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.     

A brief method for assessing expressed emotion in relatives of psychiatric patients

A measure of the attitudes and feelings that a relative expresses about a mentally ill family member, termed expressed emotion (EE), is derived from an extensive, semistructured interview, the Camberwell Family Interview (CFI). The present article describes a method for the assessment of EE attitudes that uses a variation of the 5-minute speech sample, originally developed by Gottschalk and Gleser (1969). The measure is derived from responses made by a patient's key relative when prompted to give thoughts and feelings about the patient for a 5-minute period. A coding system was developed to score behaviors analogous to those rated on the CFI, such as criticism and emotional overinvolvement. The relationship between blind EE ratings derived from the 5-minute speech samples and those from the CFI was investigated with two separate samples of relatives of schizophrenics. The relationship between the sets of ratings was very close and supports the value of the 5-minute speech sample as a brief EE screening procedure.     

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.     

Pharmacokinetics and safety of weekly dapsone and dapsone plus pyrimethamine for prevention of pneumocystis pneumonia.

The safety and pharmacokinetics of weekly dapsone and weekly dapsone plus pyrimethamine were examined in adult patients with human immunodeficiency virus infection who were at risk for pneumocystis pneumonia because of a prior episode or a CD4+ T-cell count less than 250 cells per mm3. Groups of patients received 100, 200, and 300 mg of dapsone as a single weekly dose. The maximum tolerated dose of weekly dapsone was established as 200 mg per week in patients receiving at least 500 mg of zidovudine concomitantly. This dose of dapsone was then found to be well tolerated when combined with pyrimethamine at 25 mg. Further patients were randomized to dapsone at 200 mg or dapsone at 200 mg plus pyrimethamine at 25 mg once weekly. Twenty-six patients each were followed for a median of 33 weeks on dapsone alone and 45 weeks on the combination. Seven patients in each group withdrew because of toxicity. Five patients receiving dapsone developed documented pneumocystis pneumonia, while four and two patients receiving dapsone plus pyrimethamine developed documented and presumptive pneumocystis pneumonia, respectively. To evaluate the tolerability of a higher dose of pyrimethamine, 11 patients had their regimen changed to dapsone at 200 mg plus pyrimethamine at 75 mg, which was well tolerated by 10 of the patients for a median period of 11 weeks. The pharmacokinetics of dapsone and pyrimethamine were examined by using a population pharmacokinetic model. Decreases in the apparent volume of the peripheral compartment were observed when multiple-dose regimens of dapsone were compared with single-dose dapsone and when multiple-dose regimens of dapsone with pyrimethamine were compared with multiple-dose dapsone alone. When administered weekly, dapsone at 200 mg and dapsone at 200 mg with pyrimethamine at 25 mg are both well-tolerated regimens. This preliminary study suggests that the efficacy of these regimens in preventing pneumocystis pneumonia, however, may be less than that of trimethoprim-sulfamethoxazole.     

JE-2147: A dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1

We designed, synthesized, and identified JE-2147, an allophenylnorstatine-containing dipeptide HIV protease inhibitor (PI), which is potent against a wide spectrum of HIV-1, HIV-2, simian immunodeficiency virus, and various clinical HIV-1 strains in vitro. Drug-resistant clinical HIV-1 strains, isolated from seven patients who had failed 9-11 different anti-HIV therapeutics after 32-83 months, had a variety of drug-resistance-related amino acid substitutions and were highly and invariably resistant to all of the currently available anti-HIV agents. JE-2147 was, however, extremely potent against all such drug-resistant strains, with IC(50) values ranging from 13-41 nM (<2-fold changes in IC(50) compared with that of wild-type HIV-1). The emergence of JE-2147-resistant HIV-1 variants in vitro was substantially delayed compared with that of HIV-1 resistant to another allophenylnorstatine-containing compound, KNI-272, and other related PIs. Structural analysis revealed that the presence of a flexible P2' moiety is important for the potency of JE-2147 toward wild-type and mutant viruses. These data suggest that the use of flexible components may open a new avenue for designing PIs that resist the emergence of PI-resistant HIV-1. Further development of JE-2147 for treating patients harboring multi-PI-resistant HIV-1 is warranted.     

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.     

A potential role for interleukin-7 in T-cell homeostasis

Interleukin (IL)-7 is known to up-regulate thymopoietic pathways of T-cell regeneration. Recent work also has shown it to potently enhance thymic-independent peripheral expansion and to restore immunocompetence in athymic T-cell-depleted hosts. We hypothesized that endogenous IL-7 could contribute to the restoration of T-cell homeostasis following T-cell depletion. To analyze this, we evaluated circulating IL-7 levels and lymphocyte subsets in multiple clinical cohorts with T-cell depletion of varying etiologies. In pediatric (n = 41) and adult (n = 51) human immunodeficiency virus-infected CD4-depleted patients, there were strong inverse correlations between IL-7 levels and CD4 counts (r = -0.77, P <.0001, and r = -0.68, P <.0001). Declines in IL-7 were temporally correlated with recovery of CD4 counts. Similar patterns were observed in CD4-depleted patients receiving cancer chemotherapy (r = -0.65, P =.009). Therefore, in 2 disparate clinical scenarios involving CD4 depletion, IL-7 levels dynamically respond to changes in CD4 T-cell number, making this cytokine uniquely suited as a candidate regulator of T-cell homeostasis. Furthermore, in patients with idiopathic CD4 lymphopenia, a much weaker relationship between IL-7 levels and peripheral blood CD4 counts was observed, suggesting that an impaired IL-7 response to CD4 depletion may contribute to the impaired lymphocyte homeostasis observed in this population. In light of the known effects of IL-7 on T-cell regeneration, we postulate that increased availability of IL-7 could play a critical role in restoring T-cell homeostasis following T-cell depletion.     

Anticytomegaloviral activity and safety of cidofovir in patients with human immunodeficiency virus infection and cytomegalovirus viruria.

Cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) is a nucleotide analog with activity against human cytomegalovirus (CMV). A phase I/II dose escalation trial was conducted with asymptomatic human immunodeficiency virus (HIV)-infected patients with CMV viruria to determine its pharmacokinetics, maximally tolerated dose, and preliminary antiviral activity against CMV. Qualitative CMV blood and urine cultures were monitored weekly to assess anti-CMV activity. Twenty-one HIV-infected persons with CD4 counts from 0 to 389 cells per microliters (median, 39) were enrolled in six dose-ranging groups. The first five groups enrolled four patients each to receive cidofovir infusions either weekly or biweekly for 4 weeks or every 3 weeks for 12 weeks. The sixth group enrolled one patient who received infusions of 5 mg/kg of body weight every other week. Patients receiving 0.5 or 1.5 mg/kg twice weekly experienced no serious toxicity. The first two patients who received 5 mg/kg twice weekly developed glycosuria and 2+ proteinuria. Subsequent patients received concomitant probenecid to attempt to ameliorate renal toxicity. Seventeen patients experienced proteinuria on one or more occasions; 6 of them experienced at least 2+ proteinuria. Four patients did not complete the study as planned because of renal toxicity. Positive CMV urine cultures reverted to negative in 2 of 8 patients receiving doses of < or = 1.5 mg/kg twice weekly and 11 of 13 patients receiving higher doses. Cidofovir has in vivo anti-CMV activity demonstrated by prolonged clearing of CMV viruria, although this observation is tempered by the fact that clearance of viremia could not be demonstrated. The dose-limiting toxicity is renal; however, concurrent administration of probenecid may be protective. The maximally tolerated weekly intravenous dose with probenecid is approximately 5 mg/kg. Efficacy trials with CMV disease will define the therapeutic utility and optimal dosing interval for cidofovir.