Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects

AIMS: Our aim was to investigate the effects of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide, a novel short-acting antidiabetic drug. METHODS: In a randomized crossover study with two phases, 10 healthy volunteers took 600 mg rifampicin or placebo orally once daily for 5 days. On day 6 of both phases, they ingested a single 60 mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 7 h postdose. RESULTS: Rifampicin decreased the mean AUC(0,7 h) of nateglinide by 24% (range 5-53%; P = 0.0009) and shortened its half-life (t(1/2)) from 1.6 to 1.3 h (P = 0.001). However, the peak plasma nateglinide concentration (Cmax) remained unchanged. The AUC(0,7 h) of the M7 metabolite of nateglinide was decreased by 19% (P = 0.002) and its t(1/2) was shortened from 2.1 to 1.6 h by rifampicin (P = 0.008). Rifampicin had no significant effect on the blood glucose-lowering effect of nateglinide. CONCLUSIONS: Rifampicin modestly decreased the plasma concentrations of nateglinide probably by inducing its oxidative biotransformation. In some patients, rifampicin may reduce the blood glucose-lowering effect of nateglinide.     

Three levels of dietary calcium-effects on blood pressure and electrolyte balance in spontaneously hypertensive rats

Summary The effects of three levels of calcium intake on blood pressure (BP) and electrolyte balance were studied for 12 weeks in spontaneously hypertensive rats (SHR): the chow of the SHR-1 group contained 1.1% calcium, and that of the supplemented groups 2.1% (SHR-2) and 3.1% (SHR-3) calcium. Wistar-Kyoto rats on a 1.1% calcium diet (WKY-1) served as normotensive controls. After 10 and 12 weeks BP was significantly lower in both calcium-supplemented groups than in the SHR-1 group, the SHR-2 and SHR-3 groups not deviating from each other. Platelets and lymphocytes were used as experimental cell models to study the effects of the calcium diets on intracellular free calcium ([Ca²⁺]_i) level, which was measured by the fluorescent indicator quin-2. At the end of the study [Ca²⁺]_i was lower in both cell types in SHR-2 and SHR-3 than in SHR-1, the supplemented groups being comparable to each other. In platelets [Ca²⁺]_i still remained higher in the calcium-treated than the WKY-1 group, while in lymphocytes the levels were similar between SHR-2, SHR-3 and WKY-1. Plasma sodium, calcium and magnesium levels did not differ in the SHR groups, but plasma potassium was higher in both supplemented groups than in SHR-1. Plasma renin activity was comparable in SHR-1, SHR-2 and WKY-1, but was suppressed in the SHR-3 group. Creatinine clearance in the SHR-3 group was higher than in SHR-1 and SHR-2, but still remained lower than in WKY 1. High calcium intake was associated with a dose-dependent increase in urinary magnesium excretion, while the excretions of sodium and potassium were proportional to the intakes. The tissue Na⁺ :K⁺ ratio in abdominal aorta and tail artery was reduced in SHR-2,.but only a nonsignificant tendency was observed in SHR-3 when compared with the SHR-1 group.In summary, high calcium intake reduces [Ca²⁺]_i in both platelets and lymphocytes in SHR, suggesting that alterations in cellular calcium regulation may explain the BP-lowering effect of calcium supplementation. Elevation of dietary calcium level from 1.1% to 2.1% is associated with a lowering of the Na⁺ :K⁺ ratio in the arterial wall. A further increase in calcium content from 2.1% to 3.1% appears to have a favourable effect on renal function in SHR, but also aggravates magnesium loss into the urine. During the higher supplemented calcium intake, suppression of the renin-angiotensin system seems to be involved in the lowering of BP. Correspondence to H. Wuorela at the above address     

Assessment of cardiovascular risk in primary health care

Objective

This study aimed at investigating whether cardiovascular risk factors and their impact on total risk estimation differ between men and women.

Design

Cross-sectional cohort study.

Subjects

Finnish cardiovascular risk subjects (n = 904) without established cardiovascular disease, renal disease, or known diabetes.

Main outcome measures

Ankle-brachial index (ABI), estimated glomerular filtration rate (eGFR), oral glucose tolerance test, and total cardiovascular risk using SCORE risk charts.

Results

According to the SCORE risk charts, 27.0% (95% CI 23.1–31.2) of the women and 63.1% (95% CI 58.3–67.7) of the men (p < 0.001) were classified as high-risk subjects. Of the women classified as low-risk subjects according to SCORE, 25% had either subclinical peripheral arterial disease or renal insufficiency.

Conclusions

The SCORE system does not take into account cardiovascular risk factors typical in women, and thus underestimates their total cardiovascular risk. Measurement of ABI and eGFR in primary care might improve cardiovascular risk assessment. especially in women.Key Words: Ankle-brachial index, cardiovascular risk estimation, gender difference, glucose disorders, renal functionMore women than men die from cardiovascular disease in Europe, but the non-conventional risk factors in women may remain undiagnosed or ignored.

• In a cohort of middle-aged cardiovascular risk subjects in primary care, 27% of the women and 63% of the men (p < 0.001) were classified as high-risk subjects according to the SCORE risk charts.
• Of the women classified as low-risk subjects according to SCORE, 25% had either subclinical peripheral arterial disease or renal insufficiency.
• Measurement of ABI and eGFR in primary care might improve cardiovascular risk assessment, especially in women.

     

Vascular clips in anastomoses of femoropopliteal arterial reconstruction

The vascular anastomoses are usually made with sutures. Some mainly experimental studies have been published about a new method of doing the vascular anastomoses with metal clips. We studied the suitability of vascular closure staple (VCS) clip applier system for making the anastomoses in femoropopliteal and femorotibial arterial reconstruction. During an 11-month period, VCS clips were used in 17 out of 27 patients who were operated due to severe claudication or incipient gangrena of the foot. Altogether 26 anastomoses were made with VCS clips using either great saphenous vein or PTFE graft. The making of anastomosis was easy and reliable. No postoperative bleeding was noticed. All anastomoses were patent 4–6 weeks postoperatively studied by palpation and measured by ankle brachial pressure index (mean 0.96). In Duplex Doppler examination all studied patients had well patent anastomoses on an average 11 months after the operation. With VCS clip applier system, it is possible to do anastomoses in arteriosclerotic arteries like in femoropopliteal reconstructions. This method helps making reliable anastomoses more easily.     

Use of a tracer activity for health centre evaluation

The effectiveness of five Finnish health centres was assessed on the basis of a study of their physiotherapy units. This single area of activity proved to be a valid indicator of the general state of affairs in the centres.     

Late onset reactions to oral food challenge are linked to low serum interleukin-10 concentrations in patients with atopic dermatitis and food allergy

BACKGROUND: Aberrant cytokine production in vitro has been associated with atopic disease. No study has as yet been made of the circulating cytokine profiles in atopic patients with food allergy in response to oral allergen challenge. OBJECTIVE: To assess the effect of oral allergen challenge on the serum cytokine concentrations in patients with atopic dermatitis and food allergy. METHODS: Serum concentrations of interleukin (IL)-10, transforming growth factor beta 1, IL-1ra, IL-6, IL-5, IL-4 and interferon (IFN)-gamma were measured before and after double-blind, placebo-controlled food challenges (DBPCFC) (n = 73). Before DBPCFC, combined skin prick and patch testing was performed for cow milk, egg, soybean and cereals, and production of IFNgamma, IL-4, IL-10 and tumour necrosis factor alpha (TNFalpha) was determined in supernatants of cultures of peripheral blood mononuclear cells (PBMCs) stimulated by cow milk. RESULTS: The oral food challenge triggered immediate onset exanthematous reactions in 22 cases and late onset eczematous reactions in 29. The late-reacting cases had more positive skin patch test and negative skin prick test reactivities with allergenic food, and they had lower serum IL10 concentrations than immediate-reacting cases. In challenge-positive cases, IL-10 concentrations increased from 2.9 (0.1-5.04) pg/mL to 3. 9 (1.2-8.3) pg/mL in response to DBPCFC, P = 0.05, median (interquartile ranges), but not in those tolerant to cow milk. PBMCs of patients with cow milk allergy but not of those tolerant to cow milk generated TNFalpha in response to cow milk in vitro. CONCLUSION: These results indicate that oral allergen challenge in atopic patients with food allergy triggers systemic release of IL-10. Patients with late onset reactions were found to have lower serum IL-10 concentrations than their immediate-reacting counterparts. Considering that IL-10 is an inhibitory cytokine of delayed-type hypersensitivity, low IL-10 in late-reacting patients may explain the high frequency of their positive skin patch tests combined with negative skin prick tests.     

Gastric air tonometry during laparoscopic cholecystectomy: a comparison of two PaCO2 levels

PURPOSE: Pneumoperitoneum can cause disturbances in acid-base balance and splanchnic perfusion. We studied the effect of ventilation on acid-base balance and gastric mucosal tonometric values in patients undergoing laparoscopic cholecystectomy. METHODS: Twenty-four patients (ASA I-II) were randomly allocated into two groups. In the fixed ventilation group, ventilation was constant allowing free increase in PCO2, while in the constant CO2 group end-tidal PCO2 was fixed with ventilatory adjustment. Intraabdominal pressure was limited to 12 mmHg. Arterial acid-base balance, automated air tonometric variables and gastric mucosal to arterial PCO2 gap were determined frequently from anesthesia induction until three hours postoperatively. RESULTS: During pneumoperitoneum, in the fixed ventilation group arterial PCO2 changed from 5.0 +/- 0.2 to 6.6 +/- 0.4 kPa and pH from 7.43 +/- 0.03 to 7.33 +/- 0.04, tonometric PCO2 from 5.1 +/- 0.5 to 6.9 +/- 0.4 and pH from 7.44 +/- 0.04 to 7.33 +/- 0.04. In the constant CO2 group these variables remained at control levels (P < 0.01 between groups). The PCO2 gap remained unchanged without any differences between the groups. In the recovery room all measured variables were within normal range in both groups. CONCLUSION: Despite inter-group differences in arterial and tonometric PCO2 and pH values during CO2 pneumoperitoneum, the patients did not develop splanchnic hypoperfusion detectable by air tonometric method, as indicated by normal PCO2 gap in both groups throughout the study.     

Prenatal diagnosis in Pelizaeus-Merzbacher disease using RFLP analysis

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive disorder with severe psycho-motor retardation and neurological symptoms due to an inborn abnormality of proteolipid protein (PLP), the major protein component of myelin. A tight linkage between the gene of PLP and PMD locus has been suggested. We have carried out a series of RFLP studies using a cDNA probe for PLP and an anonymous DNA-fragment DXYS12 in a large Finnish family with at least three affected individuals. DNA analysis on chorionic villus specimens allowed us to exclude the disease in a male fetus of a possible carrier mother and, likewise, to demonstrate carrier status in a female fetus in another at-risk pregnancy.