Nonhormonal Pharmacotherapies for the Treatment of Postmenopausal Vasomotor Symptoms.

An average of 60-80% of all menopausal women experience bothersome vasomotor symptoms (VMSs), such as flushing and sweating, within the first seven years of onset. However, despite increasing prevalence, these hot flashes remain hard to treat and have a negative effect on the quality of life. Though hormone replacement therapy is commonly utilized as a standard treatment for VMSs, this therapy is not recommended for all women. Specifically, the oral form of hormone replacement therapy is associated with several contraindications, including a history of thromboembolic disease, migraine headache with aura, liver failure, heart disease, and hormone-dependent cancers. For women with these medical conditions, current literature indicates that nonhormonal therapies such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are suitable alternatives to reduce the frequency and intensity of VMSs. Currently, the only SSRI that is FDA-approved for the treatment of VMSs is paroxetine, but studies show that fluoxetine, citalopram, escitalopram, and sertraline are also proven to provide similar benefits. Similarly, the SNRI venlafaxine has also been well tolerated and has been shown to reduce the frequency and severity of hot flashes. The present investigation reviews the physiology of VMSs and examines the evidence for the use of nonhormonal pharmacologic therapies as treatment for women experiencing hot flashes. These interventions should be considered whenever hormone replacement therapy is contraindicated, with therapy individualized based on the severity of symptoms.

Infigratinib for the Treatment of Metastatic or Locally Advanced Cholangiocarcinoma With Known FGFR2 Gene Fusions or Rearrangements.

Cholangiocarcinoma (CCA) is an aggressive and diverse malignancy with a poor prognosis. Related to a typical indolent course of progression, most cases of CCA are metastatic or locally advanced at the time of presentation. For patients with nonresectable tumors or metastatic disease, the mainstay of treatment is comprehensive with combination chemotherapy. The first-line chemotherapeutic combination for the treatment of CCA are cisplatin and gemcitabine-based chemotherapies. However, many locally advanced and progressive CCA cases are refractory to first-line management. Within the past few years, the increase in the incidence of metastatic CCA and its poor prognosis has brought to light the need for novel therapeutic approaches to treatment. With advancements in next-generation genome sequencing, multiple molecular pathways have been identified in the pathogenesis of CCA and have shown great potential as alternative treatments in cases of CCA refractory to surgical resection. FGFR2 fusions or rearrangements have been identified in 10-16% of all intrahepatic CCA and are thought to serve as a pathway of resistance for a number of nonresectable and refractory cases of cholangiocarcinoma. A novel therapeutic agent that has been discussed is infigratinib, a selective, ATP-competitive inhibitor of fibroblast growth factor receptor 2 (FGFR2). In a phase 1 trial, infigratinib showed a safe profile and showed remarkable clinical efficacy in advanced CCA with FGFR2 fusions or rearrangements in phase II trials. As of May 2021, the Food and Drug Administration (FDA) approved infigratinib for CCA largely based on tumor response and duration of response. As of 2021, infigratinib, futibatinib, and pemigatinib, similar novel selective FGFR inhibitors, have been approved by the FDA for the treatment of locally advanced or metastatic CCA harboring FGFR2 gene mutations. The present investigation reviews the development of infigratinib in particular and its clinical efficacy compared to other available treatment options for cholangiocarcinoma. While the side effect profile of infigratinib is minimal, particularly GI side effects, when compared with futibatinib and pemigatinib, the overall response rate (ORR) and median overall survival (mOS) for infigratinib (ORR=23.1%, mOS=3.8 months) was significantly lower than futibatinib (ORR=35.8%, mOS=21.1 months) and pemigatinib (ORR=35.5%, mOS=21.1 months). While there is ample promise for the use of infigratinib as molecular-directed therapy in the treatment of CCA harboring FGFR2 mutations, there is an appropriate concern for patient-acquired resistance. The heterogeneous nature of FGFR mutations and the emergence of different resistance mechanisms emphasize a need for more agents to inhibit FGFR rearrangements effectively.

Electronic Health Record Recording of Patient Pain: Challenges and Discrepancies.

PURPOSE OF REVIEW: In the present review, various categories of pain, clinician-observed pain scales, and patient-reported pain scales are evaluated to better understand factors that impact patient pain perceptions. Additionally, the expansion of areas that require further research to determine the optimal way to evaluate pain scale data for treatment and management are discussed. RECENT FINDINGS: Electronic health record (EHR) data provides a starting point for evaluating whether patient predictors influence postoperative pain. There are several ways to assess pain and choosing the most effective form of pain treatment. Identifying individuals at high risk for severe postoperative pain enables more effective pain treatment. However, there are discrepancies in patient pain reporting dependent on instruments used to measure pain and their storage in the EHR. Additionally, whether administered by a physician or another healthcare practitioner, differences in patient pain perception occur. While each scale has distinct advantages and limitations, pain scale data is a valuable therapeutic tool for assisting clinicians in providing patients with optimal pain control. Accurate assessment of patient pain perceptions by data extraction from electronic health records provides a potential for pain alleviation improvement. Predicting high-risk postoperative pain syndromes is a difficult clinical challenge. Numerous studies have been conducted on factors that impact pain prediction. Postoperative pain is significantly predicted by the kind of operation, the existence of prior discomfort, patient anxiety, and age.

Tocilizumab for Severe COVID-19 Infection and Multisystem Inflammatory Syndrome in Adults and Children.

Coronavirus disease 2019 (COVID-19) rapidly emerged as a global pandemic, placing imminent stress and burden on healthcare resources and workers worldwide. Many patients who present with a severe COVID-19 infection are at high risk of developing severe acute respiratory distress syndrome (ARDS), leading to a vast number of patients requiring mechanical ventilation and a high mortality rate. Similar to Middle East respiratory syndrome, COVID-19 demonstrates an initial viral replication phase that manifests as a variety of symptoms typically flu-like in nature, followed by a profound inflammatory response leading to rapid production of cytokines and uncontrolled inflammation. There have also been many cases of COVID-19 in pediatric patients presenting with elevated inflammatory markers and multisystem involvement labeled as a multisystem inflammatory syndrome (MIS-C) by the world health organization (WHO). The recent treatment of systemic inflammatory response to COVID-19 targets the secondary phase involving cytokine release syndrome. The detrimental effects of IL-6 can be profound and elevated levels are associated with a higher mortality rate and mechanical ventilation. Tocilizumab is an IL-6 inhibitor most widely investigated to target cytokine storm syndrome. Since June 2021, the FDA enacted an emergency use authorization for tocilizumab in the treatment of COVID-19. Several clinical trials have investigated tocilizumab combined with corticosteroids for treating severe ARDS associated with COVID-19. An increasing amount of evidence suggests that targeting the cytokine storm syndrome related to COVID-19 can lead to improved outcomes, especially in those patients requiring mechanical ventilation and with a critical illness. Additional studies are warranted to further look at the positive effects of tocilizumab in the COVID-19 population while additionally defining possible adverse effects.

Valley Fever: Pathogenesis and Evolving Treatment Options.

Coccidioidomycosis, also termed Valley fever, is a fungal infection caused by the inhalation of Coccidioides endospores. Once inhaled by a human host, the arthroconidia endospores travel to the lungs' alveoli to transform into spherules that grow and rupture to release more endospores. In the host immune response, macrophages, neutrophils, and dendritic cells will recognize the fungal antigen, producing pro-inflammatory cytokine. Th2 lymphocytes (type 2 helper T cells) are theorized to be the main human defense against Coccidioides given that Th2 deficiency is seen in patients with disseminated forms of the disease. A common triad of symptoms of coccidioidomycosis, also called "desert rheumatism," include fever, erythema nodosum, and arthralgia, often accompanied by a respiratory problem. In a clinical setting, along with the evaluation of symptoms, a medical provider may also test the patient's blood using antibody tests or perform microscopy to directly detect the presence of Coccidioides in a patient tissue sample for confirmation of a diagnosis. Imaging modalities may also be used to determine lung involvement and assess disease progression. A majority of coccidioidomycosis cases do not require specific treatment and will resolve on their own, so an approach with symptomatic treatment in mind is appropriate. If symptoms do not resolve, azoles or amphotericin B may be used, with the standard drug of choice being fluconazole (Diflucan, Pfizer, New York, New York, United States). Treatment varies depending on the immunocompetency of the patient. To name a few, pregnant patients and those with history of human immunodeficiency virus (HIV) or transplantation require special considerations.

Review of Teratogenic Effects of Leflunomide, Accutane, Thalidomide, Warfarin, Tetracycline, and Angiotensin-Converting Enzyme Inhibitors.

Teratogenic agents have been shown to have drastic and detrimental effects on fetuses if exposed to the agent during uterine life. The most sensitive time for a developing fetus is during the first trimester, and teratogenic exposure during this time can lead to severe deformities in the fetus. The Food and Drug Administration has categorized teratogenic agents based on the severity of their effect on the fetus; these categories include A, B, C, D, and X. Category A is the safest, with the most dangerous, and highly contraindicated in pregnant patients being Category X. This review article will discuss the teratogenic agents leflunomide, isotretinoin, thalidomide, warfarin, tetracycline, and angiotensinogen-converting enzyme inhibitors. Leflunomide can cause cranioschisis, exencephaly, and vertebral, head, and limb malformations. Isotretinoin's main teratogenic effects include central nervous system malformations, hydrocephalus, eye abnormalities, cardiac septal defects, thymus abnormalities, spontaneous abortions, and external ear abnormalities. Thalidomide has been shown to cause limb deformities, bowel atresia, and heart defects when the embryo is exposed to the agent during development. Warfarin can lead to spontaneous abortion and intrauterine death, as well as nasal hypoplasia, hypoplasia of extremities, cardiac defects, scoliosis, and mental retardation when exposed in utero. Tetracycline's teratogenic effects include gastrointestinal distress, esophageal ulceration and strictures, teeth discoloration, hepatotoxicity, and calcifications. Angiotensinogen-converting enzyme inhibitors can cause skull hyperplasia, anuria, hypotension, renal failure, lung hypoplasia, skeletal deformation, oligohydramnios, and fetal death. Teratogenic effects can be avoided if the pregnant patient is educated on the teratogenic effects of these agents.

Vitamin A-Mediated Birth Defects: A Narrative Review.

Vitamin A deficiency (VAD) or excess in expectant mothers can result in fetal abnormalities such as night blindness, bone anomalies, or epithelial cell problems. In contrast, excessive vitamin A in pregnancy can precipitate fetal central nervous system deformities. During pregnancy, a pregnant woman should monitor her vitamin A intake ensuring she gets the recommended dosage, but also ensuring she doesn't exceed the recommended dosage, because either one can result in teratogenicity in the fetus. The widespread and unregulated use of multivitamins and supplements makes consuming doses greater than the recommended quantity more common in developed countries. While vitamin A excess is more common in developed countries, deficiency is most prevalent in developing countries. With proper maintenance, regulation, and education about VAD and excess, a pregnant mother can diminish potential harm to her fetus and potential teratogenic risks.

AMONDYS 45 (Casimersen), a Novel Antisense Phosphorodiamidate Morpholino Oligomer: Clinical Considerations for Treatment in Duchenne Muscular Dystrophy.

AMONDYS 45 (casimersen) is an antisense oligonucleotide therapy used to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder characterized by a mutation in the DMD gene. Symptoms include progressive muscle weakness, respiratory and cardiac complications, and premature death. Casimersen targets a specific mutation in the DMD gene that results in the absence of dystrophin protein, a key structural component of muscle fibers. While there is currently no cure for DMD, exon-skipping therapy works by restoring the reading frame of the mutated gene, allowing the production of a partially functional dystrophin protein. Clinical trials of casimersen have shown promising results in increasing dystrophin production, as measured by polymerase chain reaction (PCR) droplets when compared to placebo. In a randomized double-blind trial, patients who received casimersen had significantly higher dystrophin levels when compared to those who received placebo. Casimersen therapy is administered through repeated intravenous infusions, although the optimal dosage and duration of treatment are still under investigation. Based on the completed and ongoing clinical trials, casimersen has been well tolerated, with most adverse events being mild and unrelated to casimersen. In 2021, AMONDYS 45 (casimersen) received approval from the US Food and Drug Administration (FDA) for the treatment of Duchene muscular dystrophy in patients with a mutation of the DMD gene that is amenable to exon 45 skipping. These collective findings indicate that casimersen has the potential to elicit functional changes in individuals with DMD, although further studies are necessary to comprehensively evaluate the specific functional improvements. Regardless, the FDA approval and ongoing clinic trials mark a significant milestone in the development of DMD treatments and offer hope for those affected by this debilitating disease.