Comparative analysis of the cytotoxicity of substituted [phenylglyoxal bis(4-methyl-3-thiosemicarbazone)] copper(II) chelates. 2. Parabolic correlations and their implications for selective toxicity.

The synthesis of an extended series of para-substituted [phenylglyoxal bis(4-methyl-3-thiosemicarbazone)] copper(II) chelates is reported. Subsequent biological evaluation and regression analysis have been performed, correlating pI50 with extrathermodynamic substituent parameters. Parabolic correlations with pi have resulted which predict optimum lipophilic character of the para substituent with respect to Ehrlich ascites cytotoxicity (pi0 = -2.13) and with respect to ascites vs. liver slice cytotoxicity (pi0 = -1.31). Results indicated clearly that the chelate most toxic to the tumor cell model may not be the most selective.

4-hydroxyquinoline-3-carboxylic acids as inhibitors of cell respiration. 2. Quantitative structure-activity relationship of dehydrogenase enzyme and Ehrlich ascites tumor cell inhibitions.

Studies on dehydrogenase enzyme inhibition have been extended with the design, synthesis, and correlation analysis of 7-[(substituted-benzyl)oxy]-, 7-[(substituted-phenethyl)oxy]-, and 7([substituted-phenoxy)ethoxy]-4-hydroxyquinoline-3-carboxylic acids. Sixteen new congeners and the fifteen molecules previously synthesized have been tested against cytoplasmic malate dehydrogenase and lactate dehydrogenase, as well as against mitochondrial malate dehydrogenase. The lipophilic congeners show a clear specificity for inhibition of the mitochondrial enzyme. Correlation analysis of the data on the three enzymes allows a comparison of the binding sites in quantitative terms, while examination of the data on inhibition of ascites tumor cell respiration affords an indication of membrane transport. A newly developed high-pressure liquid chromatography based retention index is compared to the octanol-water pi constant as a model for hydrophobic interactions.

Risk factors for varicose veins.

AIM: To determine the prevalence of varicose veins in the German population and specify possible risk factors the data of the Duesseldorf/Essen civil servants study were analysed. METHODS: From December 1989 to July 1993 a total of 9 935 employees were recruited. All volunteers filled out a questionnaire regarding family history and risk factors and were clinically examined. Venous findings were classified and adapted to the CEAP-classification. For the analysis of risk factors only volunteers classified as CEAP-class 0 or as CEAP-class II were considered: 4 250 men, 10% belonged to CEAP-class II and 2 380 women including 16% CEAP-class II. RESULTS: In general, age and gender were the most relevant risk factors for varicose veins. Odds ratio age: male: 3.4 (95%-CI: 2.6-4.4), age female 6.5 (95%-CI: 5.0-8.5), gender 2.3 (95%-CI 1.9-2.7). In addition in females the most frequent risk factors were oral contraception and in both genders a predominately sitting posture at work. Regarding the family history, varicose veins by the mother was most frequent compared to varicose veins by the father or both. After adjusting for age and gender heridity became the most important risk factor with an odds ratio of 5.2 (95%-CI:3.7-7.3-4.50) in case of varicose veins present in both parents, followed by a standing posture at work 2.2 (95%-CI: 1.2-3.9). In contrast, smoking also reached a significant level, but with a decreased odds ratio of 0.66 (95%-CI: 0.57-0.77) indicating a protective effect. CONCLUSION: In addition to age and gender a family history of varicose veins is the most important risk factor in the total population. Despite significant influence of other risk factors their relevance for varicose veins in the investigated population is low either due to low frequencies or low odds ratios.

Peripheral veins: influence of gender, body mass index, age and varicose veins on cross-sectional area.

To investigate changes in the size of the deep and superficial venous systems associated with gender, age, body mass index and varicose veins, changes to the cross-sectional area of the femoral and the long saphenous veins were analysed in the Duesseldorf/Essen civil servant study population. Between December 1989 and July 1993 a total of 9935 employees were recruited; 9261 were then evaluated for this analysis. Diameters of the long saphenous and femoral veins were determined 2-3 cm distal to the confluence in lying (after 15 min rest) and standing (after 5 min) positions. Cross-sectional areas (CSA) were calculated. A total of 63% of all people were assigned to CEAP (clinical, etiological, anatomical pathophysiological) class 0, 27% to class 1, 8.5% to class 2, while 1.5% belonged to higher CEAP classes. In people without varicose veins (CEAP class 0) the CSA of the femoral and long saphenous veins were smaller in females than in males. In people with a normal body mass index (BMI) (20-25) the mean CSA of the femoral and long saphenous veins in a standing position was similar from the third up to the sixth decade of life. The volume increase due to a standing position expressed as the absolute increase in CSA of the femoral and long saphenous veins was not age-related, either. The relative volume increase expressed as a ratio remained unchanged with age. There was a strong relationship between the CSA of both veins and increasing BMI. In a lying position, the CSA of the femoral and long saphenous veins increased only slightly with increasing CEAP classes. In a standing position, the CSA of both veins increased even in CEAP class 1 (p < 0.001). In a stepwise multivariate regression analysis, the CSA of both veins in a standing position was not age-related but associated with BMI, CEAP classes and gender. The absolute increase in CSA was influenced by all four variables, but BMI and gender were most important. In Conclusion, this study shows that aging is not necessarily associated with an increase in venous CSA of the deep and superficial venous system. BMI is the most important determinant for an increase in CSA in standing position. Varicosity of the superficial venous system is always associated with similar changes in the deep venous system.

Symptoms in individuals with small cutaneous veins.

The clinical relevance of small cutaneous veins (SCV) is still being discussed. In the Duesseldorf/Essen civil servants study, the prevalence of SCV and the individual symptoms and age-dependent changes were analysed. This cross-sectional study recruited 9935 employees; 9100 could be finally evaluated for this analysis. All volunteers were asked to fill out the questionnaire and were clinically examined. Primarily the clinical findings were documented, adapted to the Basel Study and later modified according to the CEAP classification: (a) class 0 - no visible or palpable clinical signs of venous disease, (b) class 1 - small cutaneous veins, (c) class 1 - reticular veins, (d) class 2 - varicose veins. In all, 64% of the volunteers had no signs of venous disease (class 0: age 41+/-10 years); 10% had small cutaneous veins (class 1: age 44+/-10 years). SCV was more frequent in females (25%) than in males (6%). Only 5% of those with SCV had already consulted a physician. A striking result was that individuals with SCV generally complained about more leg symptoms, of which 'leg swelling' and 'muscle cramps during the night' were the most frequent. 'Continual leg swelling' was reported by 24% of individuals with SCV as opposed to 10% of those without. 'Leg cramps' and 'restless legs' also were more often documented in individuals with SCV (29% vs 22% and 10% vs 7%). These findings were all statistically significant (p<0.001). After adjusting for age and sex, though, there were few or no differences between groups (leg swelling: odds ratio (OR) 1.3; 95% confidence interval (95% CI) 1.1-1.6 and cramps: OR 1.1; 95% CI 0.9-1.3). A gender separate estimation of the rates showed that females suffer more often from any symptom. Regarding 'leg cramps', 'restless legs' and 'itching', the OR were not different for females and males. For 'leg swelling' the age-adjusted OR were significant for women (OR 1.4; 95% Cl 1.1-1.7) compared with men (OR 1.1; 95% Cl 0.7-2). Individuals with SCV seem to have more symptoms compared with healthy people. However, this analysis shows that age and sex are the most relevant explanations for these symptoms.

comparative analysis of cellular respiratory inhibition by substituted phenylglyoxal-bis-(4-methyl-3-thiosemicarbazone) zinc chelates.

Fourteen para-substituted phenylglyoxal-bis-(4-methyl-3-thiosemicarbazone) zinc chelates have been synthesized as inhibitors of cellular respiration and therefore as potential antineoplastic agents. Each chelate has been evaluated as an inhibitor of Ehrlich ascites tumor cell and of rat liver slice respiration. The molar I50 values for respiratory inhibition have been subjected to computerized correlation to delineate quantitative relationships between biological activity and chemical structure. Activity against the tumor cell model is characterized by a positive lipophilic and a detrimental steric influence while activity against rat liver slice displays only a weak positive lipophilic effect. Quantitative comparative analysis suggests that selective action against the tumor cell system can be improved by substituents which are electron withdrawing and lipophilic in nature.