Pharmacotherapy

Study Objective. To determine if prophylaxis with nifedipine could decrease the frequency of contrast medium‐induced renal impairment.

Design. Prospective, randomized clinical trial.

Setting. A university‐affiliated hospital.

Patients. Patients undergoing scheduled radiologic examinations involving infusion of contrast media.

Interventions. Forty‐two patients were randomized to receive nifedipine 10 mg orally 1 hour before the imaging procedure, and 43 to receive no treatment.

Measurements and Main Results. Baseline serum creatinine levels were compared with maximum levels 24 and 48 hours after administration of contrast medium. No statistically significant difference was seen in either the mean change or mean percentage change in serum creatinine between the control and nifedipine groups. The mean changes in serum creatinine were +7.4 μmol/L in the control group and +2.7 μmol/L in the nifedipine group (p=0.33); the mean percentage changes were +10.2% and +4.8%, respectively (p=0.54).

Conclusion. Regardless of statistical analysis, it is unlikely that elevations in serum creatinine of this magnitude (< 0.1 mg/dl) are of clinical significance. We therefore conclude that prophylactic nifedipine is not clinically beneficial in preserving renal function in patients receiving contrast medium and that the agent should not be routinely administered for this purpose.

We assessed the prophylactic effect of intravenous magnesium sulfate on the occurrence of torsades de pointes and early after‐depolarizations, and on the QT interval (QTc) in an established rabbit model. Ten rabbits were given intravenous methoxamine to slow their heart rates. After 12 minutes five animals received a 60‐mg/kg bolus and continuous infusion of magnesium 0.6 mg/kg/minute, and five received equivolume normal saline concurrently with the class III antiarrhythmic agent clofilium 5 mg/kg over 30 minutes. Electrocardiogram lead II and the monophasic action potential were recorded continuously throughout the experiment. The magnesium group experienced significantly less torsades de pointes and early after‐depolarizations than the normal saline group (1/5 and 5/5 both parameters, respectively, p= 0.048). There were no differences between groups in QT or QTc interval at baseline or at maximum QT or QTc prolongation. Magnesium decreases the occurrence of torsades de pointes without affecting the QT or QTc interval but does decrease the occurrence of early after‐depolarizations. These findings must be validated in human studies.

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.

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.

Contrary to the literature about drug removal during hemodialysis, data regarding drug removal during plasmapheresis are sparse. Over the last 40 years, approximately 70 publications—mostly case reports of overdoses—have described the effects of plasmapheresis on pharmaceutical agents. Important issues are drug extraction during plasma exchange with chemotherapy, as well as drug classes such as antiinfectives, anticoagulants, antiepileptics, cardiovascular agents, and immunosuppressants. Other considerations are the merits and pitfalls of the different methods used in published reports and recommendations for future pharmacokinetic studies in this field.

Pharmacists should be aware of gender‐based differences and menstrual cycle‐related changes in six diseases: asthma, arthritis, migraine, diabetes, depression, and epilepsy. In general, women report symptoms of physical illness at higher rates, visit physicians more frequently, and make greater use of other health care services than men. Whereas reasons for these gender differences are not fully clear, a combination of biologic, physiologic, social, behavioral, psychologic, and cultural factors most likely contributes. A significant percentage of women with asthma, arthritis, migraine, diabetes, depression, or epilepsy experience worsening of their disease premenstrually. The mechanism is unknown, but is speculated to be multifactorial because of many endogenous and exogenous modulators and mediators of each disease. As part of general therapy for cycle‐related exacerbations of any one of these disorders, patients should be encouraged to use a menstrual calendar to track signs and symptoms for two to three cycles; if cyclic trends are identified, the women should anticipate exacerbations and avoid triggering factors. Cyclic modulation with pharmacotherapy may be attempted. If unsuccessful, a trial of medical ovulation suppression with a gonadotropin‐releasing hormone (GnRH) analog may be warranted. If that is successful, continuous therapy with a GnRH analog and steroid add‐back therapy or less expensive alternatives may be effective. If pharmacotherapy is impractical, hysterectomy and bilateral oophorectomy with estrogen replacement therapy is a last resort. Gender differences and menstrual cycle‐related changes are important areas for clinical and mechanistic research.