Cost-effectiveness of albumin in the treatment of decompensated cirrhosis in resource-limited healthcare settings.

Background: Human albumin (HA) is an effective adjuvant treatment for patients with cirrhosis developing spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS) and ascites requiring large-volume paracentesis (LVP). However, cost remains a barrier to use, particularly in resource-limited settings. This study aims to assess the cost-effectiveness of HA in patients with cirrhosis with SBP, HRS or ascites requiring LVP in the Indonesian healthcare system as a representative of a resource-limited setting. Methods: Three decision-tree models were developed to assess the cost-effectiveness of (1) antibiotics and HA versus antibiotics alone in patients with SBP, (2) terlipressin and HA versus terlipressin alone in patients with HRS, and (3) LVP and HA versus LVP and gelatine for patients with ascites. Clinical utility and economic inputs were pooled from the available literature. Time horizon was 3 months. Outcomes were expressed as incremental cost-effectiveness ratios (ICER) reported as 2021 IDR per quality-adjusted life year (QALY) (exchange rate June 30, 2021: 1 EUR = 17,245 IDR). Willingness-to-pay thresholds considered were: three times the GDP per capita (199,355,561 IDR/QALY; 11,560 EUR/QALY) and one time the GDP per capita (66,451,854 IDR/QALY; 3853 EUR/QALY). Results: The ICER for antibiotics and HA (versus antibiotics alone) for SBP was 80,562,652 IDR per QALY gained (4672 EUR/QALY). The ICER for terlipressin and HA (versus terlipressin) for HRS was 23,085,004 IDR per QALY gained (1339 EUR/QALY). The ICER for LVP and HA versus LVP and gelatine was 24,569,827 IDR per QALY gained (1425 EUR/QALY). Conclusion: Adjunctive HA may be a cost-effective treatment for SBP, HRS and LVP in resource-limited settings.

ALBUMIN VERSUS STANDARD MEDICAL TREATMENT IN BRAZILIAN PUBLIC AND PRIVATE HEALTHCARE SYSTEMS.

•To assess the economic impact of implementing long-term albumin infusions in patients with cirrhosis and ascites in Brazil •Incremental cost per cirrhotic patient treated with long-term albumin was estimated based on the rates of complications and healthcare resource utilization from the ANSWER trial and local costs from the public and private healthcare system perspective in Brazil. •Implementation of long-term albumin could save up to 118,759 BRL and 189,675 BRL per patient treated in the public and private healthcare system setting, respectively. •Should results from the ANSWER trial translate into real-world effectiveness, addition of albumin to standard medical treatment could lead to improved clinical outcomes and reduced costs. Background - Cirrhosis is one of the final stages of chronic liver disease. Common causes of cirrhosis include alcoholism and viral hepatitis infections. Cirrhosis can progress from an asymptomatic, compensated phase to decompensation and the appearance of overt symptoms. There is no specific treatment for decompensated cirrhosis. The ANSWER trial positioned long-term albumin infusions as a potential treatment for patients with cirrhosis and uncomplicated ascites. Objective - This study assesses the economic impact of albumin infusions following the ANSWER trial regimen in Brazilian patients with decompensated cirrhosis from the public and private healthcare systems perspectives. Methods - The incremental cost per patient per year was calculated for standard medical treatment (SMT) plus long-term albumin infusions versus SMT alone. Costs of diuretics and albumin were obtained from Banco de Preços em Saúde and the Drug Market Regulation Chamber. Costs for complication and procedures were gathered from the published literature. Costs were transformed to 2021 Brazilian reals (BRL). Incidences of clinical complications and treatments were gathered from the ANSWER trial. Univariate sensitivity analysis was performed by increasing and decreasing all inputs by 20%. Results - The cost per patient per year was 118,759 BRL and 189,675 BRL lower for patients treated with SMT and albumin (compared to SMT only) for the public and private healthcare systems, respectively. The additional cost of albumin was offset by reduced complications and treatments (149,526 BRL and 249,572 BRL, respectively). The univariate sensitivity analysis showed cost savings for both healthcare systems in all the scenarios assessed. Conclusion - This economic analysis suggests that, if the ANSWER trial clinical outcomes translate into real-world effectiveness, addition of albumin infusions to SMT in patients with decompensated cirrhosis may lead to cost savings for the public and private healthcare systems in Brazil.

Análise de custos de pacientes cirróticos descompensados recebendo albumina a longo prazo versus tratamento médico padrão nos sistemas de saúde público e privado do Brasil / Albumin versus standard medical treatment in brazilian public and private healthcare systems

ABSTRACT Background: Cirrhosis is one of the final stages of chronic liver disease. Common causes of cirrhosis include alcoholism and viral hepatitis infections. Cirrhosis can progress from an asymptomatic, compensated phase to decompensation and the appearance of overt symptoms. There is no specific treatment for decompensated cirrhosis. The ANSWER trial positioned long-term albumin infusions as a potential treatment for patients with cirrhosis and uncomplicated ascites. Objective: This study assesses the economic impact of albumin infusions following the ANSWER trial regimen in Brazilian patients with decompensated cirrhosis from the public and private healthcare systems perspectives. Methods: The incremental cost per patient per year was calculated for standard medical treatment (SMT) plus long-term albumin infusions versus SMT alone. Costs of diuretics and albumin were obtained from Banco de Preços em Saúde and the Drug Market Regulation Chamber. Costs for complication and procedures were gathered from the published literature. Costs were transformed to 2021 Brazilian reals (BRL). Incidences of clinical complications and treatments were gathered from the ANSWER trial. Univariate sensitivity analysis was performed by increasing and decreasing all inputs by 20%. Results: The cost per patient per year was 118,759 BRL and 189,675 BRL lower for patients treated with SMT and albumin (compared to SMT only) for the public and private healthcare systems, respectively. The additional cost of albumin was offset by reduced complications and treatments (149,526 BRL and 249,572 BRL, respectively). The univariate sensitivity analysis showed cost savings for both healthcare systems in all the scenarios assessed. Conclusion: This economic analysis suggests that, if the ANSWER trial clinical outcomes translate into real-world effectiveness, addition of albumin infusions to SMT in patients with decompensated cirrhosis may lead to cost savings for the public and private healthcare systems in Brazil.

RESUMO Contexto: A cirrose representa o estágio final da doença hepática crônica. Causas comuns de cirrose incluem alcoolismo e infecções por hepatite viral. A cirrose pode progredir de uma fase compensada assintomática para descompensação e aparecimento de sintomas evidentes. Não há tratamento específico para cirrose descompensada. O estudo ANSWER demonstrou que a administração de albumina a longo prazo pode representar um potencial tratamento para pacientes com cirrose e ascite não complicada. Objetivo: Nosso estudo avalia o impacto econômico da administração de albumina a longo prazo seguindo o protocolo do estudo ANSWER em pacientes brasileiros com cirrose descompensada, sob a perspectiva dos sistemas de saúde público e privado. Métodos: O custo incremental por paciente por ano foi calculado para o tratamento médico padrão (SMT) associado a administração de albumina a longo prazo comparado a SMT apenas. Os custos de diuréticos e albumina foram obtidos no Banco de Preços em Saúde e na Câmara de Regulação do Mercado de Medicamentos. Os custos de complicações e procedimentos foram coletados da literatura publicada. Os custos foram transformados em Reais de 2021 (BRL). As incidências de complicações clínicas e tratamentos foram coletadas do estudo ANSWER. Uma análise de sensibilidade univariada foi realizada aumentando e diminuindo todas as variáveis em 20%. Resultados: O custo por paciente por ano foi de R$ 118.759 e R$ 189.675 menor para pacientes tratados com SMT e albumina (comparado apenas com SMT) para os sistemas de saúde público e privado, respectivamente. O custo adicional da albumina foi compensado pela redução de complicações e tratamentos (149.526 BRL e 249.572 BRL, respectivamente). A análise de sensibilidade univariada mostrou redução de custos para ambos os sistemas de saúde em todos os cenários avaliados. Conclusão: Esta análise econômica sugere que, se os resultados clínicos do estudo ANSWER se confirmarem no mundo real, a administração de albumina associada ao SMT em pacientes com cirrose descompensada pode levar a redução de custos para os sistemas de saúde público e privado no Brasil.

Burden of hospitalizations and outpatient visits associated with moderate and severe acute graft-versus-host disease in Finland and Sweden: a real-world data study.

PURPOSE: The aim of this study was to describe patient characteristics and quantify hospital stays and outpatient visits (H&OV) following diagnosis with moderate-to-severe acute graft-versus-host disease (aGVHD) in Finland and Sweden. METHODS: A retrospective chart audit collected data from patient medical records of 3 specialized centers performing allogeneic hematopoietic stem cell transplantation (HSCT; Finland, n = 2; Sweden, n = 1). Eligible patients received allogeneic HSCT (January 1, 2016-June 30, 2017) from any donor source, were diagnosed with grade II-IV aGVHD (MAGIC or modified Glucksberg criteria) at any time from transplantation to 12 months before data collection, and were ≥ 18 years old at diagnosis. Criteria for comparing patients graded with modified Glucksberg and MAGIC severity scales were defined. RESULTS: Fifty-five patients (Finland, n = 45; Sweden, n = 10) were included. Myeloablative conditioning was the most common conditioning regimen (81.8%); immunosuppression regimens were based on combinations of methotrexate (96.4%), in vivo T-cell depletion (80.0%), cyclosporine (63.6%), mycophenolate (40.0%), and tacrolimus (34.5%). Sixteen patients (29.1%) developed grade III/IV aGVHD; skin was the most common organ involved (80.0%). Most patients required ≥ 1 hospital stay (89.1%; median of 2 hospitalizations per patient); 7 patients (14.3%) required admission to an intensive care unit. Median hospitalization duration from HSCT to discharge was 26 days. Most patients also required outpatient or emergency department visits (90.9%). Subgroup analyses showed longer hospital stays for patients receiving multiple treatment lines; no clear differences in H&OV were observed between prophylactic regimens. CONCLUSION: Based on this retrospective study, moderate-to-severe aGVHD is associated with considerable healthcare resource utilization in Finland and Sweden, particularly in patients who received multiple lines of therapy.

Economic evaluation of long-term albumin use in cirrhosis patients from the Mexican healthcare system perspective.

INTRODUCTION AND OBJECTIVES: Liver cirrhosis is a major public health issue associated with high morbidity and mortality. The ANSWER trial showed that long-term human albumin (LTA) infusions led to significant reduction of complications and mortality in patients with uncomplicated ascites. The present study aimed to assess the incremental cost of cirrhosis patients treated with LTA plus standard medical treatment (SMT) versus those treated with SMT from the perspective of the Mexican Social Security Institute (IMSS). MATERIAL AND METHODS: Cost of illness for patients with cirrhosis and grade 2-3 ascites treated with SMT or with SMT and LTA (following the treatment regimen from ANSWER) over a one-year period was estimated according to the IMSS perspective. Rates of treatments, complications and hospitalizations were based on results from the ANSWER trial. Unit costs from IMSS were gathered from public sources and transformed to 2020 Mexican $ (Mex$). RESULTS: The use of LTA is estimated to require additional annual expenditure derived from the pharmacological cost of human albumin and by the follow up visits required for LTA administration (Mex$28,128). However, this cost may potentially be counterbalanced by the reduction in paracentesis, cirrhosis-related complications and hospitalizations which would lead to cost savings of Mex$33,417 per patient/year. CONCLUSIONS: Based on the ANSWER trial results, our study suggests that LTA may result in improved clinical outcomes and reduced costs for the IMSS when administered to cirrhosis patients with uncomplicated ascites.

Social Restrictions versus Testing Campaigns in the COVID-19 Crisis: A Predictive Model Based on the Spanish Case.

The global COVID-19 spread has forced countries to implement non-pharmacological interventions (NPI) (i.e., mobility restrictions and testing campaigns) to preserve health systems. Spain is one of the most severely impacted countries, both clinically and economically. In an effort to support policy decision-making, we aimed to assess the impacts of different NPI on COVID-19 epidemiology, healthcare costs and Gross Domestic Product (GDP). A modified Susceptible-Exposed-Infectious-Removed epidemiological model was created to simulate the pandemic evolution. Its output was used to populate an economic model to quantify healthcare costs and GDP variation through a regression model which correlates NPI and GDP change from 42 countries. Thirteen scenarios combining different NPI were consecutively simulated in the epidemiological and economic models. Both increased testing and stringency could reduce cases, hospitalizations and deaths. While policies based on increased testing rates lead to higher healthcare costs, increased stringency is correlated with greater GDP declines, with differences of up to 4.4% points. Increased test sensitivity may lead to a reduction of cases, hospitalizations and deaths and to the implementation of pooling techniques that can increase throughput testing capacity. Alternative strategies to control COVID-19 spread entail differing economic outcomes. Decision-makers may utilize this tool to identify the most suitable strategy considering epidemiological and economic outcomes.

Scaffold-Hopping Strategy on a Series of Proteasome Inhibitors Led to a Preclinical Candidate for the Treatment of Visceral Leishmaniasis.

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.

Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice.

The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aß42/Aß40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.

Clinical approach to occult urinary incontinence: Multicenter cohort study / Enfoque clínico de la incontinencia urinaria oculta: estudio multicéntrico de cohortes

Objective: To compare the impact of pelvic organ prolapse (POP) surgery with that of combined surgery for prolapse and stress urinary incontinence (SUI) in patients with no SUI symptoms and a positive stress test result. Material and methods: We performed a subanalysis of a prospective observational cohort study in 39 gynecological units specialized in pelvic floor disorders in Spain (CIRPOP-IUE). The study population comprised patients with symptomatic grade ≥II POP with an indication for treatment using vaginal surgery. All patients underwent a standard stress test, with and without reduction of the prolapse. Patients were classified into 3 groups (Group 1, SUI symptoms and positive stress test result; Group 2, absence of symptoms and positive stress test result; and Group 3, absence of symptoms and negative stress test result). Depending on the type of surgery performed, a descriptive analysis of symptoms before surgery and 1 year after was performed in group 2. Results: Group 2 comprised 87 patients (83 patients at the follow-up visit). Of these, 32 (38.5%) underwent surgery for prolapse only and 51 (61.4%) combined surgery for prolapse and urinary incontinence. De novo symptomatic SUI was recorded in 7.3% of patients who underwent combined surgery and in 29.2% of patients who underwent prolapse surgery only. Conclusion: Postsurgical urinary incontinence symptoms were less frequent in patients who underwent combined surgery for prolapse and incontinence

Objetivos: evaluar el impacto de la cirugía de prolapso de órganos pélvicos versus cirugía combinada de prolapso e incontinencia urinaria de esfuerzo en pacientes sin síntomas de incontinencia urinaria de esfuerzo y con test de esfuerzo positivo. Material y métodos: subanálisis de un estudio observacional multicéntrico de cohortes prospectivas. Se incluyeron pacientes con prolapso de órganos pélvicos sintomático, de grado II o superior, que iban a ser sometidas a cirugía del prolapso vía vaginal. Se realizó un test de esfuerzo estandarizado a todas las pacientes, con y sin prolapso de órganos pélvicos reducido. Todas las mujeres fueron clasificadas en tres grupos (Grupo 1: síntomas de incontinencia urinaria de esfuerzo y test de esfuerzo positivo, grupo 2: ausencia de síntomas y test de esfuerzo positivo y grupo 3: ausencia de síntomas y test de esfuerzo negativo). Se realizó un análisis descriptivo de los síntomas, antes de la cirugía y un año después, según el tipo de cirugía aplicada en las pacientes del grupo 2. Resultados: se incluyeron 87 pacientes en el grupo 2 (83 pacientes en la visita poscirugía). De estas, 32 (38,5%) y 51 (61,4%) fueron sometidas a cirugía solo de prolapso y combinada de prolapso e incontinencia, respectivamente. El 7,3% de las pacientes con cirugía combinada y el 29,2% de las pacientes con cirugía solo de prolapso, desarrollaron incontinencia urinaria de esfuerzo sintomática de novo. Conclusión: la presencia de síntomas de incontinencia urinaria tras la cirugía fue menos frecuente en el grupo sometido a cirugía combinada de prolapso e incontinencia

Epidemiologic and economic burden of HPV diseases in Spain: implication of additional 5 types from the 9-valent vaccine.

BACKGROUND: A new nonavalent human papillomavirus (HPV) vaccine that includes genotypes 6/11/16/18/31/33/45/52/58 has been recently approved in Spain. A previous study has shown that attributable fraction of HPV related diseases in Spain is consistent with that reported in European and global studies. The aim of the present study was to estimate the annual direct costs associated to the following HPV-related diseases: genital warts, high grade precancerous lesions and cancer of cervix, vulva, vagina, anus and penis and head and neck cancer, caused by genotypes included in the nonavalent (9vHPV) and quadrivalent vaccines (4vHPV), in Spanish men and women. METHODS: Cancer registries and epidemiological studies were used to estimate the number of new annual cases of genital warts, anogenital precancerous lesions and cancer of cervix, vulva, vagina, anus, penis and head and neck, as well as the fraction attributable to HPV infection and to genotypes targeted by both vaccines in Spain. Costs per patient for each disease were obtained from the literature. In addition, 142 specialists were surveyed to estimate cost per patient of vulvar, vaginal, anal and penile precancerous lesions. The annual burden of diseases attributable to types targeted by both vaccines was estimated and compared. All results were validated by a panel of experts. RESULTS: In 2016, new genital warts, precancerous lesions and cancers attributable to types targeted by the 9vHPV were estimated at 49,251, 29,405 and 3381, respectively. Among them, 12,597 new precancerous lesions and 530 new cancers were related to the 5 additional types covered by the 9vHPV. Annual cost of new cases of these diseases associated to types targeted by the 4vHPV and 9vHPV were estimated at 116.7 and 150.9 million € for the Spanish National Health Service (NHS), respectively (2017 €). CONCLUSIONS: HPV-related diseases represent a major burden for the Spanish NHS. Annual new cases and costs related to the 5 additional types from the 9vHPV represent a significant burden compared with that associated to types included in the 4vHPV.

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi.

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

Synthesis and biological evaluation of N-cyanoalkyl-, N-aminoalkyl-, and N-guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents.

Current drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. The search for novel, effective, brain permeable, safe, and inexpensive antitrypanosomal compounds is therefore an urgent need. We have recently reported that the 4-aminoquinoline derivative huprine Y, developed in our group as an anticholinesterasic agent, exhibits a submicromolar potency against Trypanosoma brucei and that its homo- and hetero-dimerization can result in to up to three-fold increased potency and selectivity. As an alternative strategy towards more potent smaller molecule anti-HAT agents, we have explored the introduction of ω-cyanoalkyl, ω-aminoalkyl, or ω-guanidinoalkyl chains at the primary amino group of huprine or the simplified 4-aminoquinoline analogue tacrine. Here, we describe the evaluation of a small in-house library and a second generation of newly synthesized derivatives, which has led to the identification of 13 side chain modified 4-aminoquinoline derivatives with submicromolar potencies against T. brucei. Among these compounds, the guanidinononyltacrine analogue 15e exhibits a 5-fold increased antitrypanosomal potency, 10-fold increased selectivity, and 100-fold decreased anticholinesterasic activity relative to the parent huprine Y. Its biological profile, lower molecular weight relative to dimeric compounds, reduced lipophilicity, and ease of synthesis, make it an interesting anti-HAT lead, amenable to further optimization to eliminate its remaining anticholinesterasic activity.

Design, synthesis and biological evaluation of N-methyl-N-[(1,2,3-triazol-4-yl)alkyl]propargylamines as novel monoamine oxidase B inhibitors.

Different azides and alkynes have been coupled via Cu-catalyzed 1,3-dipolar Huisgen cycloaddition to afford a novel family of N1- and C5-substituted 1,2,3-triazole derivatives that feature the propargylamine group typical of irreversible MAO-B inhibitors at the C4-side chain of the triazole ring. All the synthesized compounds were evaluated against human MAO-A and MAO-B. Structure-activity relationships and molecular modeling were utilized to gain insight into the structural and chemical features that enhance the binding affinity and selectivity between the two enzyme isoforms. Several lead compounds, in terms of potency (submicromolar to low micromolar range), MAO-B selective recognition, and brain permeability, were identified. One of these leads (MAO-B IC50 of 3.54µM, selectivity MAO-A/MAO-B index of 27.7) was further subjected to reversibility and time-dependence inhibition studies, which disclosed a slow and irreversible inhibition of human MAO-B. Overall, the results support the suitability of the 4-triazolylalkyl propargylamine scaffold for exploring the design of multipotent anti-Alzheimer compounds endowed with irreversible MAO-B inhibitory activity.

Rhein-Huprine Derivatives Reduce Cognitive Impairment, Synaptic Failure and Amyloid Pathology in AßPPswe/PS-1 Mice of Different Ages.

Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-ß (Aß) peptide plays a key role in synaptic impairment and memory decline associated with neuronal dysfunction and intra-neuronal accumulation of hyperphosphorylated tau protein. Two novel enantiopure rhein-huprine hybrids ((+)-1 and (-)-1) exhibit potent inhibitory effects against human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE-1 and both Aß and tau antiaggregation activity in vitro and reduction on the amyloid precursor protein (APP) processing in vivo. Interestingly, in this work, we observed beneficial effects with both (+)- and (-)-1 in the reversion of the neuropathology presented in the AßPPswe/PS-1 Alzheimer´s model, including a reduction in the Aß levels, tau phosphorylation and memory impairment with both treatments. Also, in young transgenic mice that present early symptoms of synaptic failure and memory loss, we found a protection of cognitive functions, including long-term potentiation (LTP) and a reduction of the neuro-inflammation by both (+)- and (-)-1. Furthermore, animals with an advanced disease (11month-old) present an exacerbate neurodegeneration that is reversed only with the dextrorotatory enantiomer. These studies indicated that rhein-huprine derivatives with multiple properties might have interesting therapeutic potential for AD.

Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity.

Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania species, are among the most deadly neglected tropical diseases. The development of drugs that are active against several trypanosomatids is appealing from a clinical and economic viewpoint, and seems feasible, as these parasites share metabolic pathways and hence might be treatable by common drugs. From benzonapthyridine 1, an inhibitor of acetylcholinesterase (AChE) for which we have found a remarkable trypanocidal activity, we have designed and synthesized novel benzo[h][1,6]naphthyridines, pyrrolo[3,2-c]quinolines, azepino[3,2-c]quinolines, and pyrano[3,2-c]quinolines through 2-4-step sequences featuring an initial multicomponent Povarov reaction as the key step. To assess the therapeutic potential of the novel compounds, we have evaluated their in vitro activity against T. brucei, T. cruzi, and Leishmania infantum, as well as their brain permeability, which is of specific interest for the treatment of late-stage HAT. To assess their potential toxicity, we have determined their cytotoxicity against rat myoblast L6 cells and their AChE inhibitory activity. Several tricyclic heterofused quinoline derivatives were found to display an interesting multi-trypanosomatid profile, with one-digit micromolar potencies against two of these parasites and two-digit micromolar potency against the other. Pyranoquinoline 39, which displays IC50 values of 1.5 µM, 6.1 µM and 29.2 µM against T. brucei, L. infantum and T. cruzi, respectively, brain permeability, better drug-like properties (lower lipophilicity and molecular weight and higher CNS MPO desirability score) than hit 1, and the lowest AChE inhibitory activity of the series (IC50 > 30 µM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells.

Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase.

Malaria is a devastating disease in sub-Saharan Africa, and current vector control measures are threatened by emerging resistance mechanisms. With the goal of developing new, selective, resistance-breaking insecticides we explored α-fluorinated methyl ketones as reversible covalent inhibitors of Anopheles gambiae acetylcholinesterase (AgAChE). Trifluoromethyl ketones 5 demonstrated remarkable volatility in microtiter plate assays, but 5c,e-h exhibited potent (1-100 nM) inhibition of wild type (WT) AgAChE and weak inhibition of resistant mutant G119S mutant AgAChE. Fluoromethyl ketones 10c-i exhibited submicromolar to micromolar inhibition of WT AgAChE, but again only weakly inhibited G119S AgAChE. Interestingly, difluoromethyl ketone inhibitors 9c and 9g had single digit nanomolar inhibition of WT AgAChE, and 9g had excellent potency against G119S AgAChE. Approach to steady-state inhibition was quite slow, but after 23 h incubation an IC50 value of 25.1 ± 1.2 nM was measured. We attribute the slow, tight-binding G119S AgAChE inhibition of 9g to a balance of steric size and electrophilicity. However, toxicities of 5g, 9g, and 10g to adult A. gambiae in tarsal contact, fumigation, and injection assays were lower than expected based on WT AgAChE inhibition potency and volatility. Potential toxicity-limiting factors are discussed.

Multigram synthesis and in vivo efficacy studies of a novel multitarget anti-Alzheimer's compound.

We describe the multigram synthesis and in vivo efficacy studies of a donepezil‒huprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimer's disease (AD). Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic CL4176 and CL2006 Caenorhabditis elegans strains expressing human Aß42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by Aß42. However, this protective effect was not accompanied, in CL2006 worms, by a reduction of amyloid deposits. Oral administration for 3 months to transgenic APPSL mice, a well-established animal model of AD, improved short-term memory, but did not alter brain levels of Aß peptides nor cortical and hippocampal amyloid plaque load. Despite the clear protective and cognitive effects of AVCRI104P4, the lack of Aß lowering effect in vivo might be related to its lower in vitro potency toward Aß aggregation and formation as compared with its higher anticholinesterase activities. Further lead optimization in this series should thus focus on improving the anti-amyloid/anticholinesterase activity ratio.

3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae.

To identify potential selective and resistance-breaking mosquitocides against the African malaria vector Anopheles gambiae, we investigated the acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (15), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with ki values at least 10- to 600-fold higher than that of propoxur, a compound that does not kill Akron mosquitoes at the highest concentration tested. On average, inactivation of WT AgAChE by dimethylcarboxamides 14 was 10-20 fold faster than that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray crystallography of dimethylcarboxamide 14d provided insight into that reactivity, a finding that may explain the inhibitory power of structurally-related inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE inhibition selectivities of these compounds were low, suggesting the need for additional structural modification.

Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal-antiplasmodial activity.

Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.