Incorrect use and limited weight reduction of orlistat (Xenical) in clinical practice. A cohort study.

OBJECTIVE: To study the prescribing of the antiobesity drug orlistat in relation to the approved indication and its weight-reducing effect in clinical practice during the first 3 months of treatment. METHODS: Anonymous postal questionnaire survey to prescribers of orlistat concerning a random sample of 1000 of 20,000 prescriptions. PARTICIPANTS: Useful information was obtained for 789 patients. SETTING: Primary and secondary care in Sweden. MAIN OUTCOME MEASURES: Beginning and continued treatment according to the approved indication. Dropout from treatment. Weight loss during treatment. RESULTS: Four percent of the patients were prescribed orlistat despite having a body mass index (BMI) less than 28 kg/m2. Only 24% of the patients had a diet period with a weight loss of 2.5 kg or greater before the start of therapy. Half of the patients with a weight loss of less than 5% after 3 months continued the treatment. Ten percent gained weight or had no weight loss at all while 43% lost less than 5% in weight. At least one-quarter of the patients stopped the treatment within the observation period. CONCLUSION: Orlistat was not prescribed according to the approved indication in the majority of cases. The dropout rate was high and most patients had minor gain from the treatment.

Matrix-assisted in vitro refolding of Pseudomonas aeruginosa class II polyhydroxyalkanoate synthase from inclusion bodies produced in recombinant Escherichia coli.

In order to facilitate the large-scale preparation of active class II polyhydroxyalkanoate (PHA) synthase, we constructed a vector pT7-7 derivative that contains a modified phaC1 gene encoding a PHA synthase from Pseudomonas aeruginosa possessing six N-terminally fused histidine residues. Overexpression of this phaC1 gene under control of the strong Ø10 promoter was achieved in Escherichia coli BL21(DE3). The fusion protein was deposited as inactive inclusion bodies in recombinant E. coli, and contributed approx. 30% of total protein. The inclusion bodies were purified by selective solubilization, resulting in approx. 70-80% pure PHA synthase, then dissolved and denatured by 6 M guanidine hydrochloride. The denatured PHA synthase was reversibly immobilized on a Ni(2+)-nitrilotriacetate-agarose matrix. The matrix-bound fusion protein was refolded by gradual removal of the chaotropic reagent. This procedure avoided the aggregation of folding intermediates which often decreases the efficiency of refolding experiments. Finally, the refolded fusion protein was eluted with imidazole. The purified and refolded PHA synthase protein showed a specific enzyme activity of 10.8 m-units/mg employing (R/S)-3-hydroxydecanoyl-CoA as substrate, which corresponds to 27% of the maximum specific activity of the native enzyme. The refolding of the enzyme was confirmed by CD spectroscopy. Deconvolution of the spectrum resulted in the following secondary structure prediction: 10% alpha-helix, 50% beta-sheet and 40% random coil. Gel filtration chromatography indicated an apparent molecular mass of 69 kDa for the refolded PHA synthase. However, light-scattering analysis of a 10-fold concentrated sample indicated a molecular mass of 128 kDa. These data suggest that the class II PHA synthase is present in an equilibrium of monomer and dimer.

alpha 2beta 1 integrin is not recognized by rhodocytin but is the specific, high affinity target of rhodocetin, an RGD-independent disintegrin and potent inhibitor of cell adhesion to collagen.

We have recombinantly expressed a soluble form of human alpha(2)beta(1) integrin that lacks the membrane-anchoring transmembrane domains as well as the cytoplasmic tails of both integrin subunits. This soluble alpha(2)beta(1) integrin binds to its collagen ligands the same way as the wild-type alpha(2)beta(1) integrin. Furthermore, like the wild-type form, it can be activated by manganese ions and an integrin-activating antibody. However, it does not bind to rhodocytin, a postulated agonist of alpha(2)beta(1) integrin from the snake venom of Calloselasma rhodostoma, which elicits platelet aggregation. Taking advantage of the recombinantly expressed, soluble alpha(2)beta(1) integrin, an inhibition assay was established in which samples can be tested for their capability to inhibit binding of soluble alpha(2)beta(1) integrin to immobilized collagen. Thus, by scrutinizing the C. rhodostoma snake venom in this protein-protein interaction assay, we found a component of the snake venom that inhibits the interaction of soluble alpha(2)beta(1) integrin to type I collagen efficiently. N-terminal sequences identified this inhibitor as rhodocetin, a recently published antagonist of collagen-induced platelet aggregation. We could demonstrate that its inhibitory effect bases on its strong and specific binding to alpha(2)beta(1) integrin, proving that rhodocetin is a disintegrin. Standing apart from the growing group of RGD-dependent snake venom disintegrins, rhodocetin interacts with alpha(2)beta(1) integrin in an RGD-independent manner. Furthermore, its native conformation, which is stabilized by disulfide bridges, is indispensibly required for its inhibitory activity. Rhodocetin does not contain any major collagenous structure despite its high affinity to alpha(2)beta(1) integrin, which binds to collagenous molecules much more avidly than to noncollagenous ligands, such as laminin. Blocking alpha(2)beta(1) integrin as the major collagen receptor on platelets, rhodocetin is responsible for hampering collagen-induced, alpha(2)beta(1) integrin-mediated platelet activation, leading to hemorrhages and bleeding disorders of the snakebite victim. Moreover, having a widespread tissue distribution, alpha(2)beta(1) integrin also mediates cell adhesion, spreading, and migration. We showed that rhodocetin is able to inhibit alpha(2)beta(1) integrin-mediated adhesion of fibrosarcoma cells to type I collagen completely.

Fibrinolytic treatment in suspected acute myocardial infarction--use and risks in clinical practice.

OBJECTIVES: To study the adherence to guidelines concerning fibrinolytic treatment of patients with suspected myocardial infarction and to obtain information on severe events in clinical practice. METHODS: Prospective reporting of all patients admitted for suspected acute myocardial infarction during 4 months in 1994 from 69 (73.4% of all) Swedish coronary care units. RESULTS: The study covers 10,652 admissions, representing 9726 patients. The mean percentage treated with fibrinolytic drugs of patients with a positive ECG (ST-elevation and/or bundle branch block), a delay < 12 h and no contraindications was 56%. The interhospital range was 18.1-94.1%. Fibrinolytic drugs were given with a delay time > 24 h in 12.5% of women and 15.7% of men, and 36.1% of patients with verified acute myocardial infarction were given fibrinolytic drugs. Streptokinase was used in 82.7% and alteplase in 15.5% of the patients, respectively (interhospital range 0-53.3%). CONCLUSIONS: Fibrinolytic therapy seems to be used in a non-rational way at several hospitals. Local quality systems may be a way to assure better care.

No difference in blood thiamine diphosphate levels between Swedish Caucasian patients with congestive heart failure treated with furosemide and patients without heart failure.

OBJECTIVES: To determine whether furosemide treatment in congestive heart failure (CHF) patients is associated with thiamine deficiency. DESIGN: Patients without heart failure and without diuretic treatment were included to compare with patients with CHF belonging to New York Heart Association (NYHA) functional class II and III-IV, respectively, and receiving furosemide therapy. SETTING: All patients were recruited from the emergency ward of the cardiology section. Huddinge University Hospital, where they were admitted due to CHF or acute myocardial infarction. SUBJECTS: Ninety-nine patients were included from whom a blood sample was taken, as well as routine admission blood samples for the analysis of thiamine diphosphate (TPP) concentrations. Patients taking vitamin preparations were excluded. MAIN OUTCOME MEASURES: Blood TPP concentrations were measured by high performance liquid chromatography (HPLC) and compared between the patient groups by the use of ANOVA. RESULTS: No significant difference was found between the groups in blood TPP concentrations. CONCLUSIONS: Thiamine deficiency may not be a complication of furosemide treatment in the studied Swedish patient population.

Effects of "group detailing" on the prescribing of lipid-lowering drugs: a randomized controlled trial in Swedish primary care.

The objective was to study the effect of "academic group detailing" on the prescribing of lipid-lowering drugs in Swedish primary care. A randomized controlled trial was conducted, randomization being by group. Groups of doctors at 134 community health centres were randomly allocated to an intervention and a control group. The 67 intervention health centres were offered four sessions, conducted by a pharmacist, with group information on guidelines for the management of hyperlipidaemia. The number of prescriptions of lipid-lowering drugs per month increased in the intervention health centres and the increase was statistically different from the corresponding change in the control health centres among women in the age group 30-65 years (p = 0.03). The prescription of first-line lipid-lowering drugs increased by 20% in the intervention health centres (p = 0.03). "Academic group detailing" by pharmacists to primary care doctors can be an effective method for influencing prescribing practices.

Influence of angiotensin converting enzyme inhibition on relation of atrial natriuretic peptide concentration to atrial pressure in heart failure.

OBJECTIVE: To examine the relation between haemodynamics and atrial natriuretic peptide concentration during short term angiotensin converting enzyme inhibition. DESIGN: Patients were randomly allocated to receive placebo or one of three doses of the angiotensin converting enzyme inhibitor ramipril. SETTING: Cardiac units of two tertiary referral hospitals. SUBJECTS: 38 Patients with stable congestive heart failure caused by ischaemic heart disease. METHODS: Data were collected over a 24 hour period and assessed with the aim of distinguishing between the haemodynamic effects on plasma concentrations of atrial natriuretic peptide and the direct effects of the study drug, vasopressin concentrations, and angiotensin converting enzyme activity. RESULTS: Pulmonary capillary wedge pressure was the main predictor of the plasma concentration of atrial natriuretic peptide. A higher plasma concentration of this peptide with a given pulmonary capillary wedge pressure was found after 24 hours of treatment with 2.5 mg and 5 mg of ramipril. Plasma concentration of the active metabolite, change in arginine vasopressin concentration or degree of angiotensin converting enzyme inhibition did not significantly predict change in plasma concentration of atrial natriuretic peptide or in the ratio of atrial natriuretic peptide concentration to pulmonary capillary wedge pressure. CONCLUSIONS: A gradual increase in plasma concentration of atrial natriuretic peptide with a given pulmonary capillary wedge pressure, occurs during short term high degree inhibition of angiotensin converting enzyme. The causative mechanisms are yet to be identified. Such a change in the relation between central haemodynamics and atrial natriuretic peptide concentration may contribute to the beneficial effects of angiotensin converting enzyme inhibition in patients with congestive heart failure due to ischaemic heart disease.

Short-term effects of eating on vasoactive hormones and haemodynamics in patients with heart failure.

OBJECTIVES: To investigate if eating can influence the measurements of vasoactive hormones or their relationship to important haemodynamic variables. DESIGN: Haemodynamic variables and plasma concentrations of atrial natriuretic peptide (ANP), arginine vasopressin and angiotensin enzyme (ACE) activity were measured. During the 24-h study period the patients ate ordinary hospital meals and thus were studied both in the absorptive and post-absorptive phases. SETTING: Two university hospitals in Sweden participated in the study. SUBJECTS: Ten patients with heart failure, due to ischaemic heart disease. INTERVENTION: Eating. MAIN OUTCOME MEASURES: Change in haemodynamic variables and plasma concentrations of vasoactive hormones related to eating. RESULTS: After a meal (absorptive phase) pulmonary capillary wedge pressure and plasma concentrations of ANP were significantly lower compared to the postabsorptive phase, 13 +/- 1.7 vs. 16 +/- 1.9 mmHg and 57 +/- 9.5 vs. 72 +/- 12.2 pmol l-1, respectively. The relationship between ANP and its main predictor, pulmonary capillary wedge pressure, was not altered during the study period. Plasma concentration of arginine vasopressin, ACE activity and mean right atrial pressure decreased with time and the cardiac index increased with time over the study period. CONCLUSIONS: A meal may significantly influence plasma concentrations of ANP. Studies on vasodilator treatment and its interactions with ANP should take account of these basal fluctuations. The present data confirm previous reports on haemodynamic improvement during the first 24 h of supine cardiac catheterization in patients with heart failure, and add new information about decreasing concentrations of arginine vasopressin and ACE.

Acute haemodynamic effects and pharmacokinetics of ramipril in patients with heart failure. A placebo controlled three-dose study.

The aim of the present study was primarily to evaluate the haemodynamic effects of the ACE-inhibitor ramipril which is active via its metabolite ramiprilat. Ramipril 1.25, 2.5 and 5 mg and placebo was administered orally to 4 groups of 12 patients with heart failure (NYHA III) in a double-blind randomised, parallel study. Haemodynamics were monitored for 24 h and blood was sampled and urine collected for up to 96 h. In the placebo-treated group the cardiac index (CI) was significantly increased (15.8%) and right atrial pressure decreased (26.6%). Ramipril 1.25 mg had insignificant haemodynamic effects compared to placebo and the 2.5 mg dose had significant effects on some haemodynamic variables. Ramipril 5 mg had pronounced and sustained effects on pulmonary artery pressure, which fell by 43.7%, and pulmonary capillary wedge pressure (PCWP; -59.1%); systemic vascular resistance was also decreased 21%. A significant effect on CI was only seen after 2.5 mg ramipril (+7.4%). The mean maximal degree of ACE inhibition was 73.2, 90.4 and 98.5%, respectively, after the three doses of ramipril. Complete inhibition of ACE-activity was seen at a mean plasma concentration of ramiprilat of 4.7 ng.ml-1. The degree of inhibition declined with a half life of about 75 h. There was a significant relation between the degree of ACE-inhibition and change in PCWP but not with the change in SVR. Ramipril was mainly eliminated in the form of ramiprilat and inactive metabolites.

Side effects of long acting cholinesterase inhibitors.

This paper reviews the side effects of the two long acting cholinesterase inhibitors tacrine and velnacrine. It will focus on tacrine which has been most studied. The two drugs are special as the dosage of them is guided mainly by side effects and not by therapeutic effects in contrast to most drugs used for psychiatric disorders.