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Biomedical subjects

W E Haefeli

Publications and source records attributed to W E Haefeli.

At least 19 recordsLinked to original sources
PubMed2001

Disturbed ratio of erythrocyte and plasma S-adenosylmethionine/S-adenosylhomocysteine in peripheral arterial occlusive disease.

Altered homocysteine metabolism associated with peripheral arterial occlusive disease (PAOD) may lead to impairment of vital methylation reactions through accumulation of S-adenosylhomocysteine (AdoHcy) as well as through alteration of the ratio S-adenosylmethionine (AdoMet)/AdoHcy. We determined AdoMet, AdoHcy, their ratio, and homocysteine in plasma as well as AdoMet, AdoHcy, and their ratio in erythrocytes of 61 patients with PAOD (age 49-93) and 50 healthy controls (age 41-87). Geometric mean values of plasma homocysteine, AdoMet, and AdoHcy were significantly increased in patients compared with controls (15.5 vs. 10.4 micromol/l**; 107 vs. 52.3* nmol/l; 55. 0 vs. 23.1** nmol/l, respectively; *P<0.01, **P<0.001), while the ratio of AdoMet/AdoHcy was decreased in patients (1.92 vs. 2.52*). In erythrocytes patients exhibited increased levels of AdoHcy compared with controls (309 vs. 205 nmol/l**) whereas AdoMet (3351 vs. 3732 nmol/l*) and the ratio of AdoMet/AdoHcy (11.8 vs. 19.1**) were decreased. The odds ratio (OR) for developing PAOD with decreased AdoMet/AdoHcy ratio after adjustment for kidney function was significant for erythrocyte levels < or =14.2 (OR, 7.1 (6.9-7.2, 95% CI). In addition, hematocrit levels were found to be significantly decreased in patients versus controls (0.35 vs. 0.42 l/l**) and were significantly correlated with the ratio of AdoMet/AdoHcy in erythrocytes of the patients. Since the ratio of AdoMet/AdoHcy is closely linked with the activity of numerous enzymatic methylation reactions, these results suggest that methylation may be impaired in these patients.

Adult↗
PubMed2001

Drug dosage in patients with renal failure optimized by immediate concurrent feedback.

OBJECTIVE: To examine the impact of immediate concurrent feedback on dose adjustment in patients with renal failure. DESIGN: Prospective 12-month study in patients with various degrees of renal failure, with comparison to a retrospective control group. SETTING: A 39-bed unit of a university hospital providing primary and tertiary care. PATIENTS: Patients with renal failure (estimated creatinine clearance < or = 50 mL/min) receiving at least 1 pharmacologically active drug. INTERVENTIONS: Education of physicians and immediate concurrent feedback on the ward giving estimated creatinine clearance and dose recommendations for renally eliminated drugs adjusted to individual renal function. MEASUREMENTS AND MAIN RESULTS: The percentage of dosage regimens adjusted to renal function and cost assessment of drug therapy were calculated. Overall, 17% of the patients had at least 1 estimated creatinine clearance < or = 50 mL/min. In the intervention group, the dose of 81% of renally eliminated drugs was adjusted to renal function, compared with 33% in the control group ( P <.001). The mean difference in cost between standard and adjusted dose of renally eliminated drugs in the intervention and control groups was 5.3 +/- 12.3 and 0.75 +/- 2.8 Swiss francs (approximately US$3.5 and US$0.5), respectively ( P <.001), accounting for 16.5% and 2.8%, respectively, of daily medication costs of all drugs. CONCLUSIONS: The proportion of doses of renally eliminated drugs adjusted to renal function can be substantially increased by immediate concurrent feedback. This saves drug costs and has the potential to prevent adverse drug reactions.

Aged↗
PubMed2000

Correlation between apolipoprotein B and endothelin-1-induced vasoconstriction in humans.

Low-density lipoprotein (LDL) concentrations have been linked to altered responses to endogenous vasodilators and vasoconstrictors. We evaluated retrospectively the relationship between LDL and vasoconstrictor (endothelin-1, phenylephrine) responsiveness of the forearm vasculature in 15 elderly healthy volunteers with apolipoprotein B and LDL levels in the normal range. In contrast to phenylephrine, changes in forearm vascular resistance induced by endothelin-1 were correlated with apolipoprotein B, LDL, and total cholesterol concentrations in women but not in men. These findings might suggest that lipids may increase vascular tone through both impaired endothelial vasodilation and increased vasoconstriction to endothelin-1 at least in women.

Aged↗
PubMed2000

[Individualized drug therapy--need for improvement].

The lack of dose adjustment to the individual needs of a patient is a major cause for the substantial difference between the efficacy of therapies established in large trials and the therapeutic results obtained in everyday practice (reduced effectiveness). In addition, these differences affect drug safety and ultimately also costs. Hence strategies to maintain good compliance and to avoid incompatibilities, drug interactions and adverse events should be applied whenever drugs are prescribed. This supplement compiles different techniques and measures which may support health professionals in reaching these goals.

Dose-Response Relationship, Drug↗
PubMed2000

[Consideration of drug absorption in customizing drug therapy].

The rate and extent of drug absorption from the small intestine are related to the release of the active ingredient from a dosage form, its solubility in the liquid phase of gastrointestinal contents, and the transport of the dissolved compound or the intact dosage form from the stomach into the duodenum. With pharmaceutical preparations releasing the active compound within the stomach, and enteric-coated "micro"-formulations (micropellets), gastric emptying is possible during the interdigestive and the digestive period. Potential differences of drug absorption between fasting administration and intake during the digestive period are unpredictable, because they are related to the release characteristics of the dosage form. However, larger enteric-coated preparations like tablets can leave the stomach only with a phase 3 contraction of fasting motility; intake during the digestive period will result in gastric retention of this type of dosage form until all food has left the stomach and fasting motility is restored. Consequently the onset of drug absorption is delayed. This interaction between food and large enteric-coated dosage forms is predictable from pyloric function in relation to the gastric motility. As it occurs regularly, it can be taken into account when prescribing enteric-coated dosage forms. If concomitant intake of food and enteric-coated drugs is unavoidable, but a rapid onset of drug absorption is necessary, micropellets are the dosage form of choice. When the therapeutic effect is insufficient, drug dosage form and timing of drug administration should be checked before prescribing a different active compound.

Biological Availability↗
PubMed2000

[Clinically relevant adverse drug interactions].

Drug interactions may lead to adverse drug effects or therapeutic failure. Many clinically relevant unwanted interactions are caused by a change in the activity of cytochrome P450 isoenzymes or the activity of active drug transport systems (e.g. p-glycoprotein). Most drug interactions may be anticipated and prevented by dose modification or using alternative drugs.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

The mechanism of cryoinjury: In vitro studies on human internal mammary arteries.

The mechanism of cryoinjury was investigated in human internal mammary arteries (IMA) by monitoring contractile responses to ET-1 and KCl. For cryopreservation segments of IMA were equilibrated for 20 min with the cryomedium (RPMI 1640 culture medium containing 1.8 M DMSO and 0.1 M sucrose), frozen at a mean cooling rate of 1.3 degrees C min(-1) to -70 degrees C and stored in liquid nitrogen. Before use, samples were thawed slowly and the cryomedium removed by dilution. Compared to unfrozen controls, ET-1 stimulated frozen/thawed IMA with similar efficacy but at 3 fold lower concentrations (P<0.001). Addition of ET-1 (100 nM) induced maximal contraction of unfrozen IMA within 10 min, declining thereafter to 25% after 90 min. In frozen/thawed IMA the ET-1-induced contraction was sustained but could be reversed if protein kinase C was blocked by staurosporine (100 nM). Responses to ET-1 of cryostored IMA were 5 fold more susceptible to blockade by nifedipine than those of controls. After cryostorage the efficacy of KCl was diminished to 40% (P<0.05) and the KCl curve was shifted to the left (2 fold, P<0. 001). In both unfrozen and cryostored IMA the KCl (60 mM) effect was sustained and equally susceptible to nifedipine. It is suggested that the smooth muscle cell of IMA is receptive to physical forces which occur during cryopreservation. These forces modify transmembrane signal transduction and intracellular pathways, that are common to pharmacological agonists thereby changing vascular responses to several contractile agonists after thawing.

Calcium↗
PubMed2000

Auditory and electroencephalographic effects of midazolam and alpha-hydroxy-midazolam in healthy subjects.

AIMS: Whereas cortical EEG effects of benzodiazepines are well characterized, information about benzodiazepine effects in other areas of the central nervous system is sparse. This study investigated the action of midazolam and its active metabolite alpha-hydroxy-midazolam on different parts of the auditory pathway in six healthy volunteers in a randomized, double-blind, three-way cross-over study. METHODS: Acoustically evoked short (SLP) and middle (MLP) latency potentials, transitory evoked otoacoustic emissions (TEOAE), and EEG power spectra were analysed after short i. v. injections of placebo, or 0.15 mg kg-1 midazolam, or alpha-hydroxy-midazolam, respectively. RESULTS: All subjects fell asleep during the 4 min infusion of active drug. SLP showed a significant transient increase of Jewett wave V 10 min after injection for midazolam and alpha-hydroxy-midazolam while the latency of wave I was unchanged. Both benzodiazepines induced a marked and long-lasting MLP amplitude decrease for 240 min with slow recovery over the following 360 min. No changes of TEOAE were observed. In agreement with earlier reports, increases in EEG beta activity and decreases in alpha activity were observed after administration of either drug. CONCLUSIONS: Systemically administered benzodiazepines modulate the auditory pathway above the level of the cochlea. While SLP changes were closely associated with sedation and high plasma benzodiazepine concentrations, MLP effects persisted for hours after sedation even at low benzodiazepine plasma levels. Evoked potentials may therefore be more sensitive than EEG as a tool to monitor benzodiazepine effects.

Adult↗
PubMed2000

Effect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine.

AIMS: To investigate the effect of acute P-glycoprotein inhibition by the multidrug-resistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the pharmacokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). METHODS: In a double-blind, three-way crossover study, the pharmacokinetic and potentially adverse pharmacodynamic effects (reaction time, transcutaneous PCO2, blood pressure) of morphine were compared with and without acute inhibition of P-glycoprotein by PSC. The effects of PSC alone were also evaluated. The study was performed in 18 healthy male volunteers and pharmacodynamic effects analysed by measuring the area under the effect (AUE) curve. 150 mg PSC (or its placebo) was given as an i.v. infusion over 2 h. With the expected inhibition of Pgp 1 h after starting PSC infusion, 7.5 morphine HCl (or its placebo) was infused over 2 h. RESULTS: The infusion of PSC resulted in blood concentrations expected to inhibit Pgp mediated transport. While the pharmacokinetics of plasma morphine and M6G. were unaffected there was a small but statistically significant increase in the AUC and Cmax of M3G (11.8 and 8.3%, respectively). The t(1/2) and tmax were unaffected. The pharmacokinetic parameters of PSC were not affected by coadministration with morphine. PSC did not significantly affect the adverse events of morphine, as assessed by spontaneous reporting. Compared with PSC alone, morphine elicited an increase in reaction time (Emax 48 ms, compared with the predose absolute reaction time of 644 ms), which was not detected by the alertness-drowsiness score, indicating only slight sedation. There was a significant decrease in systolic blood pressure (Emin -9 mm Hg), and a trend for a fall in diastolic blood pressure (Emin -14.5 mm Hg) and respiratory rate (Emin -1.8 breath x min(-1)). For all these parameters, the effects of PSC/morphine were similar to that of PSC alone, suggesting some attenuation of morphine's effect. In contrast, morphine caused a significant increase in PCO2 (Emax 0.69 kPa) compared to PSC alone, indicating slight respiratory depression. This increase was similar to that of the PSC/morphine combination. CONCLUSIONS: Acute inhibition of P-glycoprotein by PSC in this setting does not affect the pharmacokinetic or safety-related pharmacodynamic profile of morphine in a clinically significant manner.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Overconsumption detected by electronic drug monitoring requires subtle interpretation.

BACKGROUND: Electronic compliance monitoring has provided new variables to describe drug intake behavior and new strategies to improve compliance. However, as evaluated in this study, the recording of opening events of pill bottles does not necessarily mean drug intake. METHODS: In an open 3-week trial with an oral vitamin combination, drug intake was recorded with use of an electronic pill box that contained 25 capsules and that registered each opening of the bottle. Thirty-seven patients were asked to take one capsule every morning for 21 days. Opening and closing events were related to the results of pill counts and patient interviews at the end of the trial. RESULTS: Drug consumption was 101.8% (663 recorded opening and closing events) in the 31 patients who completed the trial. Pill boxes were opened more than once by 10 patients on at least one monitored day. For seven patients the total number of openings was >25 (range, 26 to 29) and thus exceeded the number of capsules provided. A third interview of these patients revealed real overconsumption in only two patients. Six patients remembered that they had shown the device to relatives or friends or that they had checked to see whether they had closed the pill box well, thus turning a "curiosity event" into a drug intake event. CONCLUSION: In short-term studies particularly, such curiosity events may substantially modify the electronic assessment of compliance surrogates. In these trials the combined evaluation of electronic openings, pill counts, and interviews may be a suitable way to reveal such openings without pill intake.

Administration, Oral↗
PubMed2000

Inspired oxygen fraction after cardiopulmonary bypass: effects on pulmonary function with regard to endothelin-1 concentrations and venous admixture.

Twenty consecutive patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) were allocated at random to group 1 (n = 10, high inspired oxygen fraction (FIO2) after CPB), or group 2 (n = 10, moderate FIO2 after CPB). The effects of each FIO2 on arterial and mixed venous concentrations of endothelin-1 (ET-1) and its precursor, Big ET-1, were measured. Venous admixture was calculated to assess the efficiency of pulmonary gas exchange. Patients whose lungs had been ventilated with a FIO2 of 1.0 (exposure time 70 min) after weaning from the CPB machine had significantly greater arterial and mixed venous Big ET-1 concentrations and venous admixture than patients whose lungs were ventilated with a FIO2 of 0.35. In contrast, ET-1 concentrations in the two groups were not significantly different. A reduction of FIO2 from 1.0 to 0.6 reduced venous admixture without lowering endothelial peptide concentrations. On the first postoperative day all peptide concentrations were similar in the two groups, whereas venous admixture remained non-significantly higher in group 1. A short period of high FIO2 immediately after CPB increases endothelin concentrations and pulmonary venous admixture.

Aged↗
PubMed1999

[Conviction as a basis for compliance and strategies for improving compliance].

The aim of the present study was to correlate statements made by 100 patients of an internal medicine ward regarding their compliance before hospitalization, with their personal knowledge of an convictions about their own pharmacotherapy. Data were collected in structured interviews of 9 questions carried out by a medical person not involved in current treatment. The patient sample (mean age +/- SE: 6.8 +/- 1.3 years) included 42 women and 58 men whose mean number of prescribed medications before hospitalization was 4.7 +/- o.22. Good treatment compliance was reported by 78% of the patients, while 13% admitted non- compliance. Knowledge about the drugs they had been prescribed ranged from perfect (30%) to none (34%) and was significantly different between compliers and non-compliers, with patients who know their medications at least by name being fairly compliant (p = 0.048). Independently of the statement about compliance, the patients used three main strategies to ensure regular intake of daily medication: visual aids (69%), coupling to a ritual (26%) or supervision by a third person (6%). Criteria such as gender, the number of prescribed medications, personal perseverance, or personal definition of the sense of the prescribed pharmacotherapy, or the arguments expected to be used by a physician when recommending a pharmacotherapy did not differ between compliers and non-compliers. Thus, compliance appears to have its roots mainly in the conviction level of each patient : intention will be transformed into action when deemed correct according to the individual's personal criteria. This may lead to both compliance and to non-compliance with medical recommendations. This study, which is based on patient reports, supports the conclusion that drug compliance may be enhanced by increasing patient's knowledge about their own pharmacotherapy and by having patients use specific strategies to guarantee regular daily intake of drugs. Prospective studies should therefore address the question of whether providing specific information according to a patient's convictions will untimately translate into improved compliance.

Aged↗
PubMed1999

[Anticonvulsant hypersensitivity syndrome. 2 case reports and an overview].

Anticonvulsants with aromatic ring structure such as phenytoine, carbamazepine, phenobarbital and lamotrigine can induce a drug hypersensitivity syndrome ("anticonvulsant hypersensitivity syndrome", AHS). Though the incidence of AHS is low, correct and early diagnosis are crucial to stop further progression by immediately withholding the causative drug. AHS usually starts within the first 2-8 weeks after initiation of therapy with fever, followed over the next 1-2 days by a cutaneous reaction and lymphadenopathy. The skin reaction is usually exanthematous but can also manifest itself as Stevens-Johnson or Lyell syndrome. AHS is commonly associated with symptomatic or asymptomatic internal organ involvement usually affecting the liver, although haematologic, renal or pulmonary impairment may also occur. We report two cases illustrating the clinical course and discuss theories about the potential pathogenesis and the treatment of AHS.

Adult↗
PubMed1999

[Tablets in stool? A common problem!].

Patients and their physicians are often thrown into doubt by the excretion of apparently intact tablets in stools after oral drug administration. This occurs whenever patients receive certain pharmaceutical forms designed to prolong the rate of drug release. The active compound is continuously released during intestinal passage of these pharmaceutical forms and their insoluble coats are visibly excreted into stools wholly or in part. The assumption that the drug was not released from the tablet in these cases is therefore erroneous and no further action is required.

Capsules↗
PubMed1999

Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-acetyltransferase 2 and CYP1A2 activities.

OBJECTIVES: To evaluate the in vivo effect of xanthine oxidase (XO) inhibition by allopurinol on the determination of polymorphic N-acetyltransferase 2 (NAT2) and cytochrome P450 1A2 (CYP1A2) with urinary caffeine metabolic ratios. METHODS: In an open, prospective study involving 21 healthy subjects (eight fast, 13 slow NAT2 acetylators) allopurinol (300 mg perday) was administered orally on trial days 1-8, followed by a wash-out period of 8 days. Urinary caffeine tests (200 mg caffeine p.o.) were performed repetitively. Urine was collected for 8 h and venous blood samples for the determination of allopurinol, oxypurinol and uric acid were drawn. The urinary caffeine metabolites 1-methyluric acid (1MU), 1-methylxanthine (1MX), 1,7-dimethyluric acid (17MU), 1,7-dimethylxanthine (17MX), 5-acetylamino-6-formylamino-3-methyluracil (AFMU), plasma allopurinol and oxypurinol were analysed using high-performance liquid chromatography (HPLC). RESULTS: During XO inhibition by allopurinol, the formation of 1MU from 1MX and therefore the XO ratio 1MU/1MX decreased to 15.9 (1.2)% [mean with (SEM)] of baseline values (P < 0.005). The NAT2 ratio AFMU/1MX decreased likewise to 56.7 (6.3)% (P < 0.005). AFMU/(AFMU + 1MX + 1MU), an alternative NAT2 ratio, remained constant, but the CYP1A2 ratio (AFMU + 1MX + 1MU)/17MU, used to express CYP1A2 activity, transiently increased to 167 (13)% (P < 0.005). The NAT2 phenotype did not influence CYP1A2 and XO ratios or plasma oxypurinol pharmacokinetics. CONCLUSIONS: Several caffeine metabolic ratios are commonly used to express the activities of NAT2, CYP1A2 and XO both in healthy volunteers and in polymedicated patients, although their reliability has not been evaluated thoroughly during concurrent drug administration. The findings of this study suggest that NAT2 phenotyping should be performed using the ratio AFMU/(AFMU + 1MX + 1MU) if an XO inhibitor may be present. It also shows that the determination of CYP1A2 activity with caffeine as a metabolic probe is considerably altered under these conditions. Thus, concomitant drug administration may impair the robustness of multiple pathways of the complex caffeine test. This points to the need for alternative probes, designed to assess only the activity of a single enzyme because, in contrast to healthy volunteers, in patients known or unknown drug interactions may often be present.

Allopurinol↗
PubMed1999

Neurokinin-1 receptor antagonist R116301 inhibits substance P-induced venodilation.

OBJECTIVE: To test the effect of the neurokinin-1 receptor antagonist hydroxybutanedioate (R116301) in human hand veins in vivo. METHODS: In a randomized, double-blind, placebo-controlled crossover study we used the hand vein compliance method to evaluate the inhibition of the response to substance P by R116301. RESULTS: In hand veins preconstricted with phenylephrine to 21% +/- 2.6% (mean +/- SEM, placebo) and 25% +/- 3.0% (R116301) of the initial diameter, substance P resulted in a mean venodilation of 84% +/- 7% and 87% +/- 13% (P = .8) before administration of placebo and R116301, respectively. Oral administration of 300 mg R116301 resulted in peak plasma concentrations of 1.16 +/- 0.1 microg/mL within 128 +/- 14 minutes. With increasing R116301 plasma concentrations, substance P-induced venodilation decreased significantly (P < .001), whereas placebo had no effect. Mean substance P-induced venodilation was markedly reduced to 8% +/- 7%. CONCLUSION: This study confirms the presence of neurokinin-1 receptors in human veins and the effectiveness of the neurokinin-1 receptor antagonist R116301 in human hand veins.

Administration, Oral↗
PubMed1999

Circulating cell adhesion molecules and endothelial markers before and after transluminal angioplasty in peripheral arterial occlusive disease.

In the present study, the levels of soluble adhesion molecules P- and E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and of other markers of endothelial activation or injury, such as thrombomodulin, von Willebrand factor (vWF), as well as homocysteine, were prospectively investigated in 71 patients (21 women, 50 men, age 68+/-13) with predominantly femoropopliteal peripheral arterial occlusive disease (PAOD, stage II-IV, Fontaine) before and after percutaneous transluminal angioplasty (PTA). Thirty patients (42.3%) developed restenosis within 6 months, defined as a > 50% reduction of the lumen diameter at the site of PTA. At entry in the study, 46% and 58% of all patients had higher than normal levels of soluble P-selectin and VCAM-1, respectively. Thrombomodulin (P < 0.01) measured at entry, was significantly higher in patients who developed late restenosis, with trends for higher values for P-selectin, VCAM-1 and vWF. The relative risks for developing restenosis were 2.41 (CI95%: 1.23-4.75) and 1.54 (CI95%: 0.98-2.72) for thrombomodulin and P-selectin, respectively. Soluble P-selectin and the severity of PAOD (Fontaine stage III/IV) were found to be statistically indicative factors for late restenosis in a logistic regression risk factor analysis with an overall predictive value of 72%. At 6 months, those who developed restenosis had also higher soluble P-selectin (P < 0.01), VCAM-1 (P < 0.05) and a trend for higher thrombomodulin. Homocysteine was elevated in 52% of the patients at entry but neither was it associated with higher restenosis rates nor did it correlate with the levels of thrombomodulin or the other adhesion molecules. These findings indicate that patients with PAOD have to a significant proportion, elevated levels of circulating soluble adhesion molecules and markers of endothelial activation occurring in concert with an ongoing atherosclerotic process.

Aged↗