The efficacy and safety of combination warfarin and ASA therapy: a systematic review of the literature and update of guidelines

The English-language literature was systematically reviewed to clarify the role of combination antithrombotic therapy with warfarin and acetylsalicylic acid (ASA) versus monotherapy with either agent, including data from several recently published trials. Sixteen published studies with evaluable efficacy and/or safety data were identified. For patients with prosthetic heart valves at high risk of thromboembolism, combined warfarin and ASA therapy may be beneficial compared with warfarin alone. Combination therapy may also be used for primary prevention in patients at high risk for ischemic heart disease, although the expected benefits are small. Evidence does not support the use of combined antithrombotic therapy in patients with established ischemic heart disease, ischemic stroke, coronary artery bypass grafts or atrial fibrillation. Combination therapy is associated with an increased risk of minor and major bleeding. The highest dose of ASA that can be recommended in combination with warfarin is 100 mg daily.     

A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis

OBJECTIVES: The aim of this study was to compare the efficacy of mesalamine rectal suspension enema (Rowasa) alone, oral mesalamine tablets (Asacol) alone, and the combination of mesalamine enema and mesalamine tablets in patients with active mild-to-moderate distal ulcerative colitis. METHODS: Sixty outpatients with ulcerative colitis at least 5 cm above the anal verge and not more than 50 cm, inclusive, and a total disease activity index (DAI) score between 4 and 10, inclusive, were randomized to either mesalamine rectal enema (n = 18) once nightly, oral mesalamine 2.4 g/day (n = 22), or a combination of both treatments (n = 20). Placebo capsules and enemas were used to maintain a blind procedure. Total DAI scores and abbreviated DAI scores were evaluated at wk 3 and 6, and wk 1 and 2, respectively. Patients recorded the amount of blood in stools, urgency, straining at stools, and abdominal pain in daily diaries. Physicians and patients rated overall improvement at each visit. RESULTS: At wk 6, combination therapy produced a greater improvement (-5.2) in total DAI scores than did either mesalamine enema (-4.4) or mesalamine tablet (-3.9) therapy alone; similar treatment differences were observed at wk 3. Compared with patients given mesalamine enemas or mesalamine tablets, combination-therapy patients reported an absence of blood in stools significantly sooner and, at all visits, the combination therapy group had the highest percentage of patients who reported no blood in their stools. Physicians' and patients' ratings of improvement indicated that combination therapy significantly improved disease status, compared with mesalamine tablet therapy alone. All treatments were well tolerated. CONCLUSIONS: The combination of oral and rectal mesalamine therapy was well tolerated and produced earlier and more complete relief of rectal bleeding than oral or rectal therapy alone.     

The efficacy and safety of the dorzolamide-timolol combination versus the concomitant administration of its components. Dorzolamide-Timolol Study Group

OBJECTIVE: To evaluate whether a fixed combination of 2% dorzolamide and 0.5% timolol given twice daily showed equivalent efficacy to the concomitant administration of 2% dorzolamide given three times daily and 0.5% timolol given twice daily in patients whose intraocular pressure (IOP) remained elevated during monotherapy with 0.5% timolol twice daily. DESIGN: Multicenter, parallel, randomized, double-masked clinical trial with an open-label extension. PARTICIPANTS AND INTERVENTION: In the masked phase, 242 patients received either the dorzolamide-timolol combination twice daily and placebo three times daily or dorzolamide three times daily and timolol twice daily for up to 3 months. In the open-label extension, 220 patients received the dorzolamide-timolol combination twice daily for up to 9 months. MAIN OUTCOME MEASURES: The criterion for establishing treatment equivalency was a 95% or greater confidence that the absolute difference in the mean change in IOP from baseline was less than 1.5 mmHg between treatments. RESULTS: During 3 months of treatment, the dorzolamide-timolol combination reduced IOP relative to the 0.5% timolol baseline by approximately 14% at hour 0 (just before the morning dose), 20% at hour 2, and 15% at hour 8. The IOP-lowering effect of concomitant therapy with dorzolamide and timolol was approximately 16% at hour 0.20% at hour 2, and 17% at hour 8. At hours 0, 2, and 8, there was greater than 97% confidence that the treatments were equivalent. During the open-label extension, the mean IOP reduction ranged from 14% to 15% at hour 0 and from 20% to 21% at hour 2. The treatment groups were generally comparable in terms of adverse events, symptoms, ocular signs, visual acuity, visual fields, physical examination, and laboratory measures. CONCLUSIONS: The IOP-lowering effect of the dorzolamide-timolol combination is comparable to that of dorzolamide three times daily plus timolol twice daily and is maintained for up to 1 year. The dorzolamide-timolol combination provides clinically important reduction in IOP relative to baseline treatment with timolol alone and is generally well-tolerated for up to 1 year.     

Risperidone versus haloperidol: I. Meta-analysis of efficacy and safety

Stepwise solution syntheses are described of the homo-oligomers Z-(Thr)n-NHCH3 (n=1-4, I1-4), Z-?[Gal(Ac)4beta]Thr?n-NHCH3(n=1-5, II1-5) and Z-[(Galbeta)Thr]n-NHCH3 (n=1-5, III1-5). Members of the III1-5 series were obtained by de-acetylation of the corresponding oligomers of the II1-5 series. The conformational preferences of the terminally protected homo-peptides of the three series were investigated by FT-IR absorption spectroscopy both in the solid state and in CDCl3 solution, at various concentrations. Proton NMR measurements in CDCl3 and in DMSO-d6 were also carried out and the effect of temperature variation on the chemical shifts of amide protons was determined in DMSO-d6 (range 298-335 K) and in CDCl3 (range 298-320K). CD spectra were recorded in water and in TFE. Solubility problems prevented measurements in CDCl3 solution for Z-(Thr)4-NHCH3 and for the entire III1-5 series. The existence of unordered structures in the carbohydrate-free oligomers and of more or less extended, organized structures in the glycosylated derivatives is indicated by the NMR and IR measurements. The sugar moieties apparently show a structure-inducing effect on the peptide chain.     

Anticonvulsant combination therapy: rational concepts versus real effectiveness

Primary drug treatment of epilepsies is usually a monotherapy with an antiepileptic drug. This procedure causes less side effects as polytherapy and probably shows the same efficacy. Two third of patients with focal epilepsies are sufficiently treated with a single antiepileptic drug: 60% of patients with Grand mal and 22-30% of patients with complex focal seizures remain seizures free. An alternative monotherapy will suppress seizures in another 30% of patients. With polytherapy this is achieved in only 12% of the remaining patients, furthermore, side effects increase in polytherapy. Generalized epilepsies are usually treated with valproate monotherapy. Patients remain seizure free from absence in 60-90%, from myoclonic-impulsive seizures in 75-97% and from Grand mal in about 85%. Alternative monotherapy is less common because of the limited efficacy and possible side effects of drugs: ethosuximide does not control Grand mal and phenobarbitone may cause sedation. Thus, polytherapy is commonly initiated when monotherapy fails to control seizures (lamotrigine is often chosen as comedication). Rational polypharmacy is a term suggesting rational concepts in planning antiepileptic polytherapy leading to a superior anticonvulsant effect. However, this consideration is not based on or supported by clinical data. Yet, a combination of drugs which have no or little pharmacokinetic interactions seems to be a clinically relevant recommendation. Thus, newly developed drugs such as vigabatrin, lamotrigine or gabapentin are more frequently used as comedication with standard antiepileptic drugs.     

Comparison of the safety and efficacy of a combination analgesic Myprodol and Ponstan in the treatment of dental pain

A comparison of the efficacy of Myprodol, a combination analgesic (Ibuprofen, Paracetamol and Codeine phosphate) and Ponstan (Mefenamic acid) was undertaken in a randomised double blind trial of 52 patients who underwent surgical removal of impacted or unerupted teeth. Pain scores were measured for patients pre- and post operatively by means of a visual analogue scale and data was analysed using the BMPD package on the ISM main frame computer at the Medical Research Council. The results indicated that although Myprodol and Ponstan were equally adequate and well tolerated in the control of post operative dental pain, Myprodol exceeded Ponstan in duration of analgesia and in the degree of pain intensity control experienced by the patient.     

Amlodipine monotherapy, angiotensin-converting enzyme inhibition, and combination therapy with pacing-induced heart failure

In patients with congestive heart failure (CHF) receiving therapy with angiotensin-converting enzyme (ACE) inhibition, institution of calcium channel antagonism with amlodipine provided favorable effects. The goal of the present study was to define potential mechanisms for these effects by measuring left ventricular function, hemodynamics, and neurohormonal system activity in a model of CHF in which amlodipine treatment had been instituted either as a monotherapy or in combination with ACE inhibition. Thirty-two pigs were instrumented to allow measurement of cardiac index, total systemic resistance index, and neurohormonal activity in the conscious state and assigned to one of four groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n = 8), (2) amlodipine (1.5 mg x kg(-1) x d[-1]) and pacing (n = 8), (3) ACE inhibition (fosinopril 1.0 mg/kg BID) and pacing (n = 8), and (4) amlodipine and ACE inhibition (1.0 mg x kg(-1) x d(-1) and 1.0 mg/kg BID, respectively) and pacing (n = 8). Measurements were obtained in the normal control state and after the completion of the treatment protocols. With rapid pacing, basal resting cardiac index was reduced compared with control values (2.7+/-0.2 versus 4.7+/-0.1 L x min(-1) x m(-2), respectively, P<.05) and increased from rapid pacing-only values with either amlodipine or combination therapy (3.7+/-0.3 and 4.4+/-0.5 L x min(-1) x m(-2), respectively, P<.05). Basal resting total systemic resistance index was higher in the rapid pacing-only group compared with control values (2731+/-263 versus 1721+/-53 dyne x s x cm(-5) x m2, respectively, P<.05), was reduced with either amlodipine treatment or ACE inhibition (2125+/-226 and 2379+/-222 dyne x s x cm(-5) x m2, respectively, P<.05), and was normalized with combination therapy. Plasma catecholamines, renin activity, and endothelin levels were increased threefold with rapid pacing. Amlodipine, either as a monotherapy or in combination with ACE inhibition, did not result in increased plasma catecholamines and renin activity compared with the rapid pacing-only group. Furthermore, combination therapy reduced steady state norepinephrine and normalized epinephrine levels. The results of the present study demonstrated that monotherapy with either amlodipine or ACE inhibition provides beneficial effects in this pacing model of CHF. Combined amlodipine and ACE inhibition provided greater benefit with respect to vascular resistance properties and neurohormonal system activity compared with either monotherapy.     

The efficacy of hysteroscopy: a comparison of women presenting with infertility versus other gynaecological symptoms

The aim of this study was to compare the relative efficacy of hysteroscopy as a management tool in the routine initial assessment of women presenting for investigation of infertility with women presenting for investigation of other general gynaecological symptoms for which it is routinely performed. The results of 400 consecutive completed hysteroscopies performed during the primary investigation of infertility are compared with 400 consecutive completed hysteroscopies undertaken in the investigation of women with other gynaecological symptoms. Abnormalities were detected in 12.3% of the 800 hysteroscopies. Significantly less of the infertility group demonstrated abnormality (8.8%) compared to the general gynaecological group (15.8%) (p = 0.0034). There was no difference in the detection rate between primary and secondary infertility. In patients undergoing the procedure for infertility, the results of the hysteroscopy led to an alteration in management in 5.8% of the entire group and in 65.7% of those in whom an abnormality was detected. In patients undergoing the procedure for general gynaecological symptoms, the results of the hysteroscopy led to an alteration in management in 14.5% of the total group and in 97.2% of those in whom an abnormality was detected (p < 0.0001). Structural abnormality correlated with the presence of histological abnormality in 97.2% of cases. In infertile women, the use of hysteroscopy is supported as part of a comprehensive assessment of female reproductive anatomy.     

A double-blind comparison of the efficacy and safety of milnacipran and fluoxetine in depressed inpatients

External root resorption is one of the most exasperating and least understood clinical problems in orthodontics. Numerous studies have been conducted, attempting to establish the factors causing root resorption of permanent teeth. Considerable variation exists however, in the extent and distribution of root resorption, seen in the orthodontic treatment of apparently similar cases. After an excellent review of the literature, Brezniak and Wassertein (1993) concluded that the most significant disgnostic aid in predicting whether root resorption would occur during orthodontic treatment, is the radiographic evidence of root resorption before treatment. A case is reported, describing the dilemma of orthodontically treating a patient, who had previously experienced trauma to the upper right central incisor, leading to external root resorption.     

Cost-effectiveness comparison of sequential ofloxacin versus standard switch therapy

OBJECTIVE: To compare the cost-effectiveness of sequential intravenous-to-oral ofloxacin versus intravenous-to-oral standard switch therapy for the treatment of patients with sepsis who are hospitalized with bacterial infections. DESIGN: Cost-effectiveness analysis from a provider perspective, including resources important to an integrated healthcare network, of a randomized, open-label, controlled, clinical trial. SETTING: Millard Fillmore Health System, Buffalo, NY. PATIENTS: Hospitalized adults requiring parenteral antibiotics for a complicated urinary tract infection, lower respiratory tract infection, or skin and soft tissue infection. INTERVENTIONS: Sequential intravenous-to-oral ofloxacin or standard intravenous-to-oral switch antibiotics. OUTCOME MEASURES: Clinical outcomes and direct costs associated with hospitalization, primary physician services, specialist physician services, and outpatient care. RESULTS: Eighty-two of 89 patients randomized into the two treatment groups were evaluable. Standard switch therapy failed with 12 patients versus 10 patients receiving ofloxacin. Complete economic data were available for 74 patients. Sequential ofloxacin therapy resulted in a 1-day-shorter antibiotic-related hospitalization without evidence of recurrent infection during the posttherapy follow-up evaluations. An average cost savings of $399 per patient was achieved in the sequential ofloxacin group. Although this difference did not attain statistical significance (probably due to the large variance), it is an economically significant finding. The cost-effectiveness ratios were $5735 per successful outcome for the standard switch therapy group versus $5126 per successful outcome in the sequential ofloxacin group. CONCLUSIONS: Sequential ofloxacin was as effective and consistently less expensive than standard switch antibiotics in the initial evaluation and in the sensitivity analysis of room cost and drug acquisition cost. Standard switch therapy would have to be greater than 25% more effective than sequential ofloxacin therapy to change the economic decision.     

Treatment of microfilaraemia in asymptomatic brugian filariasis: the efficacy and safety of the combination of single doses of ivermectin and diethylcarbamazine

BACKGROUND: Nitric oxide (NO) seems to play an important role in modulating tissue injury during reperfusion of the liver. In this study, we have evaluated and compared the effects of FK409 (FK), a potent spontaneous NO releaser, and L-arginine in ischemia-reperfusion injury of the rat liver. METHODS: Male Sprague-Dawley rats underwent 90 min of hepatic ischemia followed by reperfusion. FK or L-arginine was used (intravenously) in two different doses for each drug (group I, 3.2 mg/kg FK; group II, 1.6 mg/kg FK; group IV, 100 mg/kg L-arginine; and group V, 300 mg/kg L-arginine). Saline was used in control animals (group III). Hepatic enzyme status, microcirculation, serum nitrite (NO2-) and nitrate (NO3-) and tissue injury score were evaluated at predetermined times. RESULTS: Serum NO2-/NO3- was elevated immediately by FK treatment dose-dependently but not by L-arginine. However, L-arginine caused late (6-24 hr) elevation of the NO metabolites dose-dependently. The elevation of serum aspartate aminotransferase and alanine aminotransferase was suppressed and hepatic microcirculation was improved in the FK-treated groups dose-dependently. L-Arginine also improved the microcirculation, but hepatic enzymes at 24 hr of reperfusion were significantly higher in group V than in the control group. These findings were well reflected by the extent of tissue injury in respective groups. CONCLUSION: FK treatment in the immediate reperfusion period improves hepatic microcirculation and confers a significant protective effect on hepatic ischemia-reperfusion injury in the rat.     

Crossover comparison of the pharmacokinetics of amlodipine and felodipine ER in hypertensive patients

The pharmacokinetics of amlodipine 5 mg and felodipine ER (extended release) 5 mg o.d. after single and 2 weeks of repeated oral doses, were compared in 28 essential hypertensive patients using a crossover design. As a secondary parameter the effects of the drugs on blood pressure were assessed. Significant differences were found between all principal pharmacokinetic variables, when comparing the 2 treatments after both single and repeated dosing. The coefficients of variation of maximal drug concentration and AUC after single dosing and at steady-state were significantly higher for felodipine ER than for amlodipine. After repeated dosing the peak-to-trough plasma concentration ratio were 1.58 and 4.43 (p < 0.001) for amlodipine and felodipine ER, respectively. Both drugs lowered systolic and diastolic blood pressure to the same extent after 2 weeks of repeated dosing. No significant differences between the blood pressure lowering vs time profile of the 2 drugs were encountered. In conclusion, the interpatient drug concentration variability and the peak-to-trough plasma concentration ratio were more favorable for amlodipine compared to felodipine ER. It remains to be established whether these characteristics are also reflected in a more smooth and consistent blood pressure control.     

Vitamins and minerals: efficacy and safety

Safety and efficacy are crucial but separate issues for vitamin and mineral supplements. Misinterpretation of "safe and adequate" to mean "safety limit" would impose restrictions on vitamin and mineral intakes that are not needed to ensure safety. Substantial evidence indicates that intakes greater than the recommended dietary allowances (RDAs) of certain vitamins and minerals such as calcium, folic acid, vitamin E, selenium, and chromium reduce the risk of certain diseases for some people. Limitation of intakes to the RDAs would preclude reductions in disease risk from these nutrients. The margin of safety between the usual dietary intake and the intake that would produce adverse effects varies greatly among the different nutrients. Very high intakes of vitamins A and D, niacin, pyridoxine, and selenium have produced adverse effects. Many widely discussed putative adverse effects of vitamin C, vitamin E, and trivalent chromium have little factual basis. There is no evidence of adverse effects from beta-carotene supplements except in current heavy smokers.     

Evaluation of the safety and efficacy of ketorolac versus morphine by patient-controlled analgesia for postoperative pain

STUDY OBJECTIVE: To compare ketorolac tromethamine with morphine for pain management after major abdominal surgery. DESIGN: Double-blind, randomized study. SETTING: Hospital recovery room and postoperative surgical unit. PATIENTS: One hundred ninety-one patients with at least moderate pain after major abdominal surgery. INTERVENTIONS: Patients received ketorolac by patient-controlled analgesia (PCA) bolus alone (Ket B), ketorolac by bolus plus infusion (Ket I), or morphine by PCA bolus (morphine), with injectable morphine available for supplementation. MEASUREMENTS AND MAIN RESULTS: Levels of sedation, pain intensity, pain relief, and adverse events were recorded at baseline, at 2, 4, and 6 hours, and at termination. Supplemental morphine was required by 71% of Ket B patients, 67% of Ket I patients, and 38% of morphine patients (p < or = 0.001 for Ket B vs morphine). Although patients receiving ketorolac required more supplemental morphine than the morphine group (6.0 mg Ket I, 6.2 mg Ket B, 4.0 mg morphine), there was a large morphine-sparing effect in both ketorolac groups (total morphine 6.0 mg Ket I, 6.2 mg Ket B, 33.3 mg morphine). Overall pain relief scores were similar for morphine and Ket I groups, and were lower for Ket B than for morphine (p = 0.002). There were no differences among groups in numbers of patients with adverse events. CONCLUSION: Ketorolac may be effective when administered by PCA device, and has a clear morphine-sparing effect.     

The safety and efficacy of electroconvulsive therapy in patients over age 75

OBJECTIVES: To examine the safety and efficacy of electroconvulsive therapy (ECT) in patients over the age of 75 years. METHOD: Retrospective study of all patients over 75 years treated with ECT in three hospitals between 1995 and 1997. RESULTS: Ninety-three ECT courses were administered during the study period. Ten patients (10.8%) suffered complications following ECT. The most common adverse events were prolonged confusion and hypomania, all of which resolved within 2 weeks of the cessation of treatment. Eighty-five per cent of patients made a marked or moderate response to treatment. CONCLUSIONS: ECT is a relatively safe and effective procedure in patients over age 75.     

Efficacy and safety of azelaic acid and glycolic acid combination therapy compared with tretinoin therapy for acne

We conducted a 12-week, multicenter, randomized, double-masked, parallel-group study of the efficacy, safety, and tolerability of azelaic acid 20% cream and glycolic acid lotion compared with tretinoin 0.025% cream and a vehicle lotion to treat mild-to-moderate facial acne vulgaris. Patients treated with azelaic/glycolic acid experienced a significantly greater reduction in the number of papules, as well as a greater reduction in the number of inflammatory lesions, than those treated with tretinoin. Overall global improvement was approximately 25% in both groups. In the physician evaluations, treatment with azelaic/glycolic acid was found to cause significantly less dryness, scaling, and erythema than tretinoin. Patients also reported significantly less dryness, redness, and peeling with azelaic/glycolic acid. Significantly more patients in the azelaic/glycolic acid group than the tretinoin group reported that they felt attractive. The combination of azelaic acid and glycolic acid is a useful alternative to tretinoin, being at least as efficacious as the latter, while offering a superior tolerability and patient approval profile.     

Treatment of malignant pleural effusions with a combination of bleomycin and tetracycline. A comparison of bleomycin or tetracycline alone versus a combination of bleomycin and tetracycline

BACKGROUND: Treatment of patients with malignant pleural effusions is mostly palliative. Tetracycline and bleomycin are the two most commonly used agents for the treatment of pleurodesis. In this study, the authors used a combination of the two drugs for this particular purpose. METHODS: Sixty patients with massive malignant pleural effusions were divided in 3 equal groups in a simple randomized manner. Tetracycline (20 mg/kg [maximum of 2 g] in 50 mL of normal saline) was administered through a chest tube in Group 1. Group 2 received bleomycin (1 U/kg [maximum of 60 U] in 50 mL of normal saline). Group 3 received the above 2 preparations (tetracycline, 20 mg/kg [maximum of 2 g] in 40 mL of normal saline and bleomycin, 1 U/kg [maximum of 60 U] in 30 mL of normal saline) instilled one after the other, while the chest tube was clamped for 5 minutes in the interim. Follow-up examinations were performed at 7 days, 30 days, 60 days, 90 days, and 6 months. RESULTS: There was no significant difference in the complete response rate of the 3 groups during the first 4 months. At the end of the study, Group 3 had a significantly higher complete response rate (70%) compared with Groups 1 and 2 (35% and 25%, respectively) (P = 0.02). CONCLUSIONS: The response to use of a combination of bleomycin and tetracycline for the treatment of patients with pleurodesis is superior to that achieved by either of these agents used alone.     

Thioguanine versus mercaptopurine for therapy of childhood lymphoblastic leukaemia: a comparison of haematological toxicity and drug metabolite concentrations

Stocks of the International Reference Preparation (IRP) for thromboplastin, human, plain, coded BCT/253 and held by the World Health Organization (WHO) are nearly exhausted and must be replaced. For practical reasons the choice of the replacement candidate was restricted to two available human recombinant preparations which were coded as X/95 and Y/95 and calibrated in an international collaborative study involving 19 laboratories from Europe, Australia, Canada and Argentina. To minimize the differences between routes of calibration, the two candidates were calibrated against the existing WHO-IRP from human, rabbit and bovine origin and the final ISI was the resultant average value. On the basis of predefined criteria (i.e., within- and between-laboratory precision of the calibration and the conformity to the calibration model), X/95 was the preferred candidate. The assigned ISI (SE of the mean) value is 0.940 (0.0060) and the interlaboratory coefficient of variation 4.7%.