Acyclovir treatment of relapsing-remitting multiple sclerosis

Acyclovir treatment was used in a randomized, double-blind, placebo-controlled clinical trial with parallel groups to test the hypothesis that herpes virus infections are involved in the pathogenesis of multiple sclerosis (MS). Sixty patients with the relapsing-remitting form of MS were randomized to either oral treatment with 800 mg acyclovir or placebo tablets three times daily for 2 years. The clinical effect was investigated by an extensive test battery consisting of neurological examinations, neuro-ophthalmological and neuropsychological tests, and evoked potentials. Results were based on intent-to-treat data and the primary outcome measure was the exacerbation rate. In the acyclovir group (n = 30), 62 exacerbations were recorded during the treatment period, yielding an annual exacerbation rate of 1.03. The placebo group (n = 30) had 94 exacerbations and an annual exacerbation rate of 1.57. Thus, 34% fewer exacerbations were encountered during acyclovir treatment. This difference in exacerbation rate between the treatment groups was not significant (P = 0.083). However, this trend to a lower disease activity in acyclovir-treated patients was supported in subsequent data analysis. If the patients were grouped according to exacerbation frequencies, i.e. into low (0–2), medium (3–5) and high (6–8) rate groups, the difference between acyclovir and placebo treatment was significant (P = 0.017). Moreover, in a subgroup of the population with a duration of the disease of at least 2 years providing an exacerbation rate base-line before entry, individual differences in exacerbation rates were compared between the 2-year pre-study period and the study period in acyclovir-treated (n = 19) and placebo (n = 20) patients and acyclovir-treated patients showed a significant reduction of exacerbations (P = 0.024). Otherwise, neurological parameters were essentially unaffected by acyclovir treatment and there were no convincing signs of reduced neurological deterioration in the acyclovir group. This study indicates that acyclovir treatment might inhibit the triggering of MS exacerbations and thus suggests that acyclovir-susceptible viruses might be involved in the pathogenesis of MS. This possibility warrants further investigation.     

Relevance of platelet serotonin and plasma tryptophan concentration in normal pregnant women and newborns to early child psychiatry

Dysfunctions of the serotonergic system are implicated in psychiatric disorders, and there is evidence that a familial element may be significant in childhood autism. The concentrations of platelet 5-HT and free and total plasma tryptophan were determined in healthy pregnant women at each month of pregnancy and, at delivery, in both maternal and umbilical cord blood. A significant rise in the level of platelet 5-HT occured during month 3 and 4 followed by a retum to normal from month 5 until the delivery. The level of total plasma tryptophan remained equal to that in normal healthy non pregnant women until the 6th month. By month 7, it had decreased significantly and remained low until the month 9. At delivery the level fell significantly by –41%. The concentration of free tryptophan varied widely from one month to another but there was a trend towards a progressive increase from month 1 to 9, and at delivery the level returned to basal values. The concentration of 5-HT in the umbilical cord blood was about half that of the maternal blood. Inversely the concentrations of both free and total plasma tryptophan in the umbilical cord blood were nearly twice that of the maternal blood.

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Zusammenfassung Dysfunktionen des serotoninergen Systems werden bei verschiedenen psychiatrischen Störungen angenommen, wobei es Hinweise für eine familiäre Komponente im Rahmen des kindlichen Autismus gibt. Die Konzentrationen der 5-Hydroxyindolessigsäure in Blutplättchen und des Tryptophans (freie und Gesamtplasmakonzentrationen) wurden in gesunden schwangeren Frauen sowohl im mütterlichen Blut als auch im Nabelschnurblut in jedem Schwangerschaftsmonat und bei der Geburt bestimmt. Ein signifikanter Anstieg der Konzentration der 5-Hydroxyindolessigsäure in Blutplättchen ereignete sich zwischen Mens III und IV, und von Mens V ab an bis zur Geburt normalisierte sich die Konzentration. Der Gesamtplasmaspiegel von Tryptophan glich dem in gesunden nicht-schwangeren Frauen bis zu Mens VI, in Mens VII war er signifikant abgefallen und blieb bis zur Mens IX niedrig. Zum Geburtstermin fiel der Spiegel signifikant um 41%. Die Konzentration des freien Tryptophans zeigte von Monat zu Monat deutliche Schwankungen, wobei es einen Trend in Richtung eines kontinuierlichen Anstiegs von Mens I–IX gab. Zum Termin fiel der Spiegel auf die basalen Werte ab. Die Konzentration der 5-Hydroxyindolessigsäure im Nabelschnurblut betrug ca. die Hälfte derer im maternalen Blut. Umgekehrt waren die Konzentrationen sowohl des freien als auch Gesamtplasmatryptophans im Nabelschnurblut ca. doppelt so hoch wie im maternalen Blut.

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Résumé Le système sérotonergique semble impliqué dans les psychoses infantiles précoces, et, dans la mesure où une prévalence familiale existe pour ces affections, il nous a paru intéressant de déterminer un profil normal de la sérotonine (5-HT) plaquettaire et du tryptophane au cours de la gestation. Ceci dans le but de puvoir interpréter des résultats trouvés pendant la grossesse de femmes déjà mères d'un enfant psychotique. Nous avons déterminé les concentrations en 5-HT plaquettaire et en tryptophane plasmatique total et libre chez des femmes enceintes témoins à chaque mois de grossesse et, à l'accouchement, dans le sang maternel et dans le sang du cordon. La concentration en 5-HT plaquettaire augmente significativement aux 3ème et 4ème mois puis revient à la normale à partir du 5ème mois jusqu'à l'accouchement. Le tryptophane total est normal jusqu'au 6ème mois, il diminue significativement au 7ème mois et reste bas jusqu'au 9ème mois. A l'accouchement, il s'effondre (–41%). Le tryptophane libre varie beaucoup d'un mois à l'autre, il augmente progressivement du début à la fin de la grossesse, à l'accouchement par contre, il est normal. Dans le sang du cordon, la concentration en 5-HT est environ la moitié de celle du sang maternel, le tryptophane total et le tryptophane libre environ deux fois plus élevés.

     

OnAmblyospora styriaca sp.nov. (Microspora,Amblyosporidae) —a microsporidian of the blackflyEusimulium costatum (Diptera,Simuliidae)

AnAmblyospora species (microspora, Abblyosporidae) collected in the southeast region of Austria was examined using light and electron microscopic methods. The hosts were larvae ofEusimulium costatum (Diptera, Simuliidae). The merogonial stages were found to be diplocaryotic. During sporogony, eight monocaryotic spores developed in a sporophorous vesicle. The truncate spores measured between 2.9×2.3 and 4.1×3.2 m and had an anisofilar polar tube, the narrow part of which was rather short. Besides tubules and homogeneous, electron-dense inclusions, unique filamentous structures were observed in the episporontal space. The microsporidian was compared with other species showing similar characteristics. Because of the variations observed in its ultrastructure as compared with that of other species, we consider this microsporidian to be a new species and have named itAmblyospora styriaca.     

Contrast enhancement of cerebral infarcts. Incidence and clinical value in different states of cerebral infarction

Summary Information obtained from CT scan after contrast administration was evaluated in 59 consecutive stroke patients. CT scans before and after contrast administration were performed 3 days and 21/2 weeks after stroke. A plain CT scan was repeated 6 months later. Contrast enhancement was practically not seen on the first examination, but was seen in 46% on the second examination. There was a close relationship between the occurrence of contrast enhancement and the socalled fogging effect. Contrast scanning gave additional information only when this effect was present. Plain CT scans 3 days after stroke were superior to contrast scans taken at any time for detecting and visualizing cerebral infarcts.     

Pharmacokinetics of the placental transfer and distribution of clorazepate and its metabolite nordiazepam in the feto-placental unit and in the neonate

Summary Clorazepate 20mg was given i. m. to 49 mothers during the first stage of labour. The elimination of the drug was studied in 27 newborns produced by these mothers. The same dose was given to 13 women who underwent amniocentesis and to 7 women who were breast-feeding. Total nordiazepam, i.e. the sum of clorazepate and its metabolite nordiazepam, was determined by gas-liquid chromatography in maternal blood, umbilical cord blood (both arterial and venous), amniotic fluid and in milk. Clorazepate was found to cross the placental barrier slowly, but nordiazepam was transferred more rapidly. Nordiazepam was found in the milk and in the blood of neonates after breast-feeding had started.     

Pharmacokinetics of methyldopa in healthy man

Summary The pharmacokinetics of 2-¹⁴C-L--methyldopa have been investigated in five healthy volunteers following intravenous and oral administration. In the intravenous study a bi-phasic plasma concentration curve was found both for chemically determined -methyldopa and for radioactivity. The plasma level of radioactivity differed significantly from chemically determined drug, a pattern which was also found in urine. This suggests the presence of unidentified metabolite(s). The difference between plasma disappearance and urine recovery of -methyldopa and radioactivity during the first 4 h after injection suggests distribution to an extravascular compartment. Plasma half-lives of total radioactivity and of unchanged drug were calculated. In three subjects, pharmacokinetic parameters for a two-compartment open body model were calculated from urine and plasma data. Urinary recovery of radioactivity was almost complete within 48 h after intravenous administration. After oral administration, however, only about 40 per cent of the radioactive dose was recovered in the urine, and it contained approximately equal amounts of unconjugated methyldopa, acid-labile conjugated methyldopa and unidentified metabolite(s). The acid-labile conjugate was found only after oral administration, which supports the theory of a mucosal conjugation process. The lack of acid-labile conjugated drug either in the plasma or urine after intravenous injection indicates that there is no enterohepatic circulation of this drug.     

Effect of agomelatine in the chronic mild stress model of depression in the rat.

Chronic mild stress (CMS), a well-validated model of depression, was used to study the effects of the melatonin agonist and selective 5-HT(2C) antagonist agomelatine (S 20098) in comparison with melatonin, imipramine, and fluoxetine. All drugs were administered either 2 h before (evening treatment) or 2 h after (morning treatment) the dark phase of the 12-h light/dark cycle. Chronic (5 weeks) evening treatment with agomelatine or melatonin (both at 10 and 50 mg/kg i.p.) dose-dependently reversed the CMS-induced reduction in sucrose consumption. The magnitude and time course of the action of both drugs was comparable to that of imipramine and fluoxetine (both at 10 mg/kg i.p.); however, melatonin was less active than agomelatine at this dose. The effect of evening administration of agomelatine and melatonin was completely inhibited by an acute injection of the MT(1)/MT(2) antagonist, S 22153 (20 mg/kg i.p.), while the antagonist had no effect in animals receiving fluoxetine or imipramine. When the drugs were administered in the morning, agomelatine caused effects similar to those observed after evening treatment (with onset of action faster than imipramine) but melatonin was ineffective. Moreover, melatonin antagonist, S 22153, did not modify the intakes in stressed animals receiving morning administration of agomelatine and in any other control and stressed groups tested in this study. These data demonstrate antidepressant-like activity of agomelatine in the rat CMS model of depression, which was independent of the time of drug administration. The efficacy of agomelatine is comparable to that of imipramine and fluoxetine, but greater than that of melatonin, which had no antidepressant-like activity after morning administration. While the evening efficacy of agomelatine can be related to its melatonin receptors agonistic properties, its morning activity, which was not inhibited by a melatonin antagonist, indicates that these receptors are certainly required, but not sufficient to sustain the agomelatine efficacy. It is therefore suggested that the antidepressant-like activity of agomelatine depends on some combination of its melatonin agonist and 5-HT(2C) antagonist properties.     

Imiquimod treatment induces expression of opioid growth factor receptor: a novel tumor antigen induced by interferon-alpha?

PURPOSE: Imiquimod represents a synthetic local immune response modifier that has demonstrated efficacy in clearing basal cell carcinoma. Via interaction with Toll-like receptor 7 on immune cells, imiquimod induces local production of cytokines, such as interferon (IFN)-alpha. EXPERIMENTAL DESIGN: To more closely define and elucidate mechanisms leading to basal cell carcinoma clearance in vivo, we examined gene expression profiles of skin basal cell carcinoma before and after treatment with 5% imiquimod cream (Aldara) by using high-density oligonucleotide arrays. RESULTS: We show that imiquimod predominantly induces genes involved in different aspects of immune response. In addition to effects on immunity, imiquimod treatment modulates the expression of genes involved in the control of apoptosis and oncogenesis. Array data indicated that imiquimod treatment induces expression of opioid growth factor receptor, a molecule recently reported to be a target for antitumor antibody responses. Immunohistochemistry revealed in vivo up-regulation of opioid growth factor receptor protein on tumor and on infiltrating cells after treatment. By using basal cell carcinoma cell lines treated with IFN-alpha or imiquimod, we show that opioid growth factor receptor up-regulation is IFN-alpha-mediated, rather then directly imiquimod-mediated. By using tissue microarray containing 52 basal cell carcinomas, we demonstrate opioid growth factor receptor expression in almost half of the cases. Expression of opioid growth factor receptor correlated with a longer recurrence-free period in basal cell carcinoma that recurred after radiotherapy (Kaplan-Meier analysis, P = 0.041). CONCLUSIONS: In addition to its immunomodulatory and antiproliferative activity, opioid growth factor receptor seems to have a prognostic significance in basal cell carcinoma patients. Our data add to the growing list of basal cell carcinoma-associated tumor antigens.