Cloxacillin concentrations in serum, subcutaneous fat, and muscle in patients with chronic critical limb ischemia.

BACKGROUND: Patients suffering from critical limb ischemia (CLI) have poor wound healing in the ankle and foot areas. Secondary wound infections are frequent and often treated with prolonged courses of antibiotics. PURPOSE: This study set out to investigate to what extent the unbound fraction of 4 g of cloxacillin i.v. reaches its target organ in poorly vascularized tissues, i.e., the calf and foot of patients suffering from CLI. METHODS: Cloxacillin concentrations were measured by HPLC in serum and in microdialysis samples from skin and muscle of the lower part of the calf and as reference subcutaneously at the pectoral level in eight patients suffering from CLI (four males, four females, mean age 78 years, range 66-85 years) and in three healthy controls (two females, one male, mean age 67, range 66-68 years). RESULTS: In patients suffering from CLI, the tissue penetration of cloxacillin after a single 4 g dose was comparable to that of healthy controls, despite impaired blood circulation. CONCLUSIONS: The reduced blood flow in the peripheral vessels of the CLI patients presented here apparently is not the rate-limiting factor for delivery or tissue penetration of cloxacillin.

High inter-individual variability of vardenafil pharmacokinetics in patients with pulmonary hypertension.

PURPOSE: To evaluate the pharmacokinetic parameters of a single oral dose of vardenafil in patients with pulmonary hypertension (PH). METHODS: Sixteen patients with PH received vardenafil in single oral doses (20, 10 or 5 mg), and repeated blood sampling for up to 9 h was performed. Vardenafil plasma concentration was determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using model-independent analysis. RESULTS: The plasma vardenafil concentration increased rapidly and exhibited a median time to maximum plasma concentration (t(max)) of 1 h and a mean elimination half-life (t(1/2)) of 3.4 h. The geometric mean and standard deviation of (1) the peak plasma concentration (C(max)) was 21.4 ± 1.7 µg/L, (2) the normalized C(max) (C(max, norm)) 79.1 ± 1.6 g/L, (3) the area under the time-concentration curve (AUC) 71.5 ± 1.6 µg · h/L and (4) the normalized AUC (AUC(norm)) 261.6 ± 1.7 g · h/L. Patients co-medicated with bosentan reached t(max) later and had a 90% reduction of C(max), C(max, norm), AUC and AUC(norm). CONCLUSION: The pharmacokinetic profile of vardenafil overall revealed considerable inter-individual variability in patients with PH. Co-medication with bosentan resulted in a pharmacokinetic drug interaction, leading to significantly decreased plasma concentrations of vardenafil. Therapeutic drug monitoring for individual dose optimization may be warranted.

[The urologist as a vaccinator]. / Der Urologe als Impfarzt.

Vaccines are one of the most effective weapons of humankind in the fight against various infectious diseases. Therefore, physicians from all specialties should not only regularly confirm their knowledge regarding vaccinations but also actively offer them in their daily routine. Urologists can use various vaccination offers to help protect their patients' future health. In addition to human papillomavirus (HPV) vaccinations for children and adolescents, this article shows how urologists who provide vaccines can fulfill their responsibility to implement the state vaccination recommendations to patients over the age of 60. Among others, HPV vaccination can have the effect of finally eradicating an evolutionary burden of humanity. In addition to standard vaccinations against tetanus, diphtheria and pertussis, special vaccinations also protect individuals over the age of 60 against pneumococci, influenza and herpes zoster. Moreover, urologists may in the future also save patients from COVID-19-the disease that actually made people aware of vaccinations again.

Changes in markers of cobalamin status after cessation of oral B-vitamin supplements in elderly people with mild cobalamin deficiency.

Mildly cobalamin-deficient elderly were supplemented with 1000 microg cobalamin (group C, n=34), 1000 microg cobalamin with 400 microg folic acid (group CF, n=31) or a placebo (n=30) for 6 months. Participants provided one single blood sample 3, 5 or 7 months after cessation of supplementation to monitor early changes in plasma concentrations of cobalamin, holotranscobalamin (holoTC) and methylmalonic acid (MMA). At the end of supplementation (groups C+CF), one participant met our criteria for mild cobalamin deficiency, as did 13, 14 and 43% of the participants assessed at respectively 3, 5 and 7 months post-supplementation. Cobalamin and holoTC declined on average with 47 and 56% relative to concentrations at the end of supplementation for the group assessed at 7 months post-supplementation. Essentially similar declines were observed for those participants assessed at 3 and 5 months post-supplementation. Mean MMA concentrations increased by 15% (P=0.07) in those participants assessed at 3 and 5 months post-supplementation, and increased by 50% (P=0.002) in those participants assessed at 7 months post-supplementation. Considering MMA as a sensitive tissue marker for cobalamin status, oral supplementation may afford adequate cobalamin status for a period of up to 5 months after cessation in the majority of participants.

Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or = 40 micromol/liter). The Hordaland Homocysteine Study.

From 1992-93, we screened 18,043 subjects, aged 40-67 yr, and found 67 cases (0.4%) with total plasma homocysteine (tHcy) > or = 40 micromol/liter. Compared to 329 controls, the cases had lower plasma folate and cobalamin levels, lower intake of vitamin supplements, consumed more coffee, and were more frequently smokers. Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene was observed in 73.1% of the cases and 10.2% of the controls. Only seven cases with cobalamin deficiency and one with homocystinuria received specific therapeutic instructions. 2 yr after the screening, 58 subjects were reinvestigated. 41 still had tHcy > 20 micromol/liter, and in 37 of these, intervention with low dose folic acid (0.2 mg/d) was started. Notably, 34 of 37 (92%) had homozygosity for the C677T mutation. Plasma tHcy was reduced in all but two after 7 wk, and became normal within 7 mo in 21 of 37 subjects. Most of the remaining subjects obtained a normal tHcy level with 5 mg/d of folic acid. We conclude that most subjects with hyperhomocysteinemia > or = 40 micromol/liter in the general population have the C677T mutation combined with low folate status. Daily supplement of low dose folic acid will reduce and often normalize their tHcy level.

Biological and clinical implications of the MTHFR C677T polymorphism.

The enzyme methylenetetrahydrofolate reductase (MTHFR) directs folate species either to DNA synthesis or to homocysteine (Hcy) remethylation. The common MTHFR C677T polymorphism affects the activity of the enzyme and hence folate distribution. Under conditions of impaired folate status, the homozygous TT genotype has been regarded as harmful because it is associated with a high concentration of plasma total Hcy, increased risk of neural tube defects and colorectal neoplasias, and can also predispose individuals to adverse effects from drugs with antifolate effects. The MTHFR C677T polymorphism shows no consistent correlation with cardiovascular risk and longevity but, in combination with positive folate balance, the TT genotype is associated with decreased risk of colorectal neoplasias. Because of the high prevalence of this polymorphism in most populations, the TT variant might represent an ancestral genetic adaptation to living constraints (tissue injury or unbalanced vitamin intake) that has become a determinant of disease profiles in modern times.

Dietary folate intake and breast cancer risk: European prospective investigation into cancer and nutrition.

BACKGROUND: There is limited evidence on the association between dietary folate intake and the risk of breast cancer (BC) by hormone receptor expression in the tumors. We investigated the relationship between dietary folate and BC risk using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: A total of 367993 women age 35 to 70 years were recruited in 10 European countries. During a median follow-up of 11.5 years, 11575 women with BC were identified. Dietary folate intake was estimated from country-specific dietary questionnaires. Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk. BC tumors were classified by receptor status. Subgroup analyses were performed by menopausal status and alcohol intake. Intake of other B vitamins was considered. All statistical tests were two-sided. RESULTS: A borderline inverse association was observed between dietary folate and BC risk (hazard ratio comparing top vs bottom quintile [HRQ5-Q1] = 0.92, 95% CI = 0.83 to 1.01, P trend = .037). In premenopausal women, we observed a statistically significant trend towards lower risk in estrogen receptor-negative BC (HRQ5-Q1 = 0.66, 95% CI = 0.45 to 0.96, P trend = .042) and progesterone receptor-negative BC (HRQ5-Q1 = 0.70, 95% CI = 0.51 to 0.97, P trend = .021). No associations were found in postmenopausal women. A 14% reduction in BC risk was observed when comparing the highest with the lowest dietary folate tertiles in women having a high (>12 alcoholic drinks/week) alcohol intake (HRT3-T1 = 0.86, 95% CI = 0.75 to 0.98, P interaction = .035). CONCLUSIONS: Higher dietary folate intake may be associated with a lower risk of sex hormone receptor-negative BC in premenopausal women.

Kinetics of total plasma homocysteine in subjects with hyperhomocysteinemia due to folate or cobalamin deficiency.

Hyperhomocysteinemia in cobalamin and folate deficiency reflects an imbalance between influx and elimination of homocysteine (Hcy) in plasma. We investigated the kinetics of total Hcy (tHcy) in plasma after peroral Hcy administration in 19 volunteers with hyperhomocysteinemia (mean +/- SD: 67.1 +/- 39.5 mumol/L; range: 23.5-142.8 mumol/L) before and after supplementation with cobalamin and/or folate. Vitamin therapy decreased plasma tHcy to 21.8 +/- 14.1 mumol/L (range: 9.6-57.9 mumol/L) but caused only a marginal decline in the area under the curve (AUC) by 8% and plasma half-life by 21%. Using the equations for steady-state kinetics, these data indicate that mean plasma tHcy clearance is normal and that massive export of Hcy from tissues into plasma is the major cause of hyperhomocysteinemia in cobalamin or folate deficiency. However, the spread in AUC and plasma half-life values was large in hyperhomocysteinemia subjects, suggesting marked individual variability in tHcy clearance. Plasma methionine after Hcy loading did not increase before (0.9 +/- 6.8 mumol/L) but increased normally (12.8 +/- 4.6 mumol/L) after vitamin therapy, and the methionine response discriminated between vitamin-deficient and vitamin-replete subjects. In cobalamin- or folate-deficient subjects, only 6.5 +/- 3.0% of the Hcy dose was excreted unchanged in the urine, demonstrating that urinary Hcy excretion does not explain normal tHcy plasma clearance in subjects with impaired Hcy remethylation. Our data suggest that hyperhomocysteinemia in folate and cobalamin deficiency is related to increased influx of Hcy to plasma, and that the methionine synthase function is not an important determinant of elimination of Hcy from plasma. The large interindividual difference in Hcy clearance may be explained by variable adaptation to impaired methionine synthase function through increased Hcy flux through alternate metabolic pathways.

Signs of impaired cognitive function in adolescents with marginal cobalamin status.

BACKGROUND: Lack of cobalamin may lead to neurologic disorders, which have been reported in strict vegetarians. OBJECTIVE: The objective of this study was to investigate whether cognitive functioning is affected in adolescents (aged 10-16 y) with marginal cobalamin status as a result of being fed a macrobiotic diet up to an average age of 6 y. DESIGN: Data on dietary intake, psychological test performance, and biochemical variables of cobalamin status were collected from 48 adolescents who consumed macrobiotic (vegan type) diets up to the age of 6 y, subsequently followed by lactovegetarian or omnivorous diets, and from 24 subjects (aged 10-18 y) who were fed omnivorous diets from birth onward. Thirty-one subjects from the previously macrobiotic group were cobalamin deficient according to their plasma methylmalonic acid concentrations. Seventeen previously macrobiotic subjects and all control subjects had normal cobalamin status. RESULTS: The control subjects performed better on most psychological tests than did macrobiotic subjects with low or normal cobalamin status. A significant relation between test score and cobalamin deficiency (P: = 0.01) was observed for a test measuring fluid intelligence (correlation coefficient: -0.28; 95% CI: -0.48, -0.08). This effect became more pronounced (P: = 0.003) within the subgroup of macrobiotic subjects (correlation coefficient: -0.38; 95% CI: -0.62, - 0.14). CONCLUSION: Our data suggest that cobalamin deficiency, in the absence of hematologic signs, may lead to impaired cognitive performance in adolescents.

Risk of persistent cobalamin deficiency in adolescents fed a macrobiotic diet in early life.

BACKGROUND: Cobalamin deficiency has been described in children consuming macrobiotic diets. OBJECTIVE: We investigated whether moderate consumption of animal products is sufficient for achieving normal cobalamin function in 73 adolescents who had received a macrobiotic diet until 6 y of age and had then switched to a lactovegetarian, lactoovovegetarian, or omnivorous diet (macrobiotic adolescents). DESIGN: Hematologic indexes and serum concentrations of methylmalonic acid (MMA), total homocysteine (tHcy), and folate were measured. Current consumption frequency of animal products and cobalamin intake from dairy products were assessed by questionnaire. Data from 94 age-matched adolescents who received an omnivorous diet from birth were used as a reference. RESULTS: Serum cobalamin concentrations were significantly lower and concentrations of MMA and folate and mean corpuscular volume (MCV) were significantly higher in macrobiotic adolescents than in control adolescents: of macrobiotic adolescents, 21% had abnormal MMA concentrations (>0.41 micromol/L), 37% had abnormal cobalamin concentrations (<218 pmol/L), 10% had abnormal tHcy concentrations (> 12.8 micromol/L), and 15% had abnormal MCV (> 89 fL). In macrobiotic adolescents, dairy products (200 g milk or yogurt and 22 g cheese/d) supplied on average 0.95 microg cobalamin/d; additionally, these adolescents consumed fish, meat, or chicken 2-3 times/wk. In girls, meat consumption contributed more to cobalamin status than the consumption of dairy products, whereas in boys these food groups were equally important. CONCLUSIONS: A substantial number of the formerly strict macrobiotic adolescents still had impaired cobalamin function. Thus, moderate consumption of animal products is not sufficient for restoring normal cobalamin status in subjects with inadequate cobalamin intake during the early years of life.