Experimental study of reflexive erection in rats

Les fibres du nerf dorsal du pénis véhiculent la sensibilité du pénis et constituent le versant afférent des réflexes sexuels. Leur stimulation par des chocs de faible durée provoque une augmentation réflexe de la pression intracavemeuse, qui est supprimée par la section bilatérale des nerfs pelviens efférents. Lorsqu’on augmente la durée des chocs, la réponse réflexe n’est obtenue qu’après section de la moelle en T8, suggérant la possibilité d’un contrôle inhibiteur descendant de ce réflexe d’érection. Chez les rats spinaux, la réponse réflexe diminue d’amplitude, lorsque l’on augmente l’intensité de la stimulation. Cette inhibition segmentaire n’est pas due au recrutement de fibres sensitives inhibitrices. Elle pourrait résulter de la mise en jeu d’un réflexe sympathique antiérectile s’opposant au réflexe d’érection.The dorsal nerve of the penis, which carries the somatic sensory information of the glans and the penile skin constitutes the afferent limb of sexual reflex responses. Its stimulation by trains of rectangular pulses of small duration (< 0,1 ms) leads to reflex increase of the intracavemous pressure which is abolished by bilateral section of the efferent pelvic nerves. Increasing pulse duration to 1 ms fails to elicit this reflex response in intact rats. Such a stimulation consistenly elicits it in rats with spinal transection at the level T8, suggesting a possible descending inhibitory action of supraspinal centers on the lombosacral spinal cord. In acute spinal rats, the reflex response progressively decreases when intensity of afferent stimulation increases. This inhibitory effect is not due to recruitment of inhibitory afferent fibers and could result from reflex activation of spinal sympathetic antirectile centers

Reversible Tumor Progression Induced by a Dexamethasone Course for Severe COVID-19 during Immune Checkpoint Inhibitor Treatment

Immunotherapies and immune checkpoint inhibitors (ICI) represent the latest revolution in oncology. Several studies have reported an association between the use of corticosteroids and poorer outcomes for patients treated with ICIs. However, it has been never established whether corticoid-induced tumor progression under ICI treatment could be reversible. We report herein transient tumor progression induced by dexamethasone for a patient treated with pembrolizumab for metastatic bladder cancer. An 82-year-old man was treated with pembrolizumab as a second-line treatment for metastatic urothelial carcinoma with stable disease for 8 months as the best tumoral response. He experienced severe coronavirus disease 2019 (COVID-19) infection and was treated with high-dose dexamethasone for ten days according to the RECOVERY protocol. Following this episode, radiological CT-scan evaluation showed tumor progression. Pembrolizumab was maintained, and subsequent radiological evaluation showed tumor shrinkage. This case highlights that the antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Clinicians should be aware that tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients. Insights: The antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients

Potential Cytochrome P450-mediated pharmacokinetic interactions between herbs, food, and dietary supplements and cancer treatments

International audienceHerbs, food and dietary supplements (HFDS), can interact significantly with anticancer drug treatments via cytochrome p450 isoforms (CYP) CYP3A4, CYP2D6, CYP1A2, and CYP2C8. The objective of this review was to assess the influence of HFDS compounds on these cytochromes. Interactions with CYP activities were searched for 189 herbs and food products, 72 dietary supplements in Web of Knowledge® databases. Analyses were made from 140 of 3,125 clinical trials and 236 of 3,374 in vitro, animal model studies or case reports. 18 trials were found to report direct interactions between 9 HFDS with 8 anticancer drugs. 21 HFDS were found to interact with CYP3A4, a major metabolic pathway for many anticancer drugs. All 261 HFDS were classified for their interaction with the main cytochromes P450 involved in the metabolism of anticancer drugs. We provided an easy-to-use colour-coded table to easily match potential interactions between 261 HFDS and 117 anticancer drugs

Reversible Tumor Progression Induced by a Dexamethasone Course for Severe COVID-19 during Immune Checkpoint Inhibitor Treatment

International audienceImmunotherapies and immune checkpoint inhibitors (ICI) represent the latest revolution in oncology. Several studies have reported an association between the use of corticosteroids and poorer outcomes for patients treated with ICIs. However, it has been never established whether corticoid-induced tumor progression under ICI treatment could be reversible. We report herein transient tumor progression induced by dexamethasone for a patient treated with pembrolizumab for metastatic bladder cancer. An 82-year-old man was treated with pembrolizumab as a second-line treatment for metastatic urothelial carcinoma with stable disease for 8 months as the best tumoral response. He experienced severe coronavirus disease 2019 (COVID-19) infection and was treated with high-dose dexamethasone for ten days according to the RECOVERY protocol. Following this episode, radiological CT-scan evaluation showed tumor progression. Pembrolizumab was maintained, and subsequent radiological evaluation showed tumor shrinkage. This case highlights that the antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Clinicians should be aware that tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients. Insights: The antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients

Anticancer drugs and COVID-19 antiviral treatments in patients with cancer: What can we safely use?

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Major pitfalls of protein kinase inhibitors prescription: a review of their clinical pharmacology for daily use

International audienceProtein kinase inhibitors (PKI) are a growing class of anticancer agents. They are prescribed with flat doses, and their oral administration is associated with interindividual variability in exposure. Patients can be over- or underexposed, due to numerous factors. We reviewed key pharmacokinetic concepts and mechanisms by which PKIs prescription could be altered. Challenging situations that could lead to increased toxicity or to therapeutic failure are described and recommendation for clinicians are proposed. Finally, the interest of therapeutic drug monitoring and indications for its use in daily practice is discussed

Anticancer drug-induced life-threatening ventricular arrhythmias: a World Health Organization pharmacovigilance study

International audienceAbstract Aims With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA). Methods and results We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 &gt;0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967–83 to 15 070 in 2014–18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P &lt; 0.0001). Concordance between these VigiBase signals and data concerning diLQT and VA/TdP identified in CredibleMeds or US Food and Drug Administration (FDA) labels was moderate (κ = 0.47 and 0.40, P &lt; 0.0001). Twenty-three drugs represent new signals, while 24 flagged by CredibleMeds or FDA had no signal in VigiBase. A three-level SD risk stratification relying on isolated long QT (low risk), associated with VA without SD (moderate risk), and VA with SD (high risk) is proposed. Conclusion This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements. Clinical trial registration NCT03530215

Increased reporting of fatal pneumonitis associated with immune checkpoint inhibitors: a WHO pharmacovigilance database analysis

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Clinical characterization of men with long QT syndrome and torsades de pointes associated with hypogonadism: A review and pharmacovigilance study

International audienceBACKGROUND:Long QT syndrome (LQTS) can cause the potentially fatal ventricular tachycardia torsades de pointes (TdP). QT interval corrected for heart rate (QTc) is shorter in men than in women, with testosterone contributing to shorten QTc. We recently described male hypogonadism as a reversible risk factor for acquired LQTS and TdP, but the clinical characteristics of such patients have not been characterized.AIMS:To describe the clinical characteristics of men with acquired LQTS or TdP associated with hypogonadism caused by endocrine conditions or androgen deprivation therapy (ADT), and to evaluate the relationship between testosterone concentrations and electrocardiographic changes.METHODS:We searched MEDLINE (to 04 January 2019) and the French pharmacovigilance database (to 09 August 2018) to identify male cases of acquired LQTS and TdP associated with endocrine hypogonadism or ADT; their narratives were gathered from reporting collaborators.RESULTS:We identified seven cases of TdP (one fatal) with endocrine hypogonadism, abnormally long QTc and morphologically abnormal T-wave notches. After reversion of low testosterone concentrations in the surviving patients (N=6), QTc shortened, T-wave morphology normalized and there was no TdP recurrence. Among these cases, none had mutation in the LQTS genes, three men required testosterone and three had reversible hypogonadism after resolution of a concurrent acute severe illness. We found an additional 27 reports of men with LQTS (N=6), TdP (N=9; 2/9 fatal) or sudden death (N=12; 10/12 fatal) suspected to be induced or favoured by ADT (24/27 for prostate cancer). Generally, after ADT withdrawal, QTc shortened and no TdP recurred.CONCLUSION:We propose seeking for hypogonadism caused by endocrine conditions or ADT in men presenting with TdP. Caution is warranted when ADT is used in situations at risk of TdP. Testosterone may be useful to treat or prevent TdP

Axon diodes for the reconstruction of oriented neuronal networks in microfluidic chambers

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