A review on pharmacophoric designs of antiproliferative agents

Past few decades have witnessed the dawn of new diseases in which cancer is a major problem and the race ensued to eradicate cancer by charting out various effective therapeutic regimens. Circumventing resistance issues and combating the toxicity and selectivity problems are matter-of-concern in cancer treatment. Persistent failure to ensure complete remission and eradication of cancer instigated the researchers to exploit the strategies of combining pharmacophores as targeted therapeutic agents. Momentous improvement in the pharmacokinetic as well as pharmacodynamic profile resulting in the enhancement of bioavailability was seen with the introduction of these pharmacophores. The scope of molecular hybridization can be clearly exemplified through the US-FDA approved estramustine and others such as CUDC-101, CBLC-137, PLX3397, E-3810, and CUDC-907 that are currently in different phases of clinical trials. This review seeks to highlight and discuss anti-proliferative activity of some important hybrid, dual, and multi-targeted pharmacophores reported to date along with their designs, structure activity relationships, scope, and limitations. Further, an emphasis has been made to summarize US-FDA approved as well as drugs currently undergoing clinical trials of anticancer drug development.     

Lymphocytic myocarditis in an overlap syndrome of systemic sclerosis and polymyositis

Clinical Rheumatology -     

White Matter Changes in Dementia: Role of Impaired Drainage of Interstitial Fluid

White matter abnormalities on magnetic resonance imaging (MRI) are associated with dementia and include white matter hyperintensities (WMH; also termed leukoaraiosis) and visible perivascular spaces (PVS). We review the potential role of impaired drainage of interstitial fluid in the pathogenesis of WMH and PVS. Whereas the volume of extracellular space in the grey matter is tightly controlled, fluid accumulates and expands the extracellular spaces of the white matter in acute hydrocephalus, vasogenic edema and WMH. Although there are no conventional lymphatic vessels in the brain, there is very effective lymphatic drainage for fluid and solutes along restricted pathways in the basement membranes of cerebral capillaries and arteries in young individuals. Lymphatic drainage of the brain is impaired with age and in association with apolipoprotein E ε4, risk factors for Alzheimer's disease and cerebral amyloid angiopathy (CAA). Deposition of proteins in the lymphatic drainage pathways in the walls of cerebral arteries with age is recognized as protein elimination failure angiopathy (PEFA), as in CAA and cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL). Facilitating perivascular lymphatic drainage from the aging brain may play a significant role in the prevention of CAA, WMH and Alzheimer's disease and may enhance the efficacy of immunotherapy for Alzheimer's disease.     

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults

BackgroundAnticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking.ObjectiveCompare risk of incident dementia and stroke by anticholinergic burden among initially healthy older people.DesignProspective cohort study.SettingPrimary care (Australia and USA).Participants19,114 community-dwelling participants recruited for the ASPREE trial, aged 70+ years (65+ if US minorities) without major cardiovascular disease, dementia diagnosis, or Modified Mini-Mental State Examination score below 78/100.MeasurementsBaseline anticholinergic exposure was calculated using the Anticholinergic Cognitive Burden (ACB) score. Dementia was adjudicated using Diagnostic and Statistical Manual of Mental Disorders volume IV criteria, and stroke using the World Health Organization definition.ResultsAt baseline, 15,000 participants (79%) had an ACB score of zero, 2930 (15%) a score of 1–2, and 1184 (6%) a score of ≥ 3 (indicating higher burden). After a median follow-up of 4.7 years and adjusting for baseline covariates, a baseline ACB score of ≥ 3 was associated with increased risk of ischemic stroke (adjusted HR 1.58, 95% CI 1.06, 2.35), or dementia (adjusted HR 1.36, 95% CI 1.01, 1.82), especially of mixed etiology (adjusted HR 1.53, 95% CI 1.06, 2.21). Results were similar for those exposed to moderate/highly anticholinergic medications.LimitationsResidual confounding and reverse causality are possible. Assessment of dose or duration was not possible.ConclusionsHigh anticholinergic burden in initially healthy older people was associated with increased risk of incident dementia and ischemic stroke. A vascular effect may underlie this association. These findings highlight the importance of minimizing anticholinergic exposure in healthy older people.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-020-06550-2.KEY WORDS: anticholinergic burden, dementia, stroke, potentially inappropriate medication     

Do race and gender influence the use of invasive procedures?

OBJECTIVE: To assess the influence of race and gender influence on the use of invasive procedures in patients with acute myocardial infarction (AMI) in community hospitals. DESIGN: Prospective, observational. SETTING: Five mid-Michigan community hospitals. PATIENTS: All patients (838) identified with AMI between January 1994 and April 1995 in 1 of these hospitals. MEASUREMENTS AND MAIN RESULTS: After adjusting for age, hospital of admission, insurance type, severity of AMI, and comorbidity, using white men as the reference group, the rate of being offered cardiac catheterization (CC) was 0.88 (95% confidence interval [95% CI], 0.60 to 1.29) for white women; 0.79 (95% CI, 0.41 to 1.50) for black men; and 1.14 (95% CI, 0.53 to 2.45)for black women. Among patients who underwent CC, after also adjusting for coronary artery anatomy, the rate of being offered angioplasty, using white men as the reference group, was 1.22 (95% CI, 0.75 to 1.98) for white women; 0.61 (5% CI, 0.29 to 1.28, P =.192) for black men; and 0.40 (95% CI, 0.14 to 1.13) for black women The adjusted rate of being offered bypass surgery was 0.47 (95% CI, 0.24 to 0.89) for white women; 0.36 (95% CI, 0.12 to 1.06) for black men; and 0.37 (95% CI, 0.11 to 1.28)for black women. CONCLUSIONS: Our study shows that white women are less likely than white men to be offered bypass surgery after AMI. Although black men and women with AMI are less likely than white men to be offered percutaneous transluminal coronary angioplasty or coronary artery bypass grafting in both unadjusted and adjusted analyses, these findings did not reach statistical significance. Our study is limited in power due to the small number of blacks in the sample.     

Biologics for treating axial spondyloarthritis

Introduction: Spondyloarthritis (SpA) encompasses a heterogeneous group of diseases sharing genetic, immunological, clinical and imaging features. Axial spondyloarthritis (axSpA) refers to a subgroup characterised predominately by inflammation of the axial skeleton with subsequent symptoms of chronic (often inflammatory) back pain and sacroiliitis. There is a strong association with the major histocompatibility complex (MHC) class I allele human leukocyte antigen (HLA) B27. In the last decade, there has been significant progress in earlier detection of the disease and the molecular mechanisms involved in its pathogenesis. The subsequent introduction of anti-tumour necrosis factor (TNF) has revolutionised the treatment of patients with axSpA.

Areas covered: In this article, we review the current biologic therapies for axSpA, the emergence of biosimilars, predictors of response, primary and secondary failure and new biologics on the horizon.

Expert opinion: There have been significant advances in the treatment of axSpA. Beyond the clear efficacy of anti-TNF inhibition, IL-17 offers an alternative therapeutic target and there is promise from inhibition of the IL-17/IL-23 pathway and small molecules, such as Janus kinase (JAK) inhibitors. Biosimilars have offered greater affordability and choice within this increasingly growing field of therapeutics.     

Household Debt and Relation to Intimate Partner Violence and Husbands' Attitudes Toward Gender Norms: A Study Among Young Married Couples in Rural Maharashtra,India

Objective

Evidence has linked economic hardship with increased intimate partner violence (IPV) perpetration among males. However, less is known about how economic debt or gender norms related to men''s roles in relationships or the household, which often underlie IPV perpetration, intersect in or may explain these associations. We assessed the intersection of economic debt, attitudes toward gender norms, and IPV perpetration among married men in India.

Methods

Data were from the evaluation of a family planning intervention among young married couples (n=1,081) in rural Maharashtra, India. Crude and adjusted logistic regression models for dichotomous outcome variables and linear regression models for continuous outcomes were used to examine debt in relation to husbands'' attitudes toward gender-based norms (i.e., beliefs supporting IPV and beliefs regarding male dominance in relationships and the household), as well as sexual and physical IPV perpetration.

Results

Twenty percent of husbands reported debt. In adjusted linear regression models, debt was associated with husbands'' attitudes supportive of IPV (b=0.015, p=0.004) and norms supporting male dominance in relationships and the household (b=0.006, p=0.003). In logistic regression models adjusted for relevant demographics, debt was associated with perpetration of physical IPV (adjusted odds ratio [AOR] = 1.4, 95% confidence interval [CI] 1.1, 1.9) and sexual IPV (AOR=1.6, 95% CI 1.1, 2.1) from husbands. These findings related to debt and relation to IPV were slightly attenuated when further adjusted for men''s attitudes toward gender norms.

Conclusion

Findings suggest the need for combined gender equity and economic promotion interventions to address high levels of debt and related IPV reported among married couples in rural India.Intimate partner violence (IPV) perpetrated by male partners or husbands occurs in high proportions globally as well as in low- to middle-income countries such as India.^1,2 One recent multi-country household study found that 37% of men in India reported having ever perpetrated physical violence against a female intimate partner in their lifetime. The health burden of IPV has been well demonstrated, with significant effects on women''s sexual and reproductive health (e.g., increased sexually transmitted infections, unintended pregnancy, and poor pregnancy outcomes),^3–5 mental health (e.g., anxiety, depression, and substance use),^6,7 as well as a multitude of other poor health outcomes among women and their children (e.g., maternal and child malnutrition and infant death).^8,9Recent research among women has identified economic hardship (e.g., financial dependence on male partners and economic instability) as increasing women''s vulnerability to IPV.^10,11 Although studies have found an association between economic stressors and reports of male IPV perpetration,^12–16 no research has examined debt in relation to these outcomes.Debt and other economic decisions in the context of marriage, particularly in rural India, are largely under the control of husbands. Taking on debt may be associated with economic hardship, heightening stress levels among men, and, in turn, IPV. Also, previous work documenting the association between economic hardship and increased IPV perpetration by males^12–15 has largely been explained by perceptions related to men''s roles financially within the family (e.g., men who do not feel that they are providing financially for their families may perceive that they are not fulfilling their roles as husbands/males, and this perception related to lack of role fulfillment may escalate into violence). Given that a decision to take on debt appears to be largely controlled by men in this context and likely tied to their perceived role of providing financially for the family, a man''s decision to take out loans may be determined, in part, by their support of masculine gender norms (e.g., a man''s role in the family and male dominance and control in the household). In addition, given previous work highlighting the association between masculine gender norms and a number of risk behaviors among boys and men (e.g., substance and tobacco use and behaviors resulting in unintentional injury),^17–21 such gender norms may also be linked to taking on risks associated with debt, as well as debt-acquiring behaviors (e.g., spending money on nonessential goods such as alcohol).Gender norms pertaining to IPV, relationships, and the household are also important driving factors in terms of understanding men''s behaviors related to IPV. Cross-cultural research has shown that societies with greater gender inequities in social norms and policies have a higher prevalence of IPV.²¹ In the context of India and elsewhere, women''s low status in families and high levels of societal tolerance and acceptance of IPV promote IPV.²²More research is needed to understand economic hardship, and debt specifically, in relation to attitudes toward gender norms and IPV perpetration. Many studies have hypothesized that stress related to economic hardship and debts increases IPV perpetration;^12–15 however, less research has sought to understand the role of attitudes supportive of men''s more traditional gender norms in relationships or households in contributing to decisions to take on debt as well as in terms of explaining its association with increased IPV perpetration. Increased understanding of the mechanisms that explain associations between economic hardship/debt and IPV is needed to inform prevention approaches, particularly given the increasing number of economic promotion interventions being implemented globally and throughout India.Thus, the primary objective of the current study was to assess household debt in relation to husbands'' support of gender-inequitable norms and norms promoting IPV as well as husbands'' use of IPV against wives. The secondary objective of this study was to assess whether or not gender-based attitudes are important factors in debt and IPV, as well as in explaining an association between debt and increased risk for IPV perpetration among husbands.