low protein binding (40%). Its elimination half‐life is less than 2 hours, and it is converted to an inactive metabolite at the site of action, bypassing hepatic metabolic pathways. Its disposition essentially is unaltered in patients with renal or hepatic impairment. It also has dose‐dependent effects on AChE inhibition. In the two large multicenter clinical trials (total 1324 patients) that used a forced‐dosage titration scheme, rivastigmine 6–12 mg/day was superior to placebo on three cognitive and functioning scales (p<0.001). Gastrointestinal symptoms are the most frequently reported adverse events. They occurred mostly during the dosage titration phase and decreased during the maintenance phase. Rivastigmine offers clinicians another therapeutic agent to treat Alzheimer's disease.