Analysis of the relationship between age and treatment response in migraine

In migraine, headache severity varies with age. As a consequence, the effectiveness of medication may also depend on a patient's age. The purpose of this study was to assess the combined effect of age and drug treatment on headache characteristics. Using data from clinical trials of sumatriptan in adolescents and adults, we show how the interaction between age and drug exposure can be parameterised as a covariate on a Markov model that describes the decline of headache severity over three clinically defined stages (no relief, relief and pain-free status). The model explains important clinical observations: (i) the rates at which the pain relief and pain-free status were attained were found to be inversely related to age; (ii) in placebo-treated patients, the mean transit time from 'no relief' to 'relief' is 3 h for young adolescents and increases to 6 h for patients aged ≥ 30 years; and (iii) sumatriptan reduces the transit time to 2 h, irrespective of age. These findings indicate that the therapeutic gain over placebo increases with age. Prospective studies of antimigraine drugs should take this relationship into account when extrapolating efficacy data from adults to adolescents.     

Bioavailability and toxicity of pentachlorophenol in contaminated soil evaluated on coelomocytes of Eisenia andrei (Annelida: Lumbricidae).

Pentachlorophenol (PCP) is widely distributed and highly persistent in soil, and represents a threat to the health of ecosystems. The present study aimed to assess the toxicity and bioavailability of PCP in soils as a function of different aging periods with the attempt to select a good toxicological assay for Eisenia andrei Bouché (Annelida: Lumbricidae). The experiments were performed on soil contaminated with PCP at 15 and 150ppm. After different aging periods (20, 60 and 120 days from spiking), bioavailability and toxicity were evaluated on E. andrei kept for 7 and 14 days in treated soils. The actual bioavailability decreased in relation to the aging for both PCP concentrations. No membrane damage was observed on coelomocytes collected by ethanol extrusion. Modifications in distribution of coelomocyte subpopulations were detected by flow cytometry on samples aged for 60 and 120 days at 150ppm PCP contamination. The reduction of lysosomal membrane stability, measured by neutral red retention time, was observed in all treatments. Worm mortality increased with aging in soils spiked with 150ppm of PCP. In conclusion, aging did not seem to reduce PCP cytotoxicity. This is the first report on in vivo toxicity of PCP evaluated on coelomocytes of E. andrei using different assays.     

Abietane diterpenoids from callus cultures of Taxus baccata

A new compound was isolated from calli of Taxus baccata L. and assigned the structure 3beta,11-dihydroxy-12-methoxyabieta-8,11,13-triene-7-one. Two other metabolites were identified as 3-oxocryptojaponol and taxamairein C, both previously isolated from Taxus mairei.     

Biotechnological engineering of heparin/heparan sulphate: a novel area of multi-target drug discovery

Heparin is a sulphated glycosaminoglycan currently used as an anticoagulant and antithrombotic drug. It consists largely of 2-O-sulphated IdoA not l&r arrow N, 6-O-disulphated GlcN disaccharide units. Other disaccharides containing unsulphated IdoA or GlcA and N-sulphated or N-acetylated GlcN are also present as minor components. This heterogeneity is more pronounced in heparan sulphate (HS), where the low-sulphated disaccharides are the most abundant. Heparin/HS bind to a variety of biologically active polypeptides, including enzymes, growth factors and cytokines, and viral proteins. This capacity can be exploited to design multi-target heparin/HS-derived drugs for pharmacological interventions in a variety of pathologic conditions besides coagulation and thrombosis, including neoplasia and viral infection. The capsular K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor N-acetyl heparosan. The possibility of producing K5 polysaccharide derivatives by chemical and enzymatic modifications, thus generating heparin/HS-like compounds, has been demonstrated. These K5 polysaccharide derivatives are endowed with different biological properties, including anticoagulant/antithrombotic, antineoplastic, and anti-AIDS activities. Here, the literature data are discussed and the possible therapeutic implications for this novel class of multi-target "biotechnological heparin/HS" molecules are outlined.     

Reduced gating of middle-latency auditory evoked potentials (P50) in migraine patients: another indication of abnormal sensory processing?

Habituation of cortical evoked responses to repetitive stimuli is reduced in migraine between attacks. To explore another aspect of information processing, we measured auditory sensory gating. The amplitude of the P50 response to the second of two homologous stimuli was significantly less reduced in migraineurs than in healthy volunteers. This lack of auditory sensory gating may be due to a hypofunction of monoaminergic subcortico-cortical pathways, which is also supposed to cause the interictal deficit of cortical habituation to repetitive stimuli.     

Population pharmacokinetic-pharmacodynamic modelling of S 15535, a 5-HT(1A) receptor agonist, using a behavioural model in rats

The pharmacokinetic-pharmacodynamic relationship of S 15535 (1-(benzodioxan-5-yl) 4-(indan-2-yl)piperazine) and its active 5-hydroxy metabolite S 32784 (1-(benzodioxan-5-yl) 4-(5-hydroxyindan-2-yl)piperazine), and buspirone as a reference, were studied in male Wistar rats using a behavioural model of anxiety by determining the reduction in the number of fear-induced ultrasonic vocalisations. S 15535 and buspirone were administered p.o. and i.v. S 32784, present in man but not in rat, was administered i.v. The pharmacokinetics and pharmacokinetic-pharmacodynamic relationships were described using non-linear mixed effects modelling. The no-drug effect was constant and all compounds were active in the model, reducing ultrasonic vocalisations immediately after administration. The sigmoid E(max) model was used to describe the pharmacokinetic-pharmacodynamic relationships, with E(max) values of a 90% decrease in baseline ultrasonic vocalisations. Corrected for plasma protein binding, all compounds showed similar potency. The study shows that ultrasonic vocalisations can be considered a suitable endpoint for the anxiolytic effect when used in conjunction with non-linear mixed effects modelling to overcome the limited sampling and effect measurements.     

Sensitivity of the Montgomery Asberg Depression Rating Scale to response and its consequences for the assessment of efficacy

An increasing body of evidence is available suggesting that the Hamilton Depression Rating Scale (HAMD) is not a sensitive measure of treatment effect. In this investigation, we explore the sensitivity of the individual items of the Montgomery Asberg Depression Rating Scale (MADRS) and compare the consequences of selecting a different scale as primary endpoint in the analysis of efficacy. A graphical approach is proposed for the evaluation of the sensitivity of individual items to response, using data from randomised, placebo-controlled clinical trials in which HAMD and MADRS were measured concurrently. Subsequently, we illustrate the impact of differences in the sensitivity of the primary endpoint for the detection of statistical significance in treatment effect. In contrast to the HAMD, our item-by-item analysis of the MADRS reveals that all individual items are sensitive to response, irrespective of treatment type. However, some HAMD subscales still outperform MADRS in the detection of treatment effect. The selection of these subscales as primary endpoints in clinical trials could save over 1/3 in patients compared to the full HAMD whilst keeping the same statistical power.     

Multiple clinical and paraclinical analyses of chronic tension-type headache associated or unassociated with disorder of pericranial muscles

Thirty-two female patients fulfilling the diagnostic criteria of chronic tension-type headache underwent multiple clinical (severity index before and after biofeedback therapy; anxiety score) and paraclinical (pericranial EMG levels and pressure-pain thresholds, temporalis exteroceptive silent period) assessments. Twenty-three patients (72%) had at least one increased EMG level and/or at least one decreased pain threshold and qualified for the subgroup" associated with disorder of pericranial muscles" (code 2.2.1). Nine patients (28%) were within the normal range for both investigations and would have been classified in the subgroup "unassociated with such disorder" (code 2.2.2). No significant differences were found between these two groups of patients for headache severity, anxiety, response to biofeedback therapy or duration of temporalis second exteroceptive silent period. The various clinical and paraclinical parameters were not significantly correlated to each other. It is therefore suggested that the subdivision of chronic tension-type headache in two subgroups based on pericranial EMG levels and/or pain sensitivity might be artificial. Since both of the latter and temporalis silent periods vary independently, they appear complementary in the study of tension-type headache patients and probably represent peripheral abnormalities, which are induced to varying intensities by a common central nervous system dysfunction.     

A colorimetric assay for releasable plasminogen activator

We describe an equilibrium assay for measuring release of plasminogen activator form blood-vessel walls and report data from 125 individuals free of overt thromboembolic disease. Excess human plasminogen is added to the euglobulin fraction of plasma obtained before and after venous occlusion at mean systolic pressure. To measure plasmin generation in these samples, we used the chromogenic plasmin substrate D-Val-Leu-Lys-p-nitroanilide, which liberates p-nitroaniline upon cleavage. Releasable plasminogen activator in 24 subjects was determined by this colorimetric assay and by the radiocasein assay previously reported by this laboratory (Am. J. Clin. Pathol. 76,403-409, 1981), and the results were compared. The correlation coefficient was 0.97. The colorimetric assay offers several advantages over the radiocasein assay: shorter incubation (6 vs 16 h) and no preparation or quantification of a radioactive substrate and its cleavage products.