Zilascorb(2H), a new reversible protein synthesis inhibitor: clinical study of an oral preparation.

The new anti-cancer drug zilascorb(2H) has shown promising activity in preclinical models. Its putative mechanism of action is reversible protein synthesis inhibition and long-term treatment is required. As a clinical treatment modality, long-term daily zilascorb(2H) infusions, as used in previous studies, are not regarded feasible. Therefore, an oral formulation of the drug was developed, and pharmacokinetic profile, toxicity and antitumor activity of zilascorb(2H) tablets were studied. Thirteen patients with advanced solid cancer not amenable to established therapy, but with adequate performance status and organ functions, were included. The treatment was given as a daily i.v. zilascorb(2H) infusion for 5 days, followed by zilascorb(2H) tablets twice daily for 3 months. Blood and urine sampling was performed when estimated plasma steady-state level was reached for each formulation, respectively. Analyses of drug concentrations in plasma and urine were performed by high performance liquid chromatography. Zilascorb(2H) in tablet formulation had a bioavailability of 32%, was quickly absorbed and slowly eliminated. Concomitant use of the H2-blocker ranitidine possibly enhanced bioavailability. Zilascorb(2H) was well tolerated. Two patients experienced drug-related fever, disturbing the treatment schedule for one of them. Moderate nausea was reported. One objective response was obtained. The bioavailability of zilascorb(2H) tablets was satisfactory. The principle of oral administration of zilascorb(2H) is feasible for long-term treatment and the side effects are acceptable. The mechanisms of action and the very low toxicity of the drug makes it a candidate for combination with other anticancer agents.

Does dietary arsenic and mercury affect cutaneous bleeding time and blood lipids in humans?

Fish species may contain considerable amounts of trace elements, such as selenium (Se), arsenic (As), and mercury (Hg). The present study investigated the relationships between dietary intake of these elements and cutaneous bleeding time and blood lipids in 32 healthy volunteers. For 6 wk, one group (n = 11) consumed approx 250 g Se-rich fish daily, providing them with an average Se intake of 115 +/- 31 micrograms Se/d, Hg intake of 18 +/- 8 micrograms/d, and As intake of 806 +/- 405 micrograms/d, all values analyzed in 4-d duplicate food collections. To study the effect of Se alone, one group (n = 11) included Se-rich bread in their normal diet, giving them a Se intake (135 +/- 25 micrograms/d) that was comparable to the fish group. A control group (n = 10) ate their normal diet, providing 77 +/- 25 micrograms Se/d, 3.1 +/- 2.5 micrograms Hg/d, and 101 +/- 33 micrograms As/d. The dietary As load strongly correlated both with bleeding times and changes in bleeding times (r = 0.48, p < 0.01 and r = 0.54, p < 0.002, respectively). Dietary Hg showed a positive correlation with LDL-cholesterol (r = 0.55, p < 0.01), whereas dietary Hg in the fish group showed a strong negative relationship with HDL-cholesterol (r = -0.76, p < 0.01). Selenium seemed to have only a modest effect on bleeding time. Our results suggest that mercury and arsenic from fish may be factors contributing to or modifying some of the known effects of fish ingestion.

Platelet selenium as indicator of wheat selenium intake.

The effect of an increased intake of wheat selenium (Se) on platelet Se, serum Se, whole-blood Se, and glutathione peroxidase (GSH-Px) levels was investigated in 14 healthy Norwegian females (age 21-53 years). The intake of 60 micrograms Se per day as wheat Se, for six weeks, significantly increased the platelet Se (mean +/- SEM) from 9.1 +/- 1.1 mumol/L to 11.4 +/- 0.9 mumol/L, the serum Se from 1.43 +/- 0.18 mumol/L to 1.63 +/- 0.25 mumol/L, and the whole blood Se from 1.77 +/- 0.18 mumol/L to 2.01 +/- 0.18 mumol/L. The increase in percent of initial Se values was twice as high for platelets as for serum and whole blood. The GSH-Px levels were not altered during the experiment. Platelet Se was not significantly correlated to the Se intake initially. At the end of the experimental period, the Se in platelets reflected the total Se intake, but not with a simple linear correlation. No significant correlation between the total Se intake and the Se concentration in whole blood or serum was found.

Gradient centrifugation to isolate platelets for determination of trace elements by neutron-activation analysis.

A nonionic iodinated compound, Nycodenz, was used for density-gradient isolation of platelets before analysis for trace elements by instrumental neutron activation. The platelet samples were almost free from plasma and erythrocytes, and the trace element contribution from additives was insignificant for the elements investigated. The reproducibility of the trace element analysis in platelets attests to the usefulness of density-gradient separation. Platelet samples were obtained twice, three weeks apart, from 10 healthy young women (ages 24 +/- 2 years). The mean (SD) concentrations were as follows: Se, 0.62 (0.16) mg/L and 4.7 (1.4) ng/10(9) platelets; Zn, 44 (10) mg/L and 333 (80) ng/10(9) platelets; Rb, 3.0 (0.5) mg/L and 23 (5) ng/10(9) platelets; and Cs, 24 (5) micrograms/L and 0.18 (0.04) ng/10(9) platelets.

The form of selenium determines the response to supplementation in a selenium replete population.

In an ongoing study of selenium bioavailability, effects of supplementation with organic and inorganic forms of selenium were investigated in healthy, Norwegian women, aged 23-50 years. In phase I of the study, 58 women received 200 micrograms selenium per day either as selenite or selenium-rich pea flour for 3 months. The selenium tablets were taken together with placebo or ascorbic acid in a double blind design. Initial blood and serum selenium concentrations were 153 +/- 15 micrograms/l and 117 +/- 12 micrograms/l, respectively. These are average values for Norwegians. Indications of increased blood levels were seen in all groups, but the rise reached significance only for the subgroup receiving selenite and ascorbic acid, 14 micrograms/l, P less than 0.05. On the other hand, selenium analysis of 72-h urine samples confirmed that at an average 50 per cent of the selenium supplements had been absorbed. In phase II of the study, 28 of the participants continued for another 5 weeks, still on 200 micrograms Se per day, but this time consuming commercially available preparations. Of four preparations that were tested, two consisted of yeast Se. Only one of these produced a significant rise in blood and serum selenium levels, 60 and 55 micrograms/l respectively. Blood glutathione peroxidase values were not affected by any supplementation. The study demonstrates that different forms of organic selenium elicit widely different responses when administered to a relatively selenium-replete population, and that the explanation for this must be sought at the metabolic level.

Vitamin E deficiency in phrynoderma cases from Sri Lanka.

Phrynoderma cases were identified in a village close to Colombo in Sri Lanka. The alpha-tocopherol level in plasma was 3.3 +/- 0.6 mumol/L among the phrynoderma patients (n = 11) and 13.0 +/- 2.3 mumol/L among the control subjects (p less than 0.002). A test on glutathione reductase activity in erythrocytes revealed a stronger riboflavin deficiency among patients than among control subjects (p less than 0.005). No significant differences were found between the groups with regard to plasma levels of retinol, retinol-binding protein, vitamin B-12, folic acid, thiamin, selenium, zinc, or essential fatty acid pattern. Primary malnutrition may partly explain the deficiency of alpha-tocopherol and riboflavin observed in phrynoderma cases.

[Dislocation of the acromioclavicular joint--conservative or surgical therapy?]. / Die Akromioklavikularluxation--konservative oder operative Therapie?

Reported in this paper are therapeutic results obtained from 54 hospitalised patients who had been treated for acromioclavicular dislocation. Indications, tactical approaches to treatment, and results are described and discussed in some detail. Good results were obtained from conservative treatment of Tossy-I injuries. However, surgery in the first place is recommended, when it comes to Tossy-II and Tossy-III serverities (ligament suture and temporary arthrodesis of the AC joint), as this has proved to yield results which were superior to secondary plastic ligament repair. Poorest results were recorded from conservative treatment of patients with Tossy-III injuries.