Efficacy of natalizumab in second line therapy of relapsing-remitting multiple sclerosis: results from a multi-center study in German speaking countries.

BACKGROUND: Natalizumab has been recommended for the treatment of relapsing-remitting multiple sclerosis (RRMS) in patients with insufficient response to interferon-beta/glatiramer acetate (DMT) or aggressive MS. The pivotal trials were not conducted to investigate natalizumab monotherapy in this patient population. METHOD: Retrospective, multicenter study in Germany and Switzerland. Five major MS centers reported all RRMS patients who initiated natalizumab >or=12 months prior to study conduction. RESULTS: Ninety-seven RRMS patients were included [69% female, mean age 36.5 years, mean Expanded Disability Status Scale (EDSS) 3.4; 93.8% were pre-treated with DMT], mean treatment duration with natalizumab was 19.3 +/- 6.1 months. We found a reduction of the annualized relapse rate from 2.3 to 0.2, 80.4% were relapse free with natalizumab. EDSS improved in 12.4% and 89.7% were progression free (change of >or= 1 EDSS point). Eighty-six per cent of patients with highly active disease (>or= 2 relapses in the year and >or= 1 Gadolinium (Gd)+ lesion at study entry, n = 20) remained relapse free. The mean number of Gd enhancing lesions was reduced to 0.1 (0.8 at baseline). Discontinuation rate was 8.2% (4.1% for antibody-positivity). CONCLUSION: Natalizumab is effective after insufficient response to other DMT and also in patients with high disease activity.

Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound.

BACKGROUND: Flupirtine is a nonopioid drug without antipyretic or antiphlogistic properties and with a favorable tolerability. It constitutes a unique class within the group of nonsteroidal analgesics and displays a peculiar pharmacodynamic profile that invites the investigation of applications beyond the pain-relieving effect. OBJECTIVE: This review describes and evaluates the pharmacologic and clinical literature regarding flupirtine and discusses its future potential. METHODS: A search of the primary literature and conference abstracts was conducted using the keyword 'flupirtine'. Resulting articles were compiled and analyzed for this review. RESULTS/CONCLUSIONS: Although flupirtine has gained a firm place in the treatment of acute and chronic pain in various clinical settings since its introduction, a broader range of applications remains to be explored in clinical trials. Possible neuroprotective effects due to N-methyl-d-aspartate antagonistic properties of flupirtine might be promising in the treatment of Creutzfeld-Jakob disease, Alzheimer's disease, and multiple sclerosis. Trials in these fields are forthcoming.

Neuropsychological status of alcohol-dependent patients: increased performance through goal-setting instructions.

AIMS: The effects of goal-setting instructions on neuropsychological performance of alcohol-dependent patients and control subjects were assessed. METHODS: 57 alcohol-dependent patients and 59 carefully age- and education-matched healthy control subjects underwent standard neuropsychological investigation. In addition, the goal-setting paradigm was used to systematically manipulate motivation. Participants were requested to calculate simple mathematical problems repeatedly within phases of a 2-min duration receiving normal or goal setting-instructions (to increase performance in the next phase by 20%). RESULTS: The patients demonstrated deficits in standard neuropsychological tests. Patients under goal-setting instructions demonstrated significantly higher improvement (correct responses: P = 0.016) relative to patients with standard instructions. Control subjects with goal-setting instructions demonstrated tendencies for higher improvement relative to control subjects with normal instructions. However, the differences were not significant. Interaction of group (patients vs. control subjects) and instructions (goal setting vs. normal) remained insignificant (P = 0.489) indicating that the increase through goal setting for the patients was not significantly higher than that for the control subjects. CONCLUSIONS: Despite of neuropsychological deficits in reasoning and psychomotor functioning, alcohol-dependent patients early in recovery are responsive to goal setting and able to increase neuropsychological performance. Therefore, goal-setting strategies might possibly be used in cognitive rehabilitation and therapy of alcohol-dependent patients. As there was no significant interaction in increase between patients and control subjects, our results do not support the hypothesis that the neuropsychological deficits are affected by or even caused by motivational limitations of the alcohol-dependent patients.

Serotonergic polymorphisms in patients suffering from alcoholism, anxiety disorders and narcolepsy.

1. Alterations in the serotonergic neurotransmission have been frequently described for patients suffering from alcoholism, anxiety disorders and narcolepsy. 2. The authors tested for association of the 5-HT2A receptor polymorphism (T102C) and the intron 7 tryptophan hydroxylase (TPH) polymorphism (A218C) among 176 alcohol dependent patients, 35 patients with panic disorder, 50 patients with generalized anxiety disorder, 55 patients with narcolepsy and 87 healthy controls. 3. Allele and genotype frequencies of the 5-HT2A receptor polymorphism (T102C), the intron 7 TPH polymorphism (A218C) were almost similar between the patients suffering from alcohol dependence, panic disorder, generalized anxiety disorder and narcolepsy. 4. There was no association between the 5-HT2A receptor polymorphism (T102C), the intron 7 TPH (A218C) polymorphisms and alcohol dependence, panic disorder, generalized anxiety disorder and narcolepsy in our subsets of German patients.

No association between the dopamine d2 receptor taqi a1 allele and earlier age of onset of alcohol dependence according to different specified criteria.

BACKGROUND: The presence of the A1 allele of the dopamine D2 receptor TaqI restriction fragment length polymorphism has been reported to be associated with an earlier age of onset of alcohol dependence as a marker for severity. METHODS: We tested this hypothesis with special regard to the definition of the age of onset of alcoholism in 243 patients with alcohol dependence, according to DSM-IV criteria assessed by the standardized interview Münchner Composite International Diagnostic Interview (M-CIDI), consecutively admitted for detoxification. Additionally, the Addiction Severity Index (ASI) was performed. The TaqIA polymorphism was amplified by polymerase chain reaction (PCR), and the PCR product was digested by the restriction enzyme TaqI. Patients were subsequently divided into an A1 (presence of at least one A1 allele, n = 88) and an A2 group (absence of an A1 allele, n = 155). The following criteria for different definitions of age of onset were used: (1) age of onset of the first occurring symptom necessary for the diagnosis of alcohol dependence according to M-CIDI; (2) age of onset of the last symptom of alcohol dependence according to M-CIDI; (3) age of onset of more than 3 drinking days per week on a regular basis according to ASI; (4) age of onset of more than 3 drinking days-of more than five drinks per drinking day-or at least one binge drinking episode per week on a regular basis according to ASI. RESULTS: The frequency of the A1 allele in our patient sample was 0.208. No statistically significant association between the A1 allele and the age of onset of alcoholism was found. The mean age of onset according to criterion 1 was 30.4 +/- 10.8 years for the A1 group and 30.2 +/- 10.2 years for the A2 group (p = 0.89); for criterion 2, it was 33.3 +/- 10.0 years for the A1 group and 33.9 +/- 10.2 years for the A2 group (p = 0.77); for criterion 3, it was 18.0 +/- 7.5 years for the A1 group and 18.1 +/- 6.1 years for the A2 group (p = 0.92); and for criterion 4, it was 22.3 +/- 9.7 years for the A1 group and 21.8 +/- 8.5 years for the A2 group (p = 0.76). CONCLUSIONS: No association was found between the A1 polymorphism and age at onset of alcohol dependence according to different specified criteria.

Vitamin B12 and hepatic enzyme serum levels correlate in male alcohol-dependent patients.

- Vitamin B12 serum levels and markers for alcohol consumption were determined in 80 male alcohol-dependent patients. Spearman correlation coefficients (r(S)) were calculated. Significant positive correlations between vitamin B12 and hepatic enzyme values were found (gamma-glutamyltransferase: r(S) = 0.58; alanine aminotransferase: r(S) = 0.43; aspartate aminotransferase: r(S) = 0.47; glutamate dehydrogenase: r(S) = 0.43; all P: < 0.001). Therefore, for a proper interpretation of vitamin B12 levels, it may be clinically relevant to take markers of hepatocellular damage into account.

The HTR1B 861G>C receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy.

The HTR1B receptor gene has been linked to antisocial alcoholism in a Finnish population and an American Indian tribe [Lappalainen et al. , Arch. Gen. Psychiatry, 55 (1998) 989]. Using a candidate gene approach, we genotyped 209 patients with alcoholism, 108 patients with major depression, 32 patients with panic disorder, 50 patients with generalized anxiety disorder, 58 patients with narcolepsy and 74 healthy volunteers for the HTR1B 861G>C polymorphism. There was a higher frequency of the HTR1B 861G alleles among the alcohol-dependent patients as compared to the control subjects (chi(2)=4.02, d.f.=2, P=0.04). However, the association resulted from higher frequencies of the opposite alleles (HTR1B 861G), as originally reported by Lappalainen et al. (1998). Although the association in our study might be due to a type I error, the higher degree of HTR1B allele sharing within both populations could also argue for another alcoholism-relevant gene within the proximity of the HTR1B gene on human chromosome 6.

Sex differences in allelic frequencies of the 5-HT2C Cys23Ser polymorphism in psychiatric patients and healthy volunteers: findings from an association study.

Polymorphisms in the serotonergic system are believed to play a role in the etiology and treatment of different psychiatric illnesses. The 5-HT2C receptor gene is X-linked, with a frequent mutation at nucleotide 68 leading to a Ser-->Cys transition at amino acid 23. Recent studies have demonstrated an impaired function of 5-HT2C receptors and an increased production of the major noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol in the cerebrospinal fluid among the subjects carrying the Ser23 allele (Lappalainen et al., 1999). Biol. Psychiatry 46:821). We genotyped patients with alcohol dependence, panic disorder without agoraphobia, generalized anxiety disorder, narcolepsy and normal healthy volunteers for the 5-HT2C Cys23Ser polymorphism. 5-HT2C Cys23Ser allele frequencies and genotypes did not differ among patients with alcohol dependence, panic disorder, generalized anxiety disorder, narcolepsy and normal healthy volunteers. In an overall analysis, female subjects (n = 173) displayed a higher frequency of 5-HT2C Ser23 alleles as compared to males (n = 298, P = 0.0178). The potential mechanisms of the observed gender difference in allele frequencies, including transmission ratio distortion, are discussed.

Reliability and validity of the German version of the European Addiction Severity Index (EuropASI).

OBJECTIVE: This study provides data on the psychometric characteristics of the German version of the European Addiction Severity Index (EuropASI). The ASI is a frequently used clinical and research instrument that measures problem severity among people with substance dependence. METHOD: The German ASI was used in a sample of 112 consecutively admitted male psychiatric inpatients seeking treatment for severe alcohol problems. The conceptual structure of the German ASI subscales was investigated by analyzing the intercorrelations of the severity ratings and composite scores. Internal consistency, interrater reliability and concurrent validity in terms of correlations with other assessment instruments were evaluated. RESULTS: The German ASI subscales proved to be independent or moderately correlated (-0.17 < r < 0.34). Each correlation coefficient between corresponding severity ratings and composite scores was significant (p < .0005), ranging from r = 0.47 to r = 0.93. Reliability measures indicated moderate to good internal consistency (Cronbach's alpha: 0.69-0.92) and moderate to excellent interrater reliability (intraclass correlation coefficient: 0.62-0.99). Validity was supported by significantly higher ratings in the alcohol section in alcohol dependent patients compared to patients without dependence (t = 2.99, 108 df, p = .004). Significant correlations (p < .001) were found between the alcohol use section and the Michigan Alcoholism Screening Test (r = 0.34 composite score and r = 0.44 severity rating) and between psychiatric status and the Symptom Checklist-90-revised (r = 0.55/0.51), supporting concurrent validity. CONCLUSIONS: The German version presented evidence of acceptable psychometric properties and its applicability in German-speaking countries could be confirmed.

Furosemide action on cerebellar GABA(A) receptors in alcohol-sensitive ANT rats.

Furosemide increases the basal tert-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding and reverses the inhibition of the binding by gamma-aminobutyric acid (GABA) in the cerebellar GABA(A) receptors containing the alpha6 and beta2/beta3 subunits. These effects are less pronounced in the alcohol-sensitive (ANT) than in the alcohol-insensitive (AT) rat line. The difference between the rat lines in the increase of basal [35S]TBPS binding was removed after a longer preincubation with ethylendiaminetetraacetic acid (EDTA) containing buffer, but long preincubation did not reduce the GABA content of the incubation fluid or remove the difference in GABA antagonism by furosemide. The GABA sensitivity of the [35S]TBPS binding did not differ between the rat lines. There was no nucleotide sequence difference in the beta2 or beta3 subunits between the rat lines and similar beta2/3 subunit-dependent agonistic actions by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in the rat lines were detected. The data suggest that there are still unknown structural alterations in the cerebellar GABA(A) receptors between the AT and ANT rat lines, possibly associated with differential alcohol sensitivity.