In Vitro Lipolysis Model to Predict Food Effect of Poorly Water-Soluble Drugs Itraconazole, Rivaroxaban, and Ritonavir.

It is desirable to predict positive food effect of oral formulations due to food mediated dissolution enhancement of lipophilic drugs. The objective was to assess the ability of in vitro lipolysis to anticipate a positive food effect. Tested formulations included rivaroxaban and itraconazole, where some formulations, but not all, exhibit a positive food effect in vivo in humans. Amorphous solid dispersion formulations of ritonavir, which exhibit a negative food effect in vivo in humans, were also studied. Fe-lipolysis and Fa-lipolysis media representing fed and fasted intestinal conditions were used. Results show frequent agreement between in vitro lipolysis predictions and in vivo human outcomes. For rivaroxaban, food effect of unformulated active pharmaceutical ingredient (API) and products were correctly predicted where 2.5 mg and 10 mg strengths did not show any food effect; however, 20 mg did show a positive food effect. For itraconazole, all four products were correctly predicted, with Sporanox, Sempera, and generic capsules having a food effect, but Tolsura not having a positive food effect. For ritonavir, lipolysis predicted a positive food effect for API and Norvir tablet and powder, but Norvir products have negative food effect in vivo in humans. Overall, the lipolysis model showed favorable predictability and merits additional evaluation.

Clinical and electrophysiological correlates of hopelessness in the context of suicide risk✰.

Hopelessness is a key risk factor for suicide. This analysis explored whether hopelessness indicates a recent suicide crisis state and is linked with magnetoencephalography (MEG) oscillatory power and effective connectivity differences. Change in hopelessness ratings and effective connectivity post-ketamine were also evaluated in a subsample of high-risk individuals to evaluate correlates of dynamic changes over time. Participants (66F;44 M;1 transgender) included individuals with suicide crisis in the last two weeks (High Risk (HR), n = 14), those with past suicide attempt but no recent suicide ideation (SI) (Low Risk (LR), n = 37), clinical controls (CC, n = 33), and healthy volunteers at minimal risk (MinR, n = 27). MEG oscillatory power and clinical hopelessness ratings (via the Beck Hopelessness Scale (BHS)) were evaluated across groups. Dynamic casual modeling (DCM) evaluated connectivity within and between the anterior insula (AI) and anterior cingulate cortex (ACC). A subsample of HR individuals who received ketamine (n = 10) were evaluated at Day 1 post-infusion. The HR group reported the highest levels of hopelessness, even when adjusting for SI. MEG results linked hopelessness with reduced activity across frequency bands in salience network regions, with no group or group-by-interaction effects. Using DCM, the HR group had reduced intrinsic drive from granular Layer IV stellate cells to superficial pyramidal cells in the ACC and AI. In the pilot HR study, reduced hopelessness was linked with increased drive for this same connection post-ketamine. Hopelessness is a possible proxy for suicide risk. Electrophysiological targets for hopelessness include widespread reductions in salience network activity, particularly in the ACC and AI.

AACP faculty affairs standing committee report of strategies for faculty self-advocacy and promotion.

OBJECTIVES: The 2020-2021 American Association of Colleges of Pharmacy Faculty Affairs Standing Committee (FASC) was charged with identifying how faculty can self-advocate and promote themselves in a social influence context. FINDINGS: The FASC identified social influence and persuasion theories and strategies that can be used by faculty to initiate self-advocacy discussions and collaborations. Social influence and persuasion theories can provide a framework for research and scholarship or for beginning discussions regarding self-advocacy. SUMMARY: This FASC report describes the Committee charge, background information, and an overview of social influence theories and how these theories can be applied in academic pharmacy. The report concludes with a summary of issues for follow-up to the Committee's work.

Sagacious Perceptive on Marburg Virus Foregrounding the Recent Findings: A Critical Review.

Infectious diseases are defined as a group of diseases caused by any infecting microorganism which are highly potent to severely affect human life. The end can vary from critical infection to mortality. Most infectious diseases are reported with a rapid rate of transmission. Marburg virus disease is a kind of infectious viral disease usually manifested as hemorrhagic fever. The latest reported case of Marburg virus disease confirmed by WHO was on 6th August 2021 in the south-western province of Guinea. Marburg virus disease exhibit similar manifestations to that of infection with the Ebola virus. Though not widely spread to emerge as a pandemic, Marburg virus disease remains a serious threat to human life. This review emphasizes the novel current facts determined through various studies related to Marburg virus infection. From these promising theories, the review tries to put forward the importance of various study conclusions, which are likely to have a major impact on the health sector in the near future.

Patients Living With HIV Are Less Likely to Receive Appropriate Statin Therapy for Cardiovascular Disease Risk Reduction.

BACKGROUND: Recent studies suggest that statins are underprescribed in patients living with HIV (PLWH) at risk for atherosclerotic cardiovascular disease (ASCVD), but none have assessed if eligible patients receive the correct statin and intensity compared to uninfected controls. OBJECTIVES: The primary objective was to determine whether statin-eligible PLWH are less likely to receive appropriate statin therapy compared to patients without HIV. METHODS: This retrospective study evaluated statin eligibility and prescribing among patients in both an HIV and internal medicine clinic at an urban, academic medical center from June-September 2018 using the American College of Cardiology/American Heart Association guideline on treating blood cholesterol to reduce ASCVD risk. Patients were assessed for eligibility and actual treatment with appropriate statin therapy. Characteristics of patients appropriately and not appropriately treated were compared with chi-square testing and predictors for receiving appropriate statin therapy were determined with logistic regression. RESULTS: A total of 221/300 study subjects were statin-eligible. Fewer statin-eligible PLWH were receiving the correct statin intensity for their risk benefit group versus the uninfected control group (30.2% vs 67.0%, p < 0.001). In the multivariable logistic regression analysis, PLWH were significantly less likely to receive appropriate statin therapy, while those with polypharmacy were more likely to receive appropriate statin therapy. CONCLUSION: Our study reveals that PLWH may be at a disadvantage in receiving appropriate statin therapy for ASCVD risk reduction. This is important given the heightened risk for ASCVD in this population, and strategies that address this gap in care should be explored.

Treatment of the hypertensive patient in 2030.

Sarah Bingham, a 45 year old carer for her grandmother who suffered a stroke 4 months ago, feels a buzz on her wrist. It's time for them both to take their medications. Sarah makes dinner and leaves for her evening run. Her smartwatch detects her exit and turns off her TV as advertisements for incentivised private health insurance commence.

Tobacco and Marijuana Initiation Among African American and White Young Adults.

INTRODUCTION: African American youth use marijuana at similar rates and tobacco at lower rates compared with white youth; however, in adulthood, tobacco use is similar. Tobacco and marijuana use are closely associated; differing initiation patterns may contribute to observed racial differences in tobacco prevalence by age. Therefore, it is important to assess tobacco and marijuana initiation patterns by race. METHODS: Data were obtained from 56,555 adults aged 18-25 who completed the 2005-2012 National Survey on Drug Use and Health. The analysis was restricted to those who reported ever use of marijuana and combustible tobacco (cigarettes and/or cigars). Three mutually exclusive categories of initiation patterns were evaluated: use of marijuana before tobacco; marijuana and tobacco at the same age; and tobacco before marijuana. Multivariable regression models were used to assess changes over time and compare these outcomes by race while controlling for sociodemographics, risk perceptions, and current substance use. RESULTS: In 2005, 26.6% of African American and 14.3% of white young adults used marijuana before tobacco, compared with 41.5% of African American and 24.0% of white young adults in 2012 (P < .001). Overall, African American young adults had greater odds of using marijuana before tobacco (AOR = 1.79; 95% CI: 1.67, 1.91) compared with whites. CONCLUSION: African American young adults were more likely than whites to use marijuana before tobacco and both groups were increasingly likely to use marijuana before tobacco over time. A greater understanding of how marijuana initiation interacts with tobacco initiation could inform more effective tobacco and marijuana use prevention efforts. IMPLICATIONS: Among ever users of combustible tobacco and marijuana, greater proportions of African American young adults used marijuana before tobacco or at the same age than their white counterparts. Moreover, both African Americans and whites were more likely to use marijuana before tobacco in 2012 compared with 2005. Tobacco control policy may benefit from a broader understanding of the patterns of initiation to tobacco and marijuana use. Some public health interventions aimed at preventing and reducing combustible tobacco use among African American young adults may be strengthened by considering marijuana use.

Parent perceptions important for HPV vaccine initiation among low income adolescent girls.

OBJECTIVE: The study aims were to assess the influence of provider recommendations on parental vaccine perceptions and identify the most potent parent vaccine perceptions for HPV vaccine series initiation considering provider recommendation strength. METHODS: We administered a questionnaire and assessed HPV vaccine claims among a stratified-random sample of parents of 9-17 year old girls enrolled in Florida's Medicaid and the Children's Health Insurance Program. Using multivariate analyses, we evaluated the associations between: (1) parent vaccine perceptions and provider recommendation strength, and (2) parent vaccine perceptions and HPV vaccine series initiation (≥1 vaccine claim or positive parental report) controlling for provider recommendation strength. RESULTS: The majority of the 2422 participating parents agreed that the HPV vaccine was safe (61%), would not make girls more likely to have sex (69%), and prevented cervical cancer (71%). About half (44%) reported receiving a strong provider recommendation. Compared to parents without recommendations, parents with strong recommendations had 2 to 7 times higher odds of agreeing that: vaccines are safe, the HPV vaccine is safe, not concerned about side effects, and the vaccine prevents cervical cancer. Even when considering provider recommendation strength, HPV vaccine series initiation was more likely among girls of parents who agreed rather than disagreed that the HPV vaccine was safe [odds ratio (OR)=5.8, 95% confidence interval (CI)=3.1, 11.1], does not cause sex (OR=2.0, 95% CI=1.2, 3.4), prevents cervical cancer (OR=2.0, 95% CI=1.0, 3.4), and prevents HPV infections (OR=1.8, 95% CI=1.0, 3.0). CONCLUSIONS: Parent concerns about HPV vaccine are similar to their concerns about other vaccines. Providers should focus HPV vaccine discussions with parents on vaccine safety and illness prevention.

Antioxidant status and oxidative stress in the circulation of younger and elderly human subjects.

Extensive research has demonstrated the protective properties of antioxidants, which scavenge reactive oxygen species and their precursors, as well as up-regulate enzymes involved in the repair of cellular damage. Several case-control studies have showed higher blood levels of antioxidants and decreased oxidative stress in younger individuals when compared with older ones. Cell damage caused by free radicals appears to be a major contributor in aging and degenerative diseases of aging such as cancer, cardiovascular disease, cataracts, compromised immune system, rheumatoid arthritis and brain dysfunction. The objective of this study was to determine the variation of Circulating levels of selected antioxidants (enzymic and non enzymic) and oxidative stress marker in younger and older humans. The results showed that a majority of the younger age group participants showed a significant increase in enzymic and nonenzymic antioxidant status and a decrease in oxidative stress when compared with the older age group.

Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma.

PURPOSE: To describe the Food and Drug Administration (FDA) review and approval of sunitinib malate (Sutent). Sunitinib received regular approval for the treatment of gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate (Gleevec). Additionally, sunitinib received accelerated approval for the treatment of advanced renal cell carcinoma. EXPERIMENTAL DESIGN: For the GIST indication, FDA reviewed data from a randomized, placebo-controlled trial with supportive evidence from a single-arm study. For the advanced renal cell carcinoma indication, FDA reviewed data from two single-arm studies of patients with cytokine-refractory metastatic renal cell carcinoma. RESULTS: In patients with imatinib refractory or intolerant GIST, time-to-tumor progression of sunitinib-treated patients was superior to that of placebo-treated patients. Median time-to-tumor progression of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (P < 0.0001). Partial responses were observed in 6.8% of sunitinib-treated patients. In patients with metastatic renal cell carcinoma, partial responses were observed in 25.5% (95% confidence interval, 17.5, 34.9) and 36.5% (95% confidence interval, 24.7, 49.6) of patients treated with sunitinib. Median response durations were 27.1 and 54 weeks. The most common adverse events attributed to sunitinib included diarrhea, mucositis, skin abnormalities, and altered taste. Reductions in left ventricular ejection fraction and severe hypertension were also more common in sunitinib-treated patients. CONCLUSIONS: On January 26, 2006, the FDA approved sunitinib for the treatment of patients with imatinib refractory or intolerant GIST. Accelerated approval was granted for the treatment of advanced renal cell carcinoma.

The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity.

Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN-38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This analysis extended the work of a previous study that examined the effect of UGT1A1 genotypes on the incidence of severe neutropenia in 86 advanced cancer patients following irinotecan treatment. Regression analysis showed that the absolute neutrophil count nadir depended on SN-38 exposure (AUC) and UGT1A1*28 homozygous 7/7 genotype. An increased SN-38 AUC and the 7/7 genotype were significantly associated with a lower absolute neutrophil count nadir (R2 = .49). An alternate model suggested that higher baseline bilirubin and the 7/7 genotype were also significantly associated with a lower absolute neutrophil count nadir, although with a lower coefficient of determination (R2 = .31). Based on these findings and other reports, the irinotecan label was modified to indicate the role of UGT1A1*28 polymorphism in the metabolism of irinotecan and the associated increased risk of severe neutropenia. The label modifications also included recommendations for lower starting doses of irinotecan in patients homozygous for the UGT1A1*28 (7/7) polymorphism.

Impact of pharmacometrics on drug approval and labeling decisions: a survey of 42 new drug applications.

The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.