Is there a relationship between antipsychotic blood levels and their clinical efficacy? An analysis of studies design and methodology

Summary— There are now more than 50 studies concerning neuroleptic blood levels and clinical outcome relationships. Haloperidol, the most studied, is the only antipsychotic permitting some conclusions. A number of authors suggest that the striking lack of agreement between different studies results from heterogeneity of their quality. Here, we have used a scoring system for assessing the quality of those studies. According to this system, none (0/14) of the studies having a score <0.60 was able to show a therapeutic window, as compared to 53% (10/19) of those having a score ≥0.60 (p = 0.002, Fisher exact test). Also, the studies able to identify the presence of a therapeutic window during haloperidol treatment were those having sample sizes >20 ( p = 0.06) and those whose patients were treated with fixed doses ( p = 0.02). The diagnosis of schizophrenia in the studies seems not to be an exclusive condition, as compared with those also including schizophreniform and schizoaffective disorders (p = 0.12). Our qualitative analysis of haloperidol blood level publications seem to indicate that an upper limit may exist for haloperidol efficacy; values above this limit seem not to provide any supplementary clinical improvement and may even reduce therapeutic effect.     

Immune information, self-organization and meaning

To effect the molecular integrity of the individual, the immune system has to gather antigenic information and respond in a meaningful way. Immunologists traditionally have focused their research on analyzing the component parts of the system. The achievements of immunology in its analytical enterprise have now made it possible to begin the task of synthesis. In this paper, we shall consider how the immune system combines germline and somatic information using a chemical language to establish the functional meaning of antigens.      

The role of reduced intracellular concentrations of active drugs in the lack of response to anticancer chemotherapy

A major difficulty in the treatment of cancers is the poor response of many tumors to pharmacological regimens. This situation can be accounted for by the existence of a variety of complex mechanisms of chemoresistance （MOCs）, leading to reduced intracellular concentrations of active agents, changes in the molecular targets of the drugs, enhanced repair of drug-induced modifications in macromolecules, stimulation of anti-apoptotic mechanisms, and inhibition of pro-apoptotic mechanisms. The present review focuses on alterations in the expression and appearance of the genetic variants that affect the genes involved in reducing the amount of active agents inside tumor cells. These alterations can occur through two mechanisms： either by lowering uptake or enhancing efflux （so-called MOC-1a and MOC-1b, respectively）, or by decreasing the activation of prodrugs or enhancing inactivation of active agents through their biotransformation （MOC-2）. The development of chemosensitizers that are useful in implementing the pharmacological manipulation of these processes constitutes a challenge to modern pharmacology. Nevertheless, the important physiological roles of the most relevant genes involved in MOC-1a, MOC-1b, and MOC-2 make it difficult to prevent the side effects of chemosensitizers. A more attainable goal in this area of pharmacological enquiry is the identification of proteomic profiles that will permit oncologists to accurately predict a lack of response to a given regimen, which would be useful for adapting treatment to the personal situation of each patient.     

FS06.7The new fragrance mix II – test results of a multicentre European Study

A new fragrance mix (FM II) with 6 frequently used chemicals was evaluated in consecutive patients patch tested in 6 dermatological centres in Europe. 28% FM II contained 5% Lyral, 1% citral, 5% farnesol, 5% coumarin, 1% citronellol and 10% alpha‐hexyl cinnamic aldehyde (AHCA); in 14% FM II the single constituents’ concentrations was lowered to 50% and in 2.8% FM II to 10%. Each patient was classified regarding a history of adverse reactions to fragrances: certain, probable, questionable and none. The frequency of positive reactions to the currently used 8% fragrance mix (FM I) and the new mix in 1703 patients was as follows: FM I, 6.6%; 2.8% FM II, 1.3%; 14% FM II, 2.9%; 28% FM II, 4.1%. The number of doubtful/irritant reactions was 7.2% for FM I and ranged from 1.8% to 10.6% for FM II. 8.7% of tested patients had a certain fragrance history. Of these 25.2% were positive to FM I, reactivity to FM II was dose‐dependent and ranged from 8.1% to 17.6% in this subgroup. Comparing 2 groups of history – certain and none – values for sensitivity (sens) and specificity (spec) were calculated. Sens: FM I, 27.2%; 2.8% FM II, 8.7%; 14% FM II, 15.9%; 28% FM II, 21.5%. Spec: FM I, 96.3%; 2.8% FM II, 99.5%; 14% FM II, 98.7%; 28% FM II, 97.9%. 31/70 (44.3%) patients positive to 28% FM II were negative to FM I. In the group of patients with a certain history a total of 6 patients was found reacting only to FM II. Simultaneous break‐down testing with the single constituents produced positive reactions in 54.3% for 28% FM II and 48% for 14% FM II. Lyral was the dominating single constituent with positive reactions (37.1% for 28% FM II, 36% for 14% FM II), followed by citral, farnesol, citronellol, AHCA and coumarin. Chemical analysis for the 6 constituents of FM II was performed on 25 products used by 12 patients being patch test positive to FM II. Lyral was detected in 76% of these products, citral in 16% and AHCA in 8%. In conclusion, the new FM II detects additional patients with contact allergy to fragrances missed by the currently used FM I. The medium concentration, 14% FM II, is probably the most useful one for diagnostic screening.     

Lack of breast feeding and early weaning in infants of Asian immigrants to Wolverhampton

Fifty Asian immigrant mothers who would have expected to breast feed their infants had they remained in rural Asia were studied. There was a striking reduction in the incidence and duration of breast feeding on arrival in the United Kingdom, and a fall in the age of weaning. The availability of an alternative to human milk is the most important factor reducing the incidence of breast feeding. Only 2 (4%) of the 46 infants followed prospectively were breast fed. Reasons for not breast feeding were sought and the results indicated that the majority of mothers were frightened, misinformed, or apathetic about breast feeding. If breast feeding is to be promoted, antenatal education and encouragement is essential. The advantages of human milk need to be stressed. Potentially serious mistakes occurred in preparing bottle feeds, and vitamin supplements were often inadequate. Later weaning could be encouraged by the staff of well baby clinics.     

Excretion of biliary compounds during intrauterine life

In adults, the hepatobiliary system, together with the kidney, constitute the main routes for the elimination of several endogenous and xenobiotic compounds into bile and urine, respectively. However, during intrauterine life the biliary route of excretion for cholephilic compounds, such as bile acids and biliary pigments, is very poor. Although very early in pregnancy the fetal liver produces bile acids, bilirubin and biliverdin, these compounds cannot be efficiently eliminated by the fetal hepatobiliary system, owing to the immaturity of the excretory machinery in the fetal liver. Therefore, the potentially harmful accumulation of cholephilic compounds in the fetus is prevented by their elimination across the placenta. Owing to the presence of detoxifying enzymes and specific transport systems at different locations of the placental barrier, such as the endothelial cells of chorionic vessels and trophoblast cells, this organ plays an important role in the hepatobiliary-like function during intrauterine life. The relevance of this excretory function in normal fetal physiology is evident in situations where high concentrations of biliary compounds are accumulated in the mother. This may result in oxidative stress and apoptosis, mainly in the placenta and fetal liver, which might affect normal fetal development and challenge the fate of the pregnancy. The present article reviews current knowledge of the mechanisms underlying the hepatobiliary function of the fetal-placental unit and the repercussions of several pathological conditions on this tandem.