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Background and ObjectivesPatients with a new diagnosis of cancer carry an increased risk of acute ischemic stroke (AIS) and this risk varies depending on age, cancer type, stage, and time from diagnosis. Whether AIS patients with a new diagnosis of neoplasm represent a distinct subset from those with a previously known active malignancy remains unclear. We aimed to estimate the rate of stroke in patients with newly diagnosed cancer and previously known active cancer and to compare the demographic and clinical features, stroke mechanisms, and long-term outcomes between groups.MethodsUsing 2003-2021 data from the ASTRAL registry, we compared patients with known active cancer to patients with newly diagnosed cancer (cancer identified during AIS hospitalization or within the following 12 months). Patients with inactive and no history of cancer were excluded. Outcomes were the modified Rankin Scale (mRS) score at 3 months and mortality and recurrent stroke at 12 months. We used multivariable regression analyses to compare outcomes between groups while adjusting for important prognostic variables.ResultsAmong 6686 patients with AIS, 362 (5.4%) had active cancer, including 102 (1.5%) with newly diagnosed cancer. Gastrointestinal and genitourinary cancers were the most frequent cancer types. Among all patients with active cancer, 152 (42.5%) AISs were classified as cancer-related, with nearly half of these cases attributed to hypercoagulability. In multivariable analysis, patients with newly diagnosed cancer had less pre-stroke disability (aOR 0.62, 95%CI 0.44-0.86) and fewer prior stroke/TIA events (aOR 0.43, 95%CI 0.21-0.88) than patients with known active cancer. 3-month mRS scores were similar between cancer groups (aOR 1.27, 95%CI 0.65-2.49), and were predominantly driven by the presence of newly diagnosed brain metastases (aOR 7.22, 95%CI 1.49-43.17) and metastatic cancer (aOR 2.19, 95%CI 1.22-3.97). At 12 months, mortality risk was higher in patients with newly diagnosed cancer versus patients with known active cancer (HR 2.11, 95%CI 1.38-3.21) while recurrent stroke risk was similar between groups (aHR 1.27, 95%CI 0.67-2.43).DiscussionIn a comprehensive institutional registry spanning nearly two decades, 5.4% of patients with AIS had active cancer, a quarter of which were diagnosed during or within 12 months after the index stroke hospitalization. Patients with newly diagnosed cancer had less disability and prior cerebrovascular disease, but a higher 1-year risk of subsequent death than patients with known active cancer.

Pain is a common symptom in patients on chronic hemodialysis (HD) but the prevalence of opioid prescriptions in this population has been poorly studied outside the United States. This study assesses the prevalence of opioid prescription in two Swiss dialysis centers. Prescriptions and clinical characteristics were retrospectively retrieved from the medical records of patients on HD for at least six months, treated at Lausanne University Hospital (academic center, AC), and the private center Clinique Cecil (PC) for the study. A total of 117 patients were included; 29.1% received at least one opioid prescription during the study period. Significantly more patients received an opioid prescription in the AC (39.1%) than in the PC (14.6%, p = 0.004). Univariate logistic regression analysis showed that center (Odds Ratio (OR) 3.76; Confidence Interval (CI) 1.48–9.6; p = 0.006), neuropathic pain (OR 2.99; CI 1.28–6.98; p = 0.011), benzodiazepine prescription (OR 2.72; CI 1.14–6.46; p = 0.024), polyneuropathy (OR 2.71; CI 1.14–6.46; p = 0.024) and amputation (OR 4.23; CI 1.1–16.1; p = 0.034) were associated with opioid prescription. The center was the only independent predictive factor in the multivariate analysis. Our results show that opioids are regularly prescribed to Swiss dialysis patients, although important differences exist between centers. The latter finding might suggest that opioid prescribing is more related to the prescriber than to the patient’s condition, but larger-scale studies are necessary to confirm this.

Fungal periprosthetic joint infections (PJI) are difficult to treat, due to important biofilm formation and limited local penetration of systemically administered antifungals. Calcium sulphate (CaSO

BackgroundThe extent of inappropriate prescribing observed in geriatric medicine has not been thoroughly evaluated in people ageing with HIV. We determined the prevalence of and risk factors for inappropriate prescribing in individuals aged ≥75 years enrolled in the Swiss HIV Cohort Study.MethodsRetrospective review of medical records was performed to gain more insights into non-HIV comorbidities. Inappropriate prescribing was screened using the Beers criteria, the STOPP/START criteria and the Liverpool drug–drug interactions (DDIs) database.ResultsFor 175 included individuals, the median age was 78 years (IQR 76–81) and 71% were male. The median number of non-HIV comorbidities was 7 (IQR 5–10). The prevalence of polypharmacy and inappropriate prescribing was 66% and 67%, respectively. Overall, 40% of prescribing issues could have deleterious consequences. Prescribing issues occurred mainly with non-HIV drugs and included: incorrect dosage (26%); lack of indication (21%); prescription omission (drug not prescribed although indicated) (17%); drug not appropriate in elderly individuals (18%) and deleterious DDIs (17%). In the multivariable logistic regression, risk factors for prescribing issues were polypharmacy (OR: 2.5; 95% CI: 1.3–4.7), renal impairment (OR: 2.7; 95% CI: 1.4–5.1), treatment with CNS-active drugs (OR: 2.1; 95% CI: 1.1–3.8) and female sex (OR: 8.3; 95% CI: 2.4–28.1).ConclusionsPolypharmacy and inappropriate prescribing are highly prevalent in elderly people living with HIV. Women are at higher risk than men, partly explained by sex differences in the occurrence of non-HIV comorbidities and medical care. Medication reconciliation and periodic review of prescriptions by experienced physicians could help reduce polypharmacy and inappropriate prescribing in this vulnerable, growing population.

Hyperuricemia is often encountered as glomerular filtration rate decreased. It is associated with a more rapid decline of the renal function, but causality has not been demonstrated. Recent studies showed that treatment of hyperuricemia did not affect the progression in chronic kidney disease (CKD) patients. Thus, treatment with hypouricemic drugs of patients suffering of CKD and displaying asymptomatic hyperuricemia is not recommended. However, patients with CKD present often with acute flairs of gout, which might be difficult to treat. Therapeutic options are discussed in this article.Une hyperuricémie apparaît précocement en cas de diminution de la filtration glomérulaire et de maladie rénale chronique. Elle est associée à un déclin plus rapide de la fonction rénale, mais un lien de causalité n’a pas été démontré. Plusieurs études récentes n’ont pas montré d’effet bénéfique d’un traitement hypo-uricémiant sur l’évolution de la fonction rénale. Ainsi, en cas d’hyper uricémie asymptomatique chez un patient souffrant de maladie rénale chronique, un traitement hypo-uricémiant n’est pas indiqué. Cependant, les patients souffrant de maladie rénale chronique font plus fréquemment des crises de goutte, et leur prise en charge est complexe car la maladie est à la fois plus résistante au traitement et les options thérapeutiques sont limitées. Celles-ci sont revues dans cet article.

The COVID-19 pandemic has stimulated the rapid development and large-scale use of technologically innovative vaccines, such as the mRNA vaccines Spikevax (Moderna) and Comirnaty (Pfizer-BioNTech). This unprecedented deployment has challenged pharmacovigilance, requiring combined skills in safety monitoring, prompt data analysis and continuous dissemination of knowledge. Main recognised adverse events of these vaccines are moderate and transient, linked to their significant reactogenicity. Active post-marketing surveillance has identified rare adverse events such as myopericarditis and a variety of skin reactions. A number of potential rare adverse events are being evaluated and could be retained at the individual level, but do not question the overall safety of these vaccines.La pandémie de Covid-19 a conduit au développement rapide de vaccins à la technologie innovante, utilisés à large échelle, dont les vaccins à ARNm Spikevax (Moderna) et Comirnaty (Pfizer-BioNTech). Ce déploiement sans précédent défie la pharmacovigilance, nécessitant d’allier un suivi attentif de la sécurité, une analyse rapide des données et une diffusion continue des connaissances. Les principaux effets indésirables reconnus pour ces vaccins sont modérés et transitoires, liés à leur importante réactogénicité. Une pharmacovigilance active a permis d’identifier des effets indésirables rares, tels que des myopéricardites et diverses réactions cutanées. Un certain nombre d’effets indésirables rares potentiels sont en cours d’évaluation et pourraient être retenus à l’échelle individuelle, mais ne remettent pas en cause la sécurité vaccinale globale.

Certain drugs may increase the risk of ischemic stroke (IS). Our goal was to review associations between frequently used drugs and IS. We created an initial list of frequently used drugs to search Pubmed/MEDLINE from 1966 to 2020 and reviewed phase III and IV data, case series, and drug authorities’ safety warnings to assess a potential association with IS. Drugs were grouped according to the World Health Organization Anatomical Therapeutic Chemical Classification System. Predefined criteria were applied to establish a level of evidence for an association, from A (high level of evidence of association) to E (high level of evidence of absence of association). In addition, we assessed relative risks and reviewed potential mechanisms of IS facilitation. We assessed 81 drugs or drug classes from 11 World Health Organization Anatomical Therapeutic Chemical Groups. We identified a high level of association for erythropoietin, combined contraceptives, oral estrogen replacement therapy, bevacizumab, tamoxifen, and antipsychotics and a moderate level for ponatinib, nilotinib, darunavir, and gonadotropin-releasing hormone agonists. Drug dose and treatment duration may modify the risk. For a substantial number of drugs, we found no association, and for others, there were insufficient data to categorize risk. We identified a high level of association of IS with a limited number of drugs, a potential association with some, and a lack of data for others. The summarized information may help clinicians to estimate the contribution of a drug to an IS, to better assess drug benefit-risk ratios, and to support decisions about using specific drugs.

Sex-related differences affecting pharmacokinetic and pharmacodynamic processes result mostly from sex dimorphisms in body composition, and liver and kidney function, in addition to hormonal regulation of enzymes, transporters and drug receptors. Gender biases have long compromised the identification of these differences in clinical trials. They also modulate prescription patterns and therapeutic benefits. Men and women would benefit from different standard dosages of some anti-infectives, anticancer agents and other treatments requiring precise dosage adjustment. This would alleviate the well-documented excess of adverse reactions affecting women. However, the variability of pharmacological responses within each sex exceeds the average male-female difference, highlighting the importance of other criteria for therapeutic individualisation.Les processus pharmacocinétiques et pharmacodynamiques reflètent les dimorphismes sexuels affectant la composition corporelle, les fonctions rénale, hépatique et la régulation des enzymes, transporteurs et récepteurs de médicaments. Des biais liés au genre ont longtemps compromis l’identification de ces différences dans les essais cliniques. Ils modulent aussi la prescription et le bénéfice thérapeutique. Des posologies standard différentes entre hommes et femmes mériteraient d’être proposées pour certains anti-infectieux, anticancéreux et autres traitements requérant un ajustement posologique précis. Cela atténuerait le surcroît démontré d’effets indésirables touchant les femmes. La variabilité des réponses pharmacologiques dans chaque sexe excède la différence moyenne hommes-femmes, rappelant l’importance d’autres critères d’individualisation thérapeutique.

Introduction: Combined antiretroviral therapy has transformed HIV infection into a chronic disease thus people living with HIV (PLWH) live longer. As a result, the management of HIV infection is becoming more challenging as elderly experience age-related comorbidities leading to complex polypharmacy and a higher risk for drug-drug or drug-disease interactions. Furthermore, age-related physiological changes affect pharmacokinetics and pharmacodynamics thereby predisposing elderly PLWH to incorrect dosing or inappropriate prescribing and consequently to adverse drug reactions and the subsequent risk of starting a prescribing cascade. Areas covered: This review discusses the demographics of the aging HIV population, physiological changes and their impact on drug response as well as comorbidities. Particular emphasis is placed on common prescribing issues in elderly PLWH including drug-drug interactions with antiretroviral drugs. A PubMed search was used to compile relevant publications until February 2019. Expert opinion: Prescribing issues are highly prevalent in elderly PLWH thus highlighting the need for education on geriatric prescribing principles. Adverse health outcomes potentially associated with polypharmacy and inappropriate prescribing should promote interventions to prevent harm including medication reconciliation, medication review, and medication prioritization according to the risks/benefits for a given patient. A multidisciplinary team approach is recommended for the care of elderly PLWH.

The main pharmacovigilance updates in 2020 are reviewed. Remdesivir in COVID-19: relatively safe but turns out to be less effective than expected. Hydroxychloroquine in COVID-19 : lack of efficacy and risk of arrhythmias. Cytokines storm in COVID-19: may impact pharmacokinetics. VEGF inhibitors: risk of aneurysm and artery dissection. Tofacitinib: dose-dependant risk of venous thromboembolic events. Ondansetron in the first trimester of pregnancy : a highly debated risk of orofacial cleft defects. Fingolimod : contraindicated during pregnancy due to suspected risk of congenital malformations. Ranitidine: global market withdrawal due to contamination with nitrosamines. Ulipristal for uterine fibroids : market withdrawal due to risk of severe liver injury. Ingenol mebutate : market withdrawal due to paradoxical risk of skin cancers.Les principales actualités de pharmacovigilance 2020 sont passées en revue. Remdésivir et Covid-19 : moins efficace qu’attendu mais assez sûr. Hydroxychloroquine et Covid-19 : absence d’efficacité et risque d’arythmies. Orage cytokinique et Covid-19 : impact possible sur les paramètres pharmacocinétiques. Inhibiteurs du VEGF : risque d’anévrisme artériel et de dissection. Tofacitinib : risque d’événements thromboemboliques. Ondansétron au 1

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating, mostly lethal complication due to an opportunistic infection of the central nervous system (CNS) by John Cunningham polyo...

The safety of NSAIDs, corticosteroids and renin-angiotensin inhibitors in COVID-19 is challenged. NSAIDs may interfere with the defense process against viral infection and are best avoided. Systemic corticosteroids have not shown benefit in viral infection, including other coronavirus; thus they should be avoided, unless prescribed for another indication. The benefit-risk ratio is however clearly in favor of continuing inhaled corticosteroids in patients with asthma or COPD. ACE inhibitors and sartans upregulate the expression of angiotensin-converting enzyme 2 (ACE2), the pulmonary receptor for SARS-CoV-2. Any possible clinical impact of these treatments on COVID-19 infection remains to be clarified; in the meantime, they should be continued.La sécurité des AINS, corticoïdes et antihypertenseurs agissant sur le système rénine-angiotensine lors d’infection à COVID-19 est mise en question. Les AINS pourraient interférer avec le processus de défense face à une infection virale ; ils sont donc plutôt à éviter. Les corticoïdes systémiques n’ont pas montré de bénéfice lors d’infections virales, y compris à d’autres coronavirus ; ils sont à éviter, sauf si prescrits pour une autre indication. Le rapport bénéfice/risque est en revanche clairement en faveur de la poursuite des corticostéroïdes inhalés chez les asthmatiques ou BPCO. Les IEC et les sartans modulent l’expression de l’enzyme de conversion de l’angiotensine 2 (ACE2), récepteur pulmonaire du SARS-CoV-2. L’impact clinique de ces traitements sur l’infection à COVID-19 reste à préciser ; en attendant, ils sont à poursuivre.

Background PIs cause drug–drug interactions (DDIs) with most statins due to inhibition of drug-metabolizing enzymes and/or the hepatic uptake transporter OATP1B1, which may alter the pharmacodynamic (PD) effect of statins. Objectives To assess the management of DDIs between antiretrovirals (ARVs) and statins in people living with HIV (PLWH) considering statin plasma concentrations, compliance with dosing recommendations and achievement of lipid targets. Methods PLWH of the Swiss HIV Cohort Study were eligible if they received a statin concomitantly with ARVs. HDL, total cholesterol (TC) and statin plasma concentration were measured during follow-up visits. Individual non-HDL and TC target values were set using the Framingham score and the 2018 European AIDS Clinical Society recommendations. Results Data were analysed for rosuvastatin (n = 99), atorvastatin (n = 92), pravastatin (n = 46) and pitavastatin (n = 21). Rosuvastatin and atorvastatin underdosing frequently led to suboptimal PD response. Insufficient lipid control was observed with PIs despite high atorvastatin concentrations, likely explained by inhibition of OATP1B1 resulting in less statin uptake in the liver. Target lipid values were more often achieved with unboosted integrase inhibitors due to both their favourable DDI profiles and neutral effect on lipids. Insufficient lipid control was common with pravastatin and pitavastatin regardless of co-administered ARVs and despite using maximal recommended statin doses. The latter suggests lower efficacy compared with rosuvastatin or atorvastatin. Conclusions Suboptimal management of DDIs with statin underdosing was observed in 29% of prescriptions. Integrase inhibitor-based regimens and/or treatment with rosuvastatin or atorvastatin should be favoured in patients with refractory dyslipidaemia.

Zusammenfassung. Denosumab ist ein monoklonaler Antikörper gegen den RANK-Liganden, der die Reifung und Aktivität von Osteoklasten hemmt. Es verringert die Knochenresorption, erhöht die Knochendichte und reduziert das Frakturrisiko. Nach dem Abbruch der Behandlung zeigt sich jedoch ein deutlicher Rebound-Effekt, der etwa zwei Jahre anhält. Es führt zu erhöhten Markern des Knochenumbaus, einem Verlust der Knochendichte, der grösser als der Gewinn sein kann, und zu einem erhöhten Risiko für multiple Wirbelfrakturen. Diese Frakturen treten mit einer Häufigkeit von 1–10 % auf. Wegen dieses hohen Risikos sollte Denosumab eine Zweitlinientherapie sein, die auf sehr spezifische Indikationen beschränkt ist. Um den Rebound-Effekt zu begrenzen, wird derzeit empfohlen, beim Abbruch der Denosumab-Behandlung ein starkes Bisphosphonat (Alendronat, Zoledronat) zu verschreiben und die Knochenresorptionsmarker regelmässig zu prüfen.

Background Antiretroviral therapy has transformed HIV infection from a deadly into a chronic condition. Aging people with HIV (PWH) are at higher risk of polypharmacy, potential drug–drug interactions (DDIs), and potentially inappropriate medications (PIMs). This study aims to compare prescribed drugs, polypharmacy, and potential DDIs between young ( Methods PWH from 2 centers within the Swiss HIV Cohort Study were asked to fill in a form with all their current medications. Polypharmacy was defined as being on ≥5 non-HIV drugs. PIMs were evaluated using Beers criteria. Potential DDIs for the most prescribed therapeutic classes were screened with the Liverpool interaction database. Results Among the 996 PWH included, 122 were ≥65 years old. Polypharmacy was more frequent in the elderly group (44% vs 12%). Medications and potential DDIs differed according to the age group: cardiovascular drugs and related potential DDIs were more common in the elderly group (73% of forms included ≥1 cardiovascular drug; 11% of cardiovascular drugs involved potential DDIs), whereas central nervous system drugs were more prescribed and involved in potential DDIs in younger PWH (26%, 11%). Potential DDIs were mostly managed through dosage adjustments. PIMs were found in 31% of the elderly group. Conclusions Potential DDIs remain common, and PIMs constitute an additional burden for the elderly. It is important that prescribers develop and maintain a proactive approach for the recognition and management of DDIs and other prescribing issues frequently encountered in geriatric medicine.

The main pharmacovigilance updates in 2018 are reviewed. Quinolones : no longer recommended for mild or moderately severe infections. Denosumab in cancer patients: increased risk of new primary malignancies. Cyproterone : increased risk of meningioma at high dose. Saccharomyces boulardii : risk of fungemia in frail patients. Ulipristal : risk of hepatotoxicity. Daclizumab : early withdrawal from the market as risks clearly outweigh benefits. Interactions between boosted antiretrovirals and anti-P2Y12 : prasugrel appears as the best option. Neural tube defects in babies born to women treated with dolutegravir : a signal to investigate. Cobicistat-boosted antiretrovirals exposure is decreased during pregnancy. Fourth generation pills containing drospirenone : a greater propensity to prolong the QT interval than 2nd generation pills.Les actualités de pharmacovigilance 2018 sont passées en revue. Quinolones : pas en première intention pour les infections simples. Dénosumab : risque accru de second cancer. Cyprotérone : à dose élevée, risque accru de méningiome.

La prescription en denominations communes internationales est simple, mais ne dispense pas le prescripteur de preciser la forme galenique lorsqu’il en existe plusieurs.

A 69-year-old man under long-term spironolactone therapy (16 years) was hospitalized with spontaneous hematoma on the trunk and extremities. Coagulation studies disclosed an acquired hemophilia that was successfully treated with human factor VIII for a few days and immunosuppressive agents for several months. Physical examination revealed bilateral gynecomastia and an upper left quadrant breast nodule. Complete staging was unremarkable. Complete left mastectomy was performed. Histopathology showed invasive ductal carcinoma, expressing positivity for estrogen and progesterone receptors. The acquired hemophilia was considered to be a paraneoplasic syndrome. The question of a linkage between long-term spironolactone therapy and breast carcinoma is discussed.

Multiple Vertebral Fractures after Denosumab Discontinuation: How to Avoid Them? Abstract. Denosumab is a monoclonal antibody raised against the RANK ligand that inhibits the maturation and activity of osteoclasts. It decreases bone resorption, increases bone density and reduces fracture risk. However, after its discontinuation, a significant rebound effect appears that lasts about two years. It results in increased markers of bone remodeling, a loss of bone density that may be greater than gain, and an increased risk of multiple vertebral fractures. These fractures occur at a frequency of 1 to 10 %. Due to this high risk, denosumab should be a second-line treatment limited to very specific indications. At denosumab discontinuation, in order to limit the rebound effect, the current recommendation is to prescribe a strong bisphosphonate (alendronate, zoledronate) and regularly monitor the bone resorption markers.Zusammenfassung. Denosumab ist ein monoklonaler Antikörper gegen den RANK-Liganden, der die Reifung und Aktivität von Osteoklasten hemmt. Es verringert die Knochenresorption, erhöht die Knochendichte und reduziert das Frakturrisiko. Nach dem Abbruch der Behandlung zeigt sich jedoch ein deutlicher Rebound-Effekt, der etwa zwei Jahre anhält. Es führt zu erhöhten Markern des Knochenumbaus, einem Verlust der Knochendichte, der grösser als der Gewinn sein kann, und zu einem erhöhten Risiko für multiple Wirbelfrakturen. Diese Frakturen treten mit einer Häufigkeit von 1–10 % auf. Wegen dieses hohen Risikos sollte Denosumab eine Zweitlinientherapie sein, die auf sehr spezifische Indikationen beschränkt ist. Um den Rebound-Effekt zu begrenzen, wird derzeit empfohlen, beim Abbruch der Denosumab-Behandlung ein starkes Bisphosphonat (Alendronat, Zoledronat) zu verschreiben und die Knochenresorptionsmarker regelmässig zu prüfen.

The main pharmacovigilance updates in 2017 are reviewed. Denosumab : rebound-associated multiple vertebral fractures after discontinuation. Canagliflozine: increased risk of foot/leg amputations. Biologic and targeted cancer therapies, direct-acting antivirals for chronic hepatitis C: risk of hepatitis B reactivation. Checkpoint inhibitors : immune-related adverse events and graft rejection. Fingolimod : rebound-associated reactivation of MS following withdrawal. Daclizumab: risk of severe liver injury leading to restricted use in MS patients. Posaconazole: risk of overexposure when switching from oral suspension to tablets. Voriconazole: cutaneous squamous cell carcinoma under long-term therapy. Proton pump inhibitors : early exposure might increase fracture risk in young children.Les actualités de pharmacovigilance 2017 sont passées en revue. Dénosumab : fractures vertébrales multiples à l’arrêt (rebond). Canagliflozine : augmentation du risque d’amputation des membres inférieurs. Biologiques, anticancéreux ciblés et nouveaux traitements de l’hépatite C : possible réactivation du virus de l’hépatite B.

In addition to tailored clinical trials in patients on chronic hemodialysis (HD) during drug development, clinician-initiated post-marketing studies and case reports on individual pharmacokinetic (PK) assessments provide an important source of information about drug dialysability and individualized dose recommendations in this vulnerable population. Areas covered: First, factors that may alter drug exposure in HD patients are explained. Second, available regulatory and methodological guidelines for PK assessments in this population are summarized. Third, a 4-step approach is proposed to develop individual dose recommendations for HD patients receiving drugs without data from a PK study: (1) literature search, (2) model-based dosage decisions, (3) validation and refinement through concentration monitoring, and (4) publication of relevant observations. Fourth, clinician-initiated PK assessments and case reports to evaluate and individualize use of drugs in HD patients are reviewed, and recommendations to enhance their quality are discussed. Expert commentary: Guidance on collecting and reporting PK information in individual HD patients is warranted to ensure completeness and consistency of such PK studies. A checklist and template for easy-to-implement PK calculations and pharmacometric modeling is provided to facilitate evaluation and individualization of dosing strategies in these patients.

Aims Calcium sulphate (CaSO4) is a resorbable material that can be used simultaneously as filler of a dead space and as a carrier for the local application of antibiotics. Our aim was to describe the systemic exposure and the wound fluid concentrations of vancomycin in patients treated with vancomycin-loaded CaSO4 as an adjunct to the routine therapy of bone and joint infections. Patients and Methods A total of 680 post-operative blood and 233 wound fluid samples were available for analysis from 94 implantations performed in 87 patients for various infective indications. Up to 6 g of vancomycin were used. Non-compartmental pharmacokinetic analysis was performed on the data from 37 patients treated for an infection of the hip. Results The overall systemic exposure remained within a safe range, even in patients with post-operative renal failure, none requiring removal of the pellets. Local concentrations were approximately ten times higher than with polymethylmethacrylate (PMMA) as a carrier, but remained below reported cell toxicity thresholds. Decreasing concentrations in wound fluid were observed over several weeks, but remained above the common minimum inhibitory concentrations for Staphylococcus up to three months post-operatively. Conclusion This study provides the first pharmacokinetic description of the local application of vancomycin with CaSO4 as a carrier, documenting slow release, systemic safety and a release profile far more interesting than from PMMA. In particular, considering in vitro data, concentrations of vancomycin active against staphylococcal biofilm were seen for several weeks. Cite this article: Bone Joint J 2017;99-B:1537–44.

Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.

Thanks to potent antiretroviral therapy, the life expectancy of people living with HIV (PLWH) has increased significantly and has become comparable to the general population.1–3 Consequently, this population is aging, living long enough to face age-related chronic comorbidities, including cardiovascular diseases, kidney disease, diabetes mellitus, chronic obstructive pulmonary disease, cancer, osteoarthritis or neurocognitive impairment.4–6 The age-related comorbidities burden leads inevitably to polypharmacy, which is commonly defined in HIV medicine as being on at least five concomitant non-HIV medications. The prevalence of polypharmacy has been shown to be high in different European and American HIV cohorts, ranging from 37% up to 94% in PLWH aged ⩾50 years up to ⩾75 years.7–12 Simulations based on the data of the Dutch HIV cohort ATHENA predicted that the median age would increase from 43 years in 2010 to 56 in 2030, resulting in 40% of HIV-infected individuals being 60 years old or older and 28% having at least three comorbidities. In 2030, about one-half of PLWH are anticipated to take comedications, compared with 13% in 2010, with 20% taking three or more comedications.13 Similar forecasts were obtained for Italian and US PLWH.14 Additional prescribing issues are emerging with the aging of the HIV population.

Outre l’efficacite d’un nouveau medicament, c’est egalement la securite des substances qui est etudiee de maniere aussi approfondie que possible avant que ne soit delivree l’autorisation de mise sur le marche. Cependant, c’est seulement une fois le medicament sur le marche, lorsqu’il a ete administre a un echantillon de population bien plus important et non selectionne, que des effets indesirables plus rares peuvent etre reveles.

The main pharmacovigilance updates in 2015are reviewed. Sofosbuvir amiodarone interaction: risk of severe bradycardia. Dasabuvir clopidogrel interaction: increased dasabuvir concentrations and potential risk of QTprolongation. SGLT2 inhibitors: risks of diabetic acidocetosis and bone fracture. Dabigatran: therapeutic drug monitoring may improve benefit-risk ratio. Ibuprofen: at higher dosage, vascular risks are comparable to coxibs. Pregabaline, gabapentine: potential for abuse and addiction. Varenicline: potentiates alcohol's effects. Codeine: contra-indicated as cough medicine under the age of twelve. Valproate: strengthened warnings on the risks of valproate use in pregnancy. Dimethylfumarate: rare observations of progressive multifocal leucoencephalopathy. Ustekinumab: rare observations of erythrodermia.

Neben der Wirksamkeit eines neuen Arzneimittels wird auch die Sicherheit von Substanzen vor der Marktzulassung so gut wie moglich untersucht. Jedoch lassen sich erst nach der Marktzulassung, wenn die Arzneimittel bei einer viel grosseren und nicht selektionierten Bevolkerungsgruppe angewendet werden, auch seltenere unerwunschte Arzneimittelwirkungen in Erfahrung bringen.

Osteoset(®) T is a calcium sulphate void filler containing 4% tobramycin sulphate, used to treat bone and soft tissue infections. Despite systemic exposure to the antibiotic, there are no pharmacokinetic studies in humans published so far. Based on the observations made in our patients, a model predicting tobramycin serum levels and evaluating their toxicity potential is presented.Following implantation of Osteoset(®) T, tobramycin serum concentrations were monitored systematically. A pharmacokinetic analysis was performed using a non-linear mixed effects model based on a one compartment model with first-degree absorption.Data from 12 patients treated between October 2006 and March 2008 were analysed. Concentration profiles were consistent with the first-order slow release and single-compartment kinetics, whilst showing important variability. Predicted tobramycin serum concentrations depended clearly on both implanted drug amount and renal function.Despite the popularity of aminoglycosides for local antibiotic therapy, pharmacokinetic data for this indication are scarce, and not available for calcium sulphate as carrier material. Systemic exposure to tobramycin after implantation of Osteoset(®) T appears reassuring regarding toxicity potential, except in case of markedly impaired renal function. We recommend in adapting the dosage to the estimated creatinine clearance rather than solely to the patient's weight.

The incidence of diabetes is increasing and affects 180 million adults worldwide, including 24 million in the United States, or 7.8% of the population. In 2007, 1.6 million new cases were diagnosed in U.S. residents aged 20 years or more.1 Despite the large number of antidiabetic agents on the market, the condition is still inadequately controlled in 30% of affected patients.2 Among available therapies, dipeptidyl-peptidase IV (DPPIV) inhibitors offer a new promising alternative for the treatment of type 2 diabetes, through their ability to improve glucose tolerance and insulin response to oral carbohydrates.3 DPPIV is involved in the rapid N-terminal cleavage of incretins, ie, peptide hormones such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), which are released from the gut in response to nutrients intake, thus enhancing glucose-stimulated insulin secretion and inhibiting glucagon secretion.3 Sitagliptin (Januvia) was the first DPPIV inhibitor marketed in the United States in 2006, subsequently approved in the European Union. Vildagliptin (Galvus) received EMEA approval in 2007 but is currently not marketed in the United States. Many analogs of DPPIV inhibitors are currently under development. A metaanalysis evaluated the efficacy and safety of DPPIV inhibitors based on 17 randomized controlled clinical trials involving 7823 patients treated with vildagliptin or sitagliptin over 12 to 52 weeks; DPPIV inhibitors appear well tolerated, with, however, an increased risk of nasopharyngitis, cystitis, and headache.4 Postmarketing surveillance of patients treated with sitagliptin and vildagliptin reported cases of angioedema, most often during the first 3 months of treatment, with some reactions observed already after the first dose. Consequently, the Summaries of Product Characteristics and Package Leaflets of both compounds were updated to include angioedema among potential adverse effects.5,6 Although DPPIV theoretically inactivates or interacts with a large number of biologically active peptides,7 …

We report the first case presenting with successive anaphylactic reaction and extra-pyramidal syndrome after treatment with thiethylperazine maleate (thiethylperazine). Both reactions were caused due to this anti-emetic drug, but an additive effect of clemastine fumarate, prescribed to treat the anaphylactic reaction, is suggested by the sequence of events. We discuss the importance of knowing the pharmacological similitudes of common prescribed drugs in order to avoid the occurrence of side effects.

Elderly people are prone to drug-induced adverse events (AEs), which often manifest as an atypical clinical picture. The differential diagnosis of any new symptom or alteration in the general state of health in the elderly must, therefore, include AEs. This article offers a practical tool designed to help clinicians to rapidly identify which drugs may induce which kind of frequent symptoms or syndromes.