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Background: The aim of this study was to evaluate the effect of bariatric surgery on the defined daily dose of levothyroxine (DDD LT4), thyroid-stimulating hormone (TSH), and free thyroxine (fT4) in female patients with hypothyroidism until 48 months after surgery., Methods: A retrospective observational study of hypothyroid patients who underwent bariatric surgery. Changes in DDD LT4, TSH, and fT4 over a 48 month period after surgery were analyzed., Results: Thirty-seven patients were included: 27 Roux-en-Y gastric bypass (RYGB), 6 sleeve gastrectomy (SG), 3 adjustable gastric band, and 1 one anastomosis gastric bypass. The median DDD LT4 decreased from 125 µg at baseline to 100 µg 12 months after surgery. From 24 to 48 months after surgery, the median DDD LT4 was stable at 125 µg. Most dose adjustments occurred during the first 24 months after surgery. In the time period of 24-48 months after surgery, the dose remained stable in 73.1% of the RYGB patients and in 60.0% of the SG patients. After 48 months in the RYGB group, no significant change in TSH and fT4 levels was observed., Conclusions: Bariatric surgery led to frequent dose adjustments during the first 2 years after surgery. However, 24-48 months after surgery in the majority of patients, the dosage remained stable. No significant change in TSH and fT4 was observed 48 months after RYGB. In the first 2 years after surgery, clinicians should frequently monitor TSH and fT4 for individual dose adjustment of levothyroxine. Thereafter, the frequency of monitoring may be decreased., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Roux-en-Y gastric bypass (RYGB) surgery induces major changes in the gastrointestinal tract that may alter the pharmacokinetics of orally administered drugs. Results from pharmacokinetic studies are sparse. This study aimed to investigate the effect of RYGB on the bioavailability of metoprolol from immediate release (IR) and controlled release (CR) tablets in female patient volunteers before and after surgery., Methods: An explorative, two-phase, single oral dose pharmacokinetic study of metoprolol in female patients undergoing RYGB was carried out. The dose was administered twice in each patient, 1 month before and 6 months after surgery. After intake of either 100 mg of metoprolol IR or CR tablet serum concentration-time profiles of metoprolol were determined. The endpoint was the ratio of AUC after /AUC before of metoprolol., Results: Twelve patients were included in the study (metoprolol IR: 7; metoprolol CR: 5). After intake of a metoprolol IR tablet major intraindividual and interindividual differences for area under the serum concentration versus time curve (AUC) of metoprolol before and after surgery were observed (range ratio AUC 0-10 hours after /AUC 0-10 hours before : 0.74-1.98). For metoprolol CR tablets a significant reduction in bioavailability of metoprolol was observed after surgery (range ratio AUC 0-24 hours after /AUC 0-24 hours before : 0.43-0.77)., Conclusion: RYGB may influence the bioavailability of metoprolol from an IR tablet. The magnitude of changes in bioavailability after RYGB requires close monitoring of patients using metoprolol IR tablets and dose adjustment if deemed necessary. RYGB clearly reduces the bioavailability of metoprolol from a CR tablet. After RYGB clinicians may consider to increase the dose according to clinical response., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

We describe a 27-year-old female with repeated episodes of pulseless electrical activity due to intoxication with a substance that was unidentified at presentation. Severe QRS widening was observed and empiric treatment with sodium bicarbonate and intravenous lipid emulsion was administered. In this case, intraosseous administration of lipid emulsion failed to improve haemodynamic parameters, suggesting that this dose remained in the bone marrow compartment. We recommend that physicians become aware of this possibility and to avoid intraosseous administration of lipid emulsion.

Background: The Roux-en-Y gastric bypass (RYGB) is a bariatric procedure, greatly reducing the stomach size and bypassing the duodenum and proximal jejunum. Hence, RYGB may reduce the absorption and bioavailability of oral medication. For clinical decisions on the use of medication, knowledge of altered modifications in drug disposition is a prerequisite. An in vitro dissolution method for solid oral medications, simulating conditions before and after RYGB, might be a valuable tool to predict the pharmaceutical availability of medicines frequently used by patients after RYGB., Objectives: To develop a gastrointestinal simulation system (GISS), mimicking conditions before and after RYGB for investigating dissolution characteristics of solid oral medications, and to assess the pharmaceutical availability of metoprolol from immediate-release (IR) and controlled-release (CR) tablets under these conditions., Methods: With an adjusted, pharmacopoeial paddle dissolution apparatus, the GISS enables variation in parameters which are relevant to drug release in vivo: pH, volume, residence time, osmolality and agitation. Metoprolol tartrate 100 mg IR tablets and metoprolol CR tablets were tested. Release profiles were determined by measuring the concentrations of metoprolol spectrophotometrically., Results: From IR tablets, under all conditions applied, >85% of metoprolol was released within 25 min. From all tested CR tablets >90% of metoprolol was released after 22 hours., Conclusions: This GISS is a suitable dissolution system to assess pharmaceutical availability before and after RYGB. In patients who have undergone RYGB, no problems in pharmaceutical availability of metoprolol IR and CR tablets are to be expected. Any changes in response to metoprolol in patients after RYGB should therefore be ascribed to changes in bioavailability., Competing Interests: Competing interests: None declared.

Background: Use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in bariatric surgery patients. If use of an NSAID is inevitable, a proton pump inhibitor (PPI) should also be used., Aim: To determine the effect of an, compared to care-as-usual, additional intervention to reduce NSAID use in patients who underwent bariatric surgery, and to determine the use of PPIs in patients who use NSAIDs after bariatric surgery., Methods: A randomized controlled intervention study in patients after bariatric surgery. Patients were randomized to an intervention or a control group. The intervention consisted of sending a letter to patients and their general practitioners on the risks of use of NSAIDs after bariatric surgery and the importance of avoiding NSAID use. The control group received care-as-usual. Dispensing data of NSAIDs and PPIs were collected from patients' pharmacies: from a period of 6 months before and from 3 until 9 months after the intervention., Results: Two hundred forty-eight patients were included (intervention group: 124; control group: 124). The number of users of NSAIDs decreased from 22 to 18 % in the intervention group and increased from 20 to 21 % in the control group (NS). The use of a PPI with an NSAID rose from 52 to 55 % in the intervention group, and from 52 to 69 % in the control group (NS)., Conclusions: Informing patients and their general practitioners by letter, in addition to care-as-usual, is not an effective intervention to reduce the use of NSAIDs after bariatric surgery (trial number NTR3665).

Purpose: Bariatric surgery can influence the prevalence and incidence of comorbidities, as well as the pharmacokinetics of drugs. This might lead to changes in the use of drugs. This study aimed to assess the influence of bariatric surgery on the use of medication in patients before and after surgery, focusing on type, number of medications, and daily dosage., Methods: In a retrospective and prospective observational study, drug dispensing data from pharmacies of patients undergoing their first bariatric surgery between January 2008 and September 2011 was collected. Dispensing data from 1 month before until 12 months after surgery was analyzed. Drugs were classified according to the WHO-ATC classification system. Dosages of drugs were compared using defined daily dose (DDD)., Results: Among 450 patients, 12 months after surgery, the mean number of drugs per patient for antidiabetics, drugs acting on the cardiovascular system, anti-inflammatory and antirheumatic drugs, and drugs for obstructed airway diseases decreased by, respectively, 71.3 % (95 % CI 57.2 to 85.4), 34.5 % (95 % CI 28.2 to 43.0), 45.5 % (95 % CI 13.3 to 72.6), and 33.1 % (95 % CI 15.3 to 53.2). Patients used lower median DDD of oral antidiabetics, beta-blocking agents, and lipid-modifying drugs., Conclusions: For some major drug classes 12 months after bariatric surgery, the use of drugs decreases in terms of mean number per patient. A reduction in dose intensity was observed for oral antidiabetics, beta-blocking agents, and lipid-modifying drugs. Dispensing data from pharmacies may provide detailed information on the use of medications by patients after bariatric surgery.

Importance: To our knowledge, an observational study on the remission of type 2 diabetes mellitus (T2DM) after different types of bariatric surgery based on data from general practice has not been carried out., Objective: To assess the effect of different types of bariatric surgery in patients with T2DM on diabetes remission compared with matched control patients, and the effect of the type of bariatric surgery on improvement of glycemic control and related clinical parameters., Design, Setting, and Participants: A retrospective cohort study conducted from May 2013 to May 2014 within the Clinical Practice Research Datalink involving 2978 patients with a record of bariatric surgery (2005-2012) and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or greater. We identified 569 patients with T2DM and matched them to 1881 patients with diabetes without bariatric surgery. Data on the use of medication and laboratory results were evaluated., Exposures: Bariatric surgery, stratified by type of surgery (gastric banding, Roux-en-Y gastric bypass, sleeve gastrectomy, or other/unknown)., Main Outcomes and Measures: Remission of T2DM (complete discontinuation of glycemic therapy, accompanied with a subsequently recorded hemoglobin A1c level<6.0%)., Results: Among patients undergoing bariatric surgery, we found a prevalence of 19.1% for T2DM. Per 1000 person-years, 94.5 diabetes mellitus remissions were found in patients who underwent bariatric surgery compared with 4.9 diabetes mellitus remissions in matched control patients. Patients with diabetes who underwent bariatric surgery had an 18-fold increased chance for T2DM remission (adjusted relative rate [RR], 17.8; 95% CI, 11.2-28.4) compared with matched control patients. The greatest effect size was observed for gastric bypass (adjusted RR, 43.1; 95% CI, 19.7-94.5), followed by sleeve gastrectomy (adjusted RR, 16.6; 95% CI, 4.7-58.4) and gastric banding (adjusted RR, 6.9; 95% CI, 3.1-15.2). Body mass index and triglyceride, blood glucose, and hemoglobin A1c levels sharply decreased during the first 2 years after bariatric surgery., Conclusions and Relevance: Population-based data show that bariatric surgery strongly increases the chance for remission of T2DM. Gastric bypass and sleeve gastrectomy have a greater effect than gastric banding. Although the risks and possible adverse effects of surgery should be weighed against its benefits, bariatric surgery and, in particular, gastric bypass or sleeve gastrectomy may be considered as new treatment options for T2DM.

The purpose of this review is to evaluate the influence of bariatric surgery on the use and pharmacokinetics of some frequently used drugs. A PubMed literature search was conducted. Literature was included on influence of bariatric surgery on pharmacoepidemiology and pharmacokinetics. Drug classes to be searched for were antidepressants, antidiabetics, statins, antihypertensive agents, corticosteroids, oral contraceptives, and thyroid drugs. A reduction in the use of medication by patients after bariatric surgery has been reported for various drug classes. Very few studies have been published on the influence of bariatric surgery on the pharmacokinetics of drugs. After bariatric surgery, theoretically, reduced drug absorption may occur. Correct dosing and choosing the right dosage form for drugs used by patients after bariatric surgery are necessary for optimal pharmacotherapy. Therefore, more clinical studies are needed on the influence of bariatric surgery on the pharmacokinetics of major drugs.

Rationale: The bronchodilating potency of magnesium sulphate (MgSO₄) has been shown in acute asthma exacerbations. We hypothesized that smooth muscle cell relaxation by magnesium might also be beneficial in chronic severe asthma with persistent airflow limitation., Aim: To investigate whether nebulised magnesium, administered according to a dosing scheme shown to be effective in acute asthma, induces bronchodilation in stable asthma patients with persistent airflow limitation., Methods: In a placebo-controlled, cross-over study, 13 severe asthma patients with postbronchodilator FEV₁ < 75% predicted received either 2.5 mL MgSO₄ 6.4% or placebo in 3 nebulisations at 30 minute intervals. Before the first and 30 minutes after the last inhalation FEV₁, exhaled nitric oxide (NO) in dyspnoea (Borg) were measured., Results: After MgSO₄ treatment no improvement in FEV₁ occurred (56.2 ± 16.8 to 55.4 ± 17.4% predicted [p = 0.5]), neither was a change in exhaled NO or Borg observed (p > 0.1). The changes in FEV₁, NO or Borg were not different between the treatment arms (p ≥ 0.09)., Conclusion: Short-term treatment with magnesium inhalations had no direct bronchodilating effect in stable severe asthma patients with persistent airflow limitation. Yet, clinical observations suggest a heterogeneity in response, probably related to treatment intensity, and support further exploration of magnesium administration in these patients.

Objectives: To study the relation between serum and peritoneal levels of amphotericin B and flucytosine during intravenous treatment in patients with abdominal sepsis due to a perforated gut., Patients and Methods: Included were consecutive patients with abdominal sepsis due to a perforated gut, who were treated intravenously with amphotericin B and/or flucytosine after surgery if an abdominal drain was present. Amphotericin B and flucytosine were measured from simultaneously collected serum and abdominal fluid samples., Results: Twenty-one consecutive patients were included. Five repeated samples were taken from three patients. The time interval between the start of the medication and the first sampling was median 4.0 days (range 2-7 days). The correlation coefficient (r(2)) between serum and peritoneal levels of amphotericin B was 0.79. In nine patients (43%) with a maximum serum level of 0.28 mg/L, amphotericin B in the peritoneal fluid was undetectable. The lowest serum level that was present with a detectable peritoneal level was 0.16 mg/L. A short duration of treatment (2 days) was associated with low serum and undetectable peritoneal levels. In seven patients, flucytosine levels were measured. Peritoneal flucytosine levels did not differ significantly from serum levels. Serum and peritoneal flucytosine levels correlated well with r(2)=0.88. Peritoneal amphotericin B level was inversely correlated with C-reactive protein level on the same day (r(2)=0.30)., Conclusions: It is shown, during continuous infusion, that peritoneal levels of amphotericin B are lower than serum levels. The amphotericin B serum levels should exceed 0.5 mg/L to obtain peritoneal levels above MIC values. Flucytosine levels in the abdominal fluid are comparable to serum levels and within MIC ranges.

Background: Leflunomide is the prodrug of the disease modifying antirheumatic metabolite A77 1726. More than 50% of patients withdraw from leflunomide treatment within one year, mainly because of adverse drug reactions. Therapeutic drug monitoring of A77 1726 may be useful in predicting the efficacy of leflunomide treatment., Objective: To study the relation between A77 1726 steady state serum concentrations and disease activity using the 28 joint (DAS28) response., Methods: Outpatients with rheumatoid arthritis on a stable leflunomide dose for >4 months were included. DAS28 score and adverse drug reactions were recorded. Blood samples were taken for determination of A77 1726 concentrations. The primary end point was the relation of serum A77 1726 concentrations with DAS28 response category., Results: Serum A77 1726 concentrations were determined in 52 patients. A receiver operating characteristic (ROC) curve showed an area under the curve (AUC) of 0.73 (95% confidence interval, 0.54 to 0.93) (p<0.05). The sensitivity exceeded 99% at concentrations below 16 mg/l. DAS28 values at the point of sampling showed no relation with A77 1726 concentrations (AUC of the ROC curve = 0.50 (0.33 to 0.67) (NS))., Conclusions: A77 1726 steady state serum concentrations show a relation with DAS28 response. Determination of serum A77 1726 concentrations in patients with insufficient response to treatment may help when decisions have to be made about continuation of treatment or dose adjustment.

Introduction: Valproic acid is increasingly used in the treatment of epilepsy, and also prescribed for bipolar affective disorders, schizoaffective disorders, schizophrenia and migraine prophylaxis. We describe two case reports involving valproic acid intoxication with ingestion of ethanol., Methods: One patient was treated by supportive care, one patient received haemodialysis., Results: From analysis of plasma concentrations before and during haemodialysis (pre- and post-filter) it is shown that valproic acid can be effectively eliminated by haemodialysis when plasma levels are way above 100 microg/ml. In the literature, plasma protein binding is reported to be around 90% for levels within the therapeutic range. In our patient plasma protein binding was around 50% after treatment with haemodialysis., Conclusion: These findings make haemodialysis in valproic acid intoxication a sensible therapeutic option with increasing efficiency when plasma concentration is high. Furthermore our findings suggest that lowering valproic acid concentrations to a therapeutic level by haemodialysis does not necessarily result in an immediate, simultaneous increase in plasma protein binding of valproic acid.

Leflunomide is a disease-modifying antirheumatic drug, which is bioactivated by formation of A77 1726. In this study a rapid and simple quantitative assay using a reversed phase HPLC-UV method is validated for detection of A77 1726 in human serum. The HPLC-UV method uses a mobile phase consisting of methanol and a KH2PO4-buffer (45 mM, pH = 3) (50:50,v/v), at a flow rate of 1 mL/min. A77 1726 is detected by UV-absorption at 295 nm with a retention time of 8.9 min. Demoxepam is used as internal standard. Validation showed lower and upper limits of quantitation of 0.5 and 100 mg/L, respectively. The assay was linear over the concentration range of 0.5-100 mg/L (r2 > 0.999). Intra- and inter-day precision showed coefficients of variation within 15% over the complete concentration range; accuracy was within 8%. Commonly prescribed drugs to treat rheumatoid arthritis like disease-modifying antirheumatic drugs, analgesics and corticosteroids, and their main metabolites, are separated from A77 1726 with a resolution >2. Serum levels of A77 1726 in 37 patients on leflunomide therapy were determined using this HPLC-UV method. Measured serum A77 1726 serum concentrations in patient samples showed large variability with a range of 3-176 mg/L.

Purpose: A three-way crossover study with seven healthy male volunteers was conducted to determine the relative bioavailability of phenobarbital after single dose administration of 100 mg of phenobarbital as oral solution in Myvacet 9-08, and as a suspension, compared with a 100 mg phenobarbital tablet., Materials and Methods: At 4-week intervals each subject received the solution in Myvacet 9-08, the suspension and the tablet in randomized order. Blood samples were collected for 48 h after each dose for analysis of phenobarbital. From the individual serum concentration-versus-time curves Cmax and Tmax were determined and AUC0-48 was calculated., Results: All three oral dosage forms of phenobarbital are bioequivalent. No significant differences in Tmax were observed., Conclusion: The oral solution in Myvacet 9-08, and the suspension of phenobarbital proved to be bioequivalent to a tablet.

Rectal absorption of morphine HCl from aqueous vehicles at different pHs in man has been compared with an orally administered solution. Plasma concentrations of morphine were measured by electrochemical HPLC analysis after a single dose of 10 mg morphine HCl, in a cross-over study in 7 volunteers. Rectal absorption of morphine was dependent on pH, which could be explained as being due to pH partitioning. The absorption rate and bioavailability could be greatly improved, as compared to orally administered morphine, by adjusting the pH. It was concluded that a rectal solution adjusted to pH 7 to 8 provided an entirely adequate dosage form.