Trimethoprim-sulfamethoxazole-induced aseptic meningitis: case report and literature review.

Aseptic meningitis is a rare adverse drug reaction, reported with non-steroidal anti-inflammatory agents (NSAIDs) and with miscellaneous drugs such as trimethoprim-sulfamethoxazole (TMP-SMX). The most common clinical findings reported are fever, headache, stiffness and altered level of consciousness. We report a case of aseptic meningitis related to TMP-SMX ingestion that caused severe derangements of the patient's vital signs, requiring Intensive Care Unit admittance. The prompt diagnosis and discontinuation of the drug resulted in complete recovery. We examine the case according to the literature on this topic. We conclude that, since the signs and symptoms of this unusual drug reaction may mimic those of central nervous system infection, the clinician should consider this etiology when he is faced with a patient with suspected meningoencephalitis, especially if the latter has already been treated at home with unknown drugs. Further studies should investigate the pathogenetic mechanism of TMP-SMX-induced aseptic meningitis.

Efficacy and tolerability of a new estradiol delivering matrix patch (Estraderm MX) in postmenopausal women.

OBJECTIVE: To examine the efficacy and tolerability of a new matrix patch delivering estradiol (E2 Matrix) at doses of 0.05 and 0.10 mg per day (Estraderm MX 50, 100) in the treatment of moderate to severe postmenopausal symptoms. METHODS: A total of 254 postmenopausal women were randomized to receive treatment with E2 Matrix 0.10 mg (N = 86), E2 Matrix 0.05 mg (N = 82), or placebo (N = 86) in a double-blind, double-dummy fashion for a period of 12 weeks continuously. Patches were applied twice weekly to the buttocks with each patient wearing two patches at all times. The primary efficacy criterion was the difference from baseline of the mean number of moderate to severe hot flushes per 24 h during the last 2 weeks of treatment. Other efficacy variables included reduction in hot flushes at 4 and 8 weeks, reduction in daytime flushing and night sweats, and Kupperman Index at 4, 8, and 12 weeks. RESULTS: E2 Matrix 0.10 and 0.05 mg were both significantly superior to placebo in reducing hot flushes per 24 h after 4, 8, and 12 weeks of treatment (P < 0.001). Also, for all other efficacy parameters studied, both dosage strengths of E2 Matrix were statistically significantly superior to placebo at all time points (P < 0.001). Local tolerability was good in both groups. A slight increase in estrogen related adverse effects (breast tenderness, leukorrhoea) was seen with the 0.10 mg patch. Adhesion of patches and compliance were good. Overall systemic tolerability was good in both treated groups. However, a 4.8% overall incidence of endometrial hyperplasia was observed in patients with an intact uterus. CONCLUSIONS: This new matrix patch offers an effective and well tolerated dosage form for delivery of 0.05 and 0.1 mg estradiol per day. It may be particularly suitable for those women who experience local sensitivity to alcohol-containing systems. In light of the observed hyperplasia after treatment in five patients, estrogen therapy should as yet be supplemented monthly with a progestogen in women with an intact uterus.

A comparison of nimesulide beta cyclodextrin and nimesulide in postoperative dental pain.

The aim of this study was to assess the efficacy and tolerability of single doses of nimesulide beta cyclodextrin compared with nimesulide in patients with dental pain following surgical procedures. This was a randomised, double-blind, between-patient, multicentre study involving 148 outpatients suffering from moderate to severe pain, who received single doses of either 400 mg nimesulide beta cyclodextrin or 100 mg nimesulide. The principal criterion for efficacy was pain intensity assessed on a visual analogue scale (VAS) 15 minutes after drug intake. Pain intensity was further evaluated 30, 45, 90, 120, 180, 240 and 360 minutes after dosing. Pain relief was evaluated at the same time points by means of a categorical scale. The time point of first pain relief, the use of rescue medication and the global evaluation of efficacy were also recorded. The reduction in pain intensity was significantly more pronounced in the nimesulide beta cyclodextrin group at 15, 30, 45 and 60 minutes (p < 0.01). Pain relief was significantly greater (p < 0.05) and more rapid with nimesulide beta cyclodextrin. In the patient overall assessment of efficacy, nimesulide beta cyclodextrin and nimesulide were rated excellent or good by 95% and 92% respectively; only one patient in the nimesulide beta cyclodextrin group needed rescue medication. Both study drugs were effective and well tolerated in the treatment of acute dental pain, with nimesulide beta cyclodextrin showing a faster onset of analgesic action.

Double-blind evaluation of short-term analgesic efficacy of orally administered diclofenac, diclofenac plus codeine, and diclofenac plus imipramine in chronic cancer pain.

A prospective double-blind randomized trial was conducted on 184 cancer patients with moderate to severe chronic pain to evaluate the analgesic efficacy and tolerability of diclofenac alone (50 mg q.i.d.) or in combination with a weak opioid (codeine 40 mg q.i.d.), or with an anti-depressant (imipramine, 10 or 25 mg t.i.d.). All demographic and clinical characteristics including cancer type, presence of bone metastases, baseline pain severity, neuropathic and nociceptive pain, and depressive state, were well balanced between the three treatment groups. The main analysis of the study was on the VAS scores at visit 2 (day 4). The mean VAS values for both associations imipramine plus diclofenac and codeine plus diclofenac were similar to the association placebo plus diclofenac. Patients on imipramine plus diclofenac and on placebo plus diclofenac were withdrawn mainly for inadequate efficacy, while patients on codeine plus diclofenac discontinued equally for inadequate efficacy or adverse events. In conclusion, in a short-term evaluation the addition of a tricyclic anti-depressant or a weak opioid to diclofenac did not provide further analgesia with respect to diclofenac administration alone.

Lack of microbial proliferation and phototoxic potential of a new matrix patch for estradiol delivery.

OBJECTIVES: To examine the potential of a new matrix system developed for estradiol delivery to cause microbial proliferation under the occluded site or to cause acute phototoxicity reactions. METHODS: Twenty healthy post-menopausal women participated in a microbial proliferation study and 11 in a phototoxicity study. Both studies were single centre, single blind and placebo controlled. Microbial proliferation was assessed by quantitative counts of the total aerobic bacterial population and of eight individual species before patch application and after removal following a 4 day application period on the abdomen. Acute phototoxicity potential was assessed following an 8 h application period on the abdomen by irradiating the application site after patch removal with ultra violet A radiation and visible light and evaluating the sites for up to 48 h post irradiation. Non-irradiated active and placebo patches on the other side of the abdomen served as controls. RESULTS: Total aerobic bacterial populations both before and after the matrix patch application period were low as expected for dry skin. Separate counts of microbial species were also low and did not change in any meaningful or consistent manner after patch application. In the phototoxicity study, mild erythema was observed in some patients at 0, 0.5 and 24 h post patch removal with no differences between irradiated and non-irradiated sites. CONCLUSIONS: These two studies demonstrate that a new matrix patch developed for estradiol delivery does not promote microbial proliferation under the occluded patch site or cause acute phototoxicity following removal.

Influence of single and repeated doses of oxcarbazepine on the pharmacokinetic profile of felodipine.

Eight healthy male volunteers (age 25-41 years) entered an open-label, within-subject study. They were treated for 13 consecutive days with felodipine (FEL) extended-release tablets, 10 mg daily. On day 6, oxcarbazepine (OXC) 600 mg was given in the morning, and from day 7 to 13, the daily dose was increased to 450 mg b.i.d. Blood samples for measurement of FEL and its pyridine metabolite (determined by gas-chromatography) were drawn just before dosing and at 2, 4, 6, 8, 10, 12, and 24 h after dosing on days 5, 6, and 13. Steady-state pharmacokinetic parameters of FEL and its pyridine metabolite were not influenced by the single dose of OXC. Repeated coadministration of OXC significantly reduced the area under the concentration-time curve (AUC0-24) of FEL by 28% and the FEL maximum plasma concentration (Cmax) by 34%. This reduction in FEL bioavailability is much smaller than that observed after co-administration of carbamazepine (CBZ) (i.e., 94%).

Changes in unbound and total valproic acid concentrations after replacement of carbamazepine with oxcarbazepine.

Total and free valproic acid (VPA) concentrations were measured in patients switched from a combined VPA and carbamazepine (CBZ) to a combined VPA and oxcarbazepine (OXC) therapy, both administered in individualized daily doses. Four young epileptic patients (13-17 years old) were studied for a 12-week period, total and free VPA concentrations being analyzed just before and 4 h after the morning dose, at the end of VPA and CBZ therapy, and 2 and 10 weeks after CBZ was replaced by OXC. The expected increase in the level/dose (L/D) ratio of total VPA observed at the end of the study was preceded by a clear-cut increase in the L/D ratio of free VPA, which led to VPA-related side effects and required the retitration of VPA daily doses.

Oxiracetam in dementia: a double-blind, placebo-controlled study.

A multicentre, double-blind, between-patient study was carried out to evaluate the efficacy and tolerability of oxiracetam (800 mg tablet), in comparison with placebo, each given twice daily for 12 weeks to patients suffering from primary degenerative, multi-infarct or mixed dementia. Efficacy was assessed by a neuropsychological battery (simple reaction time, controlled associations, short story, Raven's Progressive Matrices, token test, digit span, word list learning), administered at the beginning and at the end of the study, and by a quality of life scale, administered at entry and after 6 and 12 weeks treatment. Sixty-five patients (28 men, 37 women, mean age 71 yrs) were enrolled; 58 completed the study: 2 on oxiracetam were withdrawn because of poor tolerability, 2 (one in each group) were withdrawn for poor compliance, one (on oxiracetam) for the occurrence of a transient ischaemic attack (defined as not related to the treatment) and 2 for administrative reasons. A significantly (p < 0.01) different effect in favour of oxiracetam was observed on the quality of life scale, and confirmed by significant (defined according to the Bonferroni technique) differences in some neuropsychological tests (e.g. controlled associations, short story). Four patients in the oxiracetam group complained of a total of 5 unwanted effects, and 1 on placebo complained of 3 unwanted effects, but none of them was withdrawn from the study.

Effects of oxcarbazepine and carbamazepine on the central nervous system: computerised analysis of saccadic and smooth-pursuit eye movements.

Oxcarbazepine (OXC) is a new anti-epileptic agent structurally related to carbamazepine (CBZ). OXC seems to have a similar efficacy and a better tolerability profile than CBZ. In the present study we compared the subclinical side-effects on the CNS of OXC and CBZ using a computerised analysis of saccadic and smooth-pursuit eye movements. Six healthy male volunteers (mean age 29 yrs) participated in the study, which was conducted by a double-blind cross-over design. Each subject was given a single dose of either CBZ 400 mg or OXC 600 mg (according to the random assignment) after which the drug effects on eye movements were evaluated. One week later, the trial was repeated using the other drug. The parametrisation of both saccadic and smooth-pursuit eye movements was carried out by measuring a series of performance parameters [e.g. the maximum saccade peak velocity (MSPV) and the typical target velocity (TTV)]. OXC was found to induce a lesser degree of alteration on the values of both MSPV (p = 0.07) and TTV (p less than 0.03) than CBZ. In particular, the TTV values were virtually unaffected by OXC administration, while the effects of CBZ on both variables were particularly evident at 8 and 10 h after dosing which correspond to the time at which the plasma concentrations of CBZ and of its 10,11-epoxide reach the peak. In conclusion, our preliminary results indicate that OXC induces negligible alterations, if any, on the eye movement parameters evaluated in our study.

Antiepileptic drugs as 'tracers' of disease. A calculation of the prevalence of epilepsy through an analysis of drug consumption. The Group for the Study of Epilepsy in General Practice.

Antiepileptic drug (AED) consumption, expressed according to a standardized measurement of the average daily doses of each active principle (the defined daily dose, DDD), was assessed as a source of morbidity data to calculate the prevalence of AED takers. In a population of 51,220 from three areas in Italy (Arcisate, Treviglio, S. Giovanni Rotondo) all the patients treated with AEDs, traced by the local general practitioners, were examined by a neurologist. The diagnosis of epilepsy was confirmed in 199 of 223 AED takers, giving an overall prevalence rate of 3.94 per 1,000 (Arcisate 3.96; Treviglio 4.04; S. Giovanni Rotondo 3.89). There was a significant overlap between the observed and expected number of AED takers (the latter obtained from regional sales and expressed in DDD). Prevalence rates calculated from drug sales were 5.58 in Arcisate and 6.11 in Treviglio. The ratio of patients with epilepsy to AED takers in the two areas was 0.7 and corresponded to the mean proportion of AEDs prescribed for epilepsy in the years 1983-1988 by a sample of Italian physicians. Although the prevalence rate calculated from AED sales tends to approximate that of treated epilepsy, AEDs can be reasonably used as 'tracers' of disease for the easy access to drug sales in Italy, the appropriateness of the DDD as a standard measure of the daily doses of AED, the steady pattern of consumption, the comparability of data covering different areas and periods, and the stable proportion of drugs delivered for epilepsy.

A randomized, within-patient, cross-over, placebo-controlled trial on the efficacy and tolerability of the tricyclic antidepressants chlorimipramine and nortriptyline in central pain.

Antidepressant drugs are increasingly used in the management of chronic pain. They are mainly prescribed for cancer-related pain and central pain, e.g. phantom or stump pain, post-herpetic neuropathy. However, no controlled clinical trials have validated their in either pathology. Thus, physicians still do not know whether antidepressants are really effective and which might be best. It is still debated whether the effect of antidepressants in the management of chronic pain is limited to the amelioration of frequently concomitant depression or extends to pain itself. To verify both the analgesic effect of tricyclic antidepressants, and the possible relationship between their antidepressant effect and the relief of central pain, we carried out a randomized, within-patient (cross-over) placebo-controlled study in patients suffering from central pain. The results clearly indicate the better analgesic effect of tricyclic antidepressants over placebo (p less than 0.0001). Within the antidepressants tested, chlorimipramine, a blocker of serotonin reuptake, is significantly more effective (p less than 0.0001) than notriptyline, a blocker of noradrenaline reuptake. Finally, the antinociceptive effect is independent of the effects of the two drugs on the symptoms of depression.

Conventional vs controlled-release carbamazepine: a multicentre, double-blind, cross-over study.

The tolerability and pharmacokinetics of a new controlled-release (CR) formulation of carbamazepine (CBZ), were assessed in a multicentre, double-blind, cross-over trial, carried out in 48 epileptic patients (21 men, 27 women; mean age 34.2 years) on conventional CBZ monotherapy, but without complete seizure control (n = 22) or with intermittent side effects (n = 4), or with both (n = 22). Eligible patients were randomized to conventional CBZ or CR CBZ, each given in sequence at individualized daily doses, subdivided into the lowest number of administrations. Each period of the cross-over consisted of a first phase of optimal dose finding (lasting up to two months) and a second one of maintenance (lasting one month) used for evaluation. At the end of each period, a 10-h plasma CBZ and CBZ-epoxide concentration profile, as well as the tolerability and the efficacy of the drugs, were evaluated. The mean CBZ daily dose increased by 16% during the administration of the CR formulation. Fluctuations of total CBZ and 10, 11-epoxide plasma level daily profiles at steady-state were significantly (p less than 0.001) lower during CR CBZ treatment, leading to a significant (p less than 0.001) decrease in intermittent side effects (6 patients on CR CBZ vs 26 on conventional CBZ). Finally, 38 patients on CR CBZ (vs 15 patients on conventional CBZ) were treated with a b.i.d. regimen.

Non-steroidal anti-inflammatory drugs as the first step in cancer pain therapy: double-blind, within-patient study comparing nine drugs.

The efficacy and tolerability of acetylsalicylic acid, paracetamol, diclofenac, ibuprofen, indomethacin, pirprofen, sulindac, naproxen and suprofen were compared in the treatment of cancer pain. In a double-blind, within-patient randomized study, each drug was given for 1 week to eight patients and for another week to a further eight patients. A total of 65 patients were effectively treated; only 48 completed week 1 and 41 completed week 2. Naproxen, diclofenac and indomethacin were highly effective in pain relief (tested by means of a 100 mm visual analogue scale) and were relatively well tolerated. It is concluded that these non-steroidal anti-inflammatory drugs can be considered as first choice in the treatment of cancer pain.

Treatment of anxiety with ketazolam in elderly patients.

In a multicenter, double-blind trial, 63 elderly patients who had experienced a generalized anxiety disorder for at least one month were randomly assigned to receive 15 mg of ketazolam (n = 31) or placebo (n = 32) daily for 15 days. At the end of this period, if their total scores on the Hamilton Anxiety Rating Scale had decreased by at least 25%, treatment was continued unchanged for a further 15 days. Patients who did not respond to treatment were given an additional 15 mg of ketazolam daily. During the initial 15 days, 83% of the ketazolam-treated patients and 43% of the placebo patients responded to treatment (P < 0.01). During the second 15-day period, the anxiety scores of the ketazolam-treated patients continued to decline significantly, whereas the placebo patients showed no improvement. According to the investigators' assessments of severity of anxiety and patients' ratings of treatment effectiveness, ketazolam was significantly superior to placebo.

Low doses of ketazolam in anxiety: a double-blind, placebo-controlled study.

A multicenter, double-blind, between-patient trial comparing two doses of ketazolam (15 and 30 mg) with placebo, each given once daily, in the evening, to 92 outpatients affected by generalized anxiety disorders for at least 1 month, was carried out. After 1-week washout period 47 patients were randomized to ketazolam 15 mg, and 45 to placebo for 15 days (first period). At the end of this period, if the patient experienced a decrease on the total Hamilton Anxiety Rating Scale (HAM-A) of at least 25% of basal value, the treatment was kept unchanged for a further 15 days, otherwise 15 mg of ketazolam were added to the previous treatment (second period). Anxiety was rated after 2 and 4 weeks with the Italian HAM-A scale and with a 4-point scale (patient's assessment). Seventy-eight patients completed the first period and 75 the whole study. During the first period the percentage of responders was almost identical in both treatment groups, but during the second period a further slight improvement was observed in the early placebo responders, while the HAM-A score of patients on ketazolam continued to improve significantly (p less than 0.01) throughout the study. Likewise a significant (p less than 0.001) difference between treatments was observed, on the 4-point scale, in the population as a whole (end of first period) as well as in responder patients (end second period). Tolerability was good, except in 1 patient on placebo, who was withdrawn from the study because of severe headache.

Pharmacokinetics of pirprofen and its pyrrol metabolite in elderly patients.

Plasma concentrations of pirprofen and of its pyrrol metabolite were assessed in 9 elderly patients (3 males, 6 females; mean age 76 years) suffering from chronic degenerative disease. Pirprofen 400 mg in 4 ml was administered i.m. and the pharmacokinetic profile of the drug and the metabolite was calculated. The AUC, Cmax and t1/2 of pirprofen were similar to those found in previous studies, and, as expected, those parameters for the pyrrol metabolite were lower (Cmax = 2.8 micrograms/ml-1; tmax = 6.4 h; AUC(0-32) = 56.5 micrograms.h.ml-1). One patient (n = 8) showed different pharmacokinetic behaviour, which is discussed. The data suggest that age has little influence on the pharmacokinetic of pirprofen, although unpredictable responses should always be considered in clinical practice.

NSAID ionisation in the management of soft-tissue rheumatism: role played by the drug, electrical stimulation and suggestion.

Four treatments for soft-tissue rheumatism--sham ionisation, placebo ionisation, and pharmacological ionisation with pirprofen (two-dose levels)--were assessed in a randomized double-blind, between-patient controlled trial in 73 outpatients affected by scapulo-humeral periarthritis or elbow epicondylitis. Treatment lasted two weeks (5 sessions a week). Progress was measured by patient's assessment on pain at rest and on movement and by physician's assessment on functional impairment. At two weeks each treatment was associated with a significant degree of improvement; however, pharmacological ionisation produced a significantly higher improvement in symptoms. No differences were detected between sham ionisation and placebo ionisation. These results suggest that the ionisation procedure displays per se a moderate therapeutic effect which seems to be due more to a simple placebo effect than to the biological effect of electricity.

Baclofen prolongs the analgesic effect of fentanyl in man.

Pretreatment with baclofen prolonged the duration of fentanyl-induced analgesia from 18 to 30 min in patients undergoing neurosurgical anaesthesia (fentanyl plus nitrous oxide in oxygen). This observation is consistent with a potentiating effect of GABA on opioid analgesia.

Diclofenac and pirprofen modify pituitary and hypothalamic beta-endorphin concentrations.

We provide evidence that both Diclofenac and Pirprofen, two cyclooxygenase inhibitors with a potent analgesic effect both in the experimental animal and in man, induce a significant and long lasting decrease in pituitary beta-endorphin concentrations, together with an increase of the hypothalamic concentrations of the peptide. We suggest that this effect might participate in the potent analgesic effect of the two compounds, that exceeds the one expected by drugs of this class.