Showing papers on "Tolerability published in 1997"

Anthracyclines in the treatment of cancer. An overview.

Abstract: Anthracyclines are widely used and effective antineoplastic drugs. Although active against a wide variety of solid tumours and haematological malignancies, their clinical use is hindered by tumour resistance and toxicity to healthy tissue. Modification of the general anthracycline ring structure results in analogues with different but overlapping antitumour and tolerability profiles. Activity of the anthracyclines is related to topoisomerase II inhibition, which occurs as a result of anthracycline intercalation between adjacent DNA base pairs. Production of hydroxyl free radicals is associated with antitumour effects and toxicity to healthy tissues. Myocardial tissue is particularly susceptible to free radical damage. Development of tumour cell resistance to anthracyclines involves a number of mechanisms, including P-glycoprotein-mediated resistance. The classical dose-limiting adverse effects of this class of drugs are acute myelosuppression and cumulative dose-related cardiotoxicity. Anthracycline-induced cardiomyopathy is often irreversible and may lead to clinical congestive heart failure. Other toxicities of the anthracyclines, including stomatitis, nausea and vomiting, alopecia and 'radiation recall' reactions, are generally reversible. Anthracycline-induced cardiotoxicity may be reduced or prevented by an administration schedule that produces low peak plasma drug concentrations. Administration of dexrazoxane also provides cardioprotection. Dose intensification of anthracyclines may partly overcome resistance but is associated with reduced tolerability. Liposomal encapsulation of doxorubicin or daunorubicin alters the pharmacokinetic properties of the drugs. Increased distribution in tumours, prolonged circulation and reduced free drug concentrations in plasma may increase antitumour activity and improve the tolerability of the anthracyclines.

The new antiepileptic drugs: a systematic review of their efficacy and tolerability.

Abstract: Summary : Purpose: Gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS) are all in use as “add-on” treatment for patients with refractory epilepsy. There have been no comparative randomized controlled trials allowing an evidence-based choice between these drugs. We report a series of meta-analyses of randomized placebo-controlled add-on trials in which these drugs have been tested in patients with partial epilepsy. This work provides an estimate of each drug's efficacy and tolerability compared with placebo. These estimates are compared across drugs to give broad estimates of comparative efficacy and tolerability. Methods: Trial reports were found by searching Medline, by searching through journals by hand, and by contacting the pharmaceutical industry. The outcomes chosen were the proportion of patients who (a) have a 350% reduction in seizure frequency (50% responders); (b) withdrew from the study (any reason); or (c) reported the following side effects: ataxia, dizziness, fatigue, nausea, or somnolence. Overall odds ratio (OR) with 95% confidence intervals (CIS; 50% responders) or 99% CIS; side effects) were calculated. Results: Twenty-nine trials were included, representing 4,091 randomized patients. The ORs for 50% response (95% CI) were GBP, 2.29 (1.53–3.43); LTG, 2.32 (1.47–3.68); TGB, 3.03 (2.01–4.58); TPM, 4.07 (2.87–5.78); VGB, 3.67 (2.44–5.51); and ZNS, 2.7 (1.36–4.47). ORs for discontinuation were GBP, 1.36 (0.75–2.49); LTG, 1.19 (0.79–1.79); TGB, 1.81 (1.21–2.70); TPM, 2.56 (1.64–4.00); VGB, 2.58 (126–5.27); and ZNS, 4.23 (1.71–10.49). Conclusions: We have clear evidence that each of these drugs is better than placebo at preventing seizures. When results are compared across drugs, the confidence intervals overlap, and we have no conclusive evidence of differences in efficacy or tolerability. Despite this, the agent that appears most effective may be twice as effective as the agent that appears least effective, and the agent that appears most likely to cause discontinuation may be 4 times more likely to do so than the treatment that appears least likely to do so. Comparative randomized studies are needed further to evaluate these drugs.

Ketorolac : A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management

Abstract: Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) with strong analgesic activity. The analgesic efficacy of ketorolac has been extensively evaluated in the postoperative setting, in both hospital inpatients and outpatients, and in patients with various other acute pain states. After major abdominal, orthopaedic or gynaecological surgery or ambulatory laparoscopic or gynaecological procedures, ketorolac provides relief from mild to severe pain in the majority of patients and has similar analgesic efficacy to that of standard dosages of morphine and pethidine (meperidine) as well as less frequently used opioids and other NSAIDs. The analgesic effect of ketorolac may be slightly delayed but often persists for longer than that of opioids. Combined therapy with ketorolac and an opioid results in a 25 to 50% reduction in opioid requirements, and in some patients this is accompanied by a concomitant decrease in opioid-induced adverse events, more rapid return to normal gastrointestinal function and shorter stay in hospital. In children undergoing myringotomy, hernia repair, tonsillectomy, or other surgery associated with mild to moderate pain, ketorolac provides comparable analgesia to morphine, pethidine or paracetamol (acetaminophen). In the emergency department, ketorolac attenuates moderate to severe pain in patients with renal colic, migraine headache, musculoskeletal pain or sickle cell crisis and is usually as effective as frequently used opioids, such as morphine and pethidine, and other NSAIDs and analgesics. Subcutaneous administration of ketorolac reduces pain in patients with cancer and seems particularly beneficial in pain resulting from bone metastases. The acquisition cost of ketorolac is greater than that of morphine or pethidine; however, in a small number of studies, the higher cost of ketorolac was offset when treatment with ketorolac resulted in a reduced hospital stay compared with alternative opioid therapy. The tolerability profile of ketorolac parallels that of other NSAIDs; most clinically important adverse events affect the gastrointestinal tract and/or renal or haematological function. The incidence of serious or fatal adverse events reported with ketorolac has decreased since revision of dosage guidelines. Results from a large retrospective postmarketing surveillance study in more than 20,000 patients demonstrated that the overall risk of gastrointestinal or operative site bleeding related to parenteral ketorolac therapy was only slightly higher than with opioids. However, the risk increased markedly when high dosages were used for more than 5 days, especially in the elderly. Acute renal failure may occur after treatment with ketorolac but is usually reversible on drug discontinuation. In common with other NSAIDs, ketorolac has also been implicated in allergic or hypersensitivity reactions. In summary, ketorolac is a strong analgesic with a tolerability profile which resembles that of other NSAIDs. When used in accordance with current dosage guidelines, this drug provides a useful alternative, or adjuvant, to opioids in patients with moderate to severe pain.

Tacrolimus. An update of its pharmacology and clinical efficacy in the management of organ transplantation.

Abstract: Tacrolimus (FK 506) has been evaluated as immunosuppressive therapy in patients with a variety of solid organ and other transplants. Extensive data have now confirmed its efficacy as primary or rescue therapy in renal and hepatic transplantation. In prospective and historically controlled studies of primary therapy, tacrolimus generally demonstrated greater efficacy than the conventional formulation of cyclosporin for preventing episodes of acute rejection and allowed reduction of corticosteroid use. Chronic rejection rates were also significantly lower with tacrolimus in a large randomised liver transplantation trial. However, patient and graft survival rates were similar in both treatment groups (although numerically larger in adults with liver transplants). In children, rejection rates and corticosteroid requirements were usually lower with tacrolimus and patient and graft survival were generally similar with the 2 immunosuppressants. The finding of reduced corticosteroid requirements with tacrolimus may be of particular benefit in prepubertal children, who are still growing. A small amount of evidence has also accumulated regarding the use of tacrolimus as primary therapy in patients who have undergone bone marrow or heart and/or lung transplantation. Data are not conclusive, particularly in children, but tacrolimus appears to be useful for treating patients who have undergone these organ transplantations and may be associated with a lower incidence of obliterative bronchiolitis than cyclosporin in the latter group. Potential efficacy has also been shown in a limited number of patients with pancreas or pancreas-kidney, pancreatic islet and intestinal or multivisceral transplants, and in children who have undergone heart or heart-lung transplantation. Tacrolimus also has a use as rescue therapy in bone marrow, heart, lung and pancreatic transplantation, but data are currently insufficient for conclusions to be made. However, these results support the need for further study in these populations. Adverse effects occurring during tacrolimus therapy are generally of the type common to all immunosuppressive regimens. However, diabetes mellitus, neurotoxicity and nephrotoxicity are more common in tacrolimus than cyclosporin recipients. Hyperlipidaemia, hypertension, hirsutism and gingival hyperplasia are more common with cyclosporin. In 2 large multicentre clinical trials (US liver and European renal), tacrolimus was discontinued more frequently during the first year because of adverse events. However, the tolerability of tacrolimus appears related to dosage, improving as the dose is reduced. Tacrolimus should be considered an effective primary immunosuppressant in renal and hepatic transplantation. The drug is also a useful agent for rescue therapy in patients experiencing rejection or poor tolerability to cyclosporin. Thus, tacrolimus provides the clinician with an effective option for patients requiring immunosuppression and, with a different tolerability and efficacy profile to cyclosporin, it will better allow the tailoring of therapy to meet the needs of individual patients.

Clinical evaluation of pramipexole in advanced Parkinson's disease: Results of a double-blind, placebo-controlled, parallel-group study

Abstract: We compared the efficacy, safety, an tolerability of pramipexole, an aminobenzathiazol-derived dopamine agonist with novel properties, with those of placebo in advanced PD patients with motor fluctuations under levodopa treatment. Pramipexole improved motor function of patients during "on" and "off" periods, decreased the time spent in "off" periods, reduced the severity of "off" periods, decreased disability and PD severity during "on" and "off" periods, as assessed by the Unified Parkinson Disease Rating Scale, and permitted a reduction in levodopa dosage. Adverse effects related to the central nervous system were similar to those reported with other dopamine agonists, and the gastrointestinal and cardiovascular tolerability of the compound was satisfactory.

Vigabatrin Versus ACTH as First-Line Treatment for Infantile Spasms : A Randomized, Prospective Study

Abstract: Summary: Purpose: To compare the efficacy and tolerability of vigabatrin (VGB) and adrenocorticotrophic hormone (ACTH) as first-line therapy in infantile spasms. Methods: Forty-two infants (22 males, 20 females) aged 2–9 months with newly diagnosed infantile spasms, were included in the trial. Patients were randomized to receive VGB 100–150 mg/kg/day or Depot ACTH 10 IU/day. The alternative drug was given if spasms were not controlled within 20 days or in cases of intolerance to initial therapy. Twenty-three patients (7 cryptogenic, 16 symptomatic) received VGB as first-line therapy; 19 patients (8 cryptogenic, 11 symptomatic) received ACTH as the first drug. Results: Cessation of spasms was observed in 11 (48%) of the patients randomized to VGB and in 14 (74%) of those randomized to ACTH. Response to VGB was observed within 1–14 days, but two-thirds of patients (7/11) responded within 3 days. In the group treated with VGB, side effects such as drowsiness, hypotonia and irritability were observed in 13% of patients, compared with 37% in the group treated with ACTH. VGB was more effective than ACTH as treatment for cerebral malformations or tuberous sclerosis, whereas ACTH proved more effective in perinatal hypoxic/ischemic injury. The efficacy of the two drugs was similar in cryptogenic cases. Disappearance of interictal EEG abnormalities occurred sooner in patients randomized to ACTH than in those who received VGB as initial therapy. During the second phase, the alternative drug was given to the resistant patients. Spasms ceased in 2 of 5 patients treated with VGB and in 11 of 12 patients treated with ACTH. After 3 months, relapses of spasms were observed in 6 patients treated with ACTH and in 1 treated with VGB. VGB produced a therapeutic response in nearly half the patients receiving this drug. Conclusions: Our data lend further support to the view that VGB may be considered a first-choice drug in the treatment of IS.

Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections.

Abstract: A total of 371 children, aged 6 months to 12 years, with acute otitis media, acute sinusitis, streptococcal tonsillitis/pharyngitis, or pneumonia were included in an open, multicenter study Among them, 192 children were randomized to receive azithromycin for 3 days (10 mg/kg daily), and 179 for 5 days (10 mg/kg on day 1 and 5 mg/kg on days 2-5) The overall clinical cure rate was 957% and 961%, and bacteriological eradication rate 901% and 942% in the 3-day and 5-day groups, respectively Side effects, mostly mild gastrointestinal disturbances, were observed in 53% of children from the 3-day, and 67% from the 5-day group Only in one child (03%) was therapy discontinued due to vomiting The results of this study demonstrate that 3-day and 5-day azithromycin courses have comparable efficacy and tolerability in children with respiratory infections

Tizanidine. A review of its pharmacology, clinical efficacy and tolerability in the management of spasticity associated with cerebral and spinal disorders.

Abstract: The central alpha 2 adrenoceptor agonist tizanidine is a myotonolytic agent used in the treatment of spasticity in patients with cerebral or spinal injury. Wide interpatient variability in the effective plasma concentrations of tizanidine means that the optimal dosage must be titrated over 2 to 4 weeks for each patient (dosages of 2 to 36 mg/day have been used in clinical trials). Maximum effects occur within 2 hours of administration. Antispastic efficacy has been demonstrated for tizanidine in placebo-controlled trials, with reduction in mean muscle tone scores of 21 to 37% versus 4 to 9% for patients receiving placebo. Improvement in muscle tone occurred in 60 to 82% of tizanidine recipients, compared with 60 to 65% of baclofen and 60 to 83% of diazepam recipients. Spasm frequency and clonus are also reduced by tizanidine. The most common adverse effects associated with tizanidine are dry mouth and somnolence/drowsiness. Muscle strength, as assessed by objective means, appears not to be adversely affected by tizanidine and subjective muscle weakness is reported less often by tizanidine recipients than by those receiving baclofen or diazepam. Global tolerability was assessed as good to excellent in 44 to 100% of patients receiving tizanidine, compared with 38 to 90% of baclofen and 20 to 54% of diazepam recipients. In conclusion, tizanidine is an antispastic agent with similar efficacy to that of baclofen and a more favourable tolerability profile. While drowsiness is a frequently reported adverse effect with both agents, subjective muscle weakness appears to be less of a problem with tizanidine than with baclofen. Tizanidine, therefore, appears to be an attractive therapeutic alternative for patients with spasticity associated with cerebral or spinal damage.

Clinical experience with CD64-directed immunotherapy. An overview

Abstract: The class I IgG receptor (FcγRI or CD64 receptor), which is present on key cytotoxic effector cells, has been shown to initiate the destruction of tumor cells in vitro and has been hypothesized to play a role in the destruction of antibody-coated cells such as platelets in idiopathic thrombocytopenia purpura (ITP). This overview summarizes the clinical experience with CD64-directed immunotherapy in cancer patients with the bispecific antibodies MDX-447 [humanized Fab anti-CD64 × humanized Fab anti-(epidermal growth factor receptor, EGFR)] and MDX-H210 (humanized Fab anti-DC64 × Fab anti-HER2/neu), and with the anti-CD64 monoclonal antibody (mAB) MDX-33 (H22) in the modulation of monocyte CD64 in vivo. In an ongoing phase I/II open-label trial with progressive dose escalation (1–15 mg/m2), patients with treatment refractory EGFR-positive cancers (renal cell carcinoma (RCC), head and neck, bladder, ovarian, prostate cancer and skin cancer) are treated weekly with intravenous MDX-447, with and without granulocyte-colony-stimulating factor (G-CSF). MDX-447 has been found to be immunologically active at all doses, binding to circulating monocytes and neutrophils (when given with G-CSF), causing monocytopenia and stimulating increases in circulating plasma cytokines. MDX-447 is well tolerated, the primary toxicities being fever, chills, blood pressure lability, and pain/myalgias. Of 36 patients evaluable for response, 9 have experienced stable disease of 3–6 month’s duration. The optimal dose and the maximal tolerated dose (MTD) have yet to be defined; dose escalation continues to define better the dose, toxicity, and the potential therapeutic role of this bispecific antibody. Three MDX-H210 phase II trials are currently in progress, all using the intravenous dose of 15 mg/m2 given with granulocyte/macrophage (GM-CSF). These consist of one trial each in the treatment of RCC patients, patients with protrate cancer, and colorectal cancer patients, all of whom have failed standard therapy. At the time of writing, 11 patients have been treated in these phase II trials. Four patients have demonstrated antitumor effects. Patients demonstrating responses include 2 with RCC and 2 with prostate cancer. One RCC patient has had a 54% reduction in size of a hepatic metastatic lesion and the other has had a 49% decrease in the size of a lung metastasis with simultaneous clearing of other non-measurable lung lesions. Regarding the two patients with prostate cancer, one has had a 90% reduction in serum prostate-specific antigen (PSA; 118–11 ng/ml), which has persisted for several months; the other patient with prostate has had a 70% reduction of serum PSA (872 ng/ml to 208 ng/ml) within the first month of treatment. Both patients have also demonstrated symptomatic improvement. In a completed phase I and in ongoing phase I/II clinical trials, patients with treatment-refractory HER2/neu positive cancers (breast, ovarian, colorectal, prostate) have been treated with MDX-H210, which has been given alone and in conjunction with G-CSF, GM-CSF, and interferon γ (IFNγ). These trials have been open-label, progressive dose-escalation (0.35–135 mg/m2) studies in which single, and more often, multiple weekly doses have been administered. MDX-H210 has been well tolerated, with untoward effects being primarily mild-to-moderate flu-like symptoms. The MTD has not yet been defined. MDX-H210 is immunologically active, binding to circulating monocytes, causing monocytopenia, as well as stimulating increases in plasma cytokine levels. Furthermore, some patients have evidence of active antitumor immunity following treatment with MDX-210. Antitumor effects have been seen in response to MDX-H210 administration; these include 1 partial, 2 minor, and 1 mixed tumor response; 15 protocol-defined stable disease responses have occurred. In a completed phase I trial, MDX-33 was administered as a single intravenous dose to 17 normal subjects in order to assess its potential as an immunomodulator for the treatment of idiopathic thrombocytopenia purpura and other immune disorders. Doses of 1.5, 3.0, 5.0, and 7.5 mg/m2 were administered. The variables evaluated in response to MDX-33 were circulating monocyte and neutrophil counts, monocyte CD64-mediated phagocytosis, monocyte CD64 modulation, MDX-33 pharmocokinetics, and various safety paramenters. MDX-33 is well tolerated at doses of 5.0 mg/m2 or less, the primary toxicities being chills, low-grade fever, headache, and muscle aches. Persistent binding of MDX-33 to 80–99 % of circulating monocytes is seen for at least 6 days; down-modulation of monocyte CD64 occurs and also lasts more than 6 days. Monocyte CD64-mediated phagocytosis is significantly inhibited at all doses of MDX-33. At the 3.0 mg/m2 and 5.0-mg/m2 dose, phagocytosis is fully inhibited for at least 6 days, returning to baseline levels by 20 days after dosing. These results clearly demonstrate that immunomodulation of monocyte CD64 by the mAB MDX-33 can be accomplished with minimal clinical toxicity, and further indicate the potential of MDX-33 in the treatment of ITP and other auto-immune disorders. In conclusion, the results from completed and ongoing clinical trials with the CD64-directed bsAB MDX-447 and MDX-H210 demonstrate excellent tolerability in association with promising antitumor effects in tumors that have become refractory to all available therapies. Also promising are the results from the trial of the CD64-directed mAB, MDX-33, which show the ability to modulate monocyte CD64 in the clinical setting. Studies are currently being conducted to elucidate the full potential of these and other approaches using CD64-directed immunotherapy.

A survey of antidepressant drug use in Parkinson's disease

Abstract: Selective serotonin reuptake inhibitors (SSRIs) are a newer class of antidepressants that may have particular efficacy in Parkinson's disease (PD) given the known serotonergic alterations in this disease. These agents are also thought to have a favorable side-effect profile, particularly in the elderly. Several recent case reports, however, have raised concern that SSRIs may worsen parkinsonian motor function. We surveyed 71 Parkinson Study Group (PSG) investigators using a standardized questionnaire about their usage of antidepressants in PD. Based on estimates provided by 49 investigators (70%) (caring for approximately 23,410 PD patients) who responded, 26% of patients with PD are on pharmacotherapy for depression. These physicians use SSRIs as first line therapy 51% of the time, tricyclic antidepressants 41% of the time and other agents 8% of the time. The most common reasons for selecting SSRIs were their better side-effect profile and perceived greater efficacy. The most common reasons for selecting tricyclic antidepressants were their potential to help with sleep and the physician's experience with this class. Forty-three percent of investigators were concerned that SSRIs might worsen motor function, and 37% of them have had at least one patient in whom they believe this had occurred. Our survey confirms that for treating physicians there remain uncertainties regarding the relative efficacy and tolerability of available antidepressant medications for patients with PD. A controlled clinical trial of antidepressant therapy in PD would be valuable for settling these concerns.

The Efficacy and Six-Week Tolerability of Simvastatin 80 and 160 mg/Day

Abstract: The hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin is the most effective of the currently approved hypolipidemic drugs and has been shown to reduce mortality and coronary morbidity in patients with coronary artery disease. For these patients the United States National Cholesterol Education Program advocates reducing low-density lipoprotein (LDL) cholesterol to 160 mg/dl and triglycerides (TG) 3 times the upper limit of normal. No new or unexpected adverse effects were observed. We conclude that simvastatin at doses of 80 and 160 mg/day provides additional efficacy with a low short-term incidence of adverse effects; our results support the continued investigation of simvastatin at these doses.

Extrapyramidal Symptoms and Tolerability of Olanzapine Versus Haloperidol in the Acute Treatment of Schizophrenia

Abstract: Background: A relative lack of extrapyramidal symptoms (EPS, i.e., the syndromes of dystonia, parkinsonism, akathisia, dyskinesia) is one criterion used to determine whether an antipsychotic is atypical. The extrapyramidal symptom profiles of the novel antipsychotic olanzapine and the conventional antipsychotic haloperidol were compared in a population of 2606 patients from three well-controlled prospective clinical trials. Method: Extrapyramidal symptom data were analyzed for 1796 patients treated with olanzapine (5 to 20 mg/day) and 810 patients treated with haloperidol (5 to 20 mg/day) for up to 6 weeks of therapy. Patients were monitored weekly by three methods of extrapyramidal symptom assessment : (1) detection of extrapyramidal adverse events (signs and symptoms) by casual observation, nonprobing inquiry, and spontaneous report; (2) objective rating scale scores; and (3) use of concomitant anticholinergic medications. Emergence of EPS was assessed by (1) analysis of the incidence of extrapyramidal syndrome categories based on adverse events, (2) the incidence of extrapyramidal syndromes based on categorical analysis of rating scale scores, (3) analysis of mean maximum change in rating scale scores, and (4) categorical analysis of anticholinergic medication use. Outcome of EPS was assessed by (1) analysis of mean change in rating scale scores at endpoint and (2) mean anticholinergic use at endpoint. Results: Olanzapine was statistically significantly (p = .014, p <.001) superior to haloperidol in all four analyses related to emergence of EPS and in the two analyses related to outcome. Furthermore, during acute treatment, statistically significantly fewer patients treated with olanzapine (0.3%) discontinued the study because of any extrapyramidal adverse event than patients treated with haloperidol (2.7%, p <.001). Conclusion: Olanzapine exhibited a statistically significantly lower extrapyramidal symptom profile than the conventional antipsychotic haloperidol at comparably effective antipsychotic doses. The lower extrapyramidal symptom profile with olanzapine was evident despite statistically significantly more frequent use of anticholinergic drugs among haloperidol-treated patients. Fewer olanzapine-treated than haloperidol-treated patients discontinued because of EPS, suggesting that olanzapine should contribute to better compliance with longer term maintenance treatment, with minimal anticholinergic-associated events.

Enteric-coated peppermint-oil capsules in the treatment of irritable bowel syndrome: A prospective, randomized trial

Abstract: To determine the efficacy and tolerability of an enteric-coated peppermint-oil formulation (Colpermin), we conducted a prospective, randomized, double-blind, placebo-controlled clinical study in 110 outpatients (66 men/44 women; 18-70 years of age) with symptoms of irritable bowel syndrome. Patients took one capsule (Colpermin or placebo) three to four times daily, 15-30 min before meals, for 1 month. Fifty-two patients on Colpermin and 49 on placebo completed the study. Forty-one patients on Colpermin (79%) experienced an alleviation of the severity of abdominal pain (29 were pain-free); 43 (83%) had less abdominal distension, 43 (83%) had reduced stool frequency, 38 (73%) had fewer borborygmi, and 41 (79%) less flatulence. Corresponding figures for the placebo group were: 21 patients (43%) with reduced pain (4 were pain-free), 14 (29%) with reduced distension, 16 (32%) with reduced stool frequency, 15 (31%) with fewer borborygmi, and 11 (22%) with less flatulence. Symptom improvements after Colpermin were significantly better than after placebo (P < 0.05; Mann-Whitney U-test). One patient on Colpermin experienced heartburn (because of chewing the capsules) and one developed a mild transient skin rash. There were no significant changes in liver function test results. Thus, in this trial, Colpermin was effective and well tolerated.

LI 160, an extract of St. John's wort, versus amitriptyline in mildly to moderately depressed outpatients--a controlled 6-week clinical trial.

Abstract: Up to now, the antidepressant efficacy of the extract of St. John's wort, LI 160, has been compared to imipramine and maprotiline, demonstrating similar antidepressant efficacy in mildly to moderately depressed patients, treated either with LI 160 or the respective synthetic comparator. In the study reported here, LI 160 (total daily dose: 900 mg) was compared with the sedating tricyclic amitriptyline (total daily dose: 75 mg) in a controlled, randomized, multicentre trial. At the end of the 6-week study, the major target variable, the Hamilton Depression Scale response rate, exhibited no statistically significant difference between the groups, although a tendency for a better response rate was seen in the amitriptyline group. The secondary efficacy parameters, decreases in the total Hamilton Depression and Montgomery-Asberg scores, showed a significant advantage for amitriptyline, but only at week 6. With regard to tolerability, LI 160 was clearly superior to amitriptyline, particularly in relation to anticholinergic and Central Nervous System adverse events. Thus, 37% of the LI 160 treated patients reported adverse events, compared to 64% in the amitriptyline group. This considerable superiority in tolerability for LI 160 in relation to amitriptyline, could confer an advantage in improving compliance for antidepressant pharmacotherapy.

Long‐term efficacy and safety of cyclosporin in severe adult atopic dermatitis

Abstract: Summary A prospective, open, multicentre study was performed to investigate the efficacy and safety of longterm treatment with cyclosporin in adults with severe atopic dermatitis. Subjects were treated for a maximum of 48 weeks. For the first 8 weeks, cyclosporin was administered at 2.5 mg/kg per day. The dose was then adjusted according to response. Disease activity was monitored using the six-area. six-sign score and the proportion of skin involved. Pruritus and sleep disturbance were assessed using four-point scales. Response was further evaluated on a five-point scale. Adverse events. blood pressure and serum biochemistry were monitored. Tolerability was assessed on a five-point scale. One hundred subjects were enrolled and 65 completed 48 weeks of treatment. Withdrawals occurred due to remission (three), inadequate response (seven), protocol violations (11) and adverse events (14, of which seven were probably treatment related). Cyclosporin produced rapid and highly significant improvements in all indices of disease activity. Sixty-five subjects considered that they had shown a considerable improvement or complete clearance of disease. Most patients relapsed after cessation of treatment. but neither signs nor symptoms had returned to baseline severity 8 weeks later. Blood pressure and serum creatinine levels increased slightly. and in one subject renal impairment was a major factor contributing to withdrawal of the drug. Overall, 85 subjects rated the tolerability of cyclosporin as good or very good. The results indicate that cyclosporin has a place in the long-term treatment of severe atopic dermatitis provided that appropriate patients are selected and careful monitoring is performed.

Optimizing the dose of zolmitriptan (Zomig,* 311C90) for the acute treatment of migraine A multicenter, double-blind, placebo-controlled, dose range-finding study

Abstract: This study investigated the efficacy of zolmitriptan (Zomig, formerly 311C90) in acute migraine therapy. Patients with a history of migraine were randomized in a double-blind, multicenter, placebo-controlled, dose range-finding study of oral zolmitriptan 1, 2.5, 5, or 10 mg versus placebo for the treatment of a severe or moderate migraine headache. Patients with persistent or recurrent headache 4 to 24 hours after the initial dose, who did not take escape medication, were eligible to receive a second blinded dose of either zolmitriptan or placebo. Of 1,144 patients treated, 999 evaluable patients completed the study. The headache response rates with zolmitriptan doses ≥ 2.5 mg were 44 to 51% at 1 hour, 65 to 67% at 2 hours, and 75 to 78% at 4 hours (all significantly superior to placebo). Also, zolmitriptan effectively relieved migraine-associated symptoms such as nausea, photophobia and phonophobia, and reduced activity impairment. Rates of headache recurrence, headache persistence, and use of escape medication were lower with zolmitriptan doses ≥ 2.5 mg than with placebo. In patients with persistent or recurrent headache, a second zolmitriptan dose effectively treated both headache and nonheadache symptoms. Zolmitriptan was well tolerated, with a lower incidence of adverse events being reported with doses≤ 2.5 mg than with those ≥5 mg. Zolmitriptan is a well tolerated and effective acute migraine therapy providing rapid relief of migraine headache within 1 hour. A clear dose-response relationship between efficacy and tolerability suggests that 2.5 mg is the optimal initial dose for the acute treatment of a migraine attack.

Lamivudine. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV infection.

Abstract: Lamivudine is a dideoxynucleoside analogue which undergoes intracellular phosphorylation to the putative active metabolite, lamivudine triphosphate. Lamivudine triphosphate prevents HIV replication by competitively inhibiting viral reverse transcriptase. Lamivudine has a unique resistance profile and has the ability to delay resistance to zidovudine and restore zidovudine sensitivity in zidovudine-experienced patients. Combination antiretroviral drug therapy is now generally considered preferable to monotherapy as first-line treatment for patients with HIV infection. In double-blind trials in antiretroviral drug-experienced or -naive adults, improvements in surrogate markers of disease progression were significantly greater in patients receiving lamivudine plus zidovudine combination therapy than in patients who received either drug as monotherapy. Preliminary results of CAESAR, a large multicentre trial in patients with moderately advanced HIV infection receiving zidovudine-based treatment regimens, show a 54% reduction in the rate of disease progression or death with the addition of lamivudine, compared with the addition of placebo. Initial virological data from studies of combination regimens including lamivudine and protease inhibitors are also promising, although the longer term efficacy of these regimens remains to be established. Improvements in surrogate disease markers were also seen in children and adolescents with symptomatic HIV infection who received lamivudine monotherapy. Studies of lamivudine-containing combination therapy in children and adolescents are in progress, but few data have yet been published. Lamivudine is generally well tolerated as monotherapy or in combination with other antiretroviral agents in HIV-infected adults with CD4+ counts > or = 100 cells/microliter. Gastrointestinal disturbances were reported as the most common adverse events during lamivudine monotherapy or combination therapy. Lamivudine appears to be less well tolerated in patients with advanced disease (CD4+ cell counts < 100 cells/microliter), but more data are required to clarify its tolerability in such patients. Pancreatitis has been reported in children with advanced disease during treatment with the drug, but was not directly attributable to lamivudine therapy. Thus, lamivudine, administered in combination with zidovudine, is now established as an effective agent for the treatment of antiretroviral drug-experienced or -naive individuals with asymptomatic or symptomatic HIV disease. Moreover, encouraging preliminary data suggest that lamivudine is poised to become an important component of other regimens, in combination with drugs such as the protease inhibitors.

Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression.

Abstract: Nefazodone hydrochloride is a phenylpiperazine antidepressant with a mechanism of action that is distinct from those of other currently available drugs. It potently and selectively blocks postsynaptic serotonin (5-hydroxytryptamine; 5-HT) 5-HT2A receptors and moderately inhibits serotonin and noradrenaline (norepinephrine) reuptake. In short term clinical trials of 6 or 8 weeks' duration, nefazodone produced clinical improvements that were significantly greater than those with placebo and similar to those achieved with imipramine, and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine and sertraline. The optimum therapeutic dosage of nefazodone appears to be between 300 and 600 mg/day. Limited long term data suggest that nefazodone is effective in preventing relapse of depression in patients treated for up to 1 year. Analyses of pooled clinical trial results indicate that nefazodone and imipramine produces similar and significant improvements on anxiety- and agitation-related rating scales compared with placebo in patients with major depression. Short term tolerability data indicate that nefazodone has a lower incidence of adverse anticholinergic, antihistaminergic and adrenergic effects than imipramine. Compared with SSRIs, nefazodone causes fewer activating symptoms, adverse gastrointestinal effects (nausea, diarrhoea, anorexia) and adverse effects on sexual function, but is associated with more dizziness, dry mouth, constipation, visual disturbances and confusion. Available data also suggest that nefazodone is not associated with abnormal weight gain, seizures, priapism or significant sleep disruption, and appears to be relatively safe in overdosage. Nefazodone inhibits the cytochrome P450 3A4 isoenzyme and thus has the potential to interact with a number of drugs. Further long term and comparative studies will provide a more accurate assessment of the relative place of nefazodone in the management of major depression. Nonetheless, available data suggest that nefazodone is a worthwhile treatment alternative to tricyclic antidepressants and SSRIs in patients with major depression.

Comparison of tamsulosin with alfuzosin in the treatment of patients with lower urinary tract symptoms suggestive of bladder outlet obstruction (symptomatic benign prostatic hyperplasia)

Abstract: Objective To compare the efficacy and tolerability of the a1A-subtype selective drug tamsulosin with the non-subtype-selective agent alfuzosin in the treatment of patients with lower urinary tract symptoms (LUTS) suggestive of bladder outlet obstruction (BOO), often termed symptomatic benign prostatic hyperplasia (BPH). Patients and methods The study comprised 256 patients with benign prostatic enlargement and LUTS suggestive of BOO (symptomatic BPH) who received tamsulosin 0.4 mg once daily or alfuzosin 2.5 mg three times daily during 12 weeks of treatment. The response was assessed by measurements of maximum urinary flow rate (Qmax ), a symptom score (Boyarsky) and blood pressure at regular intervals. Results Tamsulosin and alfuzosin produced comparable improvements in Qmax and total Boyarsky symptom score. Both treatments were well tolerated with respect to adverse events. Tamsulosin had no statistically significant effect on blood pressure compared with baseline but alfuzosin induced a significant reduction in both standing and supine blood pressure, compared with baseline (P<0.05). Conclusion Tamsulosin is the first adrenoceptor antagonist that is selective for the a1A-subtype; this specificity may explain its lack of effect on blood pressure compared with alfuzosin, an agent that is not receptor subtype specific. Moreover, this finding may partly explain why tamsulosin, in contrast to other currently available a1-adrenoceptor antagonists, can be administered without dose titration. Another advantage compared with alfuzosin (and prazosin) is the once-daily dosing regimen of tamsulosin.

Clinical efficacy and tolerability of 2.5 mg zolmitriptan for the acute treatment of migraine

Abstract: Previous studies demonstrated that zolmitriptan at doses of 1 to 25 mg was highly effective in treating acute migraine attacks. The 2.5-mg dose had a favorable therapeutic effect with high efficacy and good tolerability. The objective of this study was to further evaluate the efficacy of a single 2.5-mg dose of zolmitriptan (Zomig, formerly known as 311C90) for acute treatment of a single moderate or severe migraine attack. The study was a randomized, double-blind, placebo-controlled clinical trial. Female and male patients, 12 to 65 years old, with migraine (with or without aura) for > or = 1 year, one to six migraines per month, and age at onset < 50 years were included; 327 patients were screened and randomized to receive either zolmitriptan (n = 219) or placebo (n = 108). Patients treated a single moderate or severe migraine headache with 2.5 mg zolmitriptan or placebo and recorded clinical efficacy and adverse events on a diary form. Headache response at 2 hours was 62% for zolmitriptan compared with 36% for placebo (p < 0.001); at 4 hours, headache response was 70% with zolmitriptan and 37% with placebo (p < 0.001). Headache recurrence in patients treated with 2.5 mg zolmitriptan was 22% (versus placebo 30%). The headache response at 4 hours, pain-free rate, and response rate of nonheadache symptoms favored zolmitriptan over placebo. No serious adverse events were associated with zolmitriptan treatment. A 2.5-mg dose of zolmitriptan is clinically effective and well tolerated for the acute treatment of migraine.