Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe.

BACKGROUND: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. METHODS: Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. RESULTS: The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. CONCLUSIONS: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected.

Buflomedil for intermittent claudication.

BACKGROUND: Intermittent claudication (IC) is pain caused by chronic occlusive arterial disease, that develops in a limb during exercise and is relieved with rest. Buflomedil is a vasoactive agent used to treat peripheral vascular disease. However, its clinical efficacy for IC has not yet been critically examined. OBJECTIVES: To evaluate the available evidence on the efficacy of buflomedil for IC. SEARCH STRATEGY: We searched the specialized trials register of the Cochrane Peripheral Vascular Diseases Review Group (last searched November 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 4, 2007), MEDLINE (1966 to November 2007), International Pharmaceutical Abstracts (IPA) (from inception to November 2007), Science Citation Index (from inception to November 2007). We contacted Abbott Laboratories (buflomedil distributor) for controlled clinical trial data and approached authors for additional trial information. SELECTION CRITERIA: Double-blinded, randomized controlled trials (RCTs) in patients with IC (Fontaine stage II) receiving oral buflomedil compared to placebo. Pain-free walking distance (PFWD) and maximum walking distance (MWD) were analysed by standardized exercise test. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: We included two RCTS with 127 participants. Both RCTs showed moderate improvements in PFWD for patients on buflomedil. This improvement was statistically significant for both trials (WMD 75.1 m, 95% confidence interval (CI) 20.6 to 129.6; WMD 80.6 m, 95% CI 3.0 to 158.2), the latter being a wholly diabetic population. For both RCTs, MWD gains were statistically significant with wide confidence intervals (WMD 80.7 m, 95% CI 9.4 to 152; WMD 171.4 m, 95% CI 51.3 to 291.5), respectively. AUTHORS' CONCLUSIONS: There is little evidence available to evaluate the efficacy of buflomedil for IC. Most trials were excluded due to poor quality. The two included trials showed moderately positive results; these are undermined by publication bias since we know of at least another four unpublished, irretrievable, and inconclusive studies.Buflomedil's benefit is small in relation to safety issues and its narrow therapeutic range.

Buflomedil for intermittent claudication.

BACKGROUND: Intermittent claudication (IC) is pain caused by chronic occlusive arterial disease, that develops in a limb during exercise and is relieved with rest. Buflomedil is a vasoactive agent used to treat peripheral vascular disease. However, its clinical efficacy for IC has not yet been critically examined. OBJECTIVES: To evaluate the available evidence on the efficacy of buflomedil for IC. SEARCH STRATEGY: We searched the specialized trials register of the Cochrane Peripheral Vascular Diseases Review Group (last searched August 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 3, 2007), MEDLINE (1966 to August 2007), International Pharmaceutical Abstracts (IPA) (from inception to August 2007), Science Citation Index (from inception to August 2007). We contacted Abbott Laboratories (buflomedil distributor) for controlled clinical trial data and approached authors for additional trial information. SELECTION CRITERIA: Double-blinded, randomized controlled trials (RCTs) in patients with IC (Fontaine stage II) receiving oral buflomedil compared to placebo. Pain-free walking distance (PFWD) and maximum walking distance (MWD) were analysed by standardized exercise test. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: We included two RCTS with 127 participants. Both RCTs showed moderate improvements in PFWD for patients on buflomedil. This improvement was statistically significant for both trials (WMD 75.1 m, 95% confidence interval (CI) 20.6 to 129.6; WMD 80.6 m, 95% CI 3.0 to 158.2), the latter being a wholly diabetic population. For both RCTs, MWD gains were statistically significant with wide confidence intervals (WMD 80.7 m, 95% CI 9.4 to 152; WMD 171.4 m, 95% CI 51.3 to 291.5), respectively. AUTHORS' CONCLUSIONS: There is little evidence available to evaluate the efficacy of buflomedil for IC. Most trials were excluded due to poor quality. The two included trials showed moderately positive results; these are undermined by publication bias since we know of at least another four unpublished, irretrievable, and inconclusive studies.Buflomedil's benefit is small in relation to safety issues and its narrow therapeutic range.

Mouse strain differences in autonomic responses to stress.

In humans, anxiety disorders are often accompanied by an overactive autonomic nervous system, reflected in increased body temperature (BT) and heart rate (HR). In rodents, comparable effects are found after exposure to stress. These autonomic parameters can give important information on stress and anxiety responses in mice. In the present experiments, stress reactivity of three frequently used mouse strains [129 Sv/Ev, Swiss Webster (SW) and C57 BL/6] was assessed using their autonomic stress responses. BT, HR and activity were telemetrically measured. Undisturbed circadian rhythms already showed clear differences between the mouse strains. Hereafter, autonomic responses to stressors with increasing intensity were measured. Strain differences were found in magnitude and duration of the stress responses, especially after high-intensity stressors. Generally, C57BL/6 mice showed the largest autonomic response, SW the lowest and the 129Sv/Ev the intermediate response. Interestingly, the observed ranking in autonomic stress response does not match the behavioral stress responsivity of these strains. Finally, sensitivity to the anxiolytic diazepam (0, 1, 2, 4 and 8 mg/kg) was tested using the stress-induced hyperthermia paradigm. Pharmacological sensitivity to diazepam differed between the strains with the 129Sv/Ev being most sensitive. These studies show that simultaneous measurement of behavioral and autonomic parameters under stressful conditions contributes considerably to a better interpretation of anxiety and stress levels in mice.

[Information about drugs from physicians and pharmacists]. / Informatie over geneesmiddelen aan artsen en apothekers.

Good quality information is essential for those who prescribe, deliver or use medications. This information should meet quality criteria: it should be evidence based, practice oriented, easy to find and topical. Pharmacists and physicians receive information from different sources and of valable quality. Initiatives should be taken to improve the quality. The authorities should stimulate these initiatives, and make sure that the information is evidence based. Medical schools and pharmacy schools should educate the students in these matters, and play a role in the continuing medical education thereabout. Opinion leaders should be aware of their responsibility. Existing initiatives should be expanded, and should be coordinated. Finally, there is the ethical obligation for health professionals to remain informed. One wonders in how far incentives (or even coercive measures) are necessary. There is a task there for the "Orders" of physicians and pharmacists, and the scientific and professional bodies.

Stereoselective pharmacokinetics of oxprenolol and its glucuronides in humans.

OBJECTIVE: To study the pharmacokinetics of R(+)- and S(-)-oxprenolol and their corresponding glucuronide conjugates in healthy subjects. METHODS: An oral dose of 80 mg racemic oxprenolol was given to eight male volunteers. Venous blood samples and urine were collected as a function of time. Oxprenolol enantiomers in plasma and urine were determined by an enantiospecific HPLC method. Oxyprenolol glucuronides in plasma and urine were measured as oxprenolol equivalents after enzymatic hydrolysis. RESULTS: For R-oxprenolol the area under the plasma concentration-time curve was slightly higher (R/S ratio, 1.19) and the oral clearance slightly lower (R/S ratio, 0.84) than those parameters for S-oxprenolol. The free fraction of R-oxprenolol in plasma was 4% higher than that of S-oxprenolol. The intrinsic clearance of S-oxprenolol was 1.5 times larger than that of R-oxprenolol, and a maximum of 3% of the dose was excreted as unchanged enantiomers in the urine. The plasma concentrations of S-oxprenolol glucuronide were more than three times higher than those of R-oxprenolol glucuronide. Twenty-five percent of the dose of the R-enantiomer was excreted in the urine as R-oxprenolol glucuronide; 29% of the S-enantiomer dose was excreted as S-oxprenolol glucuronide. The renal clearance of R-oxprenolol glucuronide was, on average, 172 ml/min, suggesting active tubular secretion. In contrast, the renal clearance of S-oxprenolol glucuronide was only 49 ml/min, which can be explained by the plasma binding of the compound. CONCLUSIONS: Our results show small differences in disposition between R- and S-oxprenolol but a marked difference in disposition between the glucuronides. The difference in plasma concentrations between the oxprenolol glucuronides is mainly attributable to the stereoselectivity of the renal excretion.

Stereoselective pharmacokinetics of atenolol in the rat: influence of aging and of renal failure.

The pharmacokinetics of R- and S-atenolol after intravenous administration of racemic atenolol were studied in 3-, 12- and 24-month-old rats and in 3-month-old rats with renal failure induced by uranyl nitrate. In all age groups, the area under the plasma concentration-time curves is higher for R- than for S-atenolol; volume of distribution, total clearance and renal clearance are lower for R-atenolol than for S-atenolol, but the differences are small. In function of age there is for both enantiomers a significant increase in AUC, due, at least in part, to a decreased renal clearance; the effect of aging is not stereoselective. In rats with renal failure, the AUC of both enantiomers increases, due mainly to a decrease in renal clearance, but to a lesser degree also to a decrease in nonrenal clearance. For both enantiomers, the volume of distribution decreases and the half-life increases in the uraemic rats. The total amount of both enantiomers excreted in the urine is decreased in the rats with renal failure. There are no stereoselective effects of treatment of the rats with uranyl nitrate.

Influence of age on stereoselective pharmacokinetics and metabolism of hexobarbital in the rat.

The influence of age on stereoselective pharmacokinetics and in vitro metabolism of R- and S-hexobarbital was studied in the rat. After intravenous administration of the racemate, the plasma concentrations of S-hexobarbital are markedly lower than those of R-hexobarbital. For S-hexobarbital the half-life is somewhat shorter and the volume of distribution and plasma clearance is higher than for its antipode. For both enantiomers an increase in AUC and half-life, and a decrease in clearance are observed with aging. These changes occur mainly between the 3rd and the 12th month and are slightly more pronounced for R- than for S-hexobarbital, as appears from the S/R ratios. The volume of distribution shows no changes with aging. In vitro disappearance rate in 3-month-old rats is significantly higher for S- than for R-hexobarbital. There is for both enantiomers an increase in disappearance rate in 12-month-old rats as compared to younger or older rats, but this is significant only for the R-enantiomer. There are pronounced differences in the kinetics and metabolism of both hexobarbital enantiomers; changes with aging occur, but are only slightly and not always significantly more important for R- than for S-hexobarbital.

Receptor function in heart failure.

In patients with congestive heart failure, down-regulation of beta-adrenoceptors is present, probably as a result of sympathetic overstimulation. In end-stage dilated cardiomyopathy, beta 1-adrenoceptor density is markedly reduced, while beta 2-adrenoceptor density is normal. This latter finding does not necessarily imply normal sensitivity to beta 2-stimulation, due to possible alterations in the beta-adrenoceptor/adenylate cyclase complex beyond the receptor. In some disease states, such as ischemic cardiomyopathy and mitral valve disease, there seems to be a concomitant reduction of the beta 1- and beta 2-adrenoceptor density. The finding of beta-adrenoceptor down-regulation has stimulated the search for novel therapeutic approaches in heart failure patients. Beta-agonists could even further down-regulate beta receptors, and this perhaps explains why they seem not to be useful in long-term use. Agents that directly stimulate adenylate cyclase activity, such as forskolin, or that increase cyclic adenosine monophosphate degradation, such as the phosphodiesterase inhibitors, are being tested. Beta-adrenoceptor blocking agents were used in treatment of heart failure before beta-adrenoceptor down-regulation was recognized in these patients. It is tempting to speculate that the beneficial clinical and hemodynamic effects seen in these patients treated with metoprolol is indeed due to an antagonism of the beta-adrenoceptor down-regulation. Studies testing whether beta-adrenoceptor blocking agents can improve survival in congestive heart failure patients are on-going.

The production in high yield of N'-(4-[11C]methyl)-imipramine.

A method for the routine production in high yield of N'-(4-[11C]methyl)-imipramine is presented. The label is incorporated by reaction of C-11 methyl iodide (11CH3I) upon desipramine in dimethylsulfoxide. Quaternization of the tertiary amine by 11CH3I is minimized by using an excess of desipramine. The reaction proceeds at room temperature for 10 min and the product is isolated by means of high-performance liquid chromatography (HPLC). The entire production takes only 40 min and results in a radiochemical yield of 60%. About 60 mCi of labeled product are available for medical application; the specific activity, at the time of use, is 50 mCi/mumole. The product was characterized by chromatographic and spectrometric methods.

Clinical pharmacokinetics of glyceryl trinitrate following the use of systemic and topical preparations.

Glyceryl trinitrate has been used for more than a century for the treatment of angina pectoris and, more recently, for the treatment of congestive heart failure. The introduction of transdermal delivery systems has renewed the controversy regarding the efficacy of the drug, mainly in the light of the development of tolerance. With concentrations of the order of 1 microgram/L or less, the measurement of glyceryl trinitrate in plasma is not easy: gas chromatography with electron capture detection has been used widely but recently gas chromatography-mass spectrometry has provided satisfactory results. Assay problems are most likely to be responsible for some of the unexpected results reported. Further factors which may confound the results of the study of plasma concentrations are the rapid metabolism of glyceryl trinitrate in blood in vitro, adsorption to containers and infusion sets, and the uptake and/or metabolism in vessel walls. From the intravenous infusion data, the large interindividual variability in plasma concentrations of glyceryl trinitrate is apparent. The plasma half-life is about 2 to 3 minutes; plasma clearance values reported vary from 216 to 3270 L/h, indicating extensive non-hepatic metabolism. With transdermal administration, mainly with the transdermal controlled delivery systems, plasma concentrations of glyceryl trinitrate appear to be maintained for up to 24 hours, with large interindividual variations. Despite the ability to maintain, for example with the transdermal delivery systems, relatively constant concentrations of glyceryl trinitrate, it has not been possible to find a relationship between plasma concentrations and pharmacological or clinical effects. This is in part due to the attenuation of the effects with time; from the available data it is clear that this attenuation occurs at a pharmacodynamic level (reflex adaptation and tolerance) and not at the pharmacokinetic level.

Clinical pharmacokinetics of organic nitrates.

Plasma concentrations of glyceryl trinitrate (nitroglycerin), isosorbide dinitrate and isosorbide 2- and 5-mononitrates in man have been measured after administration via different routes. Appropriate precautions have to be taken in the administration of these agents (to avoid loss during intravenous infusion), and in their sampling and assay. Pharmacokinetic calculations based on plasma concentrations should be viewed with caution, as the data on which these calculations are based are often very limited, and the very rapid disappearance of for example glyceryl trinitrate from plasma makes the choice of an appropriate kinetic model and exact calculations difficult. Glyceryl trinitrate disappears from plasma within a few minutes, and a high apparent volume of distribution and a very high systemic clearance are found. After oral administration, plasma concentrations are very low; with sublingual or cutaneous administration, higher plasma concentrations can be obtained, suggesting a high first-pass extraction after oral administration, but quantitative data on bioavailability are lacking. For isosorbide dinitrate the systemic clearance, although high, is lower than for glyceryl trinitrate; disappearance from the plasma is slower and plasma concentrations after different routes of administration are much higher. Here too, quantitative data on bioavailability are lacking. High plasma concentrations of isosorbide 2-mononitrate and isosorbide 5-mononitrate are found in plasma after administration of isosorbide dinitrate. These metabolites have a good bioavailability, and half-lives of around 2.5 hours for isosorbide 2-mononitrate and 5 hours for isosorbide 5-mononitrate. Only very limited data are available about the influence of disease states and interactions with food and other drugs on the kinetics of the organic nitrates. It is very difficult to correlate the effects of the nitrates to their plasma concentrations; counter-regulation, development of tolerance, and the presence of metabolites could disturb the interpretation of such a relationship. It is at present impossible to predict the pharmacological effects or the efficacy of organic nitrates on the basis of their plasma concentrations.

Cardiopulmonary bypass and the pharmacokinetics of drugs. An update.

Cardiopulmonary bypass is accompanied by profound changes in the organism that may alter the pharmacokinetics of drugs. Drug distribution can be altered, for example, by changes in blood flow and by haemodilution, with a decrease in protein binding; a decrease in the elimination of some drugs can be caused by impairment of renal or hepatic clearance, due, for example, to lowered perfusion and hypothermia. The subject was reviewed in the Journal in 1982, and the emphasis of the present review is on new data related to specific drugs. The following substances are dealt with: benzodiazepines, cephalosporins, digitalis glycosides, general anaesthetics, glyceryl trinitrate (nitroglycerin), lignocaine (lidocaine), muscle relaxants, nitroprusside, opiates, papaverine and propranolol. For many of these substances an abrupt decrease has been observed in serum concentration upon initiation of bypass, which is explained by haemodilution and an increase in distribution due to decreased protein binding. For nitrates and some opiates, adsorption to the bypass apparatus was shown to be important. The gradual increase in serum concentrations seen during cardiopulmonary bypass with some drugs after the initial fall is usually explained by redistribution of the drug and/or decrease in its elimination. The same phenomena are thought to explain why in the post-bypass period a concentration increase occurs, or at least a slower decrease than expected. However, drug elimination has been directly measured in only a few studies. The short duration of the bypass procedure and the continuous changes during the process hamper a rigorous pharmacokinetic evaluation. Studies allowing more precise understanding of the mechanisms underlying the observed concentration changes are needed, but are difficult to design. Similarly, more data are awaited on the pharmacodynamic and clinical consequences of the concentration changes.

Binding to serum alpha 1-acid glycoprotein and effect of beta-adrenoceptor antagonists in rats with inflammation.

The beta-blocking effect of 4 beta-adrenoceptor antagonists with different pharmacokinetic properties was studied after intravenous and intraportal administration to control rats and to rats with experimental inflammation. In rats with inflammation the effects of propranolol and oxprenolol, which are mainly bound to alpha 1-acid glycoprotein (alpha 1-AGP), were significantly less after intravenous administration, but not after intraportal administration. In contrast, for metoprolol and atenolol, which are only negligibly serum bound, no difference was observed between control rats and rats with inflammation for either route of administration. Total and unbound serum concentrations of propranolol were measured 20 min after intravenous and intraportal administration. After intravenous administration, in the rats with inflammation total concentrations of propranolol were more than twice, and unbound concentrations less than half those of control rats. After intraportal administration the total concentrations were 8 times, and the unbound concentrations 3 times higher in the rats with inflammation. There was a significant correlation between the beta-blocking effect and the unbound concentrations of propranolol after intravenous administration, but not after intraportal administration. The latter finding is probably because the unbound concentrations were supramaximal.

Hypotension produced by intravenous apomorphine in the anaesthetized dog is not centrally mediated.

1 Intravenous administration of apomorphine (1.25 to 20 microgram/kg) in the anaesthetized dog produced a dose-dependent decrease in blood pressure which was antagonized by haloperidol but not influenced by propranolol or atropine. 2 Intracarotid administration of apomorphine produced a systemic hypotension which was significantly smaller than that seen with intravenous injection. 3 Doses of apomorphine that caused a decrease in blood pressure on intravenous injection, had no effect on blood pressure or caused retching accompanied by an increase in blood pressure on intravertebral or intracisternal administration. The animals showed a marked hypotension on intravertebral or intracisternal injection of clonidine. 4 From these results it is concluded that the hypotension seen with intravenous apomorphine cannot be explained by a central site of action.

Dopamine-induced neurogenic vaso-dilatation in the intact hindleg of the dog.

1 The dopamine-induced neurogenic vasodilation, previously described in the isolated perfused hindleg of the dog, has been studied in anaesthetized dogs with intact circulation in the hindleg. Dopamine was administered intravenously and/or intra-aortically, either as a bolus injection of 4 or 1l mug/kg, or as a continuous infusion of 4, 8, 16 or 32 mug kg-1 min-1. 2 Dopamine, given as a bolus injection or by infusion reversibly inhibited synaptic transmission in the paravertebral lumbar ganglia, studied with preganglionic stimulation at 1Hz. The inhibitory effect decreased gradually when the frequency of stimulation was increased to 16 Hz. The inhibition by dopamine was also present when spontaneous postganglionic activity was recorded. These effects were more pronounced on intra-aortic than on intravenous administration of dopamine. 3 In about half of the animals studied, injection or infusion of dopamine elicited a decrease of vascular resistance in the innervated femoral artery, whereas systemic blood pressure either did not change or decreased. In the denervated femoral artery, an increase in vascular resistance was alway observed. 4 The decrease in femoral vascular resistance was considered to correspond with neurogenic vasodilation caused by paravertebral ganglionic inhibition since (i) it only occurred in the innervated hindleg, (ii) blood pressure did not rise, (iii) this decrease was insensitive to atropine or propranolol and (iv) it was blocked by small doses of haloperidol. When hypovolemic shock was produced, the incidence of the neurogenic decrease of vascular resistance was smaller. 5 Dopamine also increased renal blood flow. This increase was not reduced by the occurrence of the neurogenic vasodilation in the inervated femoral artery. 6 These results are consistent with the idea that the dopamine-induced neurogenic vasodilation, originally described in the isolated perfused hindleg of the dog, also occurs when the circulation to the hindleg is intact. This suggests that, in the dog, also occurs when the circulation to the hindleg is intact. This suggests that, in the dog. the inhibitory effect of dopamine on sympathetic ganglia modulates its peripheral vasoconstrictor effects. In hypovolemic shock, where sympathetic nervous activity is high, the inhibitory effect of dopamine on sympathetic ganglia disappears and its direct vasoconstrictor effect on the vessels dominates.

How do calcium channel blockers prevent cardiovascular events. Are they all alike?

The calcium channel blockers (calcium antagonists) have vasodilatory and cardiodepressant effects. These pharmacological properties explain, to a large extent, the antihypertensive, antianginal, and antiarrhythmic effects of these agents. Pharmacological differences between members of this class, e.g. differences in vascular selectivity, are well documented and can be exploited clinically. The efficacy of calcium channel blockers in the prevention of cardiovascular events may depend on factors other than their vasodilatory and cardiodepressive effects. Much interest, for example, has been shown in their possible antiatherosclerotic effects. It is, however, at present not possible to ascertain how important these and other ancillary effects (such as plaque stabilisation) are for the putative cardioprotective effects of calcium channel blockers. There are, moreover, few in vitro or in vivo (animal or clinical) studies allowing valid comparison of the different calcium channel blockers with regard to these ancillary properties.

Oxidative activation of 2-aminofluorene by human red blood cell cytosol.

Purified red blood cell cytosol is able to activate 2-aminofluorene (2AF) to N-hydroxy-2-aminofluorene. Apparent kinetic parameters are determined with and without methylene blue. The latter, which maintains haemoglobin in the reduced form and stimulates NADPH production, increases the affinity of the enzyme for the 2AF. This activity is inhibited by carbon monoxide while cyanide is without effect. The involvement of a peroxidative reaction or a one-electron oxidative mechanism involving free radicals may be excluded.

Enzymic N-demethylation reaction catalysed by red blood cell cytosol.

Red blood cell cytosol promotes enzymic N-demethylation reactions which display typical Michaelis-Menten kinetics with respect to N-methylaniline as substrate. The demethylase activity is linked with hemoglobin (Hb) and is enhanced in the presence of NADH and the NADH-methemoglobin reductase system. It has been adduced that Hb in its oxygenated form is involved in the reaction.

Binding of oxprenolol and propranolol to serum, albumin and alpha 1-acid glycoprotein in man and other species.

Species differences in binding of basic drugs have only occasionally been studied and we have therefore measured the binding of the beta-adrenergic blockers oxprenolol and propranolol in (1) serum of healthy humans, dogs, rats and rabbits and of rabbits with experimental arthritis, (2) a solution of albumin of these species and (3) a solution of human alpha 1-AGP. In humans, dogs, rats and arthritic rabbits, binding of oxprenolol and propranolol was much higher in serum than in albumin solution; in healthy rabbits serum binding was very low and not different from albumin binding. For both drugs, concentration-dependency was seen in serum of dogs, humans and rats and of arthritic rabbits; a similar concentration-dependency was found for human alpha 1-AGP solution, but not for human albumin and for serum of healthy rabbits. Tris (2-butoxyethyl)-phosphate (TBEP), a known displacer of drugs from alpha 1-AGP in humans, decreased binding in serum of all species except the rabbit. For both beta-blockers, species differences in capacity constants were found; species differences in affinity constants were present only for propranolol. These results suggest that in humans, dog and rat, but much less in rabbits, oxprenolol and propranolol bind mainly to alpha 1-AGP and that binding to alpha 1-AGP is more important for oxprenolol than for propranolol.