Bodil Roth

Enantiomers of thalidomide: blood distribution and the influence of serum albumin on chiral inversion and hydrolysis.

The aim of this investigation was to elucidate the distribution and reactions of the enantiomers of thalidomide at their main site of biotransformation in vivo, i.e., in human blood. Plasma protein binding, erythrocyte: plasma distribution, and the kinetics of chiral inversion and degradation in buffer, plasma, and solutions of human serum albumin (HSA) were studied by means of a stereospecific HPLC assay. The enantiomers of thalidomide were not extensively bound to blood or plasma components. The geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide. The corresponding geometric mean blood:plasma concentration ratios were 0.86 and 0.95 (at a haematocrit of 0.37) and erythrocyte:plasma distributions were 0.58 and 0.87. The rates of inversion and hydrolysis of the enantiomers increased with pH over the range 7.0-7.5. HSA, and to a lesser extent human plasma, catalysed the chiral inversion, but not the degradation, of (+)-(R)- and (-)-(S)-thalidomide. The addition of capric acid or preincubation of HSA with acetylsalicylic acid or physostigmine impaired the catalysis to varying extents. Correction for distribution in blood enhances previously observed differences between the pharmacokinetics of the enantiomers in vivo. The findings also support the notion that chiral inversion in vivo takes place mainly in the circulation and in albumin-rich extravascular spaces while hydrolysis occurs more uniformly in the body. In addition, the chiral inversion and hydrolysis of thalidomide apparently occur by several different mechanisms.

Intravenous Formulations of the Enantiomers of Thalidomide: Pharmacokinetic and Initial Pharmacodynamic Characterization in Man

Thalidomide, a racemate, is coming into clinical use as an immunomodulating and antiinflammatory drug. These effects may chiefly be exerted by S‐thalidomide, but the enantiomers are interconverted in‐vivo. Thalidomide is given orally, although parenteral administration would be desirable in some clinical situations. The aim of this study was to prepare solutions of the enantiomers of thalidomide for intravenous administration and to investigate their pharmacokinetics and sedative effects following infusion in man.

Drug Metabolism: Hydroxylated Metabolites of Thalidomide: Formation In-vitro and In-vivo in Man

There is renewed interest in the clinical use of thalidomide, because of its unique immunomodulating action. Because data on the metabolism of thalidomide in man are very sparse, the aim of this study was to develop HPLC assays for the 5‐hydroxy, 5,6‐dihydroxy, 4,5‐dihydroxy and 5′‐hydroxy metabolites of thalidomide and to investigate their possible formation in man—in‐vitro in liver homogenates and in‐vivo in healthy volunteers.

Ketamine and midazolam decrease cerebral blood flow and consequently their own rate of transport to the brain: An application of mass balance pharmacokinetics with a changing regional blood flow

Mass balance pharmacokinetics, with simultaneous blood sampling from an artery and the internal jugular vein, was used to characterize the cerebral uptake of ketamine, norketamine, and midazolam in normoventilated pigs. Intravenous injections of ketamine or midazolam decreased the cerebral blood flow (CBF)by one third, as measured by intermittent133Xewashout. By means of pharmacodynamic models, the effects on the CBFcould be predicted from the arterial drug concentrations. The high-resolution CBFvs. time curves thus generated allowed the calculation of cerebral drug levels from arteriovenous concentration gradients in spite of a continuously changing regional blood flow. By their effects on the CBF,ketamine and midazolam decreasetheir own rateof transport to the brain, the immediate 30-35% drops in CBFgiving similar reductions in initial net influx of drug. Physiological pharmacokinetic models assuming a constant regional blood flow are therefore not appropriate. Under clinical conditions, the CBFis determined mainly by the effects of the anesthetics and by the arterial CO2tension. CBFchanges in either direction influence the transport of drugs to the brain and may consequently result in impaired or exaggerated drug effects.

Acute administration of diclofenac, but possibly not long term low dose aspirin, causes detrimental renal effects in heart failure patients treated with ACE-inhibitors.

Non‐steroidal anti‐inflammatory drugs (NSAID) or high doses of aspirin (acetylsalicylic acid) can exert detrimental effects on renal function and counteract the beneficial effects of angiotensin‐converting enzyme (ACE) inhibitors in patients with congestive heart failure.

Ultralong Peripheral Nerve Block by Lidocaine:Prilocaine 1:1 Mixture in a Lipid Depot Formulation: Comparison of In Vitro, In Vivo, and Effect Kinetics.

Background:The aim of this study was to develop stable and easily injectable lipid depot preparations of local anesthetics in which the drug concentration can be varied according to desired duration of action. Methods:The formulations contained a 2.0, 5.0, 10, 20, 40, 60, 80, or 100% eutectic mixture of lidocaine and prilocaine base in medium-chain triglyceride. Duration of sciatic nerve block and local neurotoxicity was investigated in rats with 2.0% lidocaine:prilocaine HCl solution and 99.5% ethanol as controls. The rate of release of local anesthetic from the site of administration and the possibility to predict in vivo depot characteristics from in vitro release data were investigated for the 20 and 60% formulations. Results:The duration of sensory sciatic block was prolonged 3 times with the 20% formulation and approximately 180 times with the 60% formulation, in comparison with the 2% aqueous solution. With the 80 and 100% formulations, all animals still showed nerve block after 2 weeks. The in vivo release of local anesthetic could be approximately predicted from in vitro data for the 20% but not for the 60% formulation. The formulations of 60% or greater and ethanol showed neurotoxic effects. Conclusions:The pharmaceutical properties of these formulations compare favorably with those of other depot preparations. The high-percentage ones showed the longest duration of action yet reported for sciatic nerve block in rats. The possibility of using a high-concentration local anesthetic depot formulation as an alternative to ethanol or phenol for long-term nerve blocks in chronic pain merits further investigation.

Gastrointestinal symptoms and psychological well-being in patients with microscopic colitis

Abstract Objective. Microscopic colitis (MC) and irritable bowel syndrome (IBS) are both gastrointestinal disorders with female predominance that affect well-being. Autoantibodies against gonadotropin-releasing hormone (GnRH) have recently been detected in IBS patients. The purpose of this study was to compare gastrointestinal symptoms and well-being in MC female outpatients, with or without coexisting IBS-like symptoms, and to examine the prevalence of GnRH antibodies in these patients. Material and methods. Women with biopsy-verified MC, at any outpatient clinic of the Departments of Gastroenterology, Skåne, between 2002 and 2010 were invited to participate in the study. The questionnaires Gastrointestinal Symptom Rating Scale (GSRS), Psychological General Well-being Index (PGWB), Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS), and Rome III were answered and blood samples collected. Autoantibodies (IgG, IgA, and IgM) against GnRH and GnRH-R (extracellular peptide of receptor) were determined by an enzyme-linked immunosorbent assay. Results. Altogether, 158 (66%) of 240 invited patients with MC were recruited to the study. Of these, 133 (55%) patients also accepted to provide blood samples. Patients with IBS-like symptoms (55%) experienced more symptoms and worse psychological well-being in all dimensions in GSRS and PGWB, and in all symptoms but constipation in VAS-IBS compared to patients without IBS symptoms. Only a minority of patients expressed antibodies against GnRH or GnRH-R, which did not differ between groups. Conclusions. MC patients fulfilling criteria for IBS experience more gastrointestinal symptoms and worse psychological well-being than those who do not. Autoantibodies against GnRH or GnRH-R are not frequently observed in MC patients.

Autoantibodies and gastrointestinal symptoms in infertile women in relation to in vitro fertilization

BackgroundPrior reports suggest a link between gonadotropin-releasing hormone (GnRH) and gastrointestinal function. The aim of the study was to prospectively investigate women subjected to in vitro fertilization (IVF) using the GnRH analog buserelin, taking into account gastrointestinal symptoms and antibody development against buserelin, GnRH, luteinizing hormone (LH), and their receptors.MethodsGastrointestinal symptoms were registered by the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS) before and after IVF treatment, and five years later. Health-related quality of life was evaluated by the 36-item Short-Form questionnaire (SF-36). ELISA was used for antibody analyses before and after treatment. Data were compared with women from the general population.ResultsIn total, 124 patients were investigated before and after IVF, and 62 were re-evaluated after five years. Buserelin treatment led to significant impairment of constipation (p = 0.004), nausea and vomiting (p = 0.035), psychological well-being (p = 0.000), and the intestinal symptoms’ influence on daily life (p = 0.027). At 5-year follow-up, abdominal pain was worsened (p = 0.041), but psychological well-being was improved (p = 0.036), compared to prior treatment, and 15% had an observable deterioration in gastrointestinal symptoms. None developed severe dysmotility. Patients had higher prevalence of IgG antibodies against LH (p = 0.001) and its receptor (p = 0.016), and IgM antibodies against the GnRH receptor (p = 0.001) prior treatment compared with controls, but no antibody development was observed after IVF.ConclusionPatients experience gastrointestinal symptoms during buserelin treatment, and abdominal pain is still increased after five years, but buserelin does not increase antibody formation against GnRH, LH or their receptors.

Smoking- and alcohol habits in relation to the clinical picture of women with microscopic colitis compared to controls

BackgroundMicroscopic colitis (MC) induces gastrointestinal symptoms, which are partly overlapping with irritable bowel syndrome (IBS), predominately in middle-aged and elderly women. The etiology is unknown, but association with smoking has been found. The aim of this study was to examine whether the increased risk for smokers to develop MC is a true association, or rather the result of confounding factors. Therefore, patients suffering from MC and population-based controls from the same geographic area were studied regarding smoking- and alcohol habits, and other simultaneous, lifestyle factors, concerning the clinical expression of the disease.MethodsWomen at the age of 73 years or younger, who had been treated for biopsy-verified MC at any of the Departments of Gastroenterology in Skåne, between 2002 and 2010, were invited to the study (240 patients). Women (737) from the population-based prospective cohort study, Malmö Diet and Cancer Study (MDCS), served as controls. A self-administered questionnaire about lifestyle factors, gastrointestinal symptoms, medical conditions and medication at the time for the study was sent by post.ResultsAltogether, 131 women with MC could be included after age-matching with controls (median age 56 years) and exclusion of secondary MC. Patients were divided into persistent MC (MC1) and transient MC (MC2). Past smoking was associated with increased risk to develop MC2 (OR = 2.67, 95 CI = 1.15–6.23), whereas current smoking was associated with increased risk to develop MC1 (OR = 3.18, 95 CI = 1.57–6.42). Concomitant symptoms of IBS were associated with smoking (OR = 4.24, 95 CI = 1.92–9.32). Alcohol drinking had no association with MC or IBS.ConclusionsThe results suggest that past smoking is associated with transient MC, whereas current smoking is associated with persistent MC. Smoking is associated with MC patients with concomitant IBS-like symptoms.

An Okinawan-based Nordic diet improves anthropometry, metabolic control, and health-related quality of life in Scandinavian patients with type 2 diabetes: a pilot trial

Background Our hypothesis was that a modified diet would improve blood glucose control with beneficial impact on weight management and overall health in established diabetes. Objective This prospective interventional study investigated the clinical effect of an Okinawan-based Nordic diet on anthropometry, metabolic control, and health-related quality of life (HRQoL) in Scandinavian type 2 diabetes patients. Design Food was prepared and delivered to 30 type 2 diabetes patients. Clinical information along with data on HRQoL, blood samples, and urine samples were collected during 12 weeks of diet interventions, with follow-up 16 weeks after diet completion. Results After 12 weeks of dietary intervention, a reduction in body weight (7%) (p<0.001), body mass index (p<0.001), and waist circumference (7.0 cm) (p<0.001) was seen. Improved levels of proinsulin (p=0.005), insulin (p=0.011), and fasting plasma glucose (p<0.001) were found already after 2 weeks; these improved levels remained after 12 weeks when lowered levels of C-peptide (p=0.015), triglycerides (p=0.009), total cholesterol (p=0.001), and low-density lipoprotein-cholesterol (p=0.041) were also observed. Insulin resistance homeostasis model assessment for insulin resistance was lowered throughout the study, with a 20% reduction in hemoglobin A1c levels (p<0.001) at week 12, despite reduced anti-diabetes treatment. Lowered systolic blood pressure (9.6 mmHg) (p<0.001), diastolic blood pressure (2.7 mmHg) (p<0.001), and heart and respiratory rates (p<0.001) were accompanied by decreased cortisol levels (p=0.015) and improvement in HRQoL. At follow-up, increased levels of high-density lipoprotein-cholesterol were found (p=0.003). Conclusion This interventional study demonstrates a considerable improvement of anthropometric and metabolic parameters and HRQoL in Scandinavian type 2 diabetes patients when introducing a modified Okinawan-based Nordic diet, independently of exercise or other interventions. Through these dietary changes, anti-diabetes treatment could be decreased or cancelled.