Search

We report a case of cerebral venous sinus thrombosis, bilateral adrenal hemorrhage, and thrombocytopenia in a 70-year-old man found dead. He had previously received the ChAdOx1 nCoV-19 vaccine (Vaxzevria®, AstraZeneca) 18 days before, and had since developed unspecific and undiagnosed characteristics of what proved to be a rare case of vaccine-associated thrombocytopenia with thrombosis syndrome (TTS). He was found dead 1 week after the beginning of symptoms (day 25 post-vaccine). Autopsy yielded venous hemorrhagic infarction with the presence of thrombi within dural venous sinuses, and extensive hemorrhagic necrosis of the central part of the adrenal glands. Antibodies against platelet factor 4 (PF4) were strongly positive in postmortem fluids, as measured with an enzyme-linked immunosorbent assay (ELISA). This difficult diagnosis is usually made during the patient's lifetime. After eliminating differential diagnoses, we concluded on a fatal case of vaccine-induced immune TTS with positive anti-PF4 antibodies in cadaveric blood, 3 weeks after ChAdOx1 nCoV-19 vaccination. Specific search for anti-PF4 antibodies in cadaveric blood appears therefore paramount to assess postmortem cases of TTS associated with anti-COVID vaccines.

Summary Chloroquine and hydroxychloroquine are drugs that have shown in vitro activity on the replication of certain coronaviruses. In the context of the SARS-Cov-2 epidemic, the virus responsible for the novel coronavirus disease (COVID-19), these two drugs have been proposed as possible treatments. The results of the first clinical studies evaluating the effect of hydroxychloroquine do not support any efficacy of this drug in patients with COVID-19, due to major methodological weaknesses. Yet, these preliminary studies have aroused considerable media interest, raising fears of massive and uncontrolled use. In the absence of evidence of clinical benefits, the main risk is of exposing patients unnecessarily to the well-known adverse effects of hydroxychloroquine, with a possibly increased risk in the specific setting of COVID-19. In addition, widespread use outside of any recommendation risks compromising the completion of good quality clinical trials. The chloroquine hype, fueled by low-quality studies and media announcements, has yielded to the implementation of more than 150 studies worldwide. This represents a waste of resources and a loss of opportunity for other drugs to be properly evaluated. In the context of emergency, rigorous trials are more than ever needed in order to have, as soon as possible, reliable data on drugs that are possibly effective against the disease. Meanwhile, serious adverse drug reactions have been reported in patients with COVID-19 receiving hydroxychloroquine, justifying to limit its prescription, and to perform suitable cardiac and therapeutic drug monitoring.

BackgroundMediatization of bisphosphonate(BP)-related osteonecrosis of the jaw (ONJ) has hampered the treatment of osteoporosis (OP). The risk of ONJ associated with oral BP in OP and zoledronate (ZOL) in oncology has previously been reported. However, the risk of ZOL-related ONJ in OP has only been reported in Randomized clinical trials.ObjectivesTherefore, we aimed to characterize ZOL-related ONJ in OP and compare it’s incidence with oral BP in real life setting.MethodsAll reports of adverse events (AEs) of BP (ZOL, alendronate (ALN), risedronate (RIS)) were extracted from the French pharmacovigilance database (FPD) since its origin till 2020. For ZOL, cases were separated by indication, rheumatological (ZOL-R) or oncological (ZOL-K). The risk factors analyzed for ONJ were age, sex, active smoking, alcoholism, diabetes, corticotherapy, neoplasia, previous treatment by chemo or immunotherapy, recent dental care and time of exposure to BP. The association between the occurrence of ONJ and the associated BP was assessed by calculating the reporting odds ratio (ROR) in a case/non-case study. Stratification on assumed risk factors was performed to assess their impact on the risk of ONJ.The incidence of ONJ under BP between 2011 and 2020 was estimated by relating the number of ONJ cases under BP reported to the FPD to the estimated number of patients treated with ZOL, ALN and RIS over the same period according to health insurance reimbursement data of Medic AM database. Incidence rate calculation, confidence interval calculation, and comparison of incidence rates (Fischer exact test) were performed.ResultsFor ZOL 2254 AEs were reported: 568 ONJ/1103 AES with ZOL-K and 70 ONJ/1151 AEs with ZOL-R. For ZOL-R-related ONJ, 30/70 cases had recent dental care and 48.7 months of mean time of exposure to BP. Risk factors for ONJ were smoking, history of neoplasia and chemotherapy. For ALN, 1,010 AEs were reported, including 188 ONJ. 91/188 ONJ had recent dental care and 70.9 months of mean time of exposure to BP. Risk factors for ONJ were age ≥65 years, diabetes, corticotherapy, and history of neoplasia. For RIS, 771 AEs were reported including 68 cases of ONJ. 28/68 ONJ had recent dental care and 53.6 months the average time of exposure to BP. The risk factors were age ≥ 65 years, smoking, corticotherapy, history of neoplasia and chemotherapy. ROR calculation shows that corticotherapy was associated more frequently with RIS (2.10 [1.64-2.69]) and ALN (1.33 [1.04-1.70]) as compared with ZOL-R, with no other significant difference.The incidence of ONJ was significantly higher with ZOL-R than with RIS (pConclusionOur data confirm in real-life settings and a large population, that BP-related ONJ is a rare event associated with OP. The risk of BP-related ONJ appears related to the potency of bone resorption inhibition, as RIS has the lowest and ZOL-R the highest risk. Smoking appears a consistent risk factor of ONJ, as is recent dental care. However, we must stress out the usual limitations of pharmacovigilance studies, their retrospective nature, common under-reporting of adverse-events, and the fact that the Medic AM database only refers to city reimbursements.To our knowledge, this is the first study reporting the risk of ONJ under ZOL from the national pharmacovigilance database. Our study confirms the rarity, in OP, of BP-related ONJ. The risk of incidence of ONJ on ZOL-R is higher than on RIS and ALN, suggesting a risk associated with the inhibitory power of bone resorption.AcknowledgementsAcknowledgements to the French Network of Pharmacovigilance CentersDisclosure of InterestsClaire Amigues: None declared, Audrey Fresse: None declared, Christian Roux: None declared, Sophie Gauthier: None declared, Marie-Hélène Vieillard: None declared, Milou-Daniel Drici: None declared, Véronique Breuil Speakers bureau: AMGEN MSD UCB THERAMEX LILLY, Consultant of: AMGEN MSD UCB THERAMEX LILLY, Grant/research support from: AMGEN LILLY

Introduction L’alitretinoine est un retinoide indique chez l’adulte atteint d’eczema chronique severe des mains, ne repondant pas au traitement par dermocorticoides puissants. Il est commercialise en France depuis 2009. En raison d’un risque de dyslipidemie induit par le traitement, l’alitretinoine est contre-indique en cas d’hypercholesterolemie ou d’hypertriglyceridemie non controlee. L’objectif etait de rechercher un risque d’evenement cardiovasculaire grave (ECVG) associe a l’alitretinoine. Materiel et methodes Nous avons compare la population exposee a l’alitretinoine a la population generale francaise, a partir de la base medico-administrative de l’Assurance-maladie (SNDS-SNIIRAM). Nous avons inclus tous les patients ayant recu de l’alitretinoine en France jusqu’en 2016. Les ECVG retenus etaient les syndromes coronariens aigus (SCA), accidents vasculaires cerebraux (AVC) ischemiques, et arteriopathies obliterantes des membres inferieurs (AOMI). Nous avons estime des SMR (Standardized Morbidity Ratio) en standardisant l’incidence d’ECVG sur la population generale francaise (echantillon generaliste des beneficiaires), en tenant compte de l’âge, du sexe, de la presence d’une dyslipidemie, d’un antecedent d’ECVG, et apres stratification sur le risque cardiovasculaire, defini comme la presence d’au moins un facteur de risque ou antecedent d’evenement cardiovasculaire. Resultats En France, 19513 patients ont recu de l’alitretinoine entre 2009 et 2016 : 64 ont fait un ECVG pendant la cure (duree mediane des cures : 3 mois), et 292 dans les 2 ans suivant le debut des cures. Dans la sous-population sans risque cardiovasculaire, les patients recevant de l’alitretinoine ne faisaient pas plus d’ECVG que la population generale. Dans la sous-population avec au moins un antecedent ou facteur de risque cardiovasculaire, il n’a pas ete identifie de risque d’ECVG pendant les cures ; dans les 2 ans suivant le debut des cures, les patients ont le meme risque de syndrome coronarien aigu que la population generale (SMR = 0,89, IC 95 % [0,75–1,06]), mais font deux fois moins d’AVC ischemique (SMR = 0,49, IC 95 % [0,30–0,75]). Discussion Nous n’avons pas identifie d’exces de risque d’evenement cardiovasculaire grave chez les patients ayant recu de l’alitretinoine. Une diminution du risque d’AVC dans les 2 ans suivant le debut du traitement est trouvee chez les patients ayant au moins un facteur de risque ou antecedent d’evenement cardiovasculaire. Deux hypotheses sont proposees : un effet neuroprotecteur, qui pourrait etre explique par une diminution de l’atherosclerose et une inhibition de l’agregation plaquettaire observees sur modele murin. La seconde hypothese est celle d’un « healthy user effect », traduisant un plus fort recours aux soins des patients recevant de l’alitretinoine. Conclusion Il n’est pas trouve d’exces de risque d’ECVG en cours ou apres un traitement par alitretinoine.

Introduction L’ustekinumab (Stelara®) est un anticorps monoclonal anti-interleukine (IL) 12/23 commercialise depuis mars 2010. Une meta-analyse a alerte en 2011 sur un possible risque d’evenements cardiovasculaires graves (ECVG). Aucun travail n’a ete mene par la suite pour confirmer ou infirmer ce risque potentiel. L’ustekinumab pourrait destabiliser les plaques d’atherome, via l’inhibition de la population lymphocytaire T helper 17. L’objectif etait de rechercher un effet declencheur d’ECVG a l’initiation de l’ustekinumab. Patients et methodes L’ensemble des patients exposes a l’ustekinumab entre 2010 et 2016 a ete identifie a partir des bases de donnees francaises de l’Assurance maladie (SNDS-SNIIRAM). Les ECVG retenus etaient les syndromes coronariens aigus (SCA) et accidents vasculaires cerebraux (AVC) ischemiques. L’hypothese d’une periode a risque de 6 mois suivant l’initiation de l’ustekinumab a ete testee par une analyse « case-time-control ». Elle compare, chez les sujets ayant fait un ECVG, le nombre d’initiations pendant les 6 mois qui precedent les ECVG a celui des 6 mois anterieurs. Resultats Parmi les 9290 patients exposes a l’ustekinumab, 75 ont presente un SCA, un AVC ou un angor instable en cours de traitement. L’incidence d’ECVG etait de 61 pour 100 000 personnes-mois, IC 95 % [43 ; 86] dans les 6 premiers mois apres l’initiation. L’analyse « case-time-control » des 98 ECVG survenus avant, pendant ou apres la cure, et des 392 « temoins pour la tendance temporelle », a montre des OR significativement differents selon le niveau de risque cardiovasculaire du patient, estime a partir de ses facteurs de risque cardiovasculaires. Chez les patients a faible risque cardiovasculaire, on n’observait pas d’effet declencheur de l’ustekinumab (OR = 0,30, IC 95 % [0,03 ; 3,13]). Chez les patients a risque cardiovasculaire eleve, on observait un risque significatif de declenchement d’ECVG par l’ustekinumab (OR = 4,17 [1,19 ; 14,59]). Ce risque persistait dans les analyses de sensibilite ( Fig. 1 ). Discussion Nos resultats suggerent un « effet declencheur » d’ECVG dans les mois qui suivent l’initiation de l’ustekinumab, identifie chez les patients a risque cardiovasculaire eleve, en coherence avec l’hypothese physiopathologique de destabilisation des plaques d’atherome. Conclusion Ces resultats incitent a des mesures de prudence dans l’indication d’ustekinumab chez des sujets a risque cardiovasculaire. Les autres biotherapies impliquant la voie lymphocytaire T helper 17 (anti-IL17A, anti-IL17RA, anti-IL23), recemment commercialisees, pourraient etre concernees par ce signal.

Numerous drugs from diverse classes, such as antiarrhythmics, antihistamines, gastrokinetics, antipsychotics and antibiotics, share the potential to induce a prolongation of the QT interval on the electrocardiogram and torsade de pointes ventricular arrhythmias. The underlying mechanism of these side-effects is the blocking of voltage-gated potassium channels, particularly the rapid component I Kr , of the delayed rectifier I K . The risk of such drug-induced arrhythmias is far greater in women than in men. Clinical data as well as experimental studies show that, in comparison to men, the feminine gender is associated with a longer baseline QT interval, a greater response to drugs that block I Kr and a greater propensity to drug-induced torsade de pointes. This is most likely the result of a specific regulation of channel expression by and perhaps a direct non genomic effect of - sex steroids.

OBJECTIVE--To evaluate the prevalence of cardiac toxoplasmosis in a series of 182 necropsies performed between 1987 and 1991 on patients infected with the human immunodeficiency virus (HIV), to correlate this prevalence with the ante mortem diagnosis of cardiac involvement, and to assess the role of such cardiac lesions in the immediate cause of death. PATIENTS AND METHODS--Complete necropsies of 182 HIV-infected patients (48 women, 134 men) were performed consecutively between 1987 and 1991. Risk factors, identified in 174 cases, included drug abuse (111/182), homosexuality (51/182), and blood transfusions (12/182). 16 samples were systematically obtained from each heart for histological study. If trophozoites or lymphocytic myocarditis were seen, immunohistochemical investigations were carried out with polyclonal antibodies for Toxoplasma gondii. An ultrastructural study was performed in four patients with toxoplasma myocarditis. Myocardial lesions were defined by the Dallas classification. Clinical data (and information on electrocardiograms and echocardiograms) were obtained from medical records. RESULTS--Cardiac toxoplasmosis was diagnosed at necropsy in 21 (12%) patients. Cardiac lesions were associated with toxoplasmic encephalitis in 18 patients and were solitary in three patients. Acute diffuse myocarditis was present in 6/21, rare foci of myocarditis were seen in 8/21, and intramyocytic toxoplasmic cysts without any inflammatory reaction or necrosis were seen in 4/21. Anti-toxoplasma immunolabelling showed cardiac toxoplasmosis in three patients with lymphocytic myocarditis. Particles with the ultrastructural characteristics of Toxoplasma gondii trophozoites were seen in four cases. Six patients had presented with cardiac symptoms, confirmed by electrocardiographic and echocardiographic abnormalities during their disease course, and their cardiac lesions were directly responsible for the death. CONCLUSION--Cardiac toxoplasmosis was common in this necropsy series of HIV-infected patients. Cardiac toxoplasmosis had been suspected clinically in four patients. Myocardial lesions were generally asymptomatic and were not discovered until necropsy. Solitary cardiac involvement was not uncommon reflecting parasite reactivation at a myocardial site. The incidence of cardiac toxoplasmosis in this group of immunodepressed subjects from an area with a high prevalence of this parasitic disease justifies regular follow up of such patients by electrocardiography and echocardiography as well as immediate administration of anti-toxoplasma treatment should sudden heart failure occur.

To explore whether sertindole increases all-cause mortality or cardiac events requiring hospitalization, compared with risperidone.Multinational randomized, open-label, parallel-group study, with blinded classification of outcomes, in 9858 patients with schizophrenia.After 14147 person-years, there was no effect of treatment on overall mortality (sertindole 64, risperidone 61 deaths, Hazard Ratio (HR) = 1.12 (90% CI: 0.83, 1.50)) or cardiac events requiring hospitalization [sertindole 10, risperidone 6, HR = 1.73 (95% CI: 0.63, 4.78)]: Of these, four were considered arrhythmia-related (three sertindole, one risperidone). Cardiac mortality was higher with sertindole (Independent Safety Committee (ISC): 31 vs. 12, HR=2.84 (95% CI: 1.45, 5.55), P = 0.0022; Investigators 17 vs. 8, HR=2.13 (95% CI: 0.91, 4.98), P = 0.081). There was no significant difference in completed suicide, but fewer sertindole recipients attempted suicide (ISC: 68 vs. 78, HR=0.93 (95% CI: 0.66, 1.29), P = 0.65; Investigators: 43 vs. 65, HR=0.67 (95% CI: 0.45, 0.99), P = 0.044).Sertindole did not increase all-cause mortality, but cardiac mortality was higher and suicide attempts may be lower with sertindole.

The development of new antiarrhythmic drugs is mainly aimed to treat atrial fibrillation, because of its prevalence and major consequences in terms cerebral vascular thrombosis. Specific blockade of I(Na) et I(K), even if efficacious, have previously shown to be proarrhythmogenic, with a global impairment of the cardiac patient's outcome. This lead to the development of new drugs, selectively targeting atrial currents such as I(Kur) ou I(KAch). The efficacy of amiodarone in treatment of atrial fibrillation has also yielded a whole array of new antiarrhythmic drugs targeting both these atrial currents but also sharing amiodarone pharmacodynamics properties. This renders the Vaughan-Williams classification ill-adapted for such drugs.

The clinical pharmacological and therapeutic working group was particularly impressed by twelve recent publications relative to its various themes of interest. Two studies were made of the prognostic impact of non-observance of treatment which seems to be associated with an extra-mortality even when the treatment is placebo: the probable explanation is that the non-observance of drug therapy is also associated with the non observance of dietary/life style measures and with cognitive dysfunction associated with more severe cardiac disease. A recent study on n-acetyl-cysteine has rekindled the debate on this substance for preventing nephrotoxicity of radiological contrast used during angioplasty in high risk patients. The risks of AINS drug therapy has been reassessed. The increased risk of myocardial infarction is confirmed with celecoxib but not with "classical" AINS drugs if not prescribed for more than one year and without aspirin. With respect to lipid-lowering drugs, should statins be prescribed to attain a target value of LDL-cholesterol or to attain a given reduction in LDL-cholesterol? The death knell of fibrates has more or less been rung by the results of the FIELD study and the real value of OMEGA-3 drugs should be reassessed by good quality prospective studies. In the domain of hypertension, the recent arrival of aliskiren, the first of the antirenin drugs, is noteworthy although its role in the therapeutic strategy, remains to be defined. Finally, a comment is made on the results of the TROPHY study which suggest value in the possible prevention of hypertension with angiotensin II inhibitors in patients at risk of developing hypertension.

Although the year 2005 has reinforced the therapeutic advances of 2004, with confirmation of certain concepts, the 'coxib affair' has continued to provoke arguments between pharmaceutical companies, licensing agencies as well as patients, some of whom have amalgamated into consumer groups to reject en masse placing any responsibility on the prescribers in favour of an attack on the drug licensing process itself. Among the cardiovascular drugs that will soon be licensed, only ivabradine in stable angina, and remodulin in primary pulmonary arterial hypertension are new. The therapeutic advances in 2005 regarding platelet aggregation and blood coagulation have been significant, in the human, scientific and commercial context, while hypertension has not been ignored. Another new development is the ever more precise notion of the metabolic syndrome, a target of choice for the pharmaceutical industry. The potential range of applications has been widened to include obesity, hypertension, diabetes, HDL cholesterol... The licensing authorities find themselves facing a hurdle to overcome, with novel combinations of drugs (ACE inhibitors, calcium blockers/statins, statins/aspirin, ARA2/calcium blockers...).

The year 2004 was not marked by major pharmacological advances, but by confirmation of previous "evidence". Several innovative drugs for stable angina (ranolazine, ivabradine), some interesting results in acute coronary syndrome (PROVE IT study), some classic concepts (cannabinoid receptors and their antagonists such as rimonabant) applied to novel indications (treatment of obesity), hopes for the "sartans" revived in the light of new evidence (VALUE study), advances in the management of diabetes and hypertension (ASCOT and CARDS studies), nebivolol which is not just a betablocker but also produces the NO radical (is this why it decreased the mortality of heart failure in the elderly in the SENIOR study?). In contrast, although Chronadalate did not live up to expectations for coronary insufficiency, the year was marked above all by the much heralded withdrawal of Vioxx for increasing cardiovascular risk. The old adage: primum non nocere springs to mind.

Cloned HERG and KvLQT1-IsK K+ channels have been expressed in mammalian cells and assayed as a target for calcium channel blockers. These channels generate the rapid and slow components of the cardiac delayed rectifier K+ current, and mutations can affect them that lead to long QT syndromes. HERG is blocked by bepridil (EC50 = 0.55 microM), verapamil (EC50 = 0.83 microM) and mibefradil (EC50 = 1.43 microM), whereas nitrendipine and diltiazem have negligible effects. Steady-state activation and inactivation parameters are shifted to more negative values in the presence of the blockers. Similarly, KvLQT1-IsK is inhibited by bepridil (EC50 = 10.0 microM) and mibefradil (EC50 = 11.8 microM), whilst being insensitive to nitrendipine, diltiazem or verapamil. This work may help to understand the mechanisms of action of verapamil in certain ventricular tachycardias as well as some of the deleterious adverse cardiac events associated with bepridil and mibefradil.

The hallmark of long QT syndromes (LQTS) is an abnormal ventricular repolarization characterized by a prolonged QT interval on the electrocardiogram and a propensity to the occurrence of syncopes resulting from polymorphic ventricular tachycardia, called torsades de pointes. They may degenerate to ventricular fibrillation, possibly causing sudden death. Congenital LQTS, which implicates at least six chromosomal loci, LQT1 to LQT6, three of them corresponding to mutations concerning the coding of K+ channel proteins, give useful information about the mechanism underlying the arrhythmia. One of the potassium channel genes implicated in congenital LQTS is HERG, which encodes the IKr current channel protein. This current has provided a relevant insight into the occurrence of drug-acquired LQTS, since all drugs associated with torsades, such as erythromycin, terfenadine, haloperidol, or cisapride, also block IKr.

The hallmark of all long QT syndromes (LQTS) is an abnormal ventricular repolarization characterized by a prolonged QT interval on the electrocardiogram. LQTS have a drastically different prognosis whether or not they are congenital. Congenital Long QT syndrome is a rare cardiac disorder associating the occurrence of syncopes often triggered in adrenergic setting, like strenuous exercise or emotional stress (RODEN et al. 1996). Most of the times, syncopes result from polymorphic ventricular tachycardia, calledtorsades de pointes, that were described first by Dessertene who characterized their pause-dependency and their distinctive time-dependent change in electrical axis (DESSERTENNE 1966). They may degenerate into entricular fibrillation, possibly causing sudden death, and are remarkably prevented by s-adrenergic antagonists. In fact, the clinical diagnosis of LQTS can be fairly difficult in the absence of typical rhythmic problems or if the QT interval remains within the normal limits (QTc

We examined the effects of the calcium channel blockers nitrendipine, diltiazem, verapamil, bepridil, and mibefradil on the cloned HERG and KvLQT1/IsK K+ channels. These channels generate the rapid and slow components of the cardiac delayed rectifier K+ current, and mutations can affect them, which leads to long QT syndromes. When expressed in transfected COS cells, HERG is blocked in a concentration-dependent manner by bepridil (EC50 = 0.55 microM), verapamil (EC50 = 0.83 microM), and mibefradil (EC50 = 1.43 microM), whereas nitrendipine and diltiazem have negligible effects. Steady state activation and inactivation parameters are shifted to more negative values in the presence of the blockers. Similarly, KvLQT1/IsK is inhibited by bepridil (EC50 = 10.0 microM) and mibefradil (EC50 = 11.8 microM), while being insensitive to nitrendipine, diltiazem, or verapamil. These results demonstrate that both cloned K+ channels HERG and KvLQT1/IsK, which represent together the cardiac delayed rectifier K+ current, are sensitive targets to calcium channel blockers. This work may help in understanding the mechanisms of action of verapamil in certain ventricular tachycardia, as well as some of the deleterious adverse cardiac events associated with bepridil.

Cancer stem cells (CSCs) are a specific subset of cancer cells that sustain tumor growth and dissemination. They might represent a significant treatment target to reduce malignant progression and prevent tumor recurrence. In solid tumors, several hierarchically organized CSC clones coexist, even within a single tumor. Among them, CSCs displaying an embryonic stem cell ‘stemness’ signature, based on the expression of Oct-4, Nanog and Sox2, are present in distinct high-grade tumor types associated with poor prognosis. We previously designed a model to isolate pure populations of these CSCs from distinct solid tumors and used it to screen for molecules showing selective toxicity for this type of CSC. Here we show that human immunodeficiency virus (HIV)-protease inhibitors (HIV-PIs) specifically target CSCs expressing an embryonic signature derived from tumors with distinct origins. They reduced proliferation in a dose-dependent manner with a higher specificity as compared with the total population of cancer cells and/or healthy stem cells, and they were efficient in inducing cell death. Lopinavir was the most effective HIV-PI among those tested. It reduced self-renewal and induced apoptosis of CSCs, subsequently impairing in vivo CSC-induced allograft formation. Two key pharmacophores in the LPV structure were also identified. They are responsible for the specificity of CSC targeting and also for the overall antitumoral activity. These results contribute to the identification of molecules presenting selective toxicity for CSCs expressing an embryonic stemness signature. This paves the way to promising therapeutic opportunities for patients suffering from solid cancer tumors of poor prognosis.

Verapamil is a calcium channel blocker widely used as an antihypertensive agent, and its pharmacological effects may partly be due to some degree of beta blockade. In order to evaluate the changes occurring in beta-2 adrenoceptor density, 40 patients with mild to moderate hypertension received verapamil 240 mg (once a day) or captopril 20 mg (twice a day) during 30 days, in a double-blind randomized study, after a placebo run-in period. The lymphocytic membrane beta-2 adrenoceptor density (Bmax) was determined before the administration of active drugs and after a 15-day treatment. After a month of treatment, most patients showed a marked reduction of their diastolic blood pressure: from 98.2 +/- 3.2 mmHg to 81.2 +/- 4.0 mmHg (p0.05), in the verapamil group, and from 95.0 +/- 6.0 mmHg to 82.5 +/- 4.8 mmHg (p0.05) in the captopril group. After 15 days of treatment, verapamil induced an up-regulation of beta-2 adrenoceptors from 39.5 +/- 8.3 fmol/mg protein to 58.5 +/- 12.0 fmol/mg protein (p0.05), whereas the Bmax in the captopril group did not significantly change. No significant change occurred in the two dissociation constants. This up-regulation phenomenon, common among beta-2 blockers, supports the hypothesis of verapamil's beta blockade potency.

Calcium is involved in several biochemical atherogenesis processes and its activity is antagonised in cell and animal experimental models by all classes of slow channel calcium inhibitors. However, the doses required in animals to slow the development of atherosclerotic lesions are above therapeutically acceptable doses in man. The clinical relevance of their anti-atherosclerotic activity in the few clinical studies undertaken is difficult to assess because of the variable criteria of judgment used.

A placebo is a pharmacologically inactive substance that can have a therapeutic effect if administered to a patient who believes that he or she is receiving an effective treatment. It is generally admitted that the placebo effect decreases blood pressure in 20% to 30%, when evaluated by casual sphygmomanometer or ambulatory systems. In order to evaluate the occurrence of a placebo effect in cardiovascular pharmacology, we analysed two studies. One study included ten mild-to-moderate hypertensive patients, and consisted of two submaximal exercise tests separated by a single oral administration of the placebo. The other study included six healthy volunteers, receiving an oral placebo during ten days. The placebo was in both case presented as an effective antihypertensive agent. Any change on blood pressure and heart rate, both at rest and during exercise, was observed before and three hours after the placebo. After ten days of placebo administration, no statistically significant change in blood pressure or heart rate was obtained. Nor was any statistical difference observed in catecholamine plasma levels, either three hours or ten days after oral administration of the placebo. The second study did not show any evidence of changes in lymphocytic beta-adrenoceptor density after ten days of placebo. The results of these pilot studies suggest that the use of a placebo group in cardiovascular clinical pharmacology should be reconsidered. The real occurrence and characteristics of a placebo effect should be evaluated by a complementary study.

The evaluation of mild to moderate hypertension must be carried out under the conditions in which treatments are usually prescribed, i.e., in general practice. After specific training of the physicians in the methods used, we evaluated the efficacy and safety of a new formulation of verapamil by comparing it with a reference drug: captopril. The main assessment criterion was the restoration of normal blood pressure in mildly to moderately hypertensive patients (blood pressure in excess of 160/95 mmHg). Blood pressure was evaluated by two methods: a mercury column sphygmomanometer, after the patient had rested in a half-sitting position for 10 minutes, and the ambulatory measurement of blood pressure (AMBP) using the SpaceLabs system. The results of this study involving 40 patients followed up for 3 months by 8 GPs in collaboration with our blood pressure unit were as follows: on verapamil, 47% of patients recovered normal values after 30 days of treatment and 71% after 60 days (with no change in dosage). On captopril, the normalization rates were 22 and 27% respectively. The highly significant reduction of blood pressure found by the "occasional" measurement for both treatments (p less than 0.001) was only faintly reflected by AMBP. Verapamil induced a reduction of nighttime blood pressure with no significant impact on heart rate. The clinical, paraclinical and electrocardiographic safety of both treatments was good.

Dilevalol is a vasodilating beta-blocker with proven antihypertensive activity. In this study, 28 patients with mild-to-moderate uncomplicated hypertension underwent 2 submaximal exercise tests, each consisting of progressive steps of 20 watts for 2 minutes or up to 85% theoretical maximum heart rate. Five minutes after the first test, patients received either placebo or dilevalol 200 mg, 400 mg or 600 mg. The second exercise test was performed 3 hours later. Diastolic blood pressure, systolic blood pressure, heart rate and norepinephrine plasma levels were assessed before and after exercise. Dilevalol at all doses caused a significant decrease in heart rate and blood pressure both at rest and during exercise, compared to placebo. Dilevalol 600 mg had a greater effect on diastolic blood pressure than dilevalol 200 mg and 400 mg. Administration of dilevalol 200 mg and 400 mg enabled 42% of patients to increase their maximal exercise level by 20 to 60 watts. Dilevalol increased plasma norepinephrine levels at the 100 watts exercise levels from 5.1 +/- 4.0 nmol/l to 7.6 +/- 4.3 nmol/l (p less than 0.05). No adverse effects were observed during dilevalol treatment. This study shows that dilevalol is an effective antihypertensive agent that blunts heart rate and blood pressure risings during exercise.

The administration of placebo (a pharmacologically inactive substance) is justified in clinical trials of antihypertensive drugs in order to exclude the placebo effect. The evaluation of antihypertensive treatments during exercise is an interesting end point, since aerobic exercise is part of antihypertensive treatment. The aim of this study is to determine the placebo effect on blood pressure, heart rate and catecholamine secretion profiles during exercise testing.10 patients with untreated mild to moderate essential hypertension participated in a single blind study consisting of two successive submaximal exercise tests (85% of maximal predicted heart rate), separated by a single oral administration of placebo. Blood pressure and heart rate were measured after 10 minutes of rest and at the end of each effort step (2 min, 20 Watts), both before and after placebo. Blood samples (5 ml) were collected at rest and during maximal exercise before and after placebo, in order to determine the effect of placebo on circulating catecholamines.There were no significant difference between the "control" and after placebo exercise tests, neither in blood pressure or heart rate profiles, nor in values of circulating catecholamines (noradrenaline at rest: 1.88 +/- 0.96, effort: 6.43 +/- 1.93 nm/l before placebo, 1.65 +/- 0.83 nm/l and 5.71 +/- 2.12 nm/l after placebo respectively [NS]).The placebo effect, which is generally determined from blood pressure at rest by sphygmomanometry, seems devoid of any influence on blood pressure, heart rate or catecholamine profiles during exercise in patients with mild to moderate essential hypertension. Thus, antihypertensive treatments can be evaluated during exercise by comparison to baseline cardiovascular parameters without need of a placebo group.

The Alpress LP osmotic tablet enables progressive and prolonged release of prazosin into the digestive tract over a 16 hour period. This leads to the maintenance of stable plasma concentrations of the drug and the absence of high plasma peaks during the absorption of prazosin. The antihypertensive effect prazosin persists throughout the day and night, ensuring effective blood pressure regulation and treatment is well tolerated by patients.

The administration of placebo (pharmacologically inactive substance) is justified in clinical trials of antihypertensive drugs, in order to avoid the inclusion of placebo-responders. The evaluation of antihypertensive treatments during exercise is an interesting end point, since aerobic exercising is part of antihypertensive treatment. The aims of this study are to determine the placebo impact on blood pressure, heart rate and catecholamine secretion profiles during exercise testing.10 untreated essential mild to moderate hypertensives participated to a single blind study comprising two successive submaximal exercise testings (85% of maximal theoretical heart rate), separated by a single oral administration of placebo. Blood pressure and heart rate were measured after 10 minutes of resting position and at the end of each effort step (2 mm, 20 Watts), both before and after placebo. Blood samples (5 ml) were collected at rest and during maximal exercise before and after placebo, in order to determine the effect of placebo on circulating catecholamines.there was no significant variations between the "control" and exercise testings after placebo, neither on blood pressure or heart rate profiles, nor in values of circulating catecholamines [Noradrenaline at rest: 1.88 +/- 0.96, exercise: 6.43 +/- 1.93 nm/l before placebo, 1.65 +/- 0.83 nm/l and 5.71 +/- 2.12 nm/l after placebo respectively (NS)].the placebo, which effect is generally determined on blood pressure at rest by sphygmomanometry, seems devoid of any activity on blood pressure, heart rate or catecholamine profile during exercise, in essential moderate hypertensives. Thus, antihypertensive treatments at exercise can be evaluated by comparison to baseline cardiovascular parameters without placebo groups.