Potential application of the consistency approach for vaccine potency testing.

The Consistency Approach offers the possibility of reducing the number of animals used for a potency test. However, it is critical to assess the effect that such reduction may have on assay performance. Consistency of production, sometimes referred to as consistency of manufacture or manufacturing, is an old concept implicit in regulation, which aims to ensure the uninterrupted release of safe and effective products. Consistency of manufacture can be described in terms of process capability, or the ability of a process to produce output within specification limits. For example, the standard method for potency testing of inactivated rabies vaccines is a multiple-dilution vaccination challenge test in mice that gives a quantitative, although highly variable estimate. On the other hand, a single-dilution test that does not give a quantitative estimate, but rather shows if the vaccine meets the specification has been proposed. This simplified test can lead to a considerable reduction in the number of animals used. However, traditional indices of process capability assume that the output population (potency values) is normally distributed, which clearly is not the case for the simplified approach. Appropriate computation of capability indices for the latter case will require special statistical considerations.

Comparability of ELISA and toxin neutralization to measure immunogenicity of Protective Antigen in mice, as part of a potency test for anthrax vaccines.

Complexities of lethal challenge models have prompted the investigation of immunogenicity assays as potency tests of anthrax vaccines. An ELISA and a lethal toxin neutralization assay (TNA) were used to measure antibody response to Protective Antigen (PA) in mice immunized once with either a commercial or a recombinant PA (rPA) vaccine formulated in-house. Even though ELISA and TNA results showed correlation, ELISA results may not be able to accurately predict TNA results in this single immunization model.

Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample.

The serotonin transporter (5-HTT) regulates serotonergic neurotransmission and is thought to influence emotion. A 5-HTT-linked polymorphic region (5-HTTLPR) has two common variants, short (s) and long (l). We previously found population and within-family associations between the lower-expressing s allele and neuroticism, a trait related to anxiety, hostility, and depression, on a standard measure (the NEO Personality Inventory, Revised [NEO-PI-R]) in a primarily male population (n=505), and that the s allele was dominant. We investigated this association in a new sample (n=397, 84% female, primarily sib-pairs). The results robustly replicated the 5-HTTLPR neuroticism association, and the dominance of the s allele. Combined data from the two studies (n=902) showed a highly significant association between the s allele and higher NEO Neuroticism both across individuals and within families. Association between genotype and a related measure, Anxiety on the 16PF inventory, was replicated in the new population and within families in the combined sample. Association to another trait, estimated TPQ Harm Avoidance, was not replicated in the new sample but found only within the combined sibship group. Another association found in our original study, between the s allele and lower scores on NEO-PI-R Agreeableness, was also replicated and was more robust in the current and the combined samples. Associations between the functional 5-HTTLPR polymorphism were similar in women and men. These results help to define specific personality features reproducibly associated with 5-HTTLPR genotype. Such associations were strongest for traits defined by the NEO, enhancing the attractiveness of the five-factor personality model in genetic research on complex behavioral dimensions. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:202-216, 2000. Published 2000 Wiley-Liss, Inc.

Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior.

Cigarette smoking behavior is influenced by both personality traits and inherited factors. Previous research showed that neuroticism-a broad personality domain that includes anxiety, depression, impulsiveness and vulnerability-increases the risk of being a smoker, primarily because of difficulty in quitting. Neuroticism has also been associated with the 5-HTTLPR, a functional polymorphism in the promoter for the serotonin transporter gene. We used population and family-based methods to analyze the joint effects of the 5-HTTLPR and neuroticism on smoking behavior in a population of 759 never, current, and former smokers, all members of sib-pairs. Our main finding is that smoking behavior is influenced by an interaction between neuroticism and 5-HTTLPR genotype. Specifically, neuroticism was positively correlated with current smoking and negatively associated with smoking cessation in individuals and siblings with poorly transcribed 5-HTTLPR-S genotypes, but not in those with the more highly expressed 5-HTTLPR-L genotype. Individuals with both a 5-HTTLPR-S genotype and a high level of neuroticism had the greatest difficulty in quitting smoking. These data, if replicated, suggest that smoking behavior is more strongly influenced by the combination of the serotonin transporter gene and neuroticism than by either factor alone, and that personality scores and 5-HTTLPR genotype may predict the clinical efficacy of certain smoking cessation drugs.

Pleiotropy of the serotonin transporter gene for seasonality and neuroticism.

Pleiotropy refers to the ability of a single gene to influence multiple traits. A polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) has previously been found to be associated both with the personality trait of neuroticism and with seasonal changes in mood and behavior, or seasonality. Hypothesizing that the contribution of the serotonin transporter gene to seasonality is specific, i.e. independent of neuroticism, we measured 5-HTTLPR genotypes and both psychological traits in 236 healthy volunteers. The results indicated that the 5-HTTLPR contributions to variation in the two traits are largely independent; approximately three-quarters of the effect of the gene on seasonality are not related to its effects on neuroticism. Moreover, the gene has a larger effect on the covariation between neuroticism and seasonality than it does on either trait alone. Sibling-pair analysis confirmed that the effects of the 5-HTTLPR are due to genetic pleiotropy rather than population stratification.

A genetic association for cigarette smoking behavior.

Dopaminergic genes are likely candidates for heritable influences on cigarette smoking. In an accompanying article, Lerman et al. (1999) report associations between allele 9 of a dopamine transporter gene polymorphism (SLC6A3-9) and lack of smoking, late initiation of smoking, and length of quitting attempts. The present investigation extended their study by examining both smoking behavior and personality traits in a diverse population of nonsmokers, current smokers, and former smokers (N = 1,107). A significant association between SLC6A3-9 and smoking status was confirmed and was due to an effect on cessation rather than initiation. The SLC6A3-9 polymorphism was also associated with low scores for novelty seeking, which was the most significant personality correlate of smoking cessation. It is hypothesized that individuals carrying the SLC6A3-9 polymorphism have altered dopamine transmission, which reduces their need for novelty and reward by external stimuli, including cigarettes.

Autoinduction and steady-state pharmacokinetics of carbamazepine and its major metabolites.

1. The effect of carbamazepine (CBZ) dose change on mean plasma concentrations of CBZ, its two metabolites and apparent steady-state clearance was studied in 77 affectively ill patients receiving CBZ at doses of 100-1200 mg day-1. 2. Autoinduction of CBZ metabolism appeared to be complete within 1 week of starting CBZ therapy or dose change, and its degree was linearly related to CBZ daily dose. 3. Curvilinear plots were obtained for steady-state concentrations of CBZ and its -10,11-epoxide metabolite, and for the ratio of CBZ-10,11-epoxide to CBZ level, versus daily dose of CBZ. 4. On the contrary, steady-state concentration of CBZ-10,11-diol increased proportionately with the dose. This indicates that there is no dose dependency in absorption of CBZ, and that dose-dependent autoinduction of CBZ metabolism is the main cause of the curvilinear relationship between dose and steady-state concentration of CBZ and its intermediary metabolite, CBZ-10,11-epoxide.

[Mathematical aspects of clinico-pharmacokinetic prediction of the effectiveness of treatment]. / Matematicheskie aspekty kliniko-farmakokineticheskoi prediktsii éffektivnosti terapii.

The use of a discriminant analysis for the statistical processing of the findings provided by a study on the prediction of the efficacy of the course therapy was substantiated. The authors described the computer programmes used for pharmacokinetic analysis and analyzed their average statistical resistance to the erroneous measurement of the drug concentration in biomaterial. The techniques of the quantitative evaluation of the real efficacy of the course therapy based on the data on the time-course of the patient's status according to the scale proposed by the All-Union Research Center on Mental Health and the BPRS are outlined.

[Clinico-pharmacokinetic prediction of the efficacy of treatment: the test dose]. / Kliniko-farmakokineticheskoe prognozirovanie éffektivnosti lecheniia: testovaia doza.

To help individual prediction of the therapy efficacy, the authors elaborated a new method for analyzing the response of the clinical and pharmacokinetic parameters to the pre-treatment administration of the test dose of a psychotropic drug. The above approach was employed in a multicentre clinical-pharmacokinetic study of leponex ( clozapin ) which involved ten research centers from six countries and a total of 136 patients. On the basis of the clinical and pharmacokinetic parameters, a cumulative index was obtained and its prediction potentialities were established. The prognostic assessment of the affectiveness obtained on the basis of this approach was in agreement with the real efficacy of the course therapy in 84% of all cases.