Does an intrauterine exchange transfusion improve the fetal prognosis in parvovirus infection cases?

BACKGROUND: Almost 20% of parvovirus B19 foetal infections require intrauterine transfusions. In addition, myocardial dysfunction has been observed in severe parvovirus B19 infections. One objective of an intrauterine exchange transfusion (IUET) is to avoid an overload during the transfusion. Our aim was to study the obstetrical and neonatal outcomes in cases of IUETs performed for foetal parvovirus infections and to compare our survival rate to those studies in which simple in utero transfusions were chosen. STUDY DESIGN AND METHODS: This was a retrospective monocentre study of all patients followed up for parvovirus B19 infections in which IUETs were performed. An IUET was indicated when foetal hydrops was observed and/or when severe foetal anaemia was diagnosed though an elevation in the middle cerebral artery peak systolic velocity. The characteristics of each pregnancy and the neonatal outcomes were studied until hospital discharge. RESULTS: Thirty-five IUETs were performed in 26 foetuses. The median gestational age of the first IUET was 22.6 weeks. Only one foetal bradycardia incidence was recorded during the procedure. Three medical pregnancy terminations were observed in our series, secondary to severe cerebral anomalies confirmed in the magnetic resonance imaging. Five in utero deaths occurred, in which 2 of the foetuses underwent multiple IUETs. All the neonates had normal haemoglobin levels at birth, and none were transferred to the neonatal intensive care unit. The overall survival rate was 70%. CONCLUSION: IUETs exhibit a survival rate similar to that of simple intrauterine transfusions in foetal parvovirus infection cases.

Does a combination of ultrasound, MRI, and biochemical amniotic fluid analysis improve prenatal diagnosis of esophageal atresia?

OBJECTIVE: Prenatal diagnosis of esophageal atresia (EA) remains a challenge. Our objective was to evaluate the combination of sonography, magnetic resonance imaging (MRI), and amniotic fluid biochemical markers in prenatal diagnosis of EA. STUDY DESIGN: A retrospective study of all cases with prenatal suspicion of EA from January 2008 to May 2013 in our regional reference center was carried out. Patients were included if all the three tests were performed. For each test, sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) were evaluated. Each test was compared using Fisher's exact test. RESULTS: Fifteen patients were referred at a median gestational age of 28(+5) weeks (24-36) for suspicion of EA on the basis of small or non-visualized fetal stomach bubble and/or polyhydramnios. Se, Sp, PPV, and NPV for sonographic pouch sign/MRI/biochemical amniotic fluid were respectively 40/100/100/45.5%, 80/100/100/71.4%, and 90/60/81.8/75%. MRI was the best predictive test (p = 0.007). CONCLUSION: In case of ultrasound prenatal suspicion of EA (with or without visualization of the pouch sign), an MRI at 30-32 weeks using fast imaging employing steady-state acquisition should be proposed. Biochemical amniotic fluid may be helpful and should be evaluated in a larger study.

[Placenta accreta spectrum disorder: Management and morbidity in a French type-3 maternity]. / Placenta du spectre accreta : prise en charge et morbidité dans une maternité française de niveau 3.

OBJECTIVES: Placenta accreta spectrum disorder (PASD) is a rare obstetrical pathology, however its incidence is increasing. Morbidity associated with PASD is still high. Even if hysterectomy is considered to be the reference standard treatment, the conservative treatment by leaving the placenta in situ is now an approved option. The objective was to describe management and morbidity of patients with PASD, during the decade, in our French high-level maternity. METHODS: It was a retrospective study of management and morbidity of PASD in our department between 2007 and 2017. RESULTS: Forty-six PASD cases were admitted in our center. Thirty-three (71.7%) had a prenatal suspicion of PASD. Conservative treatment was considered for 22 patients (47.8%). It was successful in 12 cases (54.5%). Thirty-four (73.9%) had a primary hysterectomy, eight (17.3%) had a delayed hysterectomy, four (8.6%) had a uterine conservation. Primary Morbidity included 28 blood transfusions, 12 bladder injuries, 1 ureteral injury and 13 transfers to intensive care unit. Secondary morbidity after conservative treatment included two Hemorrhages (16.6%), five endometritis (41.6%) and three disseminated intravacular coagulations (25%). CONCLUSIONS: Morbidity associated with this pathology is severe. Conservative treatment became an option for PASD. Thanks to a better antenatal diagnosis, it can be proposed to more women. Morbidity seems the same as other centers. Our rate of primary and secondary hysterectomy is higher than other centers. Conservative treatment seems an effective option for women who desire to preserve their fertility to avoid peripartum hysterectomy and its related morbidity and consequences on fertility.

Macroscopic fibers and ribbons of oriented carbon nanotubes.

A simple method was used to assemble single-walled carbon nanotubes into indefinitely long ribbons and fibers. The processing consists of dispersing the nanotubes in surfactant solutions, recondensing the nanotubes in the flow of a polymer solution to form a nanotube mesh, and then collating this mesh to a nanotube fiber. Flow-induced alignment may lead to a preferential orientation of the nanotubes in the mesh that has the form of a ribbon. Unlike classical carbon fibers, the nanotube fibers can be strongly bent without breaking. Their obtained elastic modulus is 10 times higher than the modulus of high-quality bucky paper.

Prenatal diagnosis of esophageal atresia: A case of triple negative screening.

Esophageal atresia (EA) is prenatally diagnosed in less than one third of the cases and is usually only suspected. Recently, magnetic resonance imaging (MRI) with dynamic sequence and biochemistry of the amniotic fluid have been proposed to enhance prenatal diagnosis of EA. We report the case of a triple negative screening (ultrasound, MRI with dynamic sequence and biochemistry of the amniotic fluid) with a postnatal diagnosis of EA type III with a small defect. Even using second line tests, prenatal diagnosis of EA remains a challenge.

[Surgical therapeutic management for menorrhagia]. / Thérapeutique chirurgicale des pathologies fonctionnelles.

In patients with dysfunctionnal uterine bleeding, endometrial hypertrophy or endometrial hyperplasia without atypie, the curettage is the only surgical conservative treatment which allows preservation of fertility. Its efficacy is limited to about 50%. In women without wish for further childbearing, endometrial destruction techniques are effective with high satisfaction levels. Second generation devices should be preferred because they are as effective as first generation techniques, but are easier and faster to perform with less complications. There is no indication for systematic use of pre operative thinning agents. Endometrial destruction techniques are an alternative to hysterectomy that should be offered to women with heavy menstrual bleeding, because there are shorter operation time and hospital stay, earlier recovery and reduced post operative complications. The possibility of further surgery should however be discussed pre-operatively. In case of hysterectomy, abdominal route is not recommended, and vaginal or laparoscopic routes are preferred.

Contribution of fetal brain MRI in management of severe fetal anemia.

INTRODUCTION: Intrauterine transfusion (IUT) has changed fetal anemia prognosis. However, long-term neurodevelopmental outcome is altered in 5% of children. Our objective was to study the contribution of fetal MRI to diagnosis brain lesions in case of fetal anemia. MATERIAL AND METHODS: Retrospective monocentric descriptive study from 2005 to 2016, including all patients followed for fetal anemia requiring IUT. The indications for MRI were: hydrops fetalis and / or hemoglobin <5 g / dL and / or more than 3 IUTs and / or acute severe anemia and / or ultrasound abnormality. Fetal and neonatal outcome and pediatric neurological monitoring were studied. RESULTS: 89 patients were followed for fetal anemia with IUT and 28 (29.1%) had fetal MRI, 12 of which were abnormal. Two out of twelve had abnormal ultrasound. Seven out of twelve had poor neurological prognosis: 2 medical terminations of pregnancy were performed; 2 children had severe developmental delay and 3 children had schooling difficulties. Five out of twelve children had favorable neurological prognosis. CONCLUSION: MRI of the fetal brain makes it possible to better detect brain lesions than ultrasound does in the management of severe fetal anemia and seems particularly appropriate in cases of acute anemia.

Management of red blood cell alloimmunization in pregnancy.

The main cause of fetal anemia is maternal red blood cell alloimmunization (AI). The search of maternal antibodies by indirect antiglobulin test allows screening for AI during pregnancy. In case of AI, fetal genotyping (for Rh-D, Rh-c, Rh-E and Kell), quantification (for anti-rhesus antibodies) and antibody titration, as well as ultrasound monitoring, are performed. This surveillance aims at screening for severe anemia before hydrops fetalis occurs. Management of severe anemia is based on intrauterine transfusion (IUT) or labor induction depending on gestational age. After intrauterine transfusion, follow-up will focus on detecting recurrence of anemia and detecting fetal brain injury. With IUT, survival of fetuses with alloimmunization is greater than 90% but 4.8% of children with at least one IUT have neurodevelopmental impairment.

Link between nasal carriage of Staphylococcus aureus and infected diabetic foot ulcers.

AIMS: Nasal carriage of Staphylococcus aureus in diabetic patients may be a risk factor for diabetic foot lesion infections. The aims of this study were to compare the genotypic profiles of S. aureus strains isolated from nares and diabetic foot ulcers (DFUs) using microarray technology. METHODS: Patients were included if they were admitted for diabetic foot infection (DFI) at any of three diabetology departments of Montpellier and Nîmes University Hospitals between 1 September 2010 to 30 June 2012. All S. aureus isolates were analyzed using oligonucleotides arrays; S. aureus resistance and virulence genes were determined and each isolate was affiliated to a clonal complex. RESULTS: The prevalence of S. aureus nasal carriage among the 276 included patients was 39.5% (n=109), while 36.6% (n=101) had S. aureus at both sites (nares and foot wounds) and, of these patients, 65.3% of patients harboured the same strain at both sites. In addition, the spread of the methicillin-resistant S. aureus (MRSA) ST398 clone in DFI and its tropism for bone were also further confirmed. CONCLUSION: These findings appear to provide new arguments in favour of the systematic detection of nasal S. aureus carriage to anticipate the management of DFI.

[Iconographic imaging (ultrasound/MRI) in prenatal evaluation of cervical cystic lymphatic malformations]. / Bilan iconographique (échographie/IRM) dans l'évaluation anténatale des malformations lymphatiques kystiques cervicales.

OBJECTIVES: Assess imaging (ultrasound±MRI) in the diagnosis of cervical cystic lymphangioma. METHODS: Retrospective, descriptive study of the patients who underwent reference ultrasound screening for fetal anterior cervival masses in multidisciplinary prenatal diagnosis center of the Lille Regional University Hospital from 1997 to 2014. RESULTS: Seventeen lymphangiomas were identified. Seventy-three percent of lymphangiomas (n=12) were diagnosed in the baseline ultrasound and 85% (n=11) in MRI. An extra-cervical extension was identified in 10 (62%) with ultrasound and 11 (85%) with MRI. Main sites of mass extension objectived by ultrasound and MRI were respectively the face (4,23%/6,46%), the base of tongue (3, 18%/2, 15%) and buccal floor (3, 18%/3, 15%). Pharyngeal disease (5,38%) and mandible (4,31%) were detected by MRI and not found on ultrasound. Associated malformations detected with ultrasound were 2 (12%) urogenital malformation, 1 (6%) heart defect and 1 (6%) facial anomalies. Lymphangiomas remained stable in volume in 12 (71%) cases and disappeared before birth in 2 (12%) cases. CONCLUSION: MRI and ultrasound seem inseparable to assess and optimally manage fetal cervical masses. Detection of associated lesions seems to help in the final lymphangioma diagnosis. Most of the time, lymphangiomas seem to be stable lesion during pregnancy and a good prognosis in cases of uncomplicated cervical lymphatic mass and without pejorative extension.

[Possible responsibility of EDNRA gene triplication, coding for the endothelin 1 ET-A receptor in a case of congenital diaphragmatic hernia]. / Implication potentielle de la triplication du gène EDNRA codant pour le récepteur ET-A de l'endothéline 1 chez un fœtus porteur de hernie de coupole diaphragmatique.

Congenital diaphragmatic hernia has a physiopathology unfully understood, and is the cause of an important morbimortality. We report the case of a fetus suffering from a diaphragmatic hernia associated with a EDNRA gene triplication, coding for the endothelin 1 receptor. High-resolution genetic techniques were able to find the possible origin of this pathology, and showed that it was an isolated form with a good prognostic. ET-A receptor over-expression in lung vessels may cause a vascular remodeling and a lung arterial high blood pressure. This lung abnormality would have occurred before the diaphragmatic defect.

[Adverse effects of calcium channels blockers used as tocolytic treatment]. / Effets indésirables des inhibiteurs calciques utilisés dans le cadre de la tocolyse.

OBJECTIVE: Tocolysis with calcium channel blockers is widespread in France. However, these molecules are off label use for this indication. The objective of this work is to give an update on all the side effects of calcium channel blockers published or reported to the National Bank of Pharmacovigilance. MATERIALS AND METHODS: We conducted a literature review incorporating the animal experimental data on calcium channel blockers, retrospective and prospective studies (randomized or not) comparing different tocolytics, and the published clinical case reports. Finally we inquired the National Bank of Pharmacovigilance for reported cases of adverse effects after use of calcium channel blockers as tocolytics. RESULTS: Adverse effects are found in 2% to 6% of patients after use of nifedipine, of which 0.9% to 1.9% are severe. These are mainly headache, flushes and arterial hypotension. Data on Nicardipine are more limited. For the latter, adverse effects specifically related to the route of administration (induced phlebitis) are described but it seems that other adverse effects reported are not more frequent. Several meta-analyses have demonstrated a decrease in maternal side effects when using calcium channel blockers compared to ß-agonists. Comparison of calcium channel blockers to Atosiban is less documented. More rare serious side effects are reported as clinical cases, consisting almost exclusively of cardiovascular complications (dyspnea, pulmonary edema, myocardial infarction, arterial hypotension). They are more common with Nicardipine than Nifedipine. Similar observations are found by querying the National Bank of Pharmacovigilance. CONCLUSION: The prescription of calcium channel blockers as tocolysis exposes patients to maternal side effects, which are not serious most of the time, and less frequent than with the ß-agonist. Severe maternal complications were nonetheless reported more frequently with Nicardipine than Nifedipine, which justifies avoiding Nicardipine in tocolysis. Nifedipine is the most studied molecule. It is not possible to define a maximum posology from literature data. It seems unreasonable to associate different tocolytics and necessary to closely monitor maternal blood pressure, the occurrence of a skin reaction or hypersensitivity, dyspnea or chest pain during treatment.

[Clubfoot's prenatal ultrasound diagnosis: is amniocentesis always warranted? About 124 cases]. / Diagnostic anténatal de pied bot : la réalisation d'une amniocentèse est-elle toujours justifiée ? À propos de 124 cas.

OBJECTIVES: Analyze factors leading to isolated clubfoot's occurrence, identify clubfeet associated pathologies, and discuss the opportunity of performing an amniocentesis in cases of isolated clubfoot. PATIENTS AND METHODS: Between January 2007 and December 2011, all patients diagnosed with clubfoot in our prenatal diagnostic center were retrospectively included. We then defined and analyzed idiopathic or isolated talipses equinovarus (ITEV) and clubfeet associated with others morphologic abnormalities or syndromic talipses equinovarus (STEV). RESULTS: One hundred and twenty-four clubfeet were analyzed. Forty-seven cases of ITEV, for which 34 caryotypes were performed with a normal result. Risk factors of ITEV in our series were male gender (P=0.0017), a family history of clubfoot (P=0.001) and primiparity (P=0.04). Seventy-seven cases of STEV were diagnosed, 14 of which had chromosomal abnormalities, 18 spina bifida and 10 musculo-skeletal abnormalities. Among the 124 cases of clubfeet, 25 were unilateral and 99 were bilateral. Bilateral talipses equinovarus do not constitute a risk factor of STEV (P=0.8). DISCUSSION AND CONCLUSION: We did not find any chromosomic abnormalities in cases of ITEV. The results of our study could lead to defer systematic amniocentesis in cases of primiparous women diagnosed with an ITEV, with a familial history of clubfoot and a male fetus. A referent echographist in prenatal diagnosis should still perform a systematic morphologic echography.

[Hyperechogenic fetal bowel: Which fetal and neonatal outcome? A French study of 149 cases]. / Hyperéchogénicité intestinale fœtale : quel bilan proposer et quel pronostic ? À propos d'une série continue de 149 patientes.

OBJECTIVES: In case of hyperechogenic fetal bowel (HFB), invasive procedures such as amniocentesis are often proposed to detect an underlying cause. Our goal is to study etiologies and prognosis of HFB according to antenatal sonographic findings in order to evaluate the relevance of antenatal assessment. MATERIALS AND METHODS: It is a retrospective monocentric study lead from 2008 to 2012, including all patients with a suspicion of HFB on routine sonography. We analysed the antenatal and neonatal results, distinguishing four situations: isolated HFB, HFB+other digestive anomalies, HFB+vascular pathology, HFB+other associated anomalies. RESULTS: For 149 patients, HBF was confirmed. Sixty-nine were isolated HFB, 24 associated with other digestive anomalies, 16 with vascular pathology and 40 with other anomalies. Pregnancy outcomes were different with 92.8, 41.7, 0 and 45.0% of healthy newborns. In the case of isolated HBF, we noted 2.9% cystic fibrosis and 2.9% congenital infection. CONCLUSION: Isolated HBF seems to have a better prognosis than associated forms. However, prenatal investigations to eliminate cystic fibrosis or congenital infection should be offered and may be initially non-invasive, if a larger series confirmed the absence of dyschromosomy in this population.

Management of severe fetal anemia by Doppler measurement of middle cerebral artery: are there other benefits than reducing invasive procedures?

OBJECTIVE: Doppler measurement of peak velocity of systolic blood flow in the middle cerebral artery (PVS-MCA) can safely replace invasive testing in the diagnosis of fetal anemia in Rh-alloimmunized pregnancies and PSV-MCA is now the reference technique. However, no study has evaluated its impact in antenatal care and in survival rate. Our objective was to evaluate the impact of the measurement of PVS-MCA in antenatal management and neonatal outcome in maternal red cell alloimmunization requiring in utero transfusion (IUT). STUDY DESIGN: Retrospective study between January 1999 and January 2013. We excluded all cases of hydrops without follow-up before first IUT. From 1999 to 2006, an IUT was indicated on the optical index at 450 nm (Period 1) and was then replaced by the use of PVS-MCA (Period 2). RESULTS: 77 patients were included, 39 in Period 1 (104 IUT) and 38 in Period 2 (89 IUT). 5 cases of hydrops fetalis (12.8%) were diagnosed during the follow up in Period 1 and none during Period 2. The average number of IUT, the delays between 2 IUT and between last IUET and birth were comparable. The total rate of complication per IUT during the first period was 9.6% vs 1.1% during the second one (p=0.01). The overall survival rate in our population was 34/39 (86.8%) during Period 1 vs 38/38 (100%) during Period 2. CONCLUSION: PSV-ACM allowed an improved monitoring with fewer occurrences of hydrops. Conversely, it did not modify antenatal management and timing of delivery.

[Aortic dissection in pregnancy]. / Dissection aortique et grossesse.

During pregnancy, the occurrence of aortic dissection is a rare event immediately threatening fetal and maternal prognosis. Its occurrence is more common in cases of connective tissue disease. But the absence risk factor shall not exclude or delay diagnosis. We must learn to think about it, because the prognosis is highly dependent on time management. The clinical presentation of this medical and surgical emergency varies, and pregnancy adds its own symptoms. We have to ask without hesitation that echocardiography or chest CT be performed since these diagnostic methods are both reliable and available.

Anatomic and biochemical correlates of the dopamine transporter ligand 11C-PE2I in normal and parkinsonian primates: comparison with 6-[18F]fluoro-L-dopa.

Positron emission tomography (PET) coupled to 6-[18F]Fluoro-L-Dopa (18F-Dopa) remains the gold standard for assessing dysfunctionality concerning the dopaminergic nigrostriatal pathway in Parkinson's disease and related disorders. The use of ligands of the dopamine transporters (DAT) is an attractive alternative target; consequently, the current aim was to validate one of them, 11C-PE2I, using a multiinjection modeling approach allowing accurate quantitation of DAT densities in the striatum. Experiments were performed in three controls, three MPTP-treated (parkinsonian) baboons, and one reserpine-treated baboon. 11C-PE2I B'max values obtained with this approach were compared with 18F-Dopa input rate constant values (Ki), in vitro Bmax binding of 125I-PE2I, and the number of dopaminergic neurons in the substantia nigra estimated postmortem by stereology. In the caudate nucleus and putamen, control values for 11C-PE2I B'max were 673 and 658 pmol/mL, respectively, whereas it was strongly reduced in the MPTP-treated (B'max = 26 and 36 pmol/mL) and reserpine-treated animals (B'max = 338 and 483 pmol/mL). In vivo 11C-PE2I B'max values correlated with 18F-Dopa Ki values and in vitro 125I-PE2I Bmax values in the striatum and with the number of nigral dopaminergic neurons. Altogether, these data support the use of 11C-PE2I for monitoring striatal dopaminergic disorders and the effect of potential neuroprotective strategies.

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.

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.

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.