Pharmacokinetics and Bioavailability of the GnRH Analogs in the Form of Solution and Zn2+-Suspension After Single Subcutaneous Injection in Female Rats.

BACKGROUND AND OBJECTIVES: Although many synthetic gonadoliberin analogs have been developed, only a few of them, including buserelin, were introduced into clinical practice. Dalarelin, which differs from buserelin by just one aminoacid in the position 6 (D-Ala), is not widely used so far. Gonadotropin-releasing hormone (GnRH) analogs are used to treat many different illnesses and are available in different forms like solution for injection, nasal spray, microspheres, etc. Unfortunately, none of the above drug formulations can release the hormones for 24 h. We assumed that classical suspension could solve this problem. METHODS: Two sets of experiments were performed. In the first one, buserelin and dalarelin were injected into mature female rats in two forms: suspension, in which the analogs are bounded by Zn2+ ions and solution. The pharmacokinetic parameters and bioavailability of the analogs were calculated, based on their concentration in the plasma measured by high-performance liquid chromatography method (HPLC). In the second experiment, the hormones in two different forms were injected into superovulated immature female rats and then the concentration of Luteinizing hormone (LH), Follicle-stimulating hormone (FSH) and 17ß-estradiol in the serum was measured by radioimmunological method. RESULTS: The Extent of Biological Availability (EBA), calculated on the base of AUC0-∞, showed that in the form of solution buserelin and dalarelin display, respectively, only 13 and 8 % of biological availability of their suspension counterparts. Comparing both analogs, the EBA of dalarelin was half (53 %) that of buserelin delivered in the form of solution and 83 % when they were delivered in the form of suspension. The injection of buserelin or dalarelin, in the form of solution or suspension, into superovulated female rats increased LH, FSH and estradiol concentration in the serum. However, after injection of the analogs in the form of suspension, the high concentration of LH and FSH in the serum persisted longer. CONCLUSION: Performed studies indicate that GnRH analogs in the form of suspension have higher bioavailability than their solution counterparts. It influences the effects of their action, especially in relation to LH and FSH.

From mild cognitive impairment to Alzheimer's disease - influence of homocysteine, vitamin B12 and folate on cognition over time: results from one-year follow-up.

BACKGROUND AND PURPOSE: People with mild cognitive impairment (MCI) have higher risk of developing dementia than the general population. Currently known risk factors for dementia include older age, low education level, gait disorders, hippocampal atrophy, and apolipoprotein E allele. Vascular risk factors may modify the neurodegenerative process. The aim of this study was therefore to assess the influence of vascular (genetic and environmental) risk factors on progression to dementia in an MCI group during a one-year period. MATERIAL AND METHODS: Fifty-five MCI patients (30 men and 25 women) and 44 controls (25 men and 19 women) matched for age, gender and education were studied. Mild cognitive impairment was diagnosed according to Petersen criteria (Mayo Clinic Group). Neuropsychological evaluation was made. Assessed vascular risk factors included hypertension, cardiovascular disease, diabetes, cigarette smoking, hyperlipidaemia, hyperhomocysteinaemia with vitamin B12 and folate deficiency. Genetic risk factors (APOE polymorphism, C677T and A1298C MTHFR polymorphisms) were also assessed. RESULTS: Vascular risk factors were found significantly more often in the MCI group (p = 0.041), including APOE4 allele (p = 0.018), hyperhomocysteinaemia (p = 0.012) and folate deficiency (p = 0.023). Discriminant function analysis showed that only age and hypertension are potential factors which may have an influence on progression to dementia in the MCI group within one year of prospective observation. CONCLUSION: Vascular risk factors are associated with cognitive impairment but do not have a significant influence on progression to dementia in the MCI group.

Selenium levels in blood of upper Silesian population: evidence of suboptimal selenium status in a significant percentage of the population.

The selenium status and the relationship of whole-blood selenium and plasma homocysteine are reported for healthy human subjects living in Upper Silesia. A total of 1063 individuals (627 male and 436 female) examined for whole-blood selenium were subdivided into six groups according to age; the youngest included adolescents (n=143) aged 10-15 yr, and the oldest were centenarians (n=132). The mean Se content was relatively low (62.5+/-18.4 microg/L), and it tended to be higher in men (65.9+/-17.2 microg/L) than in women (57.5+/-18.9 microg/L). Selenium levels appeared to be age dependent, as the highest values were observed in young and middle-age adults (21-40 yr), whereas they were significantly lower in adolescents and in the elderly. In more than 40% of apparently healthy adults (aged 21-69 yr), the Se concentration was within the range 60-80 microg/L (i.e., below the lower limit of the nutritional adequacy range [80 microg/L]). A significant inverse correlation between whole-blood selenium and plasma total homocysteine was detected in a smaller population sample of middle-aged and elderly persons (n=204).

Antioxidant status in newborns and infants suffering from congenital heart defects.

There is a common view that free radicals may play an important role in tissue damage resulting from circulatory insufficiency, cardiosurgery etc. There are very few data concerning the involvement of free radical reactions in the newborns and infants suffering from congenital heart defects (CHD). Antioxidant status was evaluated in 41 newborns and infants under 1 year of age, among them 23 suffering from CHD (14 with left-to-right shunt and 9 with cyanotic heart defect) and 18 healthy controls. The study based on the assessment of activities of antioxidant enzymes in blood (superoxide dismutase, catalase and glutathione peroxidase), levels of low molecular weight antioxidants (vitamin E, uric acid and selenium) and the concentration of malondialdehyde (MDA) as a marker of lipid peroxidation. All subjects had low blood selenium concentration as compared to the level considered as being adequate. Infants suffering from CHD had lower, as compared to healthy controls, plasma vitamin E concentration. The difference was significant in the case of acyanotic ones. The activities of superoxide dismutase and catalase in infants with CHD were not significantly different from the respective values recorded in healthy controls. The activity of glutathione peroxidase in whole blood was the lowest in infants with cyanotic heart defect in whom lipid peroxidation, as evaluated by MDA level, was the most enhanced. Significantly higher plasma concentration of uric acid which may be interpreted as a positive mechanism enabling better protection of red blood cells from peroxidative damage was found in this group of infants. It is concluded that enhanced oxidative stress due to imbalance between prooxidant and antioxidant reactions appears to be associated with congenital heart defect pathology in infants.

Effects of a low carbohydrate diet and graded exercise during the follicular and luteal phases on the blood antioxidant status in healthy women.

The aim of this study was to examine the effect of a low-carbohydrate (L-CHO) diet and graded cycling exercise on the enzymatic and non-enzymatic blood antioxidant defence system in young eumenorrhoeic women. Seven healthy physical education students exercised incrementally until they were fatigued under four different phase-diet conditions of the menstrual cycle, i.e. twice either during the mid-follicular or the mid-luteal phase, in each case either after 3 days of eating a normal mixed diet (59% carbohydrate, 27% fat, 14% protein) or 3 days of eating an isoenergy L-CHO diet (5% carbohydrate, 52% fat, 43% protein). In venous blood samples obtained at rest, immediately post test and during recovery, the activity of antioxidant enzymes and concentrations of reduced glutathione and selenium were determined. Plasma samples were analysed for concentrations of malondialdehyde, vitamin E (alpha-tocopherol), uric acid and activity of creatine kinase. The 3 days of the L-CHO diet, which had been preceded by glycogen-depleting exercise, resulted in a stimulation of the blood antioxidant defence system in young eumenorrhoeic women both at rest and during the graded cycling exercise to maximal oxygen uptake. It seems justified to presume that higher daily doses of haem iron, selenium and alpha-tocopherol provided by the L-CHO diet contributed to the enhancement of catalase activity, the rise in plasma concentrations of alpha-tocopherol and selenium, which resulted in better protection of the cell membranes against damage from peroxides, as reflected by a limited release of creatine kinase into plasma. With the exception of the case of glutathione reductase, the phases of the menstrual cycle had only minor effects on the indices of the blood antioxidant defence system.