Charles Khouri

SGLT-2 inhibitors and the risk of lower-limb amputation: Is this a class effect?

Inhibitors of the sodium‐glucose co‐transporter‐2 (SGLT‐2) are a novel class of glucose‐lowering agents that show promising results. However, the use of canagliflozin has been associated with an increased risk of lower‐limb amputation. Whether this risk concerns other SGLT‐2 inhibitors is unclear, and our objective was to address this issue. We performed a disproportionality analysis using the WHO global database of individual case safety reports (VigiBase). Among the 8 293 886 reports available between January 2013 and December 2017, we identified 79 reports of lower‐limb amputation that were associated with SGLT‐2 inhibitors. Among all blood glucose lowering drugs, the proportional reporting ratio (PRR) was increased only for SGLT‐2 inhibitors (5.55 [4.23, 7.29]). While we observed an expected signal for canagliflozin (7.09 [5.25, 9.57]), the PRR was also high for empagliflozin (4.96 [2.89, 8.50]) and, for toe amputations only, for dapagliflozin (2.62 [1.33, 5.14]). In conclusion, our results reveal a positive disproportionality signal for canagliflozin, and also for empagliflozin, and, for toe amputations only, for dapagliflozin. However, our analysis relies on a limited number of cases and is exposed to the biases inherent to pharmacovigilance studies. Further prospective data are therefore needed to better characterize the risk of amputations with different SGLT‐2 inhibitors.

Targeting the Prostacyclin Pathway: Beyond Pulmonary Arterial Hypertension

Pioneering work demonstrated that an unstable substance isolated from rabbit and pig aortas could relax arterial smooth muscle and inhibit platelet aggregation. Since then, prostacyclin (prostaglandin I2, PGI2) and its analogs have raised much pharmacological interest. In this review we detail how the PGI2 signaling pathway is much more complex than was initially anticipated, involving peroxisome proliferator-activated receptors (PPARs), prostaglandin transporters (PGTs), and PGI2-thromboxane A2 (TXA2) receptor (IP TP) heterodimerization. We discuss the distinct affinities of PGI2 analogs for prostanoid receptors. In addition, we introduce the new direct and indirect pharmacological approaches to targeting the PGI2 pathway within the systemic circulation, including non-prostanoid agonists of the prostacyclin receptor (IP) and PGT inhibitors, as well as transcutaneous pathways using iontophoresis and nanostructured lipid carriers.

Drug-induced Raynaud's phenomenon: beyond β-adrenoceptor blockers

AIM Drug-induced Raynauds phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or β-adrenoceptor blockers. However, sources report extremely variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug-induced RP. METHODS A systematic review of English and French language articles was performed through Medline (1946-2015) and Embase (1974-2015). Further relevant papers were identified from the reference lists of retrieved articles. RESULTS We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by β-adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism. CONCLUSION Drug-induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered.

Drug‐induced Raynaud's phenomenon: beyond beta‐blockers

AIM Drug-induced Raynauds phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or β-adrenoceptor blockers. However, sources report extremely variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug-induced RP. METHODS A systematic review of English and French language articles was performed through Medline (1946-2015) and Embase (1974-2015). Further relevant papers were identified from the reference lists of retrieved articles. RESULTS We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by β-adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism. CONCLUSION Drug-induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered.

Comparative Safety of Drugs Targeting the Nitric Oxide Pathway in Pulmonary Hypertension: A Mixed Approach Combining a Meta-Analysis of Clinical Trials and a Disproportionality Analysis From the World Health Organization Pharmacovigilance Database

BACKGROUND: Recent guidelines recommend riociguat, a soluble guanylate cyclase (sGC) stimulator, and the type 5 phosphodiesterase inhibitor (PDE5i) tadalafil or sildenafil as treatments for pulmonary arterial hypertension. We compared the safety profiles of sildenafil, tadalafil, and riociguat in pulmonary hypertension. METHODS: We combined two approaches. First, we performed a meta‐analysis of safety data extracted from randomized controlled trials. Second, we conducted a disproportionality analysis of data from VigiBase, the World Health Organization’s global database of individual case safety reports, to compare the safety profiles with real‐life data. RESULTS: In the meta‐analysis, a significant difference between the three drugs was only detected for gastrointestinal disorders, in disfavor of riociguat (P < .01 for interaction). In the disproportionality analysis, the use of riociguat was associated with fewer reports of visual disorders but increased reporting of gastrointestinal, hemorrhagic, and musculoskeletal disorders compared with sildenafil and tadalafil. Pharmacovigilance signals of hearing/vestibular disorders were heterogeneous: vestibular disorders (dizziness) were reported more frequently for riociguat, whereas hearing disorders (deafness) were reported less frequently compared with PDE5is. CONCLUSIONS: The safety profiles of PDE5is and sGC stimulators significantly differ in pulmonary hypertension. Accordingly, there is a safety rationale in switching between PDE5is and sGC stimulators because of their different side effects. TRIAL REGISTRY: PROSPERO; No.: CRD42016051986; URL: https://www.crd.york.ac.uk/prospero/.

Hierarchical evaluation of electrical stimulation protocols for chronic wound healing: an effect size meta-analysis

Electrical stimulation (ES) has been tested for decades to improve chronic wound healing. However, uncertainty remains on the magnitude of the efficacy and on the best applicable protocol. We conducted an effect size meta‐analysis to assess the overall efficacy of ES on wound healing, to compare the efficacy of the different modalities of electrical stimulation, and to determine whether efficacy differs depending on the wound etiology, size, and age of the chronic wound. Twenty‐nine randomized clinical trials with 1,510 patients and 1,753 ulcers were selected. Overall efficacy of ES on would healing was a 0.72 SMD (95% CI: 0.48, 1) corresponding to a moderate to large effect size. We found that unidirectional high voltage pulsed current (HVPC) with the active electrode over the wound was the best evidence‐based protocol to improve wound healing with a 0.8 SMD (95% CI: 0.38, 1.21), while evaluation of the efficacy of direct current was limited by the small number of studies. ES was more effective on pressure ulcers compared to venous and diabetic ulcers, and efficacy trended to be inversely associated with the wound size and duration. This study confirms the overall efficacy of ES to enhance healing of chronic wounds and highlights the superiority of HVPC over other type of currents, which is more effective on pressure ulcers, and inversely associated with the wound size and duration. This will enable to standardize future ES practices.

Dysthyroidie sous anti-VEGF, effet indésirable de classe ? À propos d’un cas

Tyrosine-kinase inhibitors are recent therapy used in different neoplastic diseases. Dysthyroidism seems to be a class effect of these drugs with a potentially cross cumulative effect. We describe here the case of a man who first developed dysthyroidism with sunitinib, then a deep and permanent hypothyroidism when axitinib was introduced.

Proton pump inhibitors and Raynaud's phenomenon: is there a link?

Proton pump inhibitors (PPI) are a worldwide used drug class for the treatment of gastric reflux. Recent epidemiological studies have raised concern about the increased cardiovascular risk of long-term PPI use [1, 2]. One of the hypothesized pathophysiological mechanism is that PPI inhibit the degradation of plasma asymmetric dimethylarginine (ADMA) through inhibition of the dimethylarginine dimethylaminohydrolases, which largely metabolize ADMA [3]. ADMA is an endothelial nitric oxide synthase (NOS) competitive inhibitor, which is a prognostic biomarker of major cardiovascular events [4, 5]. Moreover, recent data show that treatment with esomeprazole increased superoxide anions production, decreased endothelial and inducible NOS expression and accelerates human endothelial senescence by reducing telomere length [5]. Such mechanisms are also involved in the pathophysiology of Raynaud’s phenomenon (RP) [6]. However, whether the use of PPI is associated with an increased risk of developing or aggravating RP has never been explored. To further address this issue, we performed a disproportionality analysis in the WHO pharmacovigilance database VigiBase®. Our objective was to compare the Proportional Risk Ratio (PRR) of RP associated with PPI and with histamine H2 antagonists, used as control. PRR is the ratio between the rate of reporting of one effect among all reports for a given drug and the rate of reporting of the same effect among all reports for all drugs in the database [7]. We extracted all individual cases safety reports (ICSRs) of RP associated with PPI (ATC A02BC) and H2 antagonists (ATC A02BA), considered as either suspect or concomitant medication. When a report was associated with both PPIs and H2 antagonists, it was counted in each drug class. The cut-off for signal detection was defined as a lower boundary of the PRR 95% confidence interval greater or equal to 1, and number of reports greater or equal to 3, according to the European Medicines Agency [8]. Frequencies of reports between drugs were compared using the χ test, and a P value < 0.05 was considered significant. Among the 16 403 009 ICSRs reported in VigiBase® on 2018.02.01, 753 854 were related to PPI use and 269 663 to H2 antagonists. We identified 253 reports of RP associated with PPI and 48 with H2 antagonists. The PRR was above signal detection for the PPI drug class and for each PPI, whereas the cut-off for signal detection was not reached for H2 antagonists (Figure 1). The difference in PRR between the two groups was statistically significantly. Characteristics of RP reports are presented in Supplementary Table 1. We observed no difference in potential effect modifiers (age, sex, concomitant medications or pathology known to induce RP) between groups. In conclusion, our results reveal a positive disproportionality signal of RP for PPIs, with a significantly higher reporting rate than for H2 antagonists. However, our analysis relies on a limited number of reports and is exposed to biases inherent to pharmacovigilance studies, such as selective reporting, media bias and limited ability to control for potential confounders. Further large and well-controlled epidemiological studies are therefore needed to better characterize the risk of RP with PPI.

Severe central sleep apnoea associated with nalmefene: a case report

Nalmefene, an opioid antagonist, has recently been approved for the treatment of alcohol dependence. We describe here the first case of a 52‐year‐old woman who developed a severe central sleep apnoea (CSA) 5 months after initiation of nalmefene. Scoring of ventilation during sleep recording revealed an apnoea‐hypopnoea index of 67/h with 98.7% of central events and an apnoea index of 65/h. Nalmefene was withdrawn and a new polysomnography was performed which concluded that CSA has disappeared. Pathophysiology is still unclear but could involve the κ‐opioid receptors. Physicians should be aware that CSA might affect patients treated with nalmefene. Further investigations are required to determine the pathophysiology, frequency, and treatment of CSA associated with nalmefene and other therapy for alcohol disorders.

Fluoxetine and Raynaud's phenomenon: friend or foe?

Whether fluoxetine, a selective serotonin reuptake inhibitor, is an effective treatment for Raynaud’s phenomenon (RP) has been debated for about 20 years. Based on one positive efficacy trial [5] and some preliminary observations [6], fluoxetine is recommended in RP secondary to systemic sclerosis (SSc), after failure of calcium channel blockers [7]. However, when one looks closely at the available evidence, the lack of a homogeneous effect of fluoxetine in RP patients is obvious. The crossover study comparing the efficacy of nifedipine and fluoxetine in 56 patients with primary or secondary RP showed a significant improvement in the Raynaud’s condition score (RCS) [4.35 (0.39) vs. 2.3 (0.35); P = 0.0002] and daily frequency of attacks [2.98 (0.31) vs. 1.7 (0.25); British Journal of Clinical Pharmacology Br J Clin Pharmacol (2017) 83 2307–2309 2307