Cerebrospinal fluid biogenic amine metabolites, plasma-rich platelet serotonin and [3H]imipramine reuptake in the primary fibromyalgia syndrome.

BACKGROUND: Primary fibromyalgia syndrome (PFS) is a chronic disorder commonly seen in rheumatological practice. The pathophysiological disturbances of this syndrome, which was defined by the American College of Rheumatology in 1990, are poorly understood. This study evaluated, in 30 patients, the hypothesis that PFS is a pain modulation disorder induced by deregulation of serotonin metabolism. OBJECTIVES: To compare platelet [(3)H]imipramine binding sites and serotonin (5-HT) levels in plasma-rich platelets (PRP) of PFS patients with those of matched healthy controls and to compare the levels of biogenic amine metabolites in the cerebrospinal fluid (CSF) of PFS patients with those of matched controls. METHODS: Platelet [(3)H]imipramine binding sites were defined by two criteria, B(max) for their density and K(d) for their affinity. PRP 5-HT and CSF metabolites of 5-HT (5-hydroxyindoleacetic acid, 5-HIAA), norepinephrine (3-methoxy, 4-hydroxy phenylglycol, MHPG) and dopamine (homovanillic acid, HVA) were assayed by reversed-phase high-performance liquid chromatography with coulometric detection. RESULTS: [(3)H]Imipramine platelet binding was similar (P=0.43 for B(max) and P=0.30 for K(d)) in PFS patients (B(max)=901+/-83 fmol/mg protein, K(d)=0.682+/-0.046) and in matched controls (B(max)=1017+/-119 fmol/mg protein, K(d)=0.606+/-0.056). PRP 5-HT was significantly higher (P=0.0009) in PFS patients (955+/-101 ng/10(9) platelets) than in controls (633+/-50 ng/10(9) platelets). When adjusted for age, the levels of all CSF metabolites were lower in PFS patients. The CSF metabolite of norepinephrine (MHPG) was lower (P:=0.003) in PFS patients (8.33+/-0.33 ng/ml) than in matched controls (9.89+/-0.31 ng/ml) and 5-HIAA was lower (P=0.042) in PFS female patients (22.34+/-1.78 ng/ml) than in matched controls (25.75+/-1.75 ng/ml). For HVA in females, the difference between PFS patients (36.32+/-3.20 ng/ml) and matched controls (38.32+/-2.90 ng/ml) approached statistical significance (P=0.054). CONCLUSION: Changes in metabolites of CSF biogenic amines appear to be partially correlated to age but remained diagnosis-dependent. High levels of PRP 5-HT in PFS patients were associated with low CSF 5-HIAA levels in female patients but were not accompanied by any change in serotonergic uptake as assessed by platelet [(3)H]imipramine binding sites. These findings do not allow us to confirm that serotonin metabolism is deregulated in PFS patients.

Ximoprofen in ankylosing spondylitis. A double blind placebo controlled dose ranging study.

Ximoprofen is a new propionic NSAID which has previously demonstrated its efficacy at a daily dose of 30 mg. The aim of the study was to evaluate the efficacy of different daily dosages of Ximoprofen in patients with active ankylosing spondylitis. For 2 weeks 5 parallel groups were studied: placebo and Ximoprofen at 5, 10, 20 and 30 mg daily. Response to treatment was defined as an improvement in pain (VAS 100 mm) of at least 50% during the study. 285 out of the 332 screened patients were included. At the end of the study, the percentage of responders was higher in the Ximoprofen groups (54%, 41%, 53%, 56% in the 5, 10, 20 and 30 mg groups, respectively) than in the placebo group (21%). The clearest dose related effect of Ximoprofen observed occurred after one week of treatment. This study 1/confirms the efficacy of Ximoprofen at a 30 mg daily dosage, 2/shows the persistence of this efficacy at lower dosages, 3/suggests that ankylosing spondylitis is a sensitive and relevant human model to assess NSAIDs at an early stage of clinical evaluation.

Systemic and regional hemodynamic characterization of alpha-1 and alpha-2 adrenoceptor agonists in pithed rats.

In pithed rats, blood pressure dose-response curves to i.v. cirazoline, methoxamine and phenylephrine (full alpha-1 adrenoceptor agonists) exhibited higher maxima than those to B-HT 920, M-7, UK-14,304 (full alpha-2 adrenoceptor agonists) and indanidine (Sgd 101/75: partial alpha-1 adrenoceptor agonist). For an 80 mm Hg increase in blood pressure, full alpha-1 adrenoceptor agonists enhanced total peripheral, renal and mesenteric vascular resistances significantly more than alpha-2 adrenoceptor stimulants or indanidine. In contrast, all compounds produced a similar degree of hindquarter vasoconstriction, suggesting that both types of alpha adrenoceptors have the same functional importance in this skeletal muscle vascular bed. Application of a multivariate discriminant analysis to the drug-induced changes in the total peripheral and mesenteric vascular resistances associated with a pressor effect of 80 mm Hg allowed their assignment to two distinct groups corresponding to the full alpha-1 and the full alpha-2 adrenoceptor agonists plus indanidine. All investigated compounds in low doses increased cardiac output, which returned to base-line values after high doses of alpha-1 but plateaued after high doses of alpha-2 adrenoceptor agonists or indanidine. alpha-1 adrenoceptor agonists decreased whereas alpha-2 stimulants and indanidine successively increased and then decreased renal blood flow. Finally, all investigated compounds increased hindquarter blood flow at low doses but decreased it at high doses. The ratios of the doses of cirazoline required to produce a 100% rise in systemic and local vascular resistances in the presence or in the absence of prazosin were of similar magnitude. This was also true for M-7 when studied in the presence or in the absence of yohimbine. These findings suggest pharmacological identity within alpha-1 as well as within alpha-2 adrenoceptor populations in all investigated vascular beds. Finally, the calcium entry blocker diltiazem did not affect the increases in systemic and regional resistances evoked by cirazoline but depressed profoundly the effects of M-7 and indanidine. In conclusion, full alpha-1 and alpha-2 adrenoceptor agonists can be discriminated easily on the basis of their systemic and regional hemodynamics in the pithed rat. That the hemodynamic effects of the partial alpha-1 adrenoceptor agonist indanidine are similar to those of alpha-2 adrenoceptor agonists and susceptible to calcium channel blockade suggests that the alpha-1 adrenoceptors stimulated by this drug have the same coupling modality as alpha-2 adrenoceptors and share with the latter the same functional expression when stimulated.

Learning impairment in epileptic patients.

In order to evaluate immediate recall and learning in epileptic patients, four tests were chosen: Wechsler's memory span for digits, graphic reproduction of geometric figures from the Wechsler Memory Scale, learning of a list of words from the Rey Memory Scale, and recognition of these words. These tests were performed on 200 epileptic patients over the age of 15 years, without defined cerebral lesions, and with a normal or subnormal social adjustment. Memory impairment was analyzed with respect to the following variables: seizure frequency, seizure type, duration of the disorder, and anticonvulsant medication. Patient data were compared with values obtained for a population of 100 normal subjects matched for age and level of education. Comparison between epileptics and controls clearly demonstrated a statistically significant memory impairment in the group of patients. However, the reasons for these poor performances are not clear, and none of the studied parameters (type of epilepsy, frequency of seizures, duration of the disease, and medication), if considered alone, accounts for this impairment.

Plasma levels of primidone and its metabolite phenobarbital: effect of age and associated therapy.

The effects of age and associated therapy on plasma primidone (PRM) and derived phenobarbital (PB) concentrations, and on plasma concentrations-to-PRM dose ratios (L/D ratio) were evaluated retrospectively from 408 consecutive PRM and derived PB determinations in 238 chronically treated epileptic patients (153 children and adolescents between 5 months and 15 years of age and 85 adults between 16 and 55 years of age). The correlation between PRM administered and both plasma PRM and derived PB levels was significant; the correlation between PRM and PB plasma levels was also significant, but the scatter of values for the linear regressions was such that the relationship had no predictive value. Significant differences in mean plasma PRM and PB L/D ratios were found between patients aged 0-3 years, 4-9 years, 10-15 years, and adults (16-55 years), with higher values in the older groups. The PB/PRM concentration ratios were significantly lower in children than in adolescents and adults. Concomitant treatment with carbamazepine affected PRM disposition and led to increased L/D ratios for PB and decreased L/D ratios for PRM, whereas phenytoin increased the L/D ratios for PB without any significant change in the L/D ratios for PRM. The variability in the results indicates the need for routine monitoring of PRM and derived PB plasma levels, particularly in pediatric populations, in order to tailor the dose to each patient.