A comparison of danaparoid and warfarin for prophylaxis against deep vein thrombosis after total hip replacement: The Danaparoid Hip Arthroplasty Investigators Group.

Orgaran (danaparoid sodium injection) is a novel antithrombotic agent. Early studies suggest that this compound may be beneficial in preventing deep vein thrombosis in predisposed patients. This multicenter, randomized, assessor blinded, clinical trial compared subcutaneous danaparoid with warfarin for the prevention of deep vein thrombosis in patients undergoing hip replacement surgery. Bilateral venography was used to detect thrombi. Patients also underwent follow-up examinations 1, 2, and 3 months after discontinuation of the study to determine the after effects of treatment. Nearly 27% of patients who received warfarin and 14.6% of patients who received danaparoid developed deep vein thrombosis, a risk reduction of 46%. The absolute difference in the incidence of deep vein thrombosis was 12.3% in favor of danaparoid. The incidence of venographically documented proximal deep vein thrombosis was 1.5% for danaparoid and 4.1% for warfarin. These results demonstrate that danaparoid is more effective than warfarin in preventing deep vein thrombosis following hip replacement surgery. The preoperative administration of danaparoid does not increase surgical blood loss compared with warfarin.

Danaparoid in the prevention of thromboembolic complications.

OBJECTIVE: To review the therapies used to prevent postoperative thromboembolic complications with a focus on the role of danaparoid, a new low-molecular-weight glycosaminoglycan. DATA SOURCES: A MEDLINE search was performed to identify pertinent English-language literature including studies, abstracts, and review articles. Key search terms included danaparoid, heparinoid, lomoparin, heparin, prophylaxis, thrombosis, embolism, thromboembolism, and thromboembolic and postoperative complications. The manufacturer of danaparoid was contracted for additional information related to this compound. STUDY SELECTION AND DATA EXTRACTION: All identified articles were reviewed for possible inclusion in this review. Comparisons primarily focused on data obtained from prospective, randomized, controlled, blind clinical trials. Another important consideration was the use of venography to determine the presence of deep venous thrombosis. DATA SYNTHESIS: Various therapies are available for the prevention of postoperative thromboembolic complications. Effective pharmacologic treatments currently available include adjusted-dose heparin, warfarin, aspirin, dextran, and low-molecular-weight heparins (LMWHs). Until recently, warfarin was considered the drug of choice for thromboprophylaxis in high-risk patients, including patients undergoing orthopedic surgical procedures. Because of their comparable efficacy and greater ease of use, LMWHs are gaining favor over warfarin in this patient population. In well-designed clinical trials involving patients undergoing elective total hip replacement or fractured hip surgery, danaparoid has demonstrated greater efficacy than other active treatments, including warfarin, dextran, aspirin, and heparin plus dihydroergotamine. While studies comparing danaparoid with LMWHs have not yet been published, danaparoid may be more useful in patients with heparin-associated thrombocytopenia. CONCLUSIONS: Danaparoid is an antithrombotic agent with characteristics that distinguish it from heparin and LMWHs. Based on the efficacy and safety data reviewed, danaparoid should be considered one of the drugs of choice for the prevention of thromboembolic complications in patients undergoing orthopedic hip procedures and the drug of choice for the management of any patient with heparin-induced thrombocytopenia who requires anticoagulant therapy.

Comparative role of omeprazole in the treatment of gastroesophageal reflux disease.

OBJECTIVE: To review gastroesophageal reflux disease (GERD) and its treatment, with emphasis on the use and place of omeprazole, a proton pump inhibitor. DATA SOURCES: A compilation prepared by the National Library of Medicine's Interactive Retrieval Services (Medlars II) for the period 1987 to 1994 was used as the data source. STUDY SELECTION: Focus was placed on human comparative clinical studies with well-accepted measures of esophageal healing (endoscopy) and symptom resolution. Safety data were compiled from the clinical trials literature and large postmarketing data studies. Pharmacoeconomic studies selected were judged to meet the criteria of good design, presence of sensitivity testing, and statement of perspective. DATA EXTRACTION: Data were obtained from double-blind, controlled clinical studies. Other data were extracted from pertinent literature of good design and significant results. DATA SYNTHESIS: Overall, the clinical trials of omeprazole for the treatment of patients with erosive GERD demonstrate that omeprazole provides superior therapy in terms of esophageal healing symptom resolution and patient compliance when compared with histamine2-receptor antagonists (H2RAs) and antacids. In addition, studies also indicate that omeprazole is the most effective agent for the treatment of patients with GERD refractory to other treatments. Dosage adjustment is not necessary in patients with impaired renal or hepatic function or in the elderly. Finally, although the acquisition drug cost for daily treatment of patients with GERD is highest with the use of omeprazole, pharmacoeconomic studies indicate that treatment is more cost-effective with the use of omeprazole than with H2RA or antacid treatment alone or combined with nonpharmacologic approaches. CONCLUSIONS: Based on efficacy, safety, and cost-effectiveness, omeprazole is the drug of choice for the treatment of patients with endoscopically confirmed erosive GERD.

Evaluation of the effectiveness of two support surfaces following myocutaneous flap surgery.

Recurrence of pressure ulcers is a serious problem following myocutaneous flap surgery and can lead to prolonged and expensive hospitalization. One of the most important aspects of patient care after surgery is the monitoring of reduced pressure in the area of the flap. Usually reducing pressure requires an expensive high-tech support surface. The purpose of this study was to evaluate the effectiveness of a less expensive support surface. There were 12 patients involved in a clinical trial that lasted 14 days and compared the effectiveness of the ROHO dry-floatation mattress to that of the Clinitron bed. Findings indicated that post-operative patients were effectively treated on either support surface.

Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. A clinical trial comparing efficacy and safety. Enoxaparin Clinical Trial Group.

A randomized, parallel-group, open-label clinical trial (the physicians, patients, and staff were not blinded with regard to the regimen that had been used) was conducted, between December 1988 and September 1990, to compare the safety and efficacy of enoxaparin, a low-molecular-weight heparin, with the safety and efficacy of unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. Six hundred and ten patients were randomized, and 607 patients received one of the study medications. The evaluations of efficacy included contrast-media venography, non-invasive vascular examination, and clinical examination. Data on efficacy were available for 604 patients, who had been assigned to one of three treatment groups: thirty milligrams of enoxaparin every twelve hours (194 patients), forty milligrams of enoxaparin once daily (203 patients), or 5000 units of unfractionated heparin every eight hours (207 patients). All drugs were administered subcutaneously. Dosages were not adjusted on the basis of the results of coagulation tests or the body weight of the patient. Treatment was initiated within twenty-four hours after the operation and continued for a maximum of seven days. The primary safety outcome was the occurrence of bleeding episodes. An intent-to-treat patient analysis revealed that deep venous thrombosis occurred in nine (5 per cent) of the 194 patients who received thirty milligrams of enoxaparin every twelve hours, thirty (15 per cent) of the 203 patients who received forty milligrams of enoxaparin once daily, and twenty-four (12 per cent) of the 207 patients who received unfractionated heparin. The rate of deep venous thrombosis was significantly lower in the group that received thirty milligrams of enoxaparin every twelve hours than in the group that received unfractionated heparin (p = 0.03) and in the group that received forty milligrams of enoxaparin once daily (p = 0.0002). No clinically symptomatic pulmonary embolism was observed during the treatment or follow-up phase of this study in the group that received thirty milligrams of enoxaparin every twelve hours. Analysis of evaluable patients revealed a marked reduction in the rate of deep venous thrombosis in the group that received thirty milligrams of enoxaparin every twelve hours (eight [6 per cent] of 136 patients) compared with the group that received heparin (twenty-one [15 per cent] of 145 patients) (p = 0.10); however, this difference was not significant because of the small number of patients included in this analysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Enoxaparin: the low-molecular-weight heparin for prevention of postoperative thromboembolic complications.

OBJECTIVE: To introduce readers to a new low-molecular-weight heparin (LMWH) product, enoxaparin. The chemistry, pharmacology, pharmacodynamics, clinical efficacy in thromboembolic prophylaxis following surgery, and adverse effects are reviewed. DATA SOURCES: A MEDLINE search of the English-language literature was used to identify relevant literature. STUDY SELECTION: A focus was placed on human clinical studies with well-accepted measures of antithrombotic efficacy endpoints, i.e., venography and ultrasonography. Emphasis was on pharmacologic and pharmacokinetic studies conducted in humans. DATA EXTRACTION: Most data were extracted from double-blind, controlled clinical studies. Other study designs were accepted if the results were believed to be significant. Pharmacology and pharmacokinetic data were selected from studies with exceptional design conducted in humans. DATA SYNTHESIS: Enoxaparin is a polysaccharide chain produced by the depolymerization of heparin. In comparison with heparin, which has an average molecular weight of 12,000-15,000 daltons, the average molecular weight of enoxaparin is approximately 4500 daltons. Enoxaparin does not form a complex with antithrombin III and thrombin as extensively as does heparin; however, the anti-Xa activity of enoxaparin is similar. The significance of this fact is an enhancement of antithrombotic activity and clinical efficacy. Trials comparing enoxaparin with other thromboembolic prophylaxis techniques are ongoing. CONCLUSIONS: Thromboembolism remains one of the major complications of all surgical procedures. Attempts have been made throughout the last century to develop the most effective means to prevent this complication. Clinical studies performed throughout the world have shown that enoxaparin is superior or equivalent to other antithrombotic agents, including heparin, in preventing the formation of venous thromboembolism. In addition, enoxaparin appears to possess an equivalent or lower incidence of bleeding complications when compared with heparin prophylaxis. Enoxaparin is expected to be joined by other LMWH products in the future. As a result, the methods of providing effective prophylaxis against thromboembolic complications is expected to change in the coming years.

Comparison of the Parenteral histamine2-receptor antagonists.

The chemical structure, pharmacokinetic properties, and drug-drug interaction profiles of the parenterally available histamine2 (H2)-receptor antagonists were compared. Famotidine is a guanidinothiazole derivative, ranitidine contains an aminomethylfuran ring, and cimetidine has an imidazole ring. Data from the literature indicate that because of its chemical structure famotidine has a much greater potency and affinity for the H2-receptor and a notable lack of drug-drug interactions when compared with ranitidine and cimetidine. As a result, famotidine should be considered the H2-receptor antagonist of choice for critically ill patients who require gastric-acid suppression and at the same time are being treated with other drugs that depend on the cytochrome P-450 mixed-function oxidase system for their metabolism and/or on renal tubular mechanisms for their excretion.

Cost considerations of intravenously administered histamine2-receptor antagonists.

The cost of intravenously administered histamine2 (H2)-receptor antagonists to hospitalized patients is high. Costs can be expressed as either direct or indirect. Direct costs include drug cost, labor costs (pharmacy/nursing time), and the materials required for iv administration of these agents. Indirect costs include adverse effects, drug interactions, and allergic reactions. Due to the high percentage of total cost for labor and materials associated with the iv H2-receptor antagonists, a reduction in drug cost, although certainly desired, is unlikely to substantially reduce the amount charged the patient per intravenous dose administered or the daily cost of therapy. However, if less frequent dosing were required to achieve similar therapeutic effects, the daily therapy cost for iv H2-receptor antagonists could be substantially reduced. Assuming that cimetidine, ranitidine, and famotidine are equally effective and safe, our cost analyses at the University of Tennessee Medical Center/William F. Bowld Hospital indicate that famotidine administered q12h, regardless of the iv administration technique used, is the most cost-effective H2-receptor antagonist and is the drug of choice.

Review of diclofenac and evaluation of its place in therapy as a nonsteroidal antiinflammatory agent.

Diclofenac sodium is a nonsteroidal antiinflammatory drug (NSAID) that has been used in 120 countries since its introduction in Japan in 1974. It is currently the eighth largest-selling drug and the most frequently used NSAID in the world. Diclofenac, a phenylacetic acid derivative, is a potent inhibitor of cyclooxygenase enzyme activity, and may also interact with the lipoxygenase enzyme pathway, and with the release and reuptake of arachidonic acid. Diclofenac is almost completely absorbed, highly protein-bound, penetrates well into synovial fluid, and is extensively metabolized. Comparative studies have shown that diclofenac is at least equivalent in efficacy to aspirin and other NSAID when used for the treatment of rheumatic diseases such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Diclofenac also possesses potent analgesic properties. Clinical trials suggest that diclofenac has a favorable side-effect profile, excellent patient tolerability, and a lower patient dropout rate when compared with aspirin and other NSAID.

Pharmacokinetics of cetamolol in hypertensive patients with normal and compromised renal function.

The efficacy, safety, and pharmacokinetic parameters of a 30-mg oral dose of cetamolol hydrochloride (Betacor), a new synthetic cardioselective beta-adrenoceptor antagonist, with intrinsic sympathomimetic activity, were evaluated by studying 32 hypertensive patients with normal renal function or different degrees of renal impairment. After administration of cetamolol, serial blood and urine sample collections, as well as vital sign determinations for the next 48 hours, were performed in all patients (with the exception of urine collection, which was not possible in hemodialysis patients). Results indicate that cetamolol's pharmacokinetic parameters are significantly changed in patients who have moderate or severe renal impairment. Specifically, as the severity of renal impairment increased, the maximum serum concentration (Cmax) and the area under the serum concentration-time curve (AUC) increased, whereas the renal clearance (CLR), urinary excretion, and total body clearance (CL) decreased. Additionally, significant direct or inverse correlations for AUC, CL, CLR, and urinary excretion with creatinine clearance (CLCR) were demonstrated. In the subjects with mild renal impairment, the trends toward changes in the cetamolol pharmacokinetic parameters were evident, though small and not statistically significant. Although anuric, patients on hemodialysis still retained the ability metabolically to clear cetamolol at a rate of about one-third of that found in normal subjects. Reductions in blood pressure and heart rate also were found to be greater and more prolonged as the severity of renal impairment increased. There were no adverse drug or toxic effects noted in any of the study patients. Based on these findings, dosing recommendations are suggested for patients who have compromised renal function because of the effects of renal function on the pharmacokinetics of cetamolol.

Therapeutic assessment of Slow-K and K-tab potassium chloride formulations in hypertensive patients treated with thiazide diuretics.

Therapeutic equivalency among different drug products is one of the major issues confronting many clinicians today who are functioning as members of pharmacy and therapeutic committees and state Medicaid programs (SMP). Selection of one of the available slow-release potassium chloride formulations for inclusion in a hospital formulary or SMP exemplifies one of these therapeutic equivalency issues. To evaluate this issue, we studied 20 hypertensive adult patients receiving hydrochlorothiazide 50 mg/d to determine if there are significant differences between the administration of 24 mEq of Slow-K given as 8 mEq/tablet tid, and 30 mEq of K-Tab given as a 10 mEq/tablet tid. The study was conducted in a randomized, open-label, crossover design in which the two drug formulations of potassium chloride were compared over two four-week treatment periods. Results from this study indicate that 24 mEq of Slow-K and 30 mEq of K-Tab were equally effective in maintaining serum electrolyte concentrations, blood pressure measurements, and electrocardiogram evaluations within normal limits in all 20 hypertensive patients studied. Furthermore, no adverse effects were noted with either potassium chloride formulation, and patient acceptance, tolerability, and compliance to prescribed dosing regimens were similar for both products. Based on our findings, therefore, we conclude that 24 mEq of Slow-K and 30 mEq of K-Tab given three times daily as 8 mEq and 10 mEq tablets, respectively, are therapeutically equivalent.

Drug Information Center network: need, effectiveness, and cost justification.

During the past 15 years, the pharmacy profession has experienced much change. Certain pharmacy roles are being challenged and others are coming into existence. Today, health-care practitioners and health-care providers are seeking services not sought before from pharmacists in the area of rational therapeutics. This need for information extends to all pharmacy practice settings: institutional, independent pharmacies, chain stores, governmental agencies, and the pharmaceutical industry. In order to meet this demand for drug and toxicology information, however, the pharmacist must use resources outside the immediate area of his practice. The Drug Information Center (DIC) can be used as such a resource by pharmacists in their daily practice to provide the best possible care with regard to the rational use of drugs for their patients/clients. Specifically, our data indicate that in Tennessee, there is a need for providing drug and toxicology information; pharmacists perceive their role to be providers of drug information as well as drugs; the DIC plays an integral and necessary role as a back-up information resource and in teaching, service, research, and continuing education programs; and the programs provided by the DIC are cost effective and cost justifiable.

Dialyzability and pharmacokinetics of indomethacin in adult patients with end-stage renal disease.

Indomethacin, a nonsteroidal antiinflammatory drug, has been shown to be effective for the treatment of pericarditis in chronic hemodialysis patients. Data regarding the dialyzability of indomethacin in these patients, however, is lacking. The aim of this study, therefore, was to evaluate (1) the dialyzability, and (2) the absorption and elimination kinetics of indomethacin, using six stable anephric adult patients who were maintained on chronic hemodialysis and were receiving indomethacin for the management of their uremic pericarditis. The results from this study demonstrate that indomethacin is dialyzable, but not to an appreciable extent. The mean predialysis and postdialysis indomethacin plasma levels were 3.4 and 1.6 micrograms/ml, respectively. The mean total amount of indomethacin removed by five hours of hemodialysis was 19.6 percent of the single dose of indomethacin 100 mg po. However, mean Cpmax, tmax, t1/2, and AUC0-infinity during and in the absence of hemodialysis were 5.4 and 5.4 micrograms/ml (not statistically significant [NS]), 1.9 and 2.0 h (NS), 6.1 and 5.3 h (NS), and 30.9 and 35.7 micrograms h ml-1 (NS), respectively. Based on these findings, it can be concluded that although indomethacin is dialyzable, no dosage adjustment is required in patients receiving indomethacin for the management of their uremic pericarditis when undergoing maintenance hemodialysis.

Leuprolide: a gonadotropin-releasing hormone analog for the palliative treatment of prostatic cancer.

Leuprolide is the first member of the class of gonadotropin-releasing hormone (GnRH) agonist analog to be released in the U.S. The pharmacology of leuprolide is complex and not yet completely defined. This agonist analog is more potent than natural GnRH and appears to be capable of occupying pituitary GnRH receptors. This results in a "down regulation" of the receptors' activity and gonadotropin release, ultimately decreasing serum testosterone levels to those seen following castration. Leuprolide has been found effective in the palliative treatment of advanced cases of prostatic cancer and is not associated with the cardiovascular and thromboembolic toxicity seen with conventional diethylstilbestrol therapy. Leuprolide is administered by daily subcutaneous injections and has been generally well tolerated. The most common adverse effects are hot flashes and a possible flare-up of prostatic carcinoma symptoms on initial dosing. As clinical experience grows in the use of GnRH agonist analog, GnRH will assume a greater role in the treatment of metastatic prostatic cancer.

Terfenadine, a nonsedating antihistamine.

Terfenadine is an antihistamine recently approved for use in the U.S. Terfenadine possesses a unique chemical structure when compared with other antihistamines. It is a selective inhibitor of H1-receptors with little or no anticholinergic, antiserotoninergic, or antiadrenergic effects. Comparative studies have shown that terfenadine is as effective as other antihistamines in the treatment of allergic rhinitis and other hypersensitivity conditions. This drug produces a minimal amount of central nervous system (CNS) depression, which is documented by studies demonstrating that terfenadine and its metabolites do not readily pass into the CNS and have little affinity for central H1-receptors. The lack of CNS depression and anticholinergic effects, and the long duration of action that allows twice-a-day dosing make terfenadine an attractive alternative to other antihistamines.

Liquid and solid potassium chloride: bioavailability and safety.

Studies have suggested that microencapsulated preparations of potassium chloride may pose less risk to the upper gastrointestinal mucosa than the currently available wax-matrix preparations. Based on our own clinical experience and data available from the literature, we have concluded that (1) liquid and slow-release preparations of potassium chloride are safe and effective when used appropriately and (2) at present there is no conclusive evidence to suggest that lesions of the upper gastrointestinal tract are more prevalent with one slow-release preparation than with another.

Clinical efficacy, safety, and pharmacokinetics of indapamide in renal impairment.

The efficacy and safety of a new diuretic-antihypertensive drug, indapamide (2.5 mg/day), were evaluated in hypertensive patients with normal renal function, in patients with various degrees of chronic renal failure, and in hypertensive patients undergoing long-term maintenance hemodialysis. The results obtained from single-blind, placebo-controlled studies indicate that indapamide is a safe and effective agent to use in lowering the blood pressure of hypertensive patients with normal renal function, those with various degrees of renal impairment, and those who are undergoing long-term maintenance hemodialysis. No significant side or toxic effects were noted in these studies. Furthermore, indapamide does not accumulate in the bloodstream of patients with renal impairment and is not dialyzable.

The pharmacokinetics of trichlormethiazide in hypertensive patients with normal and compromised renal function.

The pharmacokinetics of trichlormethiazide (TCZ) was studied in twelve patients after a single 4 mg dose. Seven patients had normal renal function with creatinine clearance greater than 90 ml/min. Five patients had compromised renal function with creatinine clearances averaging 48 +/- 29 ml/min. The TCZ plasma half life and area under the plasma concentration-time curve (AUC) were significantly greater in patients with impaired function, compared to patients with normal renal function. There were no significant differences between the two patient groups in terms of either rate of drug absorption or total urinary recovery of unchanged drug. Furthermore, there was no correlation between peak drug levels or AUC and renal excretion of water or electrolytes.

Clinical toxicology consultation by pharmacists.

The functions of pharmacists in a clinical toxicology consultation service are described. Pharmacists provided three basic services in conjunction with poisonings treated by the emergency department of a children's hospital: (1) assisted with obtaining the history and assessment of the toxicologic proglems, (2) recommended a plan for rational management, and (3) discussed poison prevention with the parents of the victims. Pharmacists were consulted for 189 poisoning cases over a six-month period; 80% of the cases were attended at the bedside and the remainder were monitored by telephone. Drugs were involved in 58% of the patient exposures. Median time for the pharmacist to reach the emergency room after the patient's arrival was 5 to 10 minutes. Physicians and nurses rated the pharmacists' contributions favorably. These results suggest that pharmacists can play an important role in clinical toxicology.