Preventable ADRs leading to hospitalization - results of a long-term prospective safety study with 6,427 ADR cases focusing on elderly patients.

BACKGROUND: Studies evaluating the impact of age and potentially inappropriate medication (PIM) on avoidable adverse drug reactions (ADRs) are scarce. METHODS: In this prospective, multi-center, long-term (8.5 years) observational study, we analysed ADRs leading to hospitalization in departments of internal medicine. ADRs causality and preventability were assessed using standardised algorithms. PIM was defined based on the PRISCUS-list. Multivariate analyses and estimation of ADR incidence rates were conducted. RESULTS: Of all 6,427 ADR patients, a preventable ADR was present in 1,253 (19.5%) patients (elderly patients ≥70 years: 828). Risk factors for preventable ADRs in elderly patients were multimorbidity, two to four ADR-causative drugs, and intake of particular compounds (e.g. spironolactone) but not sex, PIM usage, or the total number of drugs. Regarding particular compounds associated with preventable ADRs, highest incidence rates for preventable ADRs were found for patients aged ≥70 years for spironolactone (3.3 per 1,000 exposed persons (95% CI: 1.4-6.6)) and intermediate-acting insulin (3.3 per 1,000 exposed persons (95% CI: 1.6-6.1)). CONCLUSION: Avoiding PIM usage seems to be of limited value in increasing safety in elderly patients whereas our results underline the importance of an individualized medication review of the most commonly implicated drugs in preventable ADRs (supported by BfArM FoNr: V-11337/68605/2008-2010).

A pilot study of dual-isotope lymphoscintigraphy for breast sentinel node biopsy comparing intradermal and intraparenchymal injection.

AIMS: Identification of sentinel lymph nodes (SLN) may depend on the tissue plane of tracer injection. To explore this, we developed a dual-isotope technique to compare the lymphatic drainage basins accessed by intradermal and parenchymal injections. METHODS: Fifteen breast cancer patients had simultaneous parenchymal and intradermal injections of (99m)Tc-labelled human immunoglobulin G (HIG) and (111)In-HIG, respectively, 2-4h before axillary lymph node clearance surgery. All 228 freshly dissected nodes were assayed by well counting and examined for metastatic disease by haematoxylin/eosin staining and immuno-histochemistry. RESULTS: Total nodal uptake following intradermal injection was 10 times more than after parenchymal injection. Tracer uptake within the first three draining nodes divided patients into three groups; four (group 1) had identical 1st, 2nd and 3rd echelon nodes, six (group 2) had identical 1st and 2nd echelon nodes and five (group 3) had different 1st echelon nodes. With respect to the first, second and third groups, there was close, moderate and poor correlation (Pearson), respectively, between individual nodal counts accumulated from the two injection sites. Of eight patients with nodal disease, the SLN identified by intradermal and parenchymal injections contained disease in seven and four patients, respectively. CONCLUSIONS: Comparison of nodal tracer distributions from the two injection planes allows a functional model to be developed with two possible routes of drainage from the parenchymal plane, one joining the tract from the areolar plexus and the other passing independently to the axilla which builds upon Sappey's original anatomical model. This may explain the variable uptake, discordance and false negative SLN identification.

Myocardial kinetics of the (11)C-labeled enantiomers of the Ca(2+) channel inhibitor S11568: an in vivo study.

UNLABELLED: Ca(2+) channels play a key role in the basic working of the heart. There is one particular type of Ca(2+) channel in cardiac cells (L-type) whose gating is affected in different ways by beta-adrenoceptors and 1,4-dihydropyridines. In this study, we used ex vivo studies and PET to evaluate and compare the myocardial kinetics of the enantiomers labeled with (11)C (the more active: S12968, absolute configuration S; the less active: S12967, absolute configuration R) of the L-type Ca(2+) channel antagonist S11568 (3-ethyl 5-methyl (+/-)-2-[(2-(2-aminoethoxy)ethoxy) methyl]-4-(2,3-dichlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate). METHODS: [(11)C]S12968 was injected into the tail vein of rats (0.22 kBq--5.92 MBq) to assess the relationship between injected dose and myocardial uptake. A series of 5 rats was pretreated with 4 micromol unlabeled S12968 5 min before injection of 2.2 kBq [(11)C]S12968. In another series of 5 rats, unlabeled S12698 (4 micromol) was injected 5 min after injection of 2.2 kBq [(11)C]S12968. The animals were killed 15 min later, and the myocardial radioactivity was assessed in a gamma well counter. Beagle dogs received injections of 5-15 nmol [(11)C]S12968 or [(11)C]S12967 and were imaged with PET. Presaturation and displacement experiments using 2 micromol/kg unlabeled S12968 or 6 mol/kg S12967 were performed. RESULTS: In rats, a statistically significant relationship between myocardial uptake and injected dose of S12968 was observed. Pretreatment or displacement with unlabeled S12968 reduced myocardial radioactivity by 75% and 70%, respectively. In dogs, after injection of 5 nmol of each enantiomer, myocardial radioactivity plateaued within 3 min and the clearance from blood was rapid. Injection of 13--15 nmol [(11)C]S12968 led to a higher myocardial uptake and a more rapid washout, which were related to an increased coronary blood flow as shown by the linear relationship between k(1)--an estimate of coronary blood flow--and the mass of S12968 injected. Presaturation and displacement experiments showed that 70%--80% of S12968 binding was specific. This specificity was not observed with S12967. Plasma metabolite analysis showed that 70% of the compound was unchanged 20 min after injection. CONCLUSION: These results show the feasibility of imaging myocardial L-type Ca(2+) channels in vivo using [(11)C]S12968.

[76Br]Bromodeoxyuridine PET in tumor-bearing animals.

5-bromodeoxyuridine (BUdR) provides in vitro measures of tumor cell proliferation. We used positron emission tomography to study tissue and plasma kinetics of [76Br]BUdR in tumor-bearing animals. In order to account for the slow washout of the major plasma metabolite, [76Br]bromide, a mathematical correction for the distribution volume of [76Br]bromide was applied. However, following correction specific tumor tracer retention was low or even zero and did not correlate with independent measures of proliferation. The kinetic characteristics of [76Br]BUdR make this tracer unsuitable for proliferation imaging.

Imaging brain tumor proliferative activity with [124I]iododeoxyuridine.

Iododeoxyuridine (IUdR) uptake and retention was imaged by positron emission tomography (PET) at 0-48 min and 24 h after administration of 28.0-64.4 MBq (0.76-1.74 mCi) of [124I]IUdR in 20 patients with brain tumors, including meningiomas and gliomas. The PET images were directly compared with gadolinium contrast-enhanced or T2-weighted magnetic resonance images. Estimates for IUdR-DNA incorporation in tumor tissue (Ki) required pharmacokinetic modeling and fitting of the 0-48 min dynamically acquired data to correct the 24-h image data for residual, nonincorporated radioactivity that did not clear from the tissue during the 24-h period after IUdR injection. Standard uptake values (SUVs) and tumor:brain activity ratios (Tm:Br) were also calculated from the 24-h image data. The Ki, SUV, and Tm/Br values were related to tumor type and grade, tumor labeling index, and survival after the PET scan. The plasma half-life of [124I]IUdR was short (2-3 min), and the arterial plasma input function was similar between patients (48 +/- 12 SUV*min). Plasma clearance of the major radiolabeled metabolite ([124I]iodide) varied somewhat between patients and was markedly prolonged in one patient with renal insufficiency. It was apparent from our analysis that a sizable fraction (15-93%) of residual nonincorporated radioactivity (largely [124I]iodide) remained in the tumors after the 24-h washout period, and this fraction varied between the different tumor groups. Because the SUV and Tm:Br ratio values reflect both IUdR-DNA incorporated and exchangeable nonincorporated radioactivity, any residual nonincorporated radioactivity will amplify their values and distort their significance and interpretation. This was particularly apparent in the meningioma and glioblastoma multiforme groups of tumors. Mean tumor Ki values ranged between 0.5 +/- 0.9 (meningiomas) and 3.9 +/- 2.3 microl/min/g (peak value for glioblastoma multiforme, GBM). Comparable SUV and Tm:Br values at 24 h ranged from 0.13 +/- 0.03 to 0.29 +/- 0.19 and from 2.0 +/- 0.6 to 6.1 +/- 1.5 for meningiomas and peak GBMs, respectively. Thus, the range of values was much greater for Ki (approximately 8-fold) compared with that for SUV (approximately 2.2-fold) and Tm:Br (approximately 3-fold). The expected relationships between Ki, SUV, and Tm:Br and other measures of tumor proliferation (tumor type and grade, labeling index, and patient survival) were observed. However, greater image specificity and significance of the SUV and Tm:Br values would be obtained by achieving greater washout and clearance of the exchangeable fraction of residual (background) radioactivity in the tumors, i.e., by increased hydration and urinary clearance and possibly by imaging later than 24 h after [124I]IUdR administration.

Imaging central nicotinic acetylcholine receptors in baboons with [18F]fluoro-A-85380.

UNLABELLED: Central nicotinic acetylcholine receptors (nAChRs) have been implicated in learning-memory processes. Postmortem brain tissue of patients who suffered senile dementia or Parkinson's disease shows low density of nAChRs. In this study, we used PET to evaluate the distribution and kinetics of the fluoro derivative of the high-affinity and alpha4beta2-subtype-selective, nicotinic ligand 3-[2(S)-2-azetidinylmethoxy]pyridine (A-85380) in baboons. METHODS: After intravenous injection of 37 MBq (1 mCi, 1-1.5 nmol) [18F]fluoro-A-85380 into isoflurane-anesthetized baboons, dynamic PET data were acquired for 180 min. Time-activity curves were generated from regions of interest. Displacement experiments (80 min after injection of the radiotracer) were performed using cytisine (1 mg/kg subcutaneously) and unlabeled fluoro-A-85380 (0.1 and 0.3 mg/kg intravenously). Toxicological studies were performed in mice. RESULTS: Brain radioactivity reached a plateau within 40-50 min of injection of the tracer. In the thalamic area, radioactivity remained constant for 180 min, while clearance from the cerebellum was slow (t1/2 = 145-190 min). Cytisine and unlabeled fluoro-A-85380 reduced brain radioactivity at 180 min by 50%-60%, 30%-35% and 20%-35% of control values in the thalamus, cerebellum and frontal cortex, respectively. A slight, transient increase (20 mm Hg) in blood pressure was observed with the highest displacing dose of unlabeled fluoro-A-85380. Lethal dose in mice was found to be 2.2 mg/kg intravenously. CONCLUSION: These results demonstrate the feasibility and the safety of imaging nAChRs in vivo using labeled or unlabeled fluoro-A-85380.

Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine: a new positron emission tomography ligand for nicotinic receptors.

The lead compound of a new series of 3-pyridyl ethers, the azetidine derivative A-85380 (3-[(S)-2-azetidinylmethoxy]pyridine), is a potent and selective ligand for the human alpha4beta2 nicotinic acetylcholine receptor (nAChR) subtype. In vitro, the fluoro derivative of A-85380 (2-fluoro-3-[(S)-2-azetidinylmethoxy]pyridine or F-A-85380) competitively displaced [3H]cytisine or [3H]epibatidine with Ki values of 48 and 46 pM, respectively. F-A-85380 has been labeled with the positron emitter fluorine-18 (t1/2 (half-life) = 110 min) by no-carrier-added nucleophilic aromatic substitution by K[18F]F-K222 complex with (3-[2(S)-N-(tert-butoxycarbonyl)-2-azetidinylmethoxy]pyridin-2-yl) tri methylammonium trifluoromethanesulfonate as a highly efficient labeling precursor, followed by TFA removal of the Boc protective group. The total synthesis time was 50-53 min from the end of cyclotron fluorine-18 production (EOB). Radiochemical yields, with respect to initial [18F]fluoride ion radioactivity, were 68-72% (decay-corrected) and 49-52% (non-decay-corrected), and the specific radioactivities at EOB were 4-7 Ci/micromol (148-259 GBq/micromol). In vivo characterization of [18F]F-A-85380 showed promising properties for PET imaging of central nAChRs. This compound does not bind in vivo to alpha7 nicotinic or 5HT3 receptors. Moreover, its cerebral uptake can be modulated by the synaptic concentration of the endogenous ligand acetylcholine. The preliminary PET experiments in baboons with [18F]F-A-85380 show an accumulation of the radiotracer in the brain within 60 min. In the thalamus, a nAChR-rich area, uptake of radioactivity reached a maximum at 60 min (4% I.D./100 mL of tissue). [18F]F-A-85380 appears to be a suitable radioligand for brain imaging nAChRs with PET.

Quantitation of extrastriatal D2 receptors using a very high-affinity ligand (FLB 457) and the multi-injection approach.

The multi-injection approach has been used to study in baboon the in vivo interactions between the D2 receptor sites and FLB 457, a ligand with a very high affinity for these receptors. The model structure was composed of four compartments (plasma, free ligand, and specifically and unspecifically bound ligands) and seven parameters (including the D2 receptor site density). The arterial plasma concentration, after correction for metabolites, was used as the input function. The experimental protocol, which consisted of three injections of labeled and/or unlabeled ligand, allowed the evaluation of all model parameters from a single positron emission tomography experiment. In particular, the concentration of receptor sites available for binding (B'max) and the apparent in vivo FLB 457 affinity were estimated in seven brain regions, including the cerebellum and several cortex regions, in which these parameters are estimated in vivo for the first time (B'max is estimated to be 4.0+/-1.3 pmol/mL in the thalamus and from 0.32 to 1.90 pmol/mL in the cortex). A low receptor density was found in the cerebellum (B'max = 0.39+/-0.17 pmol/mL), whereas the cerebellum is usually used as a reference region assumed to be devoid of D2 receptor sites. In spite of this very small concentration (1% of the striatal concentration), and because of the high affinity of the ligand, we demonstrated that after a tracer injection, most of the PET-measured radioactivity in the cerebellum results from the labeled ligand bound to receptor sites. The estimation of all the model parameters allowed simulations that led to a precise knowledge of the FLB 457 kinetics in all brain regions and gave the possibility of testing the equilibrium hypotheses and estimating the biases introduced by the usual simplified approaches.

Preliminary evaluation of 2-[4-[3-tert-butylamino)-2-hydroxypropoxy]phenyl]-3-methyl-6-me thoxy-4(3H)-quinazolinone ([+/-]HX-CH 44) as a selective beta1-adrenoceptor ligand for PET.

(+/-)-3-[11C]Methyl-2-[4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]-6 -methoxy-4(3H) quinazolinone ([+/-]-[11C]HX-CH 44) was labeled with carbon-11 using [11C]iodomethane with the corresponding N-demethylated precursor. Then, 30-90 mCi (1.10-3.33 GBq) of pure [11C]HX-CH 44 were obtained 30 min after end of bombardment with specific radioactivities of 500-1,400 mCi/micromol (18.5-51.8 GBq/micromol). Myocardial uptake in dogs was 0.340+/-0.043 pmol/mL tissue per nanomole injected, 10-15 min postinjection. Heart-to-lung ratio was 3 from the 5th to the 30th minute. Only 35% of the myocardial radioactivity could be displaced. Tissue uptake could not be blocked with appropriate compounds. Therefore, (+/-)-[11C]HX-CH 44 does not appear to be a suitable ligand for the study of myocardial beta1-adrenoceptors in positron emission tomography.

Characterization of the nicotinic ligand 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine in vivo.

The biodistribution of the nicotinic acetylcholine receptor (nAChR) radioligand 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine ([18F]fluoro-A-85380, half-life of fluorine-18 = 110 min) in selected rat brain areas was assessed in vivo. The radiotracer showed a good penetration in the brain. The regional distribution of the radioligand was consistent with the density of nAChRs determined from previous studies in vitro. Sixty minutes post-injection, the highest uptake was observed in the thalamus, (1% I.D./g tissue), an intermediate one in the frontal cortex (0.78% I.D./g tissue), and the lowest in the cerebellum (0.5% I.D./g tissue). Pretreatment with several nAChR ligands (nicotine, cytisine, epibatidine, unlabeled fluoro-A-85380) substantially reduced uptake of the radioligand in the three cerebral areas. Pretreatment with the nAChR channel blocker mecamylamine or with the muscarinic receptor antagonist dexetimide had no appreciable effect on the uptake of fluoro-A-85380. These results support the high in vivo selectivity and specificity of fluoro-A-85380. Therefore, [18F]fluoro-A-85380 may be useful for positron emission tomography study of nAChRs in humans.

A selective radiobrominated cocaine analogue for imaging of dopamine uptake sites: pharmacological evaluation and PET experiments.

(E)-N-(3-bromoprop-2-enyl)-2beta-carbomethoxy-3beta-4'-tolyl -nortropane or PE2Br, an analogue of cocaine was labelled with the positron emitter 76Br (T1/2=16 h) for pharmacological evaluation in the rat and PET investigation in the monkey. [76Br]PE2Br was obtained by electrophilic substitution from the tributylstannyl precursor with radiochemical yield of 80%. In vivo biodistribution studies of [76Br]PE2Br (20 MBq/nmol) in rats showed a high uptake in the striatum (2.2% ID/g tissue at 15 min p.i.). The striatum to cerebellum radioactivity ratio was 6 at 1 hour p.i. Striatal uptake of [76Br]PE2Br was almost completely prevented by pretreatment with GBR 12909, but citalopram and maprotiline had no effect, confirming the selectivity of the radioligand for the dopamine transporter. PET imaging of the biodistribution of [76Br]PE2Br in the baboon demonstrated rapid and high uptake in the brain (5% ID at 3 min p.i.). The striatal radioactivity concentration reached a plateau at 20 min p.i. (7% ID/100 mL). The uptake in the cortex and cerebellum was very low. A significantly higher uptake in the thalamus was observed. At 1h p.i., the striatum to cerebellum ratio and thalamus to cerebellum ratio were 8 and 1.9 respectively. In competition experiments the radioactivity in the striatum and the thalamus was displaced by 5 mg/kgof cocaine and 5 mg/kg of GBR 12909, but citalopram and maprotiline had no effect. These results showed that [76Br]PE2Br is in vivo a potent and selective radioligand suitable for PET imagingof the dopamine transporter.

Radiosynthesis and quality assurance of 5-[124I]Iodo-2'-deoxyuridine for functional PET imaging of cell proliferation.

5-[124I]Iodo-2'-deoxyuridine ([124I]IUdR) was routinely produced by direct electrophilic labelling of 2'-deoxyuridine with 124I of high specific activity (12 Ci/micromol) in an Iodogen-coated ReactiVial, followed by purification on a Sep-Pak C-18 cartridge. The radiochemical purity was determined by TLC on a Silicagel-60 plate and by reverse-phase HPLC on a RP-18 column. Based upon 45 syntheses, the yield ranged from 45% to 65%. The radiochemical impurity of [124I]IUdR was determined at 2.9% by TLC (mainly iodate) and 4.3% by HPLC. The chemical stability of the solvated formulation allowed a time window of 2 days following end of synthesis (EOS) for chemical application, based upon the required 95% radiochemical purity grade of [124I]IUdR. The labelled compound was routinely used for the clinical determination of cell proliferation in glioma patients by positron emission tomography.

Radiosynthesis of [11C]brofaromine, a potential tracer for imaging monoamine oxidase A.

Brofaromine (4-5(-methoxy-7-bromobenzofuranyl)-2-piperidine-HCl) is a potent and selective inhibitor of monoamine oxidase (MAO) A. Two methods for its synthesis and a preliminary positron emission tomography (PET) evaluation in monkey brain are described. The first method, at low carrier concentration of CO2, consisted of direct O-methylation of (4-(5-hydroxy-7-bromobenzofuranyl)-2-piperidine). The total radiochemical yield achieved ranged from 30 to 50% (from end of bombardment [EOB] and decay corrected) with an overall synthesis time of 45 min. The second approach, with high carrier amounts of CO2 arising from inherent target problems, was accomplished in a three-step route involving protection of secondary amino functionality, O-methylation and deprotection. The total radiochemical yield was 10% (from EOB and decay corrected) with a total synthesis time of 70 min. For both methods methylation was achieved using the classical methylating agent [11C]CH3I, and radiochemical purity was higher than 98%. PET evaluation of the radioligand in a Rhesus monkey showed a high uptake of radioactivity in the brain. Using the irreversible MAO-A inhibitor clorgyline and reversible MAO-A inhibitors moclobemide and brofaromine, three blockade experiments were designed to determine the extent of specific binding of [11C]brofaromine to MAO-A. No apparent decrease in accumulation of radioactivity in the monkey brain was observed when compared to a baseline scan.