Efficacy and safety of tramadol HCl in breakthrough musculoskeletal pain attributed to osteoarthritis

OBJECTIVE: To evaluate the efficacy of tramadol as adjunctive therapy in patients with musculoskeletal pain attributed to osteoarthritis (OA) who experienced breakthrough pain while taking a nonsteroidal antiinflammatory drug (NSAID). METHODS: This single center, parallel, placebo controlled, 2 phase study was conducted in adults who experienced breakthrough OA pain while undergoing stable NSAID therapy. In a 24 h open label phase, patients took 100 mg of tramadol followed by 50 mg every 6 h (total 250 mg) in addition to their daily NSAID regimen. Supplemental analgesics were prohibited. Patients who met entry criteria and were willing to continue therapy were randomized to a 13 day double blind phase of adjunctive therapy with tramadol (50-100 mg every 4-6 h as needed for pain) or placebo; NSAID therapy was continued. The primary efficacy endpoint was the time to exit from the study because of therapeutic failure (i.e., insufficient pain relief or an inability to perform activities of daily living). RESULTS: The time to exit from the study because of insufficient pain relief tended to be longer in the tramadol group (250 mg/day) compared with the placebo group (p = 0.066). At the end of the double blind phase, pain at rest was significantly less severe in tramadol treated patients (p = 0.046). In addition, severity of pain on motion tended to be less severe in tramadol treated patients (p = 0.059). General severity of current pain and ability to perform activities of daily living were not significantly different with tramadol or placebo. Patients' overall assessment of therapy (p = 0.022) and investigator's rating of global improvement (p = 0.004) were significantly better with tramadol than with placebo. CONCLUSION: Tramadol may have a role as adjunctive treatment for breakthrough pain in patients receiving NSAID therapy for musculoskeletal pain attributed to OA.     

The olfactory loss that accompanies an HIV infection

Acute low back pain is a common problem in the emergency department (ED). Effective management of acute pain enhances early rehabilitation and recovery. Given the importance of inflammatory mediators in pain generation and the adverse effects associated with opioids, it is logical to expect that a non-opioid agent with antiinflammatory and analgesic properties would provide excellent analgesia with fewer adverse effects. This double-blind, randomized, multicenter clinical trial, performed in six university and community hospital EDs, compares the analgesic efficacy and adverse effects of ketorolac to those of acetaminophen-codeine in ED patients with acute musculoskeletal low back pain. Our hypothesis was that ketorolac would provide superior analgesia with fewer adverse effects. One hundred twenty-three patients with acute low back pain were randomized to receive ketorolac (KET, N = 63) or acetaminophen-codeine (ACOD, N = 60). Most (79%) were males, and the mean age was 34.5 years. After baseline clinical assessment, patients were treated with ketorolac (10 mg every 4 to 6 h as needed, up to four daily doses) or acetaminophen-codeine (600 mg-60 mg, respectively, every 4 to 6 h as needed, up to six daily doses) and followed for one week. Pain intensity was assessed on visual analogue and categorical scales. Functional capacity, overall pain relief, and overall medication rating were assessed on categorical scales. Adverse events were documented. Primary outcomes included: 1) Pain intensity differences, based on visual analogue scores, for the 0 to 6 h treatment phase. 2) Incidence of adverse events. Secondary outcomes included analgesic efficacy, functional capacity, and overall subjective drug evaluation at one week. Both drugs provided substantial pain relief, with maximal effect 2.2 h after oral dosing. There were no significant differences in analgesic efficacy, functional capacity, or overall pain relief between the two groups. Sixteen patients (10 KET vs. 6 ACOD, NS) withdrew prematurely because of drug inefficacy. Patients in the ACOD group reported significantly more adverse drug events and serious adverse drug events. Seven patients--all in the ACOD group--withdrew from the study because of adverse drug events. Based on comparable efficacy and a superior adverse event profile, ketorolac was preferable to acetaminophen with codeine for the treatment of acute low back pain in the ED.     

Chest discomfort associated with liposomal amphotericin B: report of three cases and review of the literature

Liposomal formulations of amphotericin B are designed to maintain therapeutic efficacy of amphotericin B deoxycholate while reducing its associated toxicities. In three patients chest discomfort occurred during planned 1-hour infusions of liposomal amphotericin B (AmBisome) 3 mg/kg/day during an open-label trial. The first patient experienced chest tightness and difficulty breathing and the second had dyspnea and acute hypoxia, both within 10 minutes of the start of the infusion. The third patient complained of chest pain 5 minutes after the start of two infusions. All symptoms resolved on terminating therapy. Two patients were later rechallenged with slower infusions and tolerated the drug well. A review of the English-language literature revealed only two other case reports of infusion-related chest or pulmonary reactions with the drug, although similar reactions were noted in several reports of clinical trials. Further review of the literature revealed reports of chest and pulmonary adverse events with other liposomal formulations of amphotericin B, liposomal daunorubicin, liposomal doxorubicin, and liposomes. The pathophysiology of such reactions remains unclear, and premedication with diphenhydramine did not completely prevent this reaction in one of our patients. We recommend infusing liposomal amphotericin B over at least 2 hours with careful monitoring for adverse reactions.     

A controlled, prospective, 1-year trial of citalopram in the treatment of panic disorder

BACKGROUND: The objective of this study was to evaluate the efficacy and tolerability of citalopram in the long-term treatment of adult outpatients with panic disorder with or without agoraphobia. METHOD: Patients in this double-blind, parallel-group trial were assigned to 1 of 3 fixed dosage ranges of citalopram (10 or 15 mg/day, 20 or 30 mg/day, or 40 or 60 mg/day), 1 dosage range of clomipramine (60 or 90 mg/day), or placebo. After the completed 8-week acute treatment period, the eligible patients could continue the treatment for up to 1 year. Of the 475 patients who were randomly assigned for the short-term trial, 279 agreed to continue double-blind treatment at their assigned doses. The primary efficacy measure used was the Clinical Anxiety Scale panic attack item, and the response was defined as no panic attacks (score of 0 or 1). The other key measures used were the Physician's Global Improvement Scale, the Patient's Global Improvement Scale, and the Hamilton Rating Scale for Anxiety (HAM-A). RESULTS: In all drug-treated groups, except the group receiving the lowest citalopram dose, the treatment outcome was generally better than with placebo. As determined by a life table analysis of response, the probability of response during the 12 months was significantly greater with all treatment regimens than with placebo (p < .05), with citalopram 20 or 30 mg/day demonstrating the best response. Panic attacks tended to disappear in all patients remaining in the study until the end of follow-up. Analysis of the difference in the number of patients in different treatment groups remaining in the study (perhaps the best measure of long-term efficacy) also demonstrated that the patients treated with citalopram in dosage ranges of 20 or 30 mg/day and 40 or 60 mg/day had better response than placebo-treated patients (p < .0002 and p < .004, respectively). HAM-A and Global Improvement Scale scores also showed that patients treated with active drug showed greater improvement than placebo-treated patients. All treatment groups showed no new or exceptional adverse event clusters. CONCLUSION: Citalopram in the dosage range of 20 to 60 mg/day is effective, well tolerated, and safe in the long-term treatment of patients who have panic disorder.     

Long-term drug treatment of obesity in a private practice setting

This study evaluated the long-term efficacy and safety of the combination of phentermine and fenfluramine for the treatment of obesity in a private practice setting. A total of 1388 consecutive, qualified patients presenting to a private general internal medicine practice in Charlotte, NC, were enrolled with eligibility criteria including: age 18 years to 60 years, 20% over "desirable" bodyweight or body mass index > 27, no serious medical or psychiatric disease, and no contraindications to drug therapy. Patients were instructed in diet, exercise, and behavior modification techniques and received phentermine (15 mg/day to 30 mg/day) and fenfluramine (20 mg/day to 60 mg/day) continuously for over 3 years. Average duration of treatment was 15.9 months, and average weight loss at the last visit was 11.6 kg, or 11.7% of initial bodyweight. For patients completing 1 year of drug treatment, mean weight loss was 16.5 kg, or 16% of initial weight. Weight loss persisted for 2 years, but partial regain was seen at 3 years. The dropout rates were 18% at 6 months, 39% at 1 year, 68% at 2 years, and 78% at 3 years. At 1 year, blood pressure of hypertensive patients fell from 151/95 mm Hg to 127/78 mm Hg, and serum cholesterol and triglycerides of hyperlipidemic patient fell by 0.750 mmol/L (29 mg/dL) and 0.937 mmol/L (83 mg/dL), respectively. Adverse events were modest. We conclude that, in a private practice setting, long-term treatment of obesity with the combination of phentermine, fenfluramine, and a weight maintenance program is generally safe and effective. More research is needed to determine efficacy and safety for longer than 3 years.     

Milnacipran. A review of its use in depression

Milnacipran is a cyclopropane derivative which acts by inhibiting noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake at presynaptic sites; no postsynaptic receptor activity has been demonstrated. It is most commonly administered at a dosage of 50 mg twice daily for the treatment of major depressive disorder. Improvement usually occurs within 2 weeks of treatment initiation, but some patients do respond sooner. Most studies which evaluated milnacipran were of short (4 to 8 weeks) duration and results were not published in full with rigorous peer review. Nonetheless, the drug is significantly more effective than placebo for the treatment of in- or outpatients with moderate to severe major depressive disorder. Limited data suggest that it may prevent relapse and be effective for long term use, although this requires confirmation. Milnacipran 200 mg/day is generally not significantly different from amitriptyline 150 mg/day in terms of onset and efficacy. However, when doses are titrated (not a requirement for milnacipran), milnacipran 50 or 100 mg/day has a slower onset than the tricyclic antidepressant. At a dosage of 100 mg/day for 4 to 12 weeks, milnacipran generally has similar efficacy to imipramine and clomipramine 150 mg/day, although milnacipran 50 to 150 mg/day had a faster onset of activity than imipramine 50 to 150 mg/day in Japanese patients. In a 6-month trial, milnacipran was less effective than clomipramine. Milnacipran 50 or 100 mg twice daily was as effective as fluoxetine 20 mg once daily or fluvoxamine 100 mg twice daily in 4- to 12-week studies. At a dosage of 50 then 100 mg daily it was also as effective as mianserin 30 then 60 mg daily in a 4-week study. However, when administered once daily (in the evening), milnacipran 100 mg/day was not as effective as fluoxetine 20 mg/day after 6 weeks. The drug is generally well tolerated, producing no more adverse events (including anticholinergic events) than placebo, selective serotonin reuptake inhibitors or mianserin and fewer adverse events than tricyclic antidepressants in clinical trials. However, dysuria has been reported in 7% of male patients receiving milnacipran. CONCLUSIONS: Data from predominantly short term trials suggest that milnacipran generally has similar efficacy to tricyclic antidepressants and SSRIs. Although further published data are required to confirm its efficacy, good tolerability profile and pharmacokinetic profile which suggests a low potential for drug interactions, milnacipran should be considered a promising agent for the treatment of patients with major depressive disorder.     

Mexiletine. A review of its therapeutic use in painful diabetic neuropathy

Mexiletine is an orally active local anaesthetic agent which is structurally related to lidocaine (lignocaine) and has been used for alleviating neuropathic pain of various origins. Mexiletine has been evaluated in several randomised, placebo-controlled trials in patients with painful diabetic neuropathy. The drug decreased mean visual analogue scale (VAS) pain ratings in all studies that used this measure, although in only 2 studies was this effect significantly greater than the often substantial responses seen with placebo. The clinical significance of these decreases is not clear. Statistically significant (vs placebo) reductions in VAS pain ratings were observed in 16 patients receiving mexiletine 10 mg/kg/day for 10 weeks in 1 study and in nocturnal (but not diurnal) pain in 31 patients receiving mexiletine 675 mg/day for 3 weeks in another. Retrospective analysis of another study revealed that mexiletine recipients (225 to 675 mg/day) who described their pain as stabbing, burning or formication on the pain-rating-index-total instrument of the McGill Pain Questionnaire, experienced statistically significant reductions in VAS pain scores after 5 weeks, compared with placebo recipients. Mexiletine generally did not have a significant influence on the quality of sleep in patients with diabetic neuropathy. In Japanese patients, statistically significant reductions in subjective pain ratings were achieved with mexiletine 300 mg/day in 1 study and with 450 mg/day in a further study. In controlled trials, the frequency of adverse events in patients receiving mexiletine for painful diabetic neuropathy ranged from 13.5 to 50%. Gastrointestinal complaints, of which nausea was the most frequent, were the most common adverse events in mexiletine recipients. Central nervous system complaints were uncommon, but included: sleep disturbance, headache, shakiness, dizziness and tiredness. Serious cardiac arrhythmias have not been reported in patients receiving mexiletine for painful diabetic neuropathy; however, transient tachycardia and palpitations have been reported. There are significant differences in the metabolism of mexiletine between people who have cytochrome P450 2D6 [CYP2D6; extensive metabolisers (EMs)] and those who lack this isoenzyme [poor metabolisers (PMs)]. EMs, but not PMs, are susceptible to drug interactions between mexiletine and drugs that inhibit CYP2D6 (e.g. quinidine). Moreover, mexiletine inhibits CYP2D6-mediated metabolism of metoprolol and cytochrome P450 1A2-mediated metabolism of theophylline. Phenytoin and rifampicin (rifampin) induce the metabolism of mexiletine. Clearance of mexiletine is impaired in patients with hepatic, but not renal, dysfunction. Hence, dosage adjustments may be necessary in patients with liver disease. CONCLUSIONS: Tricyclic antidepressants (TCAs) are the agents of choice for painful diabetic neuropathy; however, they are ineffective in approximately 50% of patients and are generally not well tolerated. Mexiletine is an alternative agent for the treatment of painful diabetic neuropathy in patients who have not had a satisfactory response to, or cannot tolerate, TCAs and/or other drugs.     

Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology

In the present retrospective investigation, the long-term effects of continuous intrathecal opioid therapy via implantable infusion pump systems were examined in 120 patients with chronic, nonmalignant pain syndromes. The follow-up period was 6 months to 5.7 years (mean 3.4 years +/- 1.3 standard error of the mean). Deafferentation pain and neuropathic pain showed the best long-term results, with 68% and 62% pain reduction (visual analog scale), respectively. The mean morphine dosage initially administered was 2.7 mg/day (range 0.3-12 mg/day); after an average of 3.4 years, it was 4.7 mg/day (range 0.3-12 mg/day). In a long-term observation of 28 patients who received intrathecal morphine for longer than 4 years. 18 patients (64.3%) had a constant dosage history and 10 patients (35.7%) showed an increase in morphine dosage to more than 6 mg/day 1 year after dosage determination. In seven cases, a tolerance developed: in four patients the tolerance was controlled by means of "drug holidays"; but in three patients it was necessary to remove the pump systems. Explantation of the pump system occurred in 22 additional cases for other reasons. Throughout the follow-up period, 74.2% of the patients profited from the intrathecal opiate therapy: the average pain reduction after 6 months was 67.4% and, as of the last follow-up examination, it was 58.1%. Ninety-two percent of the patients were satisfied with the therapy and 81% reported an improvement in their quality of life. The authors' 6-year experience with administration of intrathecal opioid medications for nonmalignant pain should encourage the use of this method in carefully selected patients.     

Postoperative analgesia in herniated disk surgery. Comparative study of diclofenac , lysine acetylsalicylate, and ketorolac

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in treating musculoskeletal pain and are theoretically ideal for treating postoperative pain of the lumbar column. OBJECTIVES: To compare the analgesic efficacy and side effects of treatment with 3 NSAIDs (lysine acetylsalicylate, ketorolac and diclofenac) in the treatment of pain after surgery for lumbar disc hernia. PATIENTS AND METHODS: We enrolled 75 ASA I-II patients undergoing discectomy because of lumbar disc hernia; balanced general anesthesia was used in all cases. The patients were randomly distributed in 3 groups based on type of analgesia given in the immediate postoperative period. Group A received lysine acetylsalicylate (1800 mg), group B received ketorolac (30 mg) and group C received diclofenac (75 mg). The analgesics were diluted in 100 mg of saline solution and administered through a peripheral vein over 10 min. We evaluated the analgesia attained on a visual analog scale (VAS) and the physiological response to pain was assessed by monitoring changes in arterial pressure, heart rate and breathing frequency. If analgesia was insufficient 30 min after administration of the drug, 200 mg of lysine cloximate was given as a top-up. The side effects of each drug were also recorded. RESULTS: VAS evaluation showed significant reductions in pain 60 min after administration in groups A and B and after 120 min in group C. Nine patients in each group required lysine cloximate. There were no significant differences in physiological response among the 3 groups. No patient suffered major side effects. Mild side effects were reported most often in group B. CONCLUSIONS: The NSAIDs studied were inadequately for treating pain after surgery for lumbar disc hernia. Ketorolac was no better than the other analgesics studied but was associated with a higher number of mild side effects.     

Differentiation of benign from malignant nodules by accumulation of Tc-99m pertechnetate using TI-201 delayed scans

OBJECTIVE: To report the presence of an uncommon adverse effect, pain in the tumor location, during the administration of the cytostatic agent vinorelbine. METHOD: Twenty-seven patients with non operable relapses of epidermoid carcinomas of the head and neck were treated with two combinations of cytostatics: mitomycin-c 10 mg/m2 on day 1 plus vinorelbine 25 mg/m2 on days 1, 8 and 15 in twelve patients or carboplatin 300 mg/m2 on day 1 plus vinorelbine 25 mg/m2 on days 1, 8 and 15 in fifteen patients. RESULTS: Six patients had moderate/severe pain in the tumor location; concomitantly, one patient had chest pain. Four patients required major opiates. The clinical picture reverted and no patient had acute or chronic neurotoxicity. The readministration of vinorelbine triggered pain again, and all patients refused to continue the therapeutic program. CONCLUSION: Vinorelbine can cause pain at tumor location, a nonserious adverse effect which, nevertheless, prevented the continuation of therapy.     

Double-blind comparative trial of indoprofen and acetylsalicylic acid in osteoarthritis

The effectiveness, safety and acceptability of indoprofen (IP) and acetylsalicylic acid (ASA) were assessed in patients with osteoarthritis, in a double-blind comparative trial. Each patient received IP 600 mg/day or ASA 2100 mg/day for a four-week period; after a one-week wash-out period, the same drug was given at a higher dosage (IP 800 or ASA 2800 mg/day) for another four weeks. Seventeen patients on indoprofen and 14 on SAS completed the trial. A significant improvement was obtained with indoprofen in the different parameters measuring pain, from the first treatment period; results were similar at the end of the second period. Results with ASA, at both dosages, appeared less impressive. Two patients on indoprofen and five on ASA complained of side effects.     

Efficacy and tolerance of lysine clonixinate versus paracetamol/codeine following inguinal hernioplasty

In this study lysine clonixinate, a nonsteroidal antiinflammatory agent with selective inhibition of cyclooxygenase-2 and 5-lipooxygenase in in vitro and in vivo pharmacodynamic studies, was evaluated in a prospective, randomized, double-blind, double-dummy clinical study versus paracetamol/codeine, in 151 patients with pain following inguinal hernioplasty. Patients were treated with one 125 mg tablet of lysine clonixinate or paracetamol/codeine (500 mg + 30 mg) administered at fixed doses every 4 h during 2 days. Controls were carried out 1, 2 and 4 h after the first intake of day 1 and day 2. Each control included assessment of pain at rest, when coughing, sitting and upon moderate pressure. Both treatment groups (lysine clonixinate, 77 patients and paracetamol/codeine, 74 patients) were comparable in terms of demographic and baseline pain intensities. Spontaneous pain was reduced significantly in both treatment groups from the 1st-h control. The following values were recorded in the lysine clonixinate group during day 1: baseline: 6.86 +/- 1.24; 1st h: 4.49 +/- 1.77; 2nd h: 2.96 +/- 1.74; 4th h: 2.23 +/- 1.51. The following values for the same group during day 2 were: predose: 1.70 +/- 1.64; 1st h: 1.16 +/- 1.17; 2nd h: 0.78 +/- 1.06; 4th h: 0.63 +/- 1.05. The paracetamol/codeine group revealed the following values: day 1: baseline: 6.72 +/- 1.22; 1st h: 4.57 +/- 1.72; 2nd h: 2.97 +/- 1.68; 4th h: 2.47 +/- 1.68 and day 2: predose: 2.02 +/- 1.57; 1st h: 1.32 +/- 1.23; 2nd h: 0.82 +/- 0.99; 4th h: 0.66 +/- 0.89. Reduction of pain induced by coughing, sitting and pressure showed similar behavior patterns. No significant differences between both treatment groups were encountered in terms of analgesic efficacy. Incidence of adverse effects was significantly higher in the paracetamol/codeine group (X2: p < 0.05): 11 out of 74 patients; three patients had to discontinue treatment. In the lysine clonixinate group four out of 77 patients showed side effects but these did not require treatment discontinuation.     

Domperidone. A review of its use in diabetic gastropathy

Domperidone is a selective antagonist at peripheral dopamine D2 receptors, with gastroprokinetic and antiemetic properties. It increases the frequency and duration of antral and duodenal contractions, thus decreasing/improving transit time of food through the gastrointestinal tract. Gastric emptying of liquids and solids is significantly improved with oral domperidone 40 to 120 mg/day in patients with diabetic gastropathy. Oral domperidone 40 to 80 mg/day significantly decreased the severity of symptoms of gastropathy from baseline values in 66 to 88% of patients with type 1 (insulin-dependent) or insulin-requiring diabetes mellitus. Double-blind withdrawal of domperidone from patients who had responded previously led to greater deterioration of symptoms in patients with delayed gastric emptying than in those who continued receiving the drug. Quality of life was significantly improved in patients who showed a symptomatic response to domperidone. The administration of domperidone 40 to 120 mg/day significantly reduced hospitalisation rates in patients with gastropathy. The symptomatic improvement with domperidone 80 mg/day was similar to that seen with cisapride 40 mg/day or metoclopramide 40 mg/day, and therapeutic benefits seen in symptoms of gastropathy were maintained with domperidone for up to 12 years. Domperidone 40 to 80 mg/day may be effective in patients who are refractory to metoclopramide, and a combination of domperidone 80 mg/day with cisapride 80 mg/day may improve some symptoms in patients who do not respond to either agent alone. Domperidone 40 to 120 mg/day was well tolerated for periods up to 12 years in trials in patients with diabetic gastropathy. Adverse events with domperidone 80 mg/day were similar to those seen in placebo recipients and significantly fewer than in patients receiving metoclopramide 40 mg/day. Although significant elevation of plasma prolactin levels (unrelated to dosage and duration of treatment) occurred in all domperidone recipients, prolactin-related adverse events were observed in only 10 to 20% of patients. CONCLUSIONS: The available data suggest that domperidone 40 to 80 mg/day is an effective agent for the management of symptoms of gastropathy in patients with type 1 diabetes mellitus. In addition, it may provide symptom improvement in patients with gastropathy refractory to other gastroprokinetic agents. Domperidone maintains efficacy in the long term (up to 12 years) and appears to have a better tolerability profile than metoclopramide 40 mg/day.     

Sertraline treatment of children and adolescents with obsessive-compulsive disorder or depression: pharmacokinetics, tolerability, and efficacy

OBJECTIVE: To evaluate the pharmacokinetics, safety, and efficacy of sertraline in children (6 to 12 years old) and adolescents (13 to 17 years old). METHOD: Children (n = 29) and adolescents (n = 32) with major depression, obsessive-compulsive disorder (OCD), or both received a single dose of 50 mg of sertraline followed, 1 week later, by 35 days of sertraline treatment as follows: (1) either a starting dose of 25 mg/day titrated to 200 mg/day in 25-mg increments or (2) a starting dose of 50 mg/day titrated to 200 mg/day in 50-mg increments. Sertraline and desmethylsertraline pharmacokinetics were determined approximately weekly, and efficacy measures were assessed before drug administration and at the end of treatment. RESULTS: Mean area under the plasma concentration-time curve (AUC), peak plasma concentration (Cmax), and elimination half-life (t1/2) for sertraline and desmethylsertraline were similar to previously reported adult values. No titration-dependent pharmacokinetic or safety differences were seen. While Cmax and AUC0-24 were greater for children versus adolescents, these differences disappeared after parameters were normalized for body weight. Sertraline was well tolerated in both children and adolescents, with adverse experiences similar to those previously reported by adult patients. Efficacy measurements indicated improvement (p < .001) in depression and OCD symptomatology. CONCLUSIONS: Sertraline can be safely administered to pediatric patients using the currently recommended adult titration schedule.     

Low- versus high-dose aspirin in prevention of ischemic stroke

Aspirin is the most extensively studied drug for the prevention of ischemic vascular disease. Meta-analyses confirm that aspirin is effective in prevention of ischemic events, including stroke. Recently, there has been considerable discussion about the best dose of aspirin to prevent stroke. Several studies tested aspirin in a daily dose of 975 mg or more alone or in combination with another drug, most commonly dipyridamole, and noted that aspirin was effective. Successively lower doses of aspirin were tested and recent studies demonstrate that low doses (< 100 mg/day) are effective. Only one study, enrolling patients with transient ischemic attack or minor stroke, has examined aspirin in a daily dose of approximately 325 mg. Side effects of aspirin are dose related; gastrointestinal bleeding and epigastric pain are less with low doses. Available data cannot confirm that low doses (< 100 mg/day) of aspirin are either more or less effective than larger (975 mg/day) doses. A direct comparison of the usefulness of low doses (< 100 mg/day) or large doses (approximately 1,000 mg/day) in patients at high risk of stroke is needed. Until the results of such a study are known, the better safety profile of low doses favors aspirin in a daily dose of 100 mg or less.     

Radiographic examination of the pelvis in patients under periodic hemodialysis for terminal uremia

The efficacy and tolerability of pyritinol (PY) and auranofin (AU) were compared in a multicentre double-blind study. Patients with RA received 600 mg/day PY or 6 mg/day AU for 1 year. Response was rated by a defined improvement in at least four of the following: Ritchie index, joint swelling index, rating scales for pain and general well-being, functional index, morning stiffness, ESR. Of the 139 fully evaluable PY patients 61 (44%) dropped out due to adverse events or response failure compared with 44 (31%) of the 142 AU patients. In patients treated for 1 year efficacy parameters improved more in the PY than in the AU group, with significant differences for the general well-being (P = 0.022), ESR (P = 0.029) and haemoglobin (P = 0.0042). The response rate for PY (61/78 patients, 78%) was significantly superior to AU (58/98 patients, 59% P = 0.009). An intention-to-treat analysis corroborated this result (P = 0.030). Adverse events (AE) occurred in 64% of PY patients and in 58% of AU patients: main AE were mucocutaneous symptoms (PY 36%, AU 23%) and gastrointestinal complaints (PY 30% AU 37%). Single cases of proteinuria, hepatic and haematological abnormalities were noted in both groups.     

Anagrelide, a selective thrombocytopenic agent

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of anagrelide are reviewed. Anagrelide is a selective thrombocytopenic agent with FDA-approved labeling for the treatment of essential thrombocythemia. Clinical trials have shown that the drug may have a role in the treatment of other chronic myeloproliferative disorders, including polycythemia vera, chronic myeloid leukemia, and agnogenic myeloid metaplasia. The mechanism by which anagrelide reduces platelet count is not yet clear. The current hypothesis is that anagrelide affects the late (postmitotic) phases of megakaryocyte development. Anagrelide has a large volume of distribution and is extensively metabolized; less than 1% is recovered unchanged in the urine. Plasma half-life after a 0.5-mg dose is 1.3 hours. Anagrelide's efficacy and safety have been evaluated in open-label, noncomparative trials, in which the response rate was 60-93%. Adverse effects include headache, diarrhea, edema, palpitations, and abdominal pain. Patients with renal or hepatic dysfunction need to be closely monitored for signs of toxicity. The recommended starting dosage is 0.5 mg four times a day or 1 mg twice a day, with dosage adjustment to the lowest effective amount required to reduce and maintain platelet count below 600 x 10(9)/L. The wholesale acquisition price for 0.5-mg capsules is $350 per 100. Whether anagrelide will replace hydroxyurea as first-line therapy in some or all patients remains to be determined. Anagrelide is effective in the treatment of essential thrombocythemia and may have a role in the treatment of other myeloproliferative disorders.     

Randomised comparison of ciprofloxacin suspension and pivmecillinam for childhood shigellosis

BACKGROUND: Infections caused by multiply resistant Shigella species are a major cause of childhood morbidity and mortality in Third World countries. The fluoroquinolone agent ciprofloxacin is active in vitro against these strains of bacteria, but has not been routinely used to treat acute childhood infections because of concern that quinolones may cause arthropathy in children. We undertook a randomised double-blind study to test the effects of ciprofloxacin treatment in children with shigella dysentery. METHODS: We compared the efficacy and toxic effects of ciprofloxacin suspension (10 mg/kg every 12 h for 5 days, maximum individual dose 500 mg) with those of pivmecillinam tablets (15-20 mg/kg every 8 h for 5 days, maximum individual dose 300 mg). We enrolled 143 children aged 2-15 years with dysentery of 72 h or less duration. Patients stayed in hospital for 6 days, and were followed up 7, 30, and 180 days after hospital discharge. Joint symptoms and function were assessed daily for 6 days. Clinical success was defined as the absence of frank dysentery on day 3, and on day 5 no bloody-mucoid stools, one or no watery stool, six or fewer total stools, and no fever. If no shigella were isolated from faecal samples on day 3 or thereafter, treatment was judged bacteriologically successful. FINDINGS: 13 patients were excluded since they did not meet eligibility criteria; 10 withdrew before day 5. Thus 120 patients (60 in each group) completed the study. Treatment was clinically successful in 48 (80%) of 60 patients who received ciprofloxacin and in 39 (65%) of 60 patients who received pivmecillinam (p=0.10). Treatment was bacteriologically successful in all of the patients receiving ciprofloxacin, and in 54 (90%) of the patients receiving pivmecillinam (p=0.03). Joint pain after treatment began in 13 (18%) of 71 patients who received ciprofloxacin and 16 (22%) of 72 patients who received pivmecillinam (p>0.2), and no patient had signs of arthritis. INTERPRETATION: In our trial, ciprofloxacin suspension and pivmecillinam had the same clinical efficacy. Ciprofloxacin had greater bacteriological efficacy and was not associated with the development of arthropathy. We conclude that ciprofloxacin is an effective and safe drug for use in multiply resistant childhood shigellosis.     

Bipolar disorder: dominant or recessive on chromosome 5?

Rizatriptan (MK-462) is a potent 5HTID receptor agonist. This multicenter, double-blind, placebo-controlled, outpatient study investigated the clinical efficacy, safety, and tolerability of rizatriptan (2.5, 5, and 10 mg) as a function of dose for acute migraine. Patients with moderate or severe migraine (n = 417) were treated with placebo (n = 67), rizatriptan 2.5 mg (n = 75), 5 mg (n = 130), or rizatriptan 10 mg (n = 145). Headache severity, functional disability, and migraine symptoms were measured immediately before dosing (0) and at 0.5, 1, 1.5, 2, 3, and 4 h post-dose. Patients were permitted to take a second dose of test drug at 2 h if their headache pain was moderate or severe (i.e., placebo initially-->rizatriptan 10 mg as optional second dose; rizatriptan 2.5 mg, 5 mg, or 10 mg initially-->placebo as optional second dose). An upward dose-response relationship was observed among placebo, rizatriptan 2.5 mg, 5 mg, and 10 mg in the primary efficacy measure of proportion of patients reporting pain relief, i.e., a change in headache severity to "no pain or mild pain" at 2 h post-dose. The relationship was evident even at the first recorded timepoint, 30 min, and was statistically significant at 1.5 h and beyond. At the primary timepoint of 2 h after the initial dose, the proportion of patients reporting pain relief was 47.6% for rizatriptan 10 mg; 45.4% for rizatriptan 5 mg; 21.3% for rizatriptan 2.5 mg; and 17.9% for placebo. Seventy percent of patients on rizatriptan 10 mg reported pain relief at 4 h. Patients who took rizatriptan 5 mg and 10 mg were significantly less functionally disabled than those who took placebo at 1.5 and 2 h post-dose. Rizatriptan 10 mg was consistently more effective than 5 mg, although the differences were not statistically significant. The most frequent clinical adverse events were dizziness, somnolence, and asthenia/fatigue. No patients were discontinued for any adverse experiences and there were no serious adverse experiences.     

Antifungal prophylaxis with itraconazole in neutropenic patients with acute leukaemia

The efficacy of antifungal prophylaxis with itraconazole capsules and its serum concentrations were evaluated in patients intensively treated for acute leukaemia. A consecutive group of patients without systemic antifungal prophylaxis (January 1993 to August 1994, period 1) was compared with another consecutive group of patients (period 2) who received itraconazole capsules (September 1994 to April 1995 400 mg/day, from May 1995 onwards 600 mg/day). All patients admitted with acute leukaemia and standard or high-dose chemotherapy were included into the study. Clinical endpoint was mortality from proven fungal infection. Seventy-six patients and 148 courses of cytotoxic chemotherapy were analysed in the control group as well as 47 patients and 112 treatment courses in the intervention group. Antifungal prophylaxis led to a significant decrease of mortality from invasive fungal infections (8.8%-0.9%, P = 0.005). The median trough concentration of itraconazole of all measurements was 520 ng/ml (range 230-793) in patients who received 400 mg/day and 760 ng/ml (370-1200) in patients receiving a dosage of 600 mg/day (P = 0.002). These findings suggest that itraconazole is an effective drug for antifungal prophylaxis but also that a considerable number of patients do not reach the desired trough levels (>500 ng/ml) with itraconazole capsules.