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Introduction: Tobramycin is one of the components used for selective decontamination of the digestive tract (SDD), applied to prevent colonization and subsequent infections in critically ill patients. Tobramycin is administered in the oropharynx and gastrointestinal tract and is normally not absorbed. However, critical illness may convey gut barrier failure. The aim of the study was to assess the prevalence and amount of tobramycin leakage from the gut into the blood, to quantify tobramycin excretion in urine, and to determine the association of tobramycin leakage with markers of circulation, kidney function and other organ failure.Methods: This was a prospective observational cohort study. The setting was the 20-bed closed format-mixed ICU of a teaching hospital. The study population was critically ill patients with an expected stay of more than two days, receiving SDD with tobramycin, polymyxin-E and amphotericin-B four times daily in the oropharynx and stomach. Tobramycin concentration was measured in serum (sensitive high performance liquid chromatography - mass spectrometry/mass spectrometry (HLPC-MS/MS) assay) and 24-hour urine (conventional immunoassay), in 34 patients, 24 hours after ICU admission, and in 71 patients, once daily for 7 days. Tobramycin leakage was defined as tobramycin detected in serum at least once (> 0.05 mg/L). Ototoxicity was not monitored.Results: Of the 100 patients with available blood samples, 83 had tobramycin leakage. Median highest serum concentration for each patient was 0.12 mg/L; 99% of the patients had at least one positive urinary sample (> 0.5 mg/L), 49% had a urinary concentration ≥ 1 mg/L. The highest tobramycin serum concentration was significantly associated with vasopressor support, renal and hepatic dysfunction, and C-reactive protein. At binary logistic regression analysis, high dopamine dose and low urinary output on Day 1 were the significant predictors of tobramycin leakage. Nephrotoxicity could not be shown.Conclusions: The majority of acute critically ill patients treated with enteral tobramycin as a component of SDD had traces of tobramycin in the blood, especially those with severe shock, inflammation and subsequent acute kidney injury, suggesting loss of gut barrier and decreased renal removal. Unexpectedly, urinary tobramycin was above the therapeutic trough level in half of the patients. Nephrotoxicity could not be demonstrated. [ABSTRACT FROM AUTHOR]

Background: Joint replacement surgery of the lower extremities are common procedures in elderly persons who are at increased risk of postoperative falls. The use of mental state altering medications, such as opioids, antidepressants or benzodiazepines, can further contribute to impaired balance and risk of falls. The objective of the current systematic review was to evaluate the risk of the use of mental state altering medications on postoperative falls in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA)., Methods: A comprehensive search of Medline, Embase and Cochrane Controlled Trials Register was conducted from 1 October 1975 to 1 September 2021. The search was repeated in may 2023 and conducted from 1 October 1975 to 1 June 2023. Clinical trials that evaluated the risk of medication on postoperative THA and TKA falls were eligible for inclusion. Articles were evaluated independently by two researchers for risk of bias using the Newcastle-Ottawa Scale. A meta-analysis was performed to determine the potential effect of postoperative use of mental state altering medications on the risk of falls. Lastly, a qualitative synthesis was conducted for preoperative mental state altering medications use., Results: Seven cohort studies were included, of which five studies focussed on the postoperative use of mental state altering medications and two investigated the preoperative use. Meta-analysis was performed for the postoperative mental state altering medications use. The postoperative use of mental state altering medications was associated with fall incidents (OR: 1.81; 95% CI: 1.04; 3.17) (p < 0.01) after THA and TKA. The preoperative use of opioids > 6 months was associated with a higher risk of fall incidents, whereas a preoperative opioid prescription up to 3 months before a major arthroplasty had a similar risk as opioid-naïve patients., Conclusions: The postoperative use of mental state altering medications increases the risk of postoperative falls after THA and TKA. Prior to surgery, orthopaedic surgeons and anaesthesiologists should be aware of the associated risks in order to prevent postoperative falls and associated injuries., (© 2024. The Author(s).)

Background: A short acting spinal anesthetic facilitates smooth flow since quick recovery of motor function will facilitate unassisted ambulation. The aim of this study was to estimate the effective dose (ED90) of intrathecal 2-chloroprocaine 1% in outpatient knee arthroscopy., Methods: Two cohorts were included in two different hospitals. In cohort I, a randomized biased-coin up-and-down design with 40 patients was used to find the ED90. Four dose-levels of plain 2-chloroprocaine 1% were used: 25, 30, 35 and 40 mg. The identified primary outcome, the ED90, was validated in 50 patients in cohort II with an open label design. Secondary outcomes included time to complete recovery from motor and sensory block with spinal injection as time zero, peak sensory block level, urine retention and time until hospital discharge., Results: Forty patients were included in the final analysis in cohort I. The ED90 was estimated at 27.8 mg, successful spinal anesthesia was obtained in 38 patients (95%). Fifty patients were included in the final analysis in cohort II, 49 patients had successful anesthesia with a fixed round dose of 28 mg. In this Cohort, peak sensory block was T10/T11 (range: (L4-T4)). The median time to full recovery of the motor block was 60 min (45-60) and 90 min (75-105) for the sensory block. The mean time to hospital discharge was 2.9 hours (0.7)., Conclusion: The ED90 of 2-chloroprocaine 1% in knee arthroscopy was estimated to be 27.8 mg. In an external population, the ED90 resulted in successful anesthesia in 98% of the patients (95% CI 89% to 100%)., Trial Registration Number: Netherlands Trial Registry (NL6769)., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Gamma-hydroxybutyrate (GHB) is a drug of abuse with central depressing effects, which may cause coma with a GCS score as low as 3. A rapid diagnosis 'GHB intoxication' may prevent unnecessary diagnostic work-up and may lead to guided, less invasive, treatment. The aim of this study was to evaluate if ED physicians' clinical evaluation were sufficient for diagnosis in patients with suspected GHB-intoxication., Methods: Patients presenting at the ED with a GCS<15 and a potential intoxication with drugs of abuse for whom urine toxicology screen was performed were included consecutively. After a first assessment, the ED physician registered the most likely initial diagnosis in the hospital information system. Urine of these patients was tested with a validated gas chromatography analytical method for GHB (confirmation test). The initial diagnoses were compared for agreement with the results of the confirmation test., Results: A total of 506 patients were included, 100 patients tested positive for GHB and 406 patients tested negative for GHB. Sensitivity and specificity of the ED physicians compared with the confirmation test to diagnose GHB intoxications were 63% (95% CI 52 to 73) and 93% (95% CI 90 to 95), respectively. The positive predictive value was 67% (95% CI 60 to 77) and the negative predictive value was 92% (95% CI 88 to 94)., Conclusion: Physicians underestimate the presence of GHB intoxication and can fail to diagnose GHB intoxication based on clinical observations alone. In the future, a rapid reliable initial analytical GHB test in addition to clinical judgement could be valuable to reduce false negative diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Lung cancer patients have a high risk for drug-drug interactions, as they use numerous types of concomitant medicines including antineoplastic agents, cancer treatment co-medication, and medicines aimed at several types of comorbidities. Objective The primary objective of this study is to determine the incidence and the clinical relevance of the drug-drug interactions between antineoplastic agents and regular medication used by lung cancer patients. Secondary objectives are (i) to determine the effectiveness of the medication review by the hospital pharmacists concerned, (ii) to establish which patients are most at risk of drug-drug interactions and (iii) to determine whether physicians comply with advice given by hospital pharmacists. Setting This prospective study was undertaken in a Dutch hospital pharmacy, at Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam. Methods All lung cancer patients receiving one or more cytotoxic agents during the period 21 June 2010 till 2 December 2014 at OLVG were included. The medication list of the patients was obtained electronically from the community pharmacy and checked for interactions by a hospital pharmacist. Interactions that required intervention according to the national database were the only ones taken into account. Interventions were recorded in the patients' electronic charts. All medication reviews were cross-checked and analyzed by an independent pharmacist at the end of the study period. Main outcome measure Prevalence and clinical relevance of drug-drug interactions between antineoplastic agents and other types of medication in lung cancer patients. Results A total of 298 lung cancer patients were included in this study. In 53 patients (18%), a total of 73 interactions with potential clinical relevance were found. The most frequent interaction was between cytostatics and coumarins while the most relevant one was between cisplatin and furosemide. According to statistical analysis, gender as well as the number of drugs prescribed were significant predictors for drug-drug interactions. Eighty-four percent of the interactions were discovered by pharmacists during daily routine. In 92% of the cases, the pulmonary physicians complied with the advice of the pharmacist. Conclusion Eighteen percent of lung cancer patients treated with cytotoxic therapy had one or more relevant drug-drug interactions. This study shows that medication surveillance by a hospital pharmacist is necessary to prevent possible negative drug-drug interactions. Further research should focus on the clinical outcome of the interactions as well as on interactions between cytostatics and alternative medicines and/or over-the-counter medicines.

Subjects with obesity and insulin resistance display a low response to a serotonergic challenge test. One of the hallmarks of obesity and insulin resistance is elevated plasma free fatty acids (FFAs). We hypothesize that increasing plasma FFA by infusion of a lipid emulsion, may be a contributing component leading to decreased serotonergic responsivity in healthy young men. Ten lean healthy men, 23.6 ± 5.0 years and BMI 22.6 ± 1.9 kg/m(2), were included. Serotonergic responsivity was assessed using the prolactin response to infusion with citalopram, a selective serotonin reuptake inhibitor, which is a validated tool to assess serotonergic tone. All participants received a lipid/heparin emulsion (Intralipid) infusion during 6 h. Saline infusion was used as a control. To evaluate a possible effect of heparin per se on prolactin, four out of the ten subjects also received heparin only during 6 h without the serotonergic challenge test. Plasma prolactin increased by 74.3 ± 15.5% during saline infusion. Intralipid infusion increased plasma FFA from 0.5 ± 0.05 to 2.3 ± 0.2 mmol/l (p < 0.001). The increase in plasma prolactin during Intralipid infusion was significantly lower (39.3 ± 10%; p < 0.001 compared to saline infusion). Heparin infusion per se increased plasma prolactin by 14.0 ± 1.9%. We found that during the Intralipid infusion with concomitant high plasma FFA levels the serotonergic response was decreased in healthy young men. Higher FFA levels may be the mediator of the decreased serotonergic response reported in patients with insulin resistance and obesity., (Copyright © 2012 S. Karger AG, Basel.)

Background: Therapeutic drug monitoring (TDM) is recommended in several international HIV treatment guidelines. The adherence of clinicians to these recommendations is unknown. The authors evaluated the adherence to the Dutch TDM guideline of 2005., Methods: From the ATHENA cohort study, three scenarios were selected for which the guideline recommended TDM: 1) start of a combination of lopinavir/ritonavir + efavirenz or nevirapine (drug-drug interaction); 2) start of efavirenz (routine TDM); and 3) use of nelfinavir during pregnancy. For each scenario, we determined the proportion of patients for whom TDM was performed. Multivariable logistic regression modeling was used to identify determinants for the use of TDM., Results: The adherence to the TDM guideline was 46.7% in patients who started lopinavir/ritonavir plus efavirenz or nevirapine; 9.5% for patients who started efavirenz; and 58.5% for patients who used nelfinavir during pregnancy. Patients treated in clinics that had a TDM assay available locally and patients treated in academic clinics were more likely to receive TDM. A higher baseline HIV viral load was another significant predictor for the performing TDM., Conclusion: The adherence of clinicians to the Dutch TDM guidelines varied from low to moderate for the three investigated TDM scenarios. This study identifies several determinants for the use of TDM, which may be useful information for those responsible for generating TDM guidelines.

Case: We present the case of a 75-year-old patient admitted to the emergency department after ingesting a large amount of several cardiac drugs, among which were digoxin and sotalol. Because of renal insufficiency, cardiogenic shock, and high serum digoxin levels, the patient received continuous venovenous hemofiltration (CVVH) and digoxin-specific Fab fragments. Digoxin and the digoxin-specific Fab fragments are normally cleared by the kidneys., Methods: Serum-free and total digoxin and serum sotalol concentrations were monitored for several days., Results: Less than 10% of the estimated ingested dose of digoxin was cleared by CVVH within 5 days., Conclusion: CVVH has little influence on the clearance of Fab-bound digoxin from the body. In contrast, sotalol is efficiently cleared by CVVH.

Background: Clinical positron emission tomography (PET) requires safe and effective PET radiopharmaceuticals. Tracers used for measuring oxygen consumption and blood volume are [(15)O]O(2) and [(15)O]CO, respectively. In general, these oxygen-15 labelled tracers are produced using a cyclotron that accelerates deuterons onto a target filled with (14)N(2) containing a trace of oxygen. In recent years, cyclotrons have been developed that only are capable of accelerating protons. The purpose of this study was to validate and assess such a cyclotron for production and administration of oxygen-15 labelled gasses in an hospital setting., Methods: An RDS111 cyclotron (Siemens-CTI, Knoxville, USA) was validated for bolus production of [(15)O]O(2) and [(15)O]CO gasses. In addition, equipment was developed to administer these tracers to patients., Results: Both [(15)O]O(2) and [(15)O]CO gasses could be produced in sufficient amounts, whilst meeting European Pharmacopeia requirements. Although produced oxygen-15 gasses contained a minor level of (11)C contamination, in clinical studies it was possible to correct for this contamination by delayed blood counting., Conclusion: An 11 MeV proton cyclotron combined with an in-house developed gas delivery system allows for the production and administration of sufficient amounts of [(15)O]-gasses for routine clinical PET studies in an hospital setting.

Background: In cases where patients with unipolar depression do not respond to a standard dose of selective serotonin reuptake inhibitors (SSRIS), treatment guidelines often recommend a higher dose. A systematic review of the literature revealed uncertainty about the efficacy of dose escalation and pointed to methodological weaknesses in earlier research., Aim: To review current practice and results concerning dose-escalation of SSRIS., Method: We made a summary of previously published English articles that systematically reviewed previous SSRI-dose-escalation studies in depressed patients and present the results of a recent double-blind randomised dose-escalation study of paroxetine. By means of a 123I-β-cit-spect study in a subgroup of the patients in the recent dose-escalation study it was possible to measure the amount of paroxetine bound to serotonin transporters. This provided combined clinical and pharmacological outcomes., Results: The study with paroxetine provided clinical evidence that dose-escalation of paroxetine in depression was not effective and that adverse effects increased. The occupancy of the serotonin-transporters did not increase significantly after dose-escalation, despite increases in paroxetine serum levels., Conclusion: Dose-escalation of ssris for patients with unipolar depression who did not respond to a standard dose, does not improve response or the chance of remission. The pharmacological explanation for this is that the occupancy of the serotonin-transporters does not increase following dose-escalation.

Objective: A distinctive pattern of physiological symmetrical uptake of 18F-fluorodeoxyglucose (18F-FDG) in the neck and upper chest region is a phenomenon that is sometimes observed on positron emission tomography (PET) scans of some oncologic patients. Initially, it was assumed to be muscle uptake secondary to patient anxiety or tension, which could be prevented by diazepam treatment. However, PET-computed tomography data have shown that 18F-FDG uptake is not restricted to the musculature but is also localised within the non-muscular soft tissue, such as brown adipose tissue. The efficacy of benzodiazepine treatment to reduce this uptake has not been well established. Therefore, a randomised controlled trial was conducted to decide whether diazepam would decrease physiological 18F-FDG uptake in the neck and upper chest region (FDG-NUC)., Methods: A randomised, double-blind, placebo-controlled trial was conducted to assess the effect on FDG-NUC of 5 mg diazepam, given orally 1 h before 18F-FDG injection. Patients younger than 40 years, having or suspected to have a malignancy, were eligible for inclusion. The primary endpoint was FDG-NUC, as assessed by visual analysis of whole-body PET scans by two independent observers. The secondary endpoint was clinical relevance of FDG-NUC., Results: Fifty-two patients were included between September 2003 and January 2005. Twenty-eight patients (54%) received placebo; 24 (46%) received diazepam. FDG-NUC was seen in 25% of the patients in the diazepam group versus 29% in the placebo group. This difference was not statistically significant., Conclusion: No beneficial effect of administration of diazepam could be established. Pre-medication with benzodiazepines to diminish physiological uptake of 18F-FDG in the neck and upper chest region is not indicated.

Cocaine is frequently used, especially among adolescents and by men between the age of 25 and 44. Many of them are able to use cocaine in normal day-to-day life, without any problems. Reduced prices of cocaine and other recreational drugs such as MDMA (ecstasy) and gamma hydroxybutyrate (GHB) has led to an increased incidence of intoxications with these drugs. Since the production of cocaine is illegal, it may be impure and mixtures with other drugs such as atropine may occur. The treatment of patients with an acute cocaine intoxication can be complicated. Combination of cocaine with other drugs results in clinical pictures which are difficult to discriminate and that may have important consequences for treatment.

Dose escalation is often used in depressed patients who fail to respond to standard doses of selective serotonin reuptake inhibitors, but clinical efficacy is equivocal. We aimed to reassess the efficacy of paroxetine dose escalation and quantify whether paroxetine dose escalation increases occupancy of the serotonin transporter (SERT) more than placebo dose escalation in a randomized controlled trial. We recruited 107 nonpsychotic, unipolar depressed outpatients (18-70 years; Hamilton Depression Rating Scale (HDRS(17)) >18) from primary care and psychiatric outpatient departments. After 6 weeks, open-label paroxetine 20 mg per day (T0), nonresponding patients (HDRS(17) decrease <50%; n=60) were randomized to double-blind paroxetine (30-50 mg per day as tolerable) or placebo dose escalation (paroxetine 20 mg per day+placebo). Patients were followed until 6 weeks after randomization (T1). Forty-nine patients, drug free at study entry, underwent single-photon emission-computed tomography (SPECT) scanning before treatment and were scanned repeatedly at T0 and T1. Paroxetine serum concentrations and SERT occupancy were determined at T0 and T1 (n=32). We terminated the dose-escalation trial after an interim analysis. Thirty nonresponding patients were randomized to paroxetine (46.7+/-5.5 mg per day), 27 to placebo dose escalation. Response rates were 10/30 (33.3%) and 10/27 (37.0%), respectively. Repeated measurement analyses showed no significant effect for treatment (p=0.88, exceeding a priori stopping rules for futility (p>0.5)). Overall dropout was higher for placebo (26.7%) than paroxetine (3.3%; p=0.03). Paroxetine dose escalation increased paroxetine serum concentrations (p<0.001). SPECT measurements (12 patients randomized to paroxetine (46.9+/-4.8 mg) and 14 to placebo dose escalation) showed no significant increase of midbrain SERT occupancy (2.5+/-26.4%, paroxetine; 3.1+/-25.8% placebo; p=0.687) nor in diencephalon (p=0.529). Paroxetine dose escalation in depressed patients has no clinical benefit over placebo dose escalation. This is explained by the absence of significant increases of SERT occupancy by paroxetine dose escalation, despite increased paroxetine serum concentrations (ISRCTN44111488).

In this article, 2 cases of intentional dothiepin intoxication are presented. Both patients survived after receiving appropriate supportive care. The dothiepin and metabolite levels were measured at different times after ingestion. The initial levels of dothiepin were 1900 microg/L in case 1 and 5500 microg/L in case 2. In case 1, a toxicokinetic model was fitted, suggesting a higher peak level, corresponding with the QRS duration and clinical symptoms. In case 2, a combined dothiepin-ethanol intoxication was seen, complicating the interpretation of clinical parameters, such as the QRS duration. In conclusion, the severity of dothiepin intoxication is poorly predicted by plasma levels alone, as time of ingestion can be critical for interpretation. However, especially in combined intoxications, interpretation of the QRS duration may also fail. Therefore, it is important to evaluate the whole range of clinical parameters, QRS duration, clinical symptoms, dothiepin concentration(s), and other possible intoxications.

A case of intravenous precipitation of erythromycin is reported along with the patient history, pathologic findings, and a description of the analytical methods and results. The patient was a 75-year-old woman with a history of myocardial infarction, deep venous thrombosis, and diabetes mellitus who underwent aortic valve replacement. She developed endocarditis and recurrent episodes of urosepsis, with multiple organ failure including severe gastric retention, for which she was treated with erythromycin intravenously. She died because of refractory septic shock. Autopsy revealed aortic valve endocarditis, thrombi in the right femoral vein, arterial (nonfungal) thromboemboli in the celiac trunk, and coarse material in the right femoral vein where the tip of the central venous catheter had been located. Microscopical examination of the coarse material showed that it was birefringent crystalline material. Part of the postmortem material was analyzed in the laboratory of the department of clinical pharmacy and revealed the presence of erythromycin. Erythromycin was detected using Fourier transform infrared spectroscopy. An additional specific color test and thin-layer chromatography confirmed this finding. On the basis of the postmortem findings, patient history, and analytical-toxicologic results, we conclude that erythromycin precipitation can occur in vivo after intravenous administration in patients with impaired blood flow.

After oral administration of tobramycin, as part of selective decontamination of the digestive tract (SDD) in critically ill patients, absorption of tobramycin from the gut into the blood may take place. To quantify low concentrations of tobramycin in human plasma, we developed and validated a simple (sample pre-treatment consisting of protein precipitation with acetonitrile using 200microl plasma), rapid (runtime 3min using a Pathfinder MR reversed-phase column) and sensitive (concentration range of 0.05-1.0mg/l using MS/MS detection) method.

Background: Clinically significant pharmacokinetic and pharmacodynamic changes occurring with age make older patients more prone to the consequences of inappropriate prescribing. The combination of higher use of medicines resulting from a higher disease burden with suboptimal treatment monitoring results in a higher risk of unwanted drug effects from sometimes inappropriate choice of drugs, doses and durations of treatment. Pharmacy services are increasingly being targeted to minimize the overall number of unnecessary and potential harmful medicines., Objective: To investigate the impact of a pharmacist-led medication review on quality of prescribing by a healthcare professional team consisting of a general practitioner (GP), care home staff and a pharmacist., Methods: This observational study compared outcome measurements before and after a pharmacist-led review of medications for patients under the care of a healthcare professional team consisting of a GP, care home staff and pharmacist. The procedure for conducting and recording the medication review consisted of the preparation of a patient medication profile, which combined the patient's medical records with his or her complete prescription record (current and previous [last 3 years] medication history) and pharmaceutical record (electronic journal entries for the patient over the same period). Laboratory values were evaluated in clinical context. Recommendations for the pharmaceutical plan were discussed at a conference involving the clinical pharmacist and other healthcare team members. Patients were recruited for medication review over the 12-month period 1 April 2003 to 1 April 2004. Medication appropriateness was assessed by an independent panel of clinical pharmacists using the Medication Appropriateness Index (MAI)., Results: A total of 54 patients were eligible according to the inclusion criteria, of whom 24 were subsequently excluded for various reasons; thus, 30 patients were eligible for assessment on the MAI. There was a statistically significant difference between overall pre- and post-intervention summed MAI scores (p=0.013). The pharmacist identified 115 drug-related problems, and the total number of accepted recommendations was 78 (67.8%). Use of a medication review as an intervention by a clinical pharmacist was associated with an improvement in appropriateness of prescribing., Conclusion: This study provides evidence supporting the formal integration of a clinical pharmacist into the healthcare team with the aim of improving prescribing appropriateness for institutionalized elderly Dutch patients. Overall MAI scores for all long-term medications used by a group of elderly patients improved significantly after a pharmacist-led medication review. This is an important finding because quality of prescribing is assuming increasing importance as a means of preventing avoidable medication-related harm.

Two young men, 25 and 32 years old, presented with severe automutilation by knife wounds after consumption of hallucinogenic mushrooms. The first patient had also used cocaine, cannabis and alcohol, while the second patient had only used the hallucinogenic mushrooms. Both patients were treated symptomatically and survived despite their severe stab wounds. Psilocybin-containing mushrooms are used as mind-altering drugs. These drugs may sometimes induce 'bad trips', a psychotic reaction accompanied by fear, panic, and dangerous behaviour, especially when used in combination with other drugs and alcohol or by psychiatrically unstable patients. During a bad trip, patients may hurt themselves. Because the duration of the psychotic and sympathicomimetic effects of psilocybin after ingestion of mushrooms is short (up to 6 h), and since psilocin itself causes no permanent organ toxicity, the treatment of psilocybin intoxication is only symptomatic. The diagnosis ofpsilocybin intoxication is hampered by the lack of routinely available, rapid and sensitive, analytical methods for the quantification ofpsilocybin and its active metabolite psilocin.

A 67-year-old female with insulin-dependent diabetes mellitus underwent an uncomplicated partial liver resection under combined epidural and general anaesthesia. After surgery, 50 U of insulin were accidentally infused into her epidural space over a period of 5 h in addition to her prescribed intravenous insulin infusion. After recognition of the accidental epidural administration, the patient was closely monitored for any neurological signs or symptoms. Blood glucose levels decreased significantly from 17.4 to 6.8 mmol.l(-1) over a period of 7 h. Despite the hazard of potentially neurotoxic preservatives in the insulin preparation, she suffered no neurological sequelae and made an uncomplicated recovery.

A 39-year-old woman with type-2 diabetes mellitus presented with metabolic acidosis due to an attempted suicide with metformin. Despite treatment with activated charcoal and laxation, she experienced cardiac arrest, which required resuscitation. After transfer to another hospital, she was treated with high-volume continuous venovenous haemofiltration. However, she died due to multiple organ failure. Metformin is the most widely used oral antidiabetic agent in the world and the first-choice treatment for patients with type-2 diabetes mellitus. Metformin overdose can cause lactic acidosis, which usually manifests as abdominal pain, vomiting and diarrhoea. Although rare, metformin-associated lactic acidosis carries a high mortality risk. The treatment of choice is immediate haemodialysis and orally administered activated charcoal. If a patient treated with metformin presents with metabolic acidosis, lactic acidosis due to metformin overdose should be suspected and appropriate treatment should be initiated immediately.

Diminished P-glycoprotein (P-gp)-mediated transport across the blood-brain barrier may play an important role in several neurodegenerative disorders. In previous studies, a racemic mixture of (R)-[(11)C]verapamil and (S)-[(11)C]verapamil has been used as tracer for assessing P-gp function using positron emission tomography (PET). Quantification, however, is compromised by potential differences in kinetics between these two isomers. The aim of the present study was to evaluate the kinetics of pure (R)-[(11)C]verapamil in humans and to develop a tracer kinetic model for the analysis of P-gp-mediated transport of (R)-[(11)C]verapamil, including the putative contribution of its radioactive metabolites. Dynamic (R)-[(11)C]verapamil PET scans of 10 male volunteers were analysed with various single- or two-tissue compartment models, with separate compartments for N-dealkylated and N-demethylated metabolites, assuming that either (R)-[(11)C]verapamil alone or (R)-[(11)C]verapamil and any combination of metabolites cross the BBB. In addition, six of the subjects underwent two (R)-[(11)C]verapamil scans to evaluate test-retest reliability. One hour after injection, 50% of total plasma radioactivity consisted of labelled metabolites. Most models fitted the data well and the analysis did not point to a definite 'best' model, with differences in optimal model between subjects. The lowest mean test-retest variability (2.9%) was found for a single-tissue model without any metabolite correction. Models with separate metabolite compartments lead to high test-retest variability. Assuming that differences in kinetics of (R)-[(11)C]verapamil and N-dealkylated metabolites are small, a one input, one-tissue model with correction for N-demethylated metabolites only leads to a good compromise between fit quality and test-retest variability.

Introduction: P-glycoprotein (P-gp) is an efflux transporter responsible for the transport of various drugs across the blood-brain barrier (BBB). Loss of P-gp function with age may be one factor in the development and progression of neurodegenerative diseases. The aim of this study was to assess the effect of aging on BBB P-gp function. Furthermore, the relationship between BBB P-gp activity and peripheral P-gp activity in CD3-positive leukocytes was investigated. Finally, plasma pharmacokinetics of carbon 11-labeled (R)-verapamil was evaluated., Methods: (R)-[(11)C]verapamil and positron emission tomography were used to assess gray matter P-gp function. Because (R)-[(11)C]verapamil is a substrate for P-gp, the volume of distribution of (R)-[(11)C]verapamil in the brain inversely reflects P-gp function in the BBB., Results: Mean volume of distribution values for 5 young healthy volunteers (age range, 21-27 years) and 5 elderly healthy volunteers (age range, 59-68 years) were 0.62+/-0.10 and 0.73+/-0.07, respectively (P=.03). The activity index of P-gp activity in CD3-positive leukocytes was 2.88+/-0.77 in young volunteers and 1.76+/-0.58 in elderly volunteers (P=.02)., Conclusion: This study showed decreased P-gp activity during aging. Consequently, the brain may be exposed to higher drug and toxin levels in elderly subjects.

We present a case of intensified therapeutic drug monitoring (TDM) of citalopram in mother and newborn infant after clinically observed selective serotonin reuptake inhibitor (SSRI)-associated symptoms 2 weeks until 2 months after delivery. The SSRI-associated symptoms observed in the infant (up to 3 weeks after delivery) were irregular breathing, sleep disorders, hypotonia, and hypertonia. We conclude that the SSRI-associated symptoms in the infant represent citalopram withdrawal effects rather than side effects caused by breastfeeding. This case illustrates the importance of a flexible TDM program and a multidisciplinary approach in a hospital setting to deal with cases of drug-associated adverse effects, such as SSRI withdrawal effects.

Objective: The objectives of the study were to develop a population pharmacokinetic model for (11)C-flumazenil at tracer concentrations, to assess the effects of patient-related covariates and to derive an optimal sampling protocol for clinical use., Methods: A population pharmacokinetic model was developed using nonlinear mixed effects modelling (NONMEM) with data obtained from 51 patients with either depression or epilepsy. Each patient received approximately 370 MBq (1-4 microg) of (11)C-flumazenil. The effects of selected covariates (gender, weight, type of disease and age) were investigated. The model was validated using a bootstrap method. Finally, an optimal sampling design was established., Results: The population pharmacokinetics of tracer quantities of (11)C-flumazenil were best described by a two compartment model. Type of disease and weight were identified as significant covariates (P < 0.002). Mean population pharmacokinetic parameters (percent coefficient of variation) were: CL 1530 mL min(-1) (6.6%), V(1) 24.8 x 10(3) mL (3.8%), V(2) 27.3 x 10(3) mL (5.4%), and Q 2510 mL min(-1) (6.5%). CL was 20% lower in patients with epilepsy, and the influence of weight on V(1) was 0.55% kg(-1). For the prediction of the AUC, a combination of two time points at t = 30 and 60 min post injection was considered optimal (bias -0.7% (95% CI -2.2 to 0.8%), precision 5.7% (95% CI 4.5-6.9%)). The optimal sampling strategy was cross-validated (observed AUC = 296 MBql(-1) min(-1) (95% CI 102-490), predicted AUC = 288 MBql(-1) min(-1) (95% CI 70-506))., Conclusions: The population pharmacokinetics of tracer quantities of (11)C-flumazenil are well described by a two-compartment model. Inclusion of weight and type of disease as covariates significantly improved the model. Furthermore, an optimal sampling procedure may increase the feasibility and applicability of (11)C-flumazenil PET.

(R)-[11C]PK11195 is used as a positron emission tomography tracer for activated microglia in several neurological disorders. Quantification of specific binding requires a metabolite-corrected plasma input function. In this study, a high-performance liquid chromatography (HPLC) procedure with online solid phase extraction was modified for analyzing (R)-[11C]PK11195 plasma samples, yielding total sample recoveries of more than 98%. When applied to human studies, the use of two HPLC systems enabled analysis of up to seven plasma samples under regular conditions. Online radioactivity detection was compared with offline sample measurements of HPLC profiles. Offline measurements provided the most reliable results especially for late plasma samples. In 10 patients, an average decrease of parent compound from 94.6% at 2.5 min to 45.2% at 1 h after administration was observed.

There is evidence that P-glycoprotein (P-gp) in the blood-brain barrier (BBB) may be involved in the aetiology of neurological disorders. For quantification of P-gp function in vivo, (R)-[11C]verapamil can be used as a positron emission tomography (PET) tracer, provided that a mathematical model describing kinetics of uptake and clearance of verapamil is available. To develop and validate such a model, the kinetic profile and metabolism of (R)-[11C]verapamil have to be known. The aim of this study was to investigate the presence of labeled metabolites of [11C]verapamil in the plasma and (brain) tissue of Wistar rats. For this purpose, extraction and high-performance liquid chromatography (HPLC) methods were developed. The radioactive metabolites of (R)-[11C]verapamil in the liver were N-dealkylated compounds, O-demethylated compounds and a polar fraction formed from N-demethylation products of (R)-[11C]verapamil. Apart from this [11C] polar fraction, other radioactive metabolites of [11C]verapamil were not detected in the brain tissue. Thirty minutes after injection, unmetabolized (R)-[11C]verapamil accounted for 47% of radioactivity in the plasma and 69% in the brain. Sixty minutes after injection, unmetabolized (R)-[11C] verapamil was 27% and 48% in the plasma and the brain, respectively.

Objective: The purpose of this study was to assess (patient) characteristics that might influence the prevalence of physiological uptake of [18F]fluorodeoxyglucose (FDG) in the neck and upper chest region (FDG NUC) in positron emission tomography (PET) imaging., Methods: Retrospective study of static FDG PET scans in patients with malignant lymphoma, head and neck, lung or thyroid malignancy. The investigated determinants were gender, age, body mass index (BMI), tumour type, referring centre (community or university hospital), first or later PET scan, and use of benzodiazepines., Results: Eighty (31%) of 260 scans showed FDG NUC. We found a strong inverse relation between age and FDG NUC (P<0.001). After adjusting for age, older head and neck tumour patients were more at risk for developing FDG NUC compared with other tumours (P=0.011). Gender, use of benzodiazepines, referring specialist, first or later PET scan or low BMI (<20 kg.m(-2)) did not influence the prevalence of FDG NUC., Conclusion: Multivariate logistic regression showed a strong inverse association between age and FDG NUC. No association between low BMI and FNUC could be established. In our hospital no protective effect of benzodiazepines could be determined. These data suggest that a trial designed to evaluate the efficiency of interventions to diminish FDG NUC should focus on younger patients.

This article reviews positron emission tomography (PET) studies of labeled enantiomers of different PET-tracers from the early 1980s. Comparative studies on stereoselective behavior of the transport of tracers across the blood-brain barrier (BBB) are discussed. Tracers are transported through the BBB into the brain, via diffusion or via several transport systems. These transport systems are able to transport endogenous and exogenous compounds from the blood into the brain, and visa versa. A clear difference exists in BBB transport of the enantiomers of several tracers. In addition, in most cases, binding of these labeled enantiomers to receptors/transporters is stereoselective. Finally, use of the biological inactive labeled enantiomer for the measurement of nonspecific binding is discussed. Given the differences in transport and binding, it is concluded that quantitative PET studies can only be performed using pure enantiomers.

Objectives: The purpose of this study was to verify the accuracy and reproducibility of a multiwell counter to assess its suitability for use within human PET studies in which metabolizing (11)C tracers are used. Such tracers often require metabolite analysis for deriving plasma metabolite-corrected input curves. High-pressure liquid chromatography (HPLC) with on-line activity measurement is often unreliable for later plasma samples due to the poor sensitivity of the on-line activity detector. Fraction collector obtained HPLC samples that are counted in a separate high-sensitivity well counter can be an alternative to overcome poor counting statistics., Methods: Several experiments to evaluate background counting, reproducibility, and linearity were performed to validate the accuracy, precision, and detection limits of the well counter. In addition, measurements on a series of samples resembling activity profiles as seen within human (11)C-flumazenil studies were performed to evaluate the performance of the well counter for clinically relevant data., Results: The tests proved that the well counter detection limit, linearity, and reproducibility were more than sufficient in circumstances as seen during patient studies for samples with both high and low activity., Conclusion: The use of a multiwell counter is a good alternative for the on-line activity detector of the HPLC, allowing derivation of plasma metabolite fractions with high accuracy and reproducibility.

Objective: The purpose of this study was to compare the accuracy and reliability of 2 well counter methods for measuring the activity concentration of (18)F-FDG in blood samples., Methods: Three to 5 blood samples from 154 patient studies were weighed and measured in a well counter. The (18)F-FDG activity concentration was derived using, first, a direct calibration factor to convert measured well counter readings into activity concentration and, second, a comparison of measured counts with those of a specified standard solution., Results: The ratio between the activity concentration results of the 2 methods was 0.996 +/- 0.033, indicating that the methods provided equal results., Conclusion: Because the standard solution method is more prone to human error, less reproducible, and more labor intensive, preference should be given to the direct calibration method.

The mdr1 gene product P-glycoprotein (P-gp) is involved in the bioavailability and pharmacokinetics of various drugs. Racemic [(11)C]verapamil has been used to image P-gp expression in vivo. A racemic tracer, however, is not suitable for quantification. The purpose of the present study was to identify the most appropriate enantiomer of [(11)C]verapamil as a potential PET-tracer for quantifying P-gp function. The two enantiomers, (R)- and (S)-[(11)C]verapamil, were synthesized and studied in vivo. For the in vivo model mdr1a/1b double gene knock-out and wild type mice were used. The in vitro study made use of the LLC-PK1 MDR cell line to examine the P-gp mediated transport of both enantiomers. The biodistribution of (R)- and (S)-[(11)C]verapamil in dKO and WT mice demonstrated no stereoselectivity of verapamil for P-gp in the blood-brain barrier and in the testes. In addition, no significant differences in P-gp transport for both enantiomers were observed in the in vitro experiments. Previous studies have shown that (R)-verapamil is metabolized less in man and that it has lower affinity for calcium channels. Since (R)- and (S)-verapamil have equal transport for P-gp, the (R)-enantiomer seems to be the best and safest candidate as PET-tracer for measuring P-gp function in vivo.

After the Twin Tower attack on 11 September 2001, much attention is being given to possible terrorist attacks on nuclear targets. However, most of this interest is in countries outside of the Netherlands. Iodine is a simple and effective means of preventing part of the radiation damage following a nuclear disaster. Non-radioactive (stable) iodine plays an important part in blocking the absorption of radioactive iodine by the thyroid gland, if it is administered as soon as possible after the nuclear accident has occurred. Prophylaxis with 100 mg non-radioactive iodide has a minimal toxic effect. Effective iodine prophylaxis is dependent on the government ensuring a well-regulated distribution. The government and hospitals should have thorough protocols that staff are sufficiently familiar with.

Two cases are presented of intentional intoxications with the tricyclic antidepressants (TCAs) nortriptyline (NT) and amitriptyline (AT). The peak plasma concentrations were 2290 microg/L and 2900 microg/L, respectively. The active metabolites E-10-hydroxynortriptyline (EHNT) and Z-10-hydroxynortriptyline (ZHNT) profiles were quite different as monitored for 5 to 10 days after presumed drug intake. In conclusion, these cases illustrate that (1) metabolite formation and elimination after intake of an overdose dose of NT and AT are stereoselective, and (2) NT and EHNT toxicokinetics and toxicodynamics are quite different. It also shows that a patient with a severe TCA overdose can still survive if he or she receives appropriate and quick supportive care, even if the prognostic markers QRS time, coma grade, and serum TCA levels predict poor outcome.

Palivizumab is a humanized, monoclonal antibody used to protect at-risk infants against respiratory syncytial virus (RSV) infection. The regular dosage scheme causes a low initial trough level and accumulation of the antibody after subsequent injections. Using a simple pharmacokinetic model, the authors devised an alternative dosage regimen that might correct these problems while cutting costs by 35%. To spare health care budgets, dosage schemes for future monoclonal antibodies must be chosen carefully.

Objective: To evaluate [11C]verapamil kinetics in humans., Methods: After intravenous injection of [11C]verapamil (370 MBq, specific activity >1,600 GBq/mmol), kinetics were evaluated in five cancer patients using positron emission tomography (PET)., Results: One hour after injection, accumulation of [11C] in lungs, heart and tumour was 43.0%, 1.3% and 0.9% of the injected verapamil dose, respectively. Half-lives of [11C]verapamil in these tissues were 46.2 min, 73.8 min and 23.7 min, respectively., Conclusions: Intravenously administered [11C] was mainly extracted by the lungs. Transport of a [11C]verapamil bolus out of solid tumour tissue is relatively fast.

The toxicity and pharmacokinetic properties of a drug determine whether hemodialysis and/or hemoperfusion are indicated in acute intoxications. Valproic acid is considered unremovable by hemodialysis because of the high protein binding of 90%-95%. A 27-year-old male with a history of seizures was admitted to the emergency room because of coma, hypernatriemia, and respiratory failure caused by an intoxication with a large dose of valproic acid. At admission, the plasma valproic acid level was 1414 mg/L (9.9 mmol/L) (therapeutic range: 50-100 mg/L (350-700 micromol/ L). The anion gap was 26 mmol/L (normal <12-14 mmol/L) and corresponded fairly well with this valproic acid level. Because of the potential toxicity of this high valproic acid level serial hemodialysis and hemoperfusion was performed. The first session was done with a charcoal column and the second session with a resin column. The patient recovered during the course of treatment. The valproic acid plasma clearances during treatment were: 80 mL/min (hemodialysis); 40 mL/min (hemoperfusion by charcoal) and 80 mL/min (hemoperfusion by resin, only in the first hour). The protein binding of valproic acid in plasma was only 32% at the start and was 54% at the end of the two sessions. In this specific case of a severe valproic acid intoxication, saturated protein binding resulted in an increased fraction of unbound valproic acid. This made hemodialysis an effective treatment, while hemoperfusion was relatively less effective because of saturation of the column. In conclusion, the toxicokinetics of valproate are quite different from the pharmacokinetics at therapeutic levels. The anion gap and protein binding are important parameters in toxicokinetics.

Drug resistance is a major cause of chemotherapy failure in cancer treatment. One reason is the overexpression of the drug efflux pump P-glycoprotein (P-gp), involved in multidrug resistance (MDR). In vivo pharmacokinetic analysis of P-gp transport might identify the capacity of modulation by P-gp substrate modulators, such as cyclosporin A. Therefore, P-gp function was measured in vivo with positron emission tomography (PET) and [11C]verapamil as radiolabeled P-gp substrate. Studies were performed in rats bearing tumors bilaterally, a P-gp-negative small cell lung carcinoma (GLC4) and its P-gp-overexpressing subline (GLC4/P-gp). For validation, in vitro and biodistribution studies with [11C]daunorubicin and [11C]verapamil were performed. [11C]Daunorubicin and [11C]verapamil accumulation were higher in GLC4 than in GLC4/P-gp cells. These levels were increased after modulation with cyclosporin A in GLC4/P-gp. Biodistribution studies showed 159% and 185% higher levels of [11C]daunorubicin and [11C]verapamil, respectively, in GLC4 than in GLC4/P-gp tumors. After cyclosporin A, [11C]daunorubicin and [11C]verapamil content in the GLC4/P-gp tumor was raised to the level of GLC4 tumors. PET measurements demonstrated a lower [11C]verapamil content in GLC4/P-gp tumors compared with GLC4 tumors. Pretreatment with cyclosporin A increased [11C]verapamil levels in GLC4/P-gp tumors (184%) and in brains (1280%). This pharmacokinetic effect was clearly visualized with PET. These results show the feasibility of in vivo P-gp function measurement under basal conditions and after modulation in solid tumors and in the brain. Therefore, PET and radiolabeled P-gp substrates may be useful as a clinical tool to select patients who might benefit from the addition of a P-gp modulator to MDR drugs.

Background: Our aim was to determine the value of 99mTc-Sestamibi scanning as functional detection method of P-glycoprotein (Pgp) blockade by PSC 833 in solid tumour patients., Patients and Methods: Day 1 and day 4 after 2,200 mg orally administered PSC 833 the tumour area was scanned after intravenous (i.v.) administration of 400 MBq 99mTc-Sestamibi. In tumours with net 99mTc-Sestamibi uptake and in the hepatic region K-efflux was determined. Whole blood was analyzed for 99mTc-Sestamibi, and PSC 833 levels., Results: Fourteen patients were included. In the only Pgp-positive tumour with positive 99mTc-Sestamibi scanning K-efflux of 99mTc-Sestamibi decreased significantly after PSC 833 intake. A net inhibition of liver efflux of Sestamibi after PSC 833 intake was observed in all evaluable patients. PSC 833 blood levels were all above 2 mg/L during scanning; 99mTc-Sestamibi blood levels post versus pre PSC 833 were unchanged., Conclusions: PSC 833 induced modulation of K-efflux of 99mTc-Sestamibi in a Pgp positive tumour and in all patients in the liver.

Biopsy of the first tumour-draining lymph node (sentinel node, SN) is bound to become the procedure of choice in regional staging of melanoma and breast cancer patients. Several radiopharmaceuticals have been developed for lymphoscintigraphy. In this paper we review the most frequently used radiopharmaceuticals for their appropriateness in the sentinel-node procedure. We conclude that accurate localization of SNs is demonstrated using technetium-99m-sulfur colloid (99mTc-SC), 99mTc antimony trisulfide colloid (99mTc-ATC) [10] and 99mTc nanocolloidal albumin (99mTc-CA). 99mTc-Ca and 99mTc-SC are both available in Europe. In the United States 99mTc-SC is the only registered tracer for lymphoscintigraphy.

Various mechanisms are involved in multidrug resistance (MDR) for chemotherapeutic drugs, such as the drug efflux pumps, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). In this review the mechanisms involved in MDR are described and results are reviewed with particular attention to the in vivo imaging of Pgp and MRP. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However, these methods do not yield information about the dynamic function of Pgp and MRP in vivo. For the study of Pgp- and MRP-mediated transport, single-photon emission tomography (SPET) and positron emission tomography (PET) are available. Technetium-99m sestamibi is a substrate for Pgp and MRP, and has been used in clinical studies for tumour imaging, and to visualize blockade of Pgp-mediated transport after modulation of the Pgp pump. Other 99mTc radiopharmaceuticals, such as 99mTc-tetrofosmin and several 99Tc-Q complexes, are also substrates for Pgp, but to date only results from in vitro and animal studies are available for these compounds. Several agents, including [11C]colchicine, [11C]verapamil and [11C]daunorubicin, have been evaluated for the quantification of Pgp-mediated transport with PET in vivo. The results suggest that radiolabelled colchicine, verapamil and daunorubicin are feasible substrates with which to image Pgp function in tumours. Uptake of [11C]colchicine and [11C]verapamil is relatively high in the chest area, reducing the value of both tracers for monitoring Pgp-mediated drug transport in tumours located in this region. In addition, it has to be borne in mind that only comparison of Pgp-mediated transport of radioalabelled substrates in the absence and in the presence of Pgp blockade gives quantitative information on Pgp-mediated pharmacokinetics. Leukotrienes are specific substrates for MRP. Therefore, N-[11C]acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively. Results obtained in MRP2 mutated GY/TR rats have demonstrated visualization of MRP-mediated transport. This tracer permits the study of MRP transport function abnormalities in vivo, e.g. in Dubin-Johnson patients, who are MRP2 gene deficient. Results obtained show the feasibility of using SPET and PET to study the functionality of MDR transporters in vivo.

Unlabelled: L-3-[123I]-Iodo-alpha-methyl-tyrosine (IMT) is a modified amino acid. It is reported to be avidly taken up in brain tumors, reflecting amino acid transport and is suitable for SPECT., Methods: To determine whether tumors outside the brain can also accumulate this tracer, we injected 300-450 MBq IMT into 20 patients with different tumors [5 breast cancers, 4 lung tumors (1 benign), 2 carcinoid liver metastases, 4 soft-tissue tumors (1 benign), 3 malignant lymphomas and 2 primary brain tumors]. Tumor size ranged from 1-12 cm. Imaging was repeated after radiotherapy in two patients with breast cancer. Histology was available in all cases. Dynamic scans, whole-body imaging and SPECT were performed during the first hour and 3 hr after injection. Plasma samples were analyzed for IMT, free 1231 and other metabolites., Results: All primary tumors were visualized. Tumor-to-background ratios ranged from 1.1 to 3.8 on planar and from 1.3 to 6.2 on SPECT images. Tumor uptake peaked in the first hour. Two carcinoid lesions in the liver tumors exhibited no IMT uptake above liver background. Tumor-to-background ratios in a benign bone inflammatory process and a focal pulmonary vasculitis were less than 1.2 (planar) and 1.9 (SPECT) and could be differentiated from uptake in all malignant nonbrain tumors. IMT was rapidly cleared from the plasma [3.6% +/- 0.6% (mean +/- s.d.) injected dose/liter at 10 min postinjection]. Minor in vivo deiodination was present (<1% of injected dose 1 hr postinjection). No other metabolites were found. Normal distribution consists of some uptake in the brain, liver, spleen, muscles, pancreatic region and intestinal structures and massive uptake and excretion in the kidneys and bladder., Conclusion: IMT has potential as a metabolic tracer in tumors outside the brain.