Which side effects should I inform patients about?

The law requires that healthcare professionals adequately inform patients about possible side effects when they prescribe new pharmacological treatments. There are several reasons (lack of time, fear of nocebo effect, patient and prescriber preferences) why informing patients in detail could be undesirable or even harmful. Prescribers should focus on two types of side effects: (a) common side effects with significant impact on the quality of life and (b) side effects that should be recognised in time to prevent further harm. During treatment, patients should be monitored regularly for efficacy and side effects in order to weigh benefits and risks and to stop or switch therapy when necessary.</p

4-Sodium phenyl butyric acid has both efficacy and counter-indicative effects in the treatment of Col4a1 disease

Mutations in the collagen genes COL4A1 and COL4A2 cause Mendelian eye, kidney and cerebrovascular disease including intracerebral haemorrhage, and common collagen IV variants are a risk factor for sporadic intracerebral haemorrhage. COL4A1 and COL4A2 mutations cause endoplasmic reticulum (ER) stress and basement membrane (BM) defects, and recent data suggest an association of ER stress with intracerebral haemorrhage due to a COL4A2 mutation. However, the potential of ER-stress as a therapeutic target for the multi-systemic COL4A1 pathologies remains unclear. We performed a preventative oral treatment of Col4a1 mutant mice with the chemical chaperone phenyl butyric acid (PBA), which reduced adult intracerebral haemorrhage. Importantly, treatment of adult mice with established disease also reduced intracerebral haemorrhage. However, PBA treatment did not alter eye and kidney defects, establishing tissue specific outcomes of targeting Col4a1-derived ER stress, and therefore this treatment may not be applicable for patients with eye and renal disease. While PBA treatment reduced ER-stress and increased collagen IV incorporation into BMs, the persistence of defects in BM structure and reduced ability of the BM to withstand mechanical stress indicate PBA may be counter-indicative for pathologies caused by matrix defects. These data establish that treatment for COL4A1 disease requires a multi-pronged treatment approach that restores both ER homeostasis and matrix defects. Alleviating ER-stress is a valid therapeutic target for preventing and treating established adult intracerebral haemorrhage, but collagen IV patients will require stratification based on their clinical presentation and mechanism of their mutations

A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases

Cerebral small vessel disease (SVD) affects the small vessels in the brain and is a leading cause of stroke and dementia. Emerging evidence supports a role of the extracellular matrix (ECM), at the interface between blood and brain, in the progression of SVD pathology, but this remains poorly characterized. To address ECM role in SVD, we developed a co-culture model of mural and endothelial cells using human induced pluripotent stem cells from patients with COL4A1/A2 SVD-related mutations. This model revealed that these mutations induce apoptosis, migration defects, ECM remodeling, and transcriptome changes in mural cells. Importantly, these mural cell defects exert a detrimental effect on endothelial cell tight junctions through paracrine actions. COL4A1/A2 models also express high levels of matrix metalloproteinases (MMPs), and inhibiting MMP activity partially rescues the ECM abnormalities and mural cell phenotypic changes. These data provide a basis for targeting MMP as a therapeutic opportunity in SVD.</p

Tendon Is Covered by a Basement Membrane Epithelium That Is Required for Cell Retention and the Prevention of Adhesion Formation

The ability of tendons to glide smoothly during muscle contraction is impaired after injury by fibrous adhesions that form between the damaged tendon surface and surrounding tissues. To understand how adhesions form we incubated excised tendons in fibrin gels (to mimic the homeostatic environment at the injury site) and assessed cell migration. We noticed cells exiting the tendon from only the cut ends. Furthermore, treatment of the tendon with trypsin resulted in cell extravagation from the shaft of the tendons. Electron microscopy and immunolocalisation studies showed that the tendons are covered by a novel cell layer in which a collagen type IV/laminin basement membrane (BM) overlies a keratinised epithelium. PCR and western blot analyses confirmed the expression of laminin β1 in surface cells, only. To evaluate the cell retentive properties of the BM in vivo we examined the tendons of the Col4a1+/Svc mouse that is heterozygous for a G-to-A transition in the Col4a1 gene that produces a G1064D substitution in the α1(IV) chain of collagen IV. The flexor tendons had a discontinuous BM, developed fibrous adhesions with overlying tissues, and were acellular at sites of adhesion formation. In further experiments, tenotomy of wild-type mice resulted in expression of laminin throughout the adhesion. In conclusion, we show the existence of a novel tendon BM-epithelium that is required to prevent adhesion formation. The Col4a1+/Svc mouse is an effective animal model for studying adhesion formation because of the presence of a structurally-defective collagen type IV-containing BM

Malaria treatment failures after artemisinin-based therapy in three expatriates: could improved manufacturer information help to decrease the risk of treatment failure ?

BACKGROUND: Artemisinin-containing therapies are highly effective against Plasmodium falciparum malaria. Insufficient numbers of tablets and inadequate package inserts result in sub-optimal dosing and possible treatment failure. This study reports the case of three, non-immune, expatriate workers with P. falciparum acquired in Africa, who failed to respond to artemisinin-based therapy. Sub-therapeutic dosing in accordance with the manufacturers' recommendations was the probable cause. METHOD: Manufacturers information and drug content included in twenty-five artemisinin-containing specialities were reviewed. RESULTS: A substantial number of manufacturers do not follow current WHO recommendations regarding treatment duration and doses. CONCLUSION: This study shows that drug packaging and their inserts should be improved

Rationale and design of the PRAETORIAN-COVID trial:A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease

There is much debate on the use of angiotensin receptor blockers (ARBs) in severe acute respiratory syndrome–coronavirus-2 (SARS-CoV-2)–infected patients. Although it has been suggested that ARBs might lead to a higher susceptibility and severity of SARS-CoV-2 infection, experimental data suggest that ARBs may reduce acute lung injury via blocking angiotensin-II–mediated pulmonary permeability, inflammation, and fibrosis. However, despite these hypotheses, specific studies on ARBs in SARS-CoV-2 patients are lacking. Methods: The PRAETORIAN-COVID trial is a multicenter, double-blind, placebo-controlled 1:1 randomized clinical trial in adult hospitalized SARS-CoV-2–infected patients (n = 651). The primary aim is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death within 14 days of randomization. The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160 mg bid, and the placebo arm will receive matching placebo. Treatment duration will be 14 days, or until the occurrence of the primary end point or until hospital discharge, if either of these occurs within 14 days. The trial is registered at clinicaltrials.gov (NCT04335786, 2020). The PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of valsartan compared to placebo on the occurrence of ICU admission, mechanical ventilation, and death in hospitalized SARS-CoV-2–infected patients. The results of this study might impact the treatment of SARS-CoV-2 patients globally

Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease

The extracellular matrix (ECM) is a key interface between the cerebrovasculature and adjacent brain tissues. Deregulation of the ECM contributes to a broad range of neurological disorders. However, despite this importance, our understanding of the ECM composition remains very limited mainly due to difficulties in its isolation. To address this, we developed an approach to extract the cerebrovascular ECM from mouse and human post-mortem normal brain tissues. We then used mass spectrometry with off-line high-pH reversed-phase fractionation to increase the protein detection. This identified more than 1000 proteins in the ECM-enriched fraction, with > 66% of the proteins being common between the species. We report 147 core ECM proteins of the human brain vascular matrisome, including collagens, laminins, fibronectin and nidogens. We next used network analysis to identify the connection between the brain ECM proteins and cerebrovascular diseases. We found that genes related to cerebrovascular diseases, such as COL4A1, COL4A2, VCAN and APOE were significantly enriched in the cerebrovascular ECM network. This provides unique mechanistic insight into cerebrovascular disease and potential drug targets. Overall, we provide a powerful resource to study the functions of brain ECM and highlight a specific role for brain vascular ECM in cerebral vascular disease

Comparison of Bioavailability Between the Most Available Generic Tablet Formulation Containing Artemether and Lumefantrine on the Tanzanian Market and the Innovator's Product.

Existence of anti-malarial generic drugs with low bioavailability marketed on sub-Saharan Africa has raised a concern on patients achieving therapeutic concentrations after intake of these products. This work compared bioavailability of one generic tablet formulation with innovator's product. Both were fixed dose combination tablet formulations containing artemether and lumefantrine.MethodologyThe study was conducted in Dar Es Salaam, Tanzania, in which a survey of the most abundant generic containing artemether-lumefantrine tablet formulation was carried out in retail pharmacies. The most widely available generic (Artefan(R), Ajanta Pharma Ltd, Maharashtra, India) was sampled for bioavailability comparison with Coartem(R) (Novartis Pharma, Basel, Switzerland) - the innovator's product. A randomized, two-treatment cross-over study was conducted in 18 healthy Tanzanian black male volunteers. Each volunteer received Artefan(R) (test) and Coartem(R) (as reference) formulation separated by 42 days of drug-free washout period. Serial blood samples were collected up to 168 hours after oral administration of a single dose of each treatment. Quantitation of lumefantrine plasma levels was done using HPLC with UV detection. Bioequivalence of the two products was assessed in accordance with the US Food and Drug Authority (FDA) guidelines. The most widely available generic in pharmacies was Artefan(R) from India. All eighteen enrolled volunteers completed the study and both test and reference tablet formulations were well tolerated. It was possible to quantify lumefantrine alone, therefore, the pharmacokinetic parameters reported herein are for lumefantrine. The geometric mean ratios for Cmax, AUC0-t and AUC0-[infinity] were 84% in all cases and within FDA recommended bioequivalence limits of 80% -- 125%, but the 90% confidence intervals were outside FDA recommended limits (CI 49--143%, 53 - 137%, 52 - 135% respectively). There were no statistical significant differences between the two formulations with regard to PK parameters (P > 0.05). Although the ratios of AUCs and Cmax were within the acceptable FDA range, bioequivalence between Artefan(R) and Coartem(R) tablet formulations was not demonstrated due to failure to comply with the FDA 90 % confidence interval criteria. Based on the observed total drug exposure (AUCs), Artefan(R) is likely to produce a similar therapeutic response as Coartem(R)