Frailty, multimorbidity and polypharmacy: exploratory analyses of the effects of empagliflozin from the EMPA-KIDNEY trial.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk-benefit profile in a post-hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. METHODS: The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2, or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. RESULTS: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. CONCLUSIONS: These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy.

Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA-KIDNEY.

BACKGROUND: EMPA-KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. METHODS: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20 < 45; or ≥ 45 < 90 ml/min/1.73m2 with a urinary albumin-to-creatinine ratio (uACR) of ≥ 200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR decline to < 10 ml/min/1.73m2 or ≥ 40% from randomization, or renal death) or cardiovascular death. In post-hoc analyses, we explored the effects of empagliflozin in participants from Japan vs. non-Japan regions, including additional models assessing whether differences in treatment effects between these regions could result from differences in baseline characteristics. RESULTS: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64-0.82; P < 0.0001). Among the participants from non-Japan regions, there were 399 vs. 494 primary outcomes (0.75, 0.66-0.86), and 33 vs. 64 (0.49, 0.32-0.75; heterogeneity p = 0.06) in Japan. Results were similar when models explicitly considered treatment interactions with diabetes status, categories of eGFR/uACR, and recruitment in Japan (heterogeneity p = 0.08). Safety outcomes were broadly comparable between the two groups, and by Japanese status. CONCLUSIONS: Empagliflozin safely reduced the risk of "kidney disease progression or cardiovascular death" in patients with CKD, with consistent effects in participants from Japan.

Single and combination treatment of Toxoplasma gondii infections with a bumped kinase inhibitor and artemisone in vitro and with artemiside in experimentally infected mice.

In previous studies, the artemisinin derivatives artemisone, its pro-drug artemiside and the bumped-kinase inhibitor BKI-1748 were effective against T. gondii via different modes of action. This suggests that they may act synergistically resulting in improved efficacies in vitro and in vivo. To test this hypothesis, the compounds were applied alone and in combination to T. gondii infected human fibroblast host cells in order to determine their inhibition constants and effects on cellular ultrastructure. In addition, the efficacy of either single- or combined treatments were assessed in an acute TgShSp1-oocyst infection model based on CD1 outbred mice. Whereas the IC50 of the compounds in combination (42 nM) was close to the IC50 of BKI-1748 alone (46 nM) and half of the IC50 of artemisone alone (92 nM), the IC90 of the combination was half of the values found with the single compounds (138 nM vs. ca. 270 nM). Another indication for synergistic effects in vitro were distinct alterations of the cellular ultrastructure of tachyzoites observed in combination, but not with the single compounds. These promising results could not be reproduced in vivo. There was no decrease in number of T. gondii positive brains by either treatment. However, the levels of infection in these brains, i. e. the number of tachyzoites, was significantly decreased upon BKI-1748 treatment alone, and the combination with artemiside did not produce any further decrease. The treatment with artemiside alone had no significant effects. A vertical transmission model could not be established since artemiside strongly interfered with pregnancy and caused abortion. These results show that is difficult to extrapolate from promising in vitro results to the situation in vivo.

Epimacular brachytherapy for previously treated neovascular age-related macular degeneration: month 36 results of the MERLOT randomised controlled trial.

BACKGROUND/AIM: To assess the long-term safety and efficacy of epimacular brachytherapy (EMB) for chronic, active, neovascular age-related macular degeneration (nAMD). METHODS: This pivotal, randomised, controlled surgical device trial recruited patients with chronic nAMD receiving intravitreal ranibizumab from 24 UK hospitals. Participants were randomised to either pars plana vitrectomy with 24 Gray EMB and pro re nata (PRN) ranibizumab (n=224) or PRN ranibizumab monotherapy (n=119). Although masking was not possible, masked clinicians assessed best-corrected visual acuity (BCVA) and imaging. After month 24, participants reverted to standard care, with either ranibizumab or aflibercept, returning for a month 36 study visit. RESULTS: Of 363 participants, 309 (85.1%) completed month 36. The number of injections was 12.1±8.1 in the EMB group versus 11.4±6.1 in the ranibizumab group (difference 0.7, 95% CI of difference -0.9 to 2.3, p=0.41) between months 1 and 36, and 3.6±3.3 (n=200) versus 3.9±2.7 (n=102) (difference -0.3, 95% CI of difference -1.0 to 0.4, p=0.43) between months 25 and 36 (standard care). Over 36 months, BCVA change was -19.7±18.5 letters in the EMB group and -4.8±12.5 in the ranibizumab group (difference -14.9, 95% CI of difference -18.5 to -11.2, p<0.0001). The month 36 BCVA of 20 EMB-treated participants with microvascular abnormalities (MVAs) at month 24 was similar to EMB-treated participants without MVAs (-21.8 vs -19.4 letters, p=0.65). CONCLUSION: EMB does not reduce the number of anti-vascular endothelial growth factor (VEGF) injections, either within or outside of a trial setting, and is associated with worse BCVA than anti-VEGF monotherapy. TRIAL REGISTRATION NUMBER: NCT01006538.

Efficacies and ADME properties of redox active methylene blue and phenoxazine analogues for use in new antimalarial triple drug combinations with amino-artemisinins.

Efforts to develop new artemisinin triple combination therapies effective against artemisinin-tolerant strains of Plasmodium falciparum based on rational combinations comprising artemisone or other amino-artemisinins, a redox active drug and a third drug with a different mode of action have now been extended to evaluation of three potential redox partners. These are the diethyl analogue AD01 of methylene blue (MB), the benzo [α]phenoxazine PhX6, and the thiosemicarbazone DpNEt. IC50 values in vitro against CQ-sensitive and resistant P. falciparum strains ranged from 11.9 nM for AD01-41.8 nM for PhX6. PhX6 possessed the most favourable pharmacokinetic (PK) profile: intrinsic clearance rate CLint was 21.47 ± 1.76 mL/min/kg, bioavailability was 60% and half-life was 7.96 h. AD01 presented weaker, but manageable pharmacokinetic properties with a rapid CLint of 74.41 ± 6.68 mL/min/kg leading to a half-life of 2.51 ± 0.07 h and bioavailability of 15%. DpNEt exhibited a half-life of 1.12 h and bioavailability of 8%, data which discourage its further examination, despite a low CLint of 10.20 mL/min/kg and a high Cmax of 6.32 µM. Efficacies of AD01 and PhX6 were enhanced synergistically when each was paired with artemisone against asexual blood stages of P. falciparum NF54 in vitro. The favourable pharmacokinetics of PhX6 indicate this is the best partner among the compounds examined thus far for artemisone. Future work will focus on extending the drug combination studies to artemiside in vitro, and conducting efficacy studies in vivo for artemisone with each of PhX6 and the related benzo[α]phenoxazine SSJ-183.

Antimalarial and antitumour activities of the steroidal quinone-methide celastrol and its combinations with artemiside, artemisone and methylene blue.

Artemisinin, isolated from the traditional Chinese medicinal plant qing hao (Artemisia annua) and its derivatives are used for treatment of malaria. With treatment failures now being recorded for the derivatives and companion drugs used in artemisinin combination therapies new drug combinations are urgently required. The amino-artemisinins artemiside and artemisone display optimal efficacies in vitro against asexual and sexual blood stages of the malaria parasite Plasmodium falciparum and are active against tumour cell lines. In continuing the evolution of combinations of the amino-artemisinins with new drugs, we examine the triterpenoid quinone methide celastrol isolated from the traditional Chinese medicinal plant léi gong téng (Tripterygium wilfordii). This compound is redox active, and has attracted considerable attention because of potent biological activities against manifold targets. We report that celastrol displays good IC50 activities ranging from 0.50-0.82 µM against drug-sensitive and resistant asexual blood stage Pf, and 1.16 and 0.28 µM respectively against immature and late stage Pf NF54 gametocytes. The combinations of celastrol with each of artemisone and methylene blue against asexual blood stage Pf are additive. Given that celastrol displays promising antitumour properties, we examined its activities alone and in combinations with amino-artemisinins against human liver HepG2 and other cell lines. IC50 values of the amino-artemisinins and celastrol against HepG2 cancer cells ranged from 0.55-0.94 µM. Whereas the amino-artemisinins displayed notable selectivities (SI > 171) with respect to normal human hepatocytes, in contrast, celastrol displayed no selectivity (SI < 1). The combinations of celastrol with artemiside or artemisone against HepG2 cells are synergistic. Given the promise of celastrol, judiciously designed formulations or structural modifications are recommended for mitigating its toxicity.

Intracellular Accumulation of Novel and Clinically Used TB Drugs Potentiates Intracellular Synergy.

The therapeutic repertoire for tuberculosis (TB) remains limited despite the existence of many TB drugs that are highly active in in vitro models and possess clinical utility. Underlying the lack of efficacy in vivo is the inability of TB drugs to penetrate microenvironments inhabited by the causative agent, Mycobacterium tuberculosis, including host alveolar macrophages. Here, we determined the ability of the phenoxazine PhX1 previously shown to be active against M. tuberculosis in vitro to differentially penetrate murine compartments, including plasma, epithelial lining fluid, and isolated epithelial lining fluid cells. We also investigated the extent of permeation into uninfected and M. tuberculosis-infected human macrophage-like Tamm-Horsfall protein 1 (THP-1) cells directly and by comparing to results obtained in vitro in synergy assays. Our data indicate that PhX1 (4,750 ± 127.2 ng/ml) penetrates more effectively into THP-1 cells than do the clinically used anti-TB agents, rifampin (3,050 ± 62.9 ng/ml), moxifloxacin (3,374 ± 48.7 ng/ml), bedaquiline (4,410 ± 190.9 ng/ml), and linezolid (770 ± 14.1 ng/ml). Compound efficacy in infected cells correlated with intracellular accumulation, reinforcing the perceived importance of intracellular penetration as a key drug property. Moreover, we detected synergies deriving from redox-stimulatory combinations of PhX1 or clofazimine with the novel prenylated amino-artemisinin WHN296. Finally, we used compound synergies to elucidate the relationship between compound intracellular accumulation and efficacy, with PhX1/WHN296 synergy levels shown to predict drug efficacy. Collectively, our data support the utility of the applied assays in identifying in vitro active compounds with the potential for clinical development. IMPORTANCE This study addresses the development of novel therapeutic compounds for the eventual treatment of drug-resistant tuberculosis. Tuberculosis continues to progress, with cases of Mycobacterium tuberculosis (M. tuberculosis) resistance to first-line medications increasing. We assess new combinations of drugs with both oxidant and redox properties coupled with a third partner drug, with the focus here being on the potentiation of M. tuberculosis-active combinations of compounds in the intracellular macrophage environment. Thus, we determined the ability of the phenoxazine PhX1, previously shown to be active against M. tuberculosis in vitro, to differentially penetrate murine compartments, including plasma, epithelial lining fluid, and isolated epithelial lining fluid cells. In addition, the extent of permeation into human macrophage-like THP-1 cells and H37Rv-infected THP-1 cells was measured via mass spectrometry and compared to in vitro two-dimensional synergy and subsequent intracellular efficacy. Collectively, our data indicate that development of new drugs will be facilitated using the methods described herein.

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.

TaleNeprilysin and Neprilysin inhibition in chronic kidney disease.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is associated with increased risk of progression to end-stage kidney disease and cardiovascular events. There is limited evidence that available treatments have beneficial effects on cardiorenal outcomes in all people with nondiabetic CKD. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. RECENT FINDINGS: NEPi enhances the activity of the natriuretic peptide system producing natriuresis, diuresis and inhibition of the renin-angiotensin system and sympathetic nervous system. Sacubitril/valsartan is the first Angiotensin receptor-neprilysin inhibitor (ARNI) to be produced and has been shown to substantially improve cardiovascular outcomes in heart failure and delay progression of kidney disease in this population. Although ARNIs have not shown similar effects on kidney function in the short-to-medium term in people with CKD, they are associated with substantial reductions in cardiac biomarkers and blood pressure in CKD. SUMMARY: These data suggest that NEPi with an ARNI could benefit patients with CKD by reducing the risk of cardiovascular disease and have the possibility of retarding the progression of CKD (hence delaying the need for renal replacement therapy).

Multiple Therapy Approach for Stage 3 Coats Disease: Long-Term Follow-Up.

PURPOSE: To assess long-term efficacy of a multiple therapy approach in the treatment and management of unilateral stage 3 Coats disease with exudative retinal detachment. METHODS: 2 eyes of 2 young patients suffering from unilateral stage 3 Coats disease underwent a multiple therapy approach consisting of surgical drainage of exudative subretinal fluid + one simultaneous and up to one subsequent intravitreal injection of bevacizumab + multiple (up to 3) laser photocoagulation sessions of retinal nonperfusion areas and leaking Coats vasculature. RESULTS: Complete reabsorption of SRF and retinal reattachment were observed in both cases over the follow-up. In no cases, we observed progression to phthisis bulbi. No bevacizumab-related complications were observed. Epiretinal membrane onset was detected in one eye at the end of follow-up. CONCLUSION: The management and treatment of this rare and degenerative disease in young subjects are still a challenge. The described technique is less invasive than conventional intraocular surgery and may be preferable to halt the devastating progression of the disease.

Anti-Melanoma Activities of Artemisone and Prenylated Amino-Artemisinins in Combination With Known Anticancer Drugs.

The most frequently occurring cancers are those of the skin, with melanoma being the leading cause of death due to skin cancer. Breakthroughs in chemotherapy have been achieved in certain cases, though only marginal advances have been made in treatment of metastatic melanoma. Strategies aimed at inducing redox dysregulation by use of reactive oxygen species (ROS) inducers present a promising approach to cancer chemotherapy. Here we use a rational combination of an oxidant drug combined with a redox or pro-oxidant drug to optimize the cytotoxic effect. Thus we demonstrate for the first time enhanced activity of the amino-artemisinin artemisone and novel prenylated piperazine derivatives derived from dihydroartemisinin as the oxidant component, and elesclomol-Cu(II) as the redox component, against human malignant melanoma cells A375 in vitro. The combinations caused a dose dependent decrease in cell numbers and increase in apoptosis. The results indicate that oxidant-redox drug combinations have considerable potential and warrant further investigation.

Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom.

AIMS: Statins are widely used to prevent cardiovascular events, but little is known about the impact of different risk factors for statin-related myopathy or their relevance to reports of other types of muscle symptom. METHODS AND RESULTS: An observational analysis was undertaken of 171 clinically adjudicated cases of myopathy (defined as unexplained muscle pain or weakness with creatine kinase >10× upper limit of normal) and, separately, of 15 208 cases of other muscle symptoms among 58 390 individuals with vascular disease treated with simvastatin for a mean of 3.4 years. Cox proportional hazards models were used to identify independent predictors of myopathy. The rate of myopathy was low: 9 per 10 000 person-years of simvastatin therapy. Independent risk factors for myopathy included: simvastatin dose, ethnicity, sex, age, body mass index, medically treated diabetes, concomitant use of niacin-laropiprant, verapamil, beta-blockers, diltiazem and diuretics. In combination, these risk factors predicted more than a 30-fold risk difference between the top and bottom thirds of a myopathy risk score (hazard ratio : 34.35, 95% CI: 12.73-92.69, P across thirds = 9·1 × 10-48). However, despite the strong association with myopathy, this score was not associated with the other reported muscle symptoms (P across thirds = 0.93). Likewise, although SLCO1B1 genotype was associated with myopathy, it was not associated with other muscle symptoms. CONCLUSIONS: The absolute risk of simvastatin-related myopathy is low, but individuals at higher risk can be identified to help guide patient management. The lack of association of the myopathy risk score with other muscle symptoms reinforces randomized placebo-controlled evidence that statins do not cause the vast majority of reported muscle symptoms.

Evaluation of Month-24 Efficacy and Safety of Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration: The MERLOT Randomized Clinical Trial.

Importance: Although anti-vascular endothelial growth factor (VEGF) treatment offers better outcomes than the natural history of neovascular age-related macular degeneration (ARMD), a less burdensome, less expensive, and more durable treatment is needed. Objective: To assess the efficacy and safety of epimacular brachytherapy (EMB) for chronic, active, neovascular ARMD. Design, Setting, and Participants: The Macular Epiretinal Brachytherapy vs Ranibizumab (Lucentis) Only Treatment (MERLOT) pivotal device trial was conducted at 24 National Health Service hospitals across the UK. Patients who had neovascular ARMD and received intravitreal ranibizumab were enrolled between November 10, 2009, and January 30, 2012. Eligible patients were randomized 2:1 and were stratified by lens status and angiographic lesion type to receive either EMB plus as-needed ranibizumab or as-needed ranibizumab monotherapy. Participants were followed up monthly for 24 months and then assessed at a final visit at month 36. Masking of participants and clinicians was not possible, but best-corrected visual acuity (BCVA) and imaging were analyzed by masked assessors. Analysis followed the intent-to-treat approach. Interventions: Pars plana vitrectomy with 24 Gy EMB plus as-needed ranibizumab vs as-needed ranibizumab monotherapy. Main Outcomes and Measures: Coprimary outcomes were the number of as-needed ranibizumab injections and the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA with a noninferiority margin of -5 ETDRS letters. Secondary outcomes were the percentage of participants losing fewer than 15 ETDRS letters and gaining 0 or more or 15 or more ETDRS letters and the mean change in angiographic total lesion size, choroidal neovascularization size, and foveal thickness on optical coherence tomography. Results: Of 363 participants, 329 (90.6%) completed 24 months of follow-up (222 participants in the EMB group and 107 in the ranibizumab group). The mean (SD) age of the combined groups was 76.5 (7.4) years. The mean (SD) number of ranibizumab injections was 9.3 (6.7) in the EMB group and 8.3 (4.5) in the ranibizumab group, with a difference of 1.0 injection (95% CI, -0.3 to 2.3; P = .13). The mean (SD) BCVA change was -11.2 (15.7) ETDRS letters in the EMB group and -1.4 (10.9) ETDRS letters in the ranibizumab group, with a difference of 9.8 ETDRS letters (95% CI, -6.7 to -12.9). In the EMB group, 65.6% of participants (160 of 244) lost fewer than 15 ETDRS letters vs 86.6% (103 of 119) in the ranibizumab group, with a difference of 21% (95% CI, 12.4%-29.5%; P < .001). Microvascular abnormalities occurred in 20 of 207 eyes (9.7%) in the EMB group and 1 of 97 eyes (1.0%) in the ranibizumab group. These abnormalities occurred outside the foveal center, and there were no unexpected safety concerns. Conclusions and Relevance: The MERLOT trial found that despite the acceptable safety of EMB, it did not reduce the number of ranibizumab injections and was associated with worse visual acuity than anti-VEGF treatment alone; these results do not support EMB use as an adjunct treatment for chronic, active neovascular ARMD. Trial Registration: ClinicalTrials.gov Identifier: NCT01006538.

Chronic kidney disease, heart failure and neprilysin inhibition.

Patients with chronic kidney disease are at increased risk of cardiovascular disease and this often manifests clinically like heart failure. Conversely, patients with heart failure frequently have reduced kidney function. The links between the kidneys and cardiovascular system are being elucidated, with blood pressure being a key risk factor. Patients with heart failure have benefitted from many trials which have now established a strong evidence based on which to base management. However, patients with advanced kidney disease have often been excluded from these trials. Nevertheless, there is little evidence that the benefits of such treatments are modified by the presence or absence of kidney disease, but more direct evidence among patients with advanced kidney disease is required. Neprilysin inhibition is the most recent treatment to be shown to improve outcomes among patients with heart failure. The UK HARP-III trial assessed whether neprilysin inhibition improved kidney function in the short- to medium-term and its effects on cardiovascular biomarkers. Although no effect (compared to irbesartan control) was found on kidney function, allocation to neprilysin inhibition (sacubitril/valsartan) did reduce cardiac biomarkers more than irbesartan, suggesting that this treatment might improve cardiovascular outcomes in this population. Larger clinical outcomes trials are needed to test this hypothesis.

Anti-Mycobacterial Peroxides: A New Class of Agents for Development Against Tuberculosis.

BACKGROUND: With few exceptions, existing tuberculosis drugs were developed many years ago and resistance profiles have emerged. This has created a need for new drugs with discrete modes of action. There is evidence that tuberculosis (like other bacteria) is susceptible to oxidative pressure and this has yet to be properly utilised as a therapeutic approach in a manner similar to that which has proven highly successful in malaria therapy. OBJECTIVE: To develop an alternative approach to the incorporation of bacterial siderophores that results in the creation of antitubercular peroxidic leads for subsequent development as novel agents against tuberculosis. METHODS: Eight novel peroxides were prepared and the antitubercular activity (H37Rv) was compared to existing artemisinin derivatives in vitro. The potential for toxicity was evaluated against the L6 rat skeletal myoblast and HeLa cervical cancer lines in vitro. RESULTS: The addition of a pyrimidinyl residue to an artemisinin or, preferably, a tetraoxane peroxidic structure results in antitubercular activity in vitro. The same effect is not observed in the absence of the pyrimidine or with other heteroaromatic substituents. CONCLUSION: The incorporation of a pyrimidinyl residue adjacent to the peroxidic function in an organic peroxide results in anti-tubercular activity in an otherwise inactive peroxidic compound. This will be a useful approach for creating oxidative drugs to target tuberculosis.

Pathophysiology and management of monoclonal gammopathy of renal significance.

Recent years have witnessed a rapid growth in our understanding of the pathogenic property of monoclonal proteins. It is evident that some of these small monoclonal proteins are capable of inducing end-organ damage as a result of their intrinsic physicochemical properties. Hence, an umbrella term, monoclonal gammopathy of clinical significance (MGCS), has been coined to include myriad conditions attributed to these pathogenic proteins. Because kidneys are the most commonly affected organ (but skin, peripheral nerves, and heart can also be involved), we discuss MGRS exclusively in this review. Mechanisms of renal damage may involve direct or indirect effects. Renal biopsy is mandatory and demonstration of monoclonal immunoglobulin in kidney, along with the corresponding immunoglobulin in serum or urine, is key to establish the diagnosis. Pitfalls exist at each diagnostic step, and a high degree of clinical suspicion is required to diagnose MGRS. Recognition of MGRS by hematologists and nephrologists is important, because timely clone-directed therapy improves renal outcomes. Autologous stem cell transplant may benefit selected patients.

Long term outcomes in monoclonal gammopathy of renal significance.

Unlike AL amyloid and cast nephropathy, the long-term outcomes of monoclonal gammopathy of renal significance (MGRS) patients with other renal histopathologies remain unclear. It is uncertain if early intervention improves renal outcomes, because of a lack of evidence from prospective studies. In this retrospective study, we examined outcomes of 41 MGRS patients treated between 2004 and 2017 across five centres: four in the UK and one in the Republic of Ireland. The primary outcome measure was renal survival estimated by Kaplan-Meier product-limit method. Thirty-three patients (80·5%) were kappa light chain (LC) restricted. Twenty-seven patients (65·9%) presented with LC deposition disease on renal histology. At 24 months follow-up, estimated renal survival was 81·6% for the whole cohort. The estimated overall survival was 80·3% at 48 months. At 24 months, patients who had chronic kidney disease (CKD) stage 2-3b at diagnosis showed an estimated renal survival of 100% compared to 80·7% in those with CKD stage 4-5 at diagnosis (P = 0·04). Poorer outcomes in MGRS patients were historically attributed to delayed diagnosis due to small plasma cell clones, as well as the need for renal biopsy.