Eric J. F. Franssen

Radiopharmaceuticals in sentinel lymph-node detection – an overview

Abstract. 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

Effect of age on functional P‐glycoprotein in the blood‐brain barrier measured by use of (R)‐[11C]verapamil and positron emission tomography

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.

(R)- and (S)-[11C]verapamil as PET-tracers for measuring P-glycoprotein function: in vitro and in vivo evaluation

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.

Evaluation of Tracer Kinetic Models for Quantification of P-Glycoprotein Function using (R)-[11C]Verapamil and PET

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)-[11C]verapamil and (S)-[11C]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)-[11C]verapamil in humans and to develop a tracer kinetic model for the analysis of P-gp-mediated transport of (R)-[11C]verapamil, including the putative contribution of its radioactive metabolites. Dynamic (R)-[11C]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)-[11C]verapamil alone or (R)-[11C]verapamil and any combination of metabolites cross the BBB. In addition, six of the subjects underwent two (R)-[11C]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)-[11C]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.

Appropriateness of prescribing among elderly patients in a dutch residential home observational study of outcomes after a pharmacist-led medication review

AbstractBackground: 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.n 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.n 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).n 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.n 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.

Physiological uptake of [18F]fluorodeoxyglucose in the neck and upper chest region: are there predictive characteristics?

ObjectiveThe 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. MethodsRetrospective 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. ResultsEighty (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 (<20u2009kg·m−2) did not influence the prevalence of FDG NUC. ConclusionMultivariate 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.

A randomised controlled trial assessing the effect of oral diazepam on 18F-FDG uptake in the neck and upper chest region.

ObjectiveA 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).MethodsA randomised, double-blind, placebo-controlled trial was conducted to assess the effect on FDG-NUC of 5xa0mg diazepam, given orally 1xa0h before 18F-FDG injection. Patients younger than 40xa0years, 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.ResultsFifty-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.ConclusionNo 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.

Toxicokinetics of nortriptyline and amitriptyline: two case reports.

Two cases are presented of intentional intoxications with the tricyclic antidepressants (TCAs) nortriptyline (NT) and amitriptyline (AT). The peak plasma concentrations were 2290 &mgr;g/L and 2900 &mgr;g/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.

Imaging P‐glycoprotein at the human blood‐brain barrier

. Rodrigues AD, Yang Z, Chen C, Pray D, Kim S, Sinz M. Is celecoxib an inducer of cytochrome P450 3A4 in subjects carrying the CYP2C9*3 allele [letter]? Clin Pharmacol Ther. In press 2006. . Tang C, Shou M, Rushmore TH, Mei Q, Sandhu P, Woolf EJ, et al. In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics. Pharmacogenetics 2001;11:223-35. . Sandberg M, Yasar U, Strömberg P, Höög JO, Eliasson E. Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase. Br J Clin Pharmacol 2002;54:423-9. . Lundblad MS, Ohlsson S, Johansson P, Lafolie P, Eliasson E. Accumulation of celecoxib with a 7-fold higher drug exposure in individuals homozygous for CYP2C9*3. Clin Pharmacol Ther 2006;79:287-8. . Kirchheiner J, Stormer E, Meisel C, Steinbach N, Roots I, Brockmoller J. Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics 2003;13:473-80. . Christensen M, Andersson L, Dalen P, Mirghani RA, Muirhead GJ, Nordmark A, et al. The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin Pharmacol Ther 2003;73:517-28.

Pharmaceutical preparation of oxygen-15 labelled molecular oxygen and carbon monoxide gasses in a hospital setting

Background:u2002 Clinical positron emission tomography (PET) requires safe and effective PET radiopharmaceuticals. Tracers used for measuring oxygen consumption and blood volume are [15O]O2 and [15O]CO, respectively. In general, these oxygen‐15 labelled tracers are produced using a cyclotron that accelerates deuterons onto a target filled with 14N2 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.