Established Efficacy Research Articles

Exploration of the Supraspinal Hypotheses about Spinal Cord Stimulation and Dorsal Root Ganglion Stimulation: A Systematic Review

Despite the established efficacy and effectiveness of Spinal Cord Stimulation (SCS), there is still no consensus on the supraspinal mechanisms of action of this therapy. The purpose of this study was to systematically review previously raised hypotheses concerning supraspinal mechanisms of action of SCS based on human, animal and computational studies. Searches were conducted using four electronic databases (PubMed, EMBASE, SCOPUS and Web of Science), backward reference searching and consultation with experts. The study protocol was registered prior to initiation of the review process (PROSPERO CRD42020161531). A total of 54 publications were included, 21 of which were animal studies, and 33 were human studies. The supraspinal hypotheses (n = 69) identified from the included studies could be categorized into six groups concerning the proposed supraspinal hypothesis, namely descending pathways (n = 24); ascending medial pathway (n = 13); ascending lateral pathway (n = 10); affective/motivational influences (n = 8); spinal–cerebral (thalamic)-loop (n = 3) and miscellaneous (n = 11). Scientific support is provided for the hypotheses identified. Modulation of the descending nociceptive inhibitory pathways, medial and lateral pathways were the most frequently reported hypotheses about the supraspinal mechanisms of action of SCS. These hypotheses were mainly supported by studies with a high or moderate confidence in the body of evidence.

Platelet-rich plasma in interventional dermatology and trichology: How far have we come?

Platelet-rich plasma (PRP) contains several growth factors and cellular adhesion molecules which promote wound healing, angiogenesis and accelerate the rejuvenation of skin and hair follicles. With its proven regenerative and regrowth potential in a plethora of conditions, PRP has been deemed as the “futuristic elixir.” Current evidence suggests that PRP effectively stimulates angiogenesis, collagen as well as elastin regeneration, and is a safe, easy to prepare, minimally invasive technique with limited downtime, and negligible risk of allergic/hypersensitivity reactions owing to its autologous nature. It has shown excellent results when utilized as monotherapy or in combination with microneedling or ablative lasers in acne scars, post-burn or post-traumatic scars, melasma, striae distensae, chronic ulcers, and lichen sclerosus. PRP injections or PRP combined with microneedling are increasingly being utilized for skin rejuvenation and recently have been utilized to provide non-invasive face lifts. A novel technique combining non-cultured epidermal cell suspension suspended in PRP results in superior repigmentation outcomes in case of vitiligo. Use of PRP alone or in combination with hair transplant in androgenetic alopecia is another well-researched indication and its use has been successfully extrapolated to indications such as alopecia areata, chronic telogen effluvium, and cicatricial alopecia. In spite of its established efficacy in such a vast number of indications, PRP should be used with utmost caution. These growth mediators exert their own endocrine, paracrine, and enzymatic effects, the complete influence of which still remains a mystery and only years of experience, in the times to come will unravel the absolute power of our “mighty dragon warrior.”

Tilidine and dipyrone (metamizole) in cold pressor pain: A pooled analysis of efficacy, tolerability, and safety in healthy volunteers.

The cold pressor test (CPT) is widely implemented and offers a simple, experimental acute pain model utilizing cold pain. Previous trials have frequently paired the CPT with opioids in order to investigate the mechanisms underlying pharmacological analgesia, due to their known analgesic efficacy. However, opioid side effects may lead to unblinding and raise concerns about the safety of the experimental setting. Despite the established clinical efficacy of dipyrone (metamizole), its efficacy, tolerability, and safety in cold pressor pain has not been systematically addressed to date. This pooled analysis included data of 260 healthy volunteers from three randomized, placebo‐controlled, double‐blind substudies using the CPT following a pre‐test‐post‐test‐design. These substudies allow for comparing a single dose of 800 mg dipyrone with two different doses of the opioid tilidine/naloxone (50/4 mg and 100/8 mg, respectively). Outcomes included pain intensity ratings, pain tolerance, medication‐attributed side effects, as well as changes of blood pressure and heart rate. We demonstrate that both opioid doses and dipyrone had a comparable, significant analgesic effect on cold pressor pain. However, dipyrone was associated with significantly less self‐reported adverse effects and these were not significantly different from those under placebo. These results indicate that the combination of dipyrone and the CPT provides a safe, tolerable, and effective experimental model for the study of pharmacological analgesia. In combination with a CPT, dipyrone may be useful as a positive control, or baseline medication for the study of analgesic modulation.

Molecular insights into phytochemicals exhibiting anti-arthritic activity: systematic review : John Di Battista.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with an unclear etiology causing severe inflammation, joint pain, and destruction that increases the chance of disability over time. Dysregulation of various immune signaling cascades regulates the formation of synovial hyperplasia and pannus formation. Imbalance in cytokine levels, predominantly proinflammatory cytokines like TNF-α, IL-1, IL-6, IL-17, and IL-12p70 profoundly influences the disease's pathogenesis. Even though various strategies are adopted to treat arthritis, their side effects and cost limit their usage. This review discusses the multiple pathways involved in the pathogenesis of rheumatoid arthritis, provides a systematic analysis of various phytochemicals, and discusses their potential molecular targets in RA treatment. The literature mining was done from scientific databases such as PubMed, Europe PMC, Web of Science, Scopus, etc. The terminologies used for literature mining were Rheumatoid arthritis, phytochemicals, cell signaling pathways, molecular mechanism, etc. RESULTS: NF-κB, MAPKs, and JAK-STAT are the key pathways potentially targeted for RA treatment. However, specific susceptible pathways and potential targets remain unexplored. Besides, the phytochemicals remain an immense source to be exploited for the effective treatment of RA, overcoming the demerits of the conventional strategies. Various in vitro and in vivo findings suggest that polyphenols and flavonoids effectively treat RA conditions overcoming the demerits, such as limitations in usage and toxicity. The phytochemicals should be explored in par with the pathological mechanisms with all the available targets to determine their therapeutic efficacy. Through the established therapeutic efficacy, phytochemicals can help developing therapeutics that are safe and efficacious for RA treatment.

Cross-cultural Comparison of Perceptions and Knowledge About Electroconvulsive Therapy Among Adults Who Screened Positive for Depression in the United States, India, and China.

Despite the established efficacy of electroconvulsive therapy (ECT), negative perceptions and inaccurate knowledge about ECT in the United States and other countries persist. This study examined ECT perceptions and knowledge in the 3 most populous countries in the world. We recruited participants who screened positive for depression on the Patient Health Questionnaire 9 (PHQ-9) in the United States (n = 1643), India (n = 1469), and China (n = 328) and compared responses on the ECT-Perception and Knowledge Scale. Although the US sample had significantly higher PHQ-9 scores than the India and China samples, the US sample was less likely to have been offered ECT or to have ever received ECT. Moreover, the US sample scored lower on the ECT Perception and Knowledge subscales than the other samples indicating more negative perceptions and inaccurate knowledge about ECT. Across samples, there were moderate fears about ECT being painful or causing brain damage, and misconceptions about ECT being outdated and adverse effects of induced seizures. Higher PHQ-9 scores were correlated with more negative perceptions. Greater public education is needed about ECT, particularly in the United States. Misperceptions and lack of knowledge may hinder utilization of ECT in India, China, and the United States.

Phase III study of local or systemic therapy INtensification DIrected by PET in prostate CAncer patients with post-prostaTEctomy biochemical recurrence (INDICATE): ECOG-ACRIN EA8191.

TPS5098 Background: Radiation therapy (RT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). Fluciclovine-PET/CT imaging is FDA-approved in this setting, with improved accuracy for detection of metastases not identified with conventional imaging (CIM). Given PET's greater sensitivity and specificity, its findings are increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for local or systemic treatment intensification of the otherwise non-tailored SOC approach. Improved systemic control and disease detection with molecular imaging have led to increasing use of focally ablative metastasis-directed RT, to delay or enhance systemic therapy through increased local control. There is also interest in earlier use of systemic therapy; apalutamide (Apa) is a nonsteroidal antiandrogen with established efficacy in improving overall and radiographic progression-free survival (PFS) for non-metastatic castration-resistant and metastatic castration-sensitive PC. This study will evaluate whether pts with PET-detected lesions benefit from such local or systemic treatment intensification approaches. Methods: PC pts with post-RP BCR (PSA>0.5ng/mL; >0.2ng/mL if within 12 mos of RP) and no metastases on CIM who are candidates for SOC ST (RT to prostate bed and pelvic nodes with STAD) are eligible. Prior to study registration, pts undergo SOC baseline PET (18F-fluciclovine but PSMA radiotracers permitted pending commercial availability). Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic metastases). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- metastasis-directed RT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of metastasis-directed RT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified log-rank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish 5-year PFS rate of 76.5% in the experimental arm from 61.5% in the control arm. Secondary endpoints include overall and event-free survival, toxicity, and PET progression. Clinical trial information: NCT04423211.

Pre-clinical evaluation of PV-10 for in vitro anti-tumor activity in refractory and high-risk adult solid tumors.

e14544 Background: PV-10 (10% rose bengal disodium; 4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein) is a novel therapeutic agent previously shown to have potent anti-tumor activity following intratumoral injection in melanoma and refractory neuroblastoma, and currently is undergoing clinical testing as a single-agent for refractory metastatic neuroendocrine cancer (NCT02693067) and in combination with checkpoint inhibitors for metastatic melanoma (NCT02557321) and metastatic uveal melanoma (NCT00986661). Given the established clinical efficacy of PV-10 in adult melanoma and hepatic cancers via intratumoral injection, there is a need to evaluate the therapeutic potential of PV-10 in high-risk and refractory adult solid tumors via systemic administration. Our study aims to identify the clinical potential of systemically-delivered PV-10 by first generating prerequisite in vitro data for adult malignancies. Methods: Cytotoxicity assays were performed using the Alamar Blue assay to study the effects of PV-10 in vitro 96-hours post-treatment against a panel of adult solid tumor cell lines derived from breast (MCF-7, T-47D, MDA-MB-231), colorectal (HCT-116, LoVo, T-84), head and neck (CAL-27, Detroit-562, FaDu, UM-SCC-1), and testicular (NCC-IT, NTERA-2, TCAM-2) tissues. Light microscopy and Western blotting were used to investigate apoptosis induction and target modulation in tumor cells after PV-10 treatment. Results: In vitro results from our study demonstrate that PV-10 is cytotoxic at pharmacologically relevant concentrations across the indicated cell lines. Specifically, tumor cell lines originating from testicular tissues were highly sensitive to PV-10 treatment (Mean ± SD IC50: 37.5 ± 16.4 µM; n = 3) compared to breast (117.5 ± 71.0 µM; n = 3), colorectal (64.79 µM; n = 3), and head and neck (106.6 ± 29.2 µM; n = 4) cell lines. Western blot analyses showed dose- and time-dependent activation of pro-apoptotic protein markers in caspase-3 and PARP cleavage, indicating drug-induced apoptosis. Conclusions: This study provides the first pre-clinical results of PV-10 as a novel systemically-delivered therapeutic agent for a range of high-risk and refractory adult solid tumors. Data obtained from our in vitro experiments using a broad repertoire of cell lines that represent diverse molecular and phenotypic subtypes of solid tumors in adults can serve as prerequisite pre-clinical data to establish clinical testing in these populations.

Fixed dose combination of olmesartan and amlodipine in patients with hypertension and abdominal obesity. Data of 3-month observation of efficacy and adherence to therapy

Abstract Funding Acknowledgements Type of funding sources: None. Background Essential hypertension (H), which is combined with abdominal obesity (AO), is characterized by the early formation of refractoriness to antihypertensive therapy. In this regard, it is urgent to search for the most effective therapy regimens, among which fixed combinations (FC) of drugs have recently attracted considerable interest. Purpose To study the efficacy of FC olmesartan (O) and amlodipine (F) and adherence to it in patients with H and AO. Methods. 60 patients with grade 2 H with AO of I-II degrees (36 men and 24 women aged 48 to 62 years) were examined using standard clinical, biochemical and instrumental methods. Before enrollment in the study, all patients received various non-FC two-component combinations of antihypertensive drugs, however, target blood pressure (BP) levels were not achieved by any patient. After inclusion in the study, all patients were transferred to FC O and A, which was prescribed once a day , taking into account BP levels in the following daily doses: 20/5 mg; 40/5 mg and 40/10 mg. The examination was carried out for 3 months with dose adjustments every 7-10 days. Results. The use of FC O and A made it possible to achieve the target BP level after 3 month of therapy in 72% of patients with H and AO. At the same time, high adherence to this therapy was also noted: 80% of patients continued to receive this therapy for 3 months. It was found that in order to achieve target BP levels, in 84% of patients it was necessary to use O and A in a daily dose of 40/10 mg, in 16% of patients -in a dose of 40/5 mg. The tested FC was characterized by a low incidence of side effects, the most frequent of which was leg edema (in 7% of patients) and good tolerability (therapy withdrawal rate was 3%). Conclusion. The established high antihypertensive efficacy and tolerability of FC O and A in patients with H and AO indicates the promise of its widespread use in this category of patients.

Characterizing the need for multiple epidural blood patches in the treatment of postdural puncture headache: an observational study

Epidural blood patch (EBP) is an accepted treatment modality for postdural puncture headache (PDPH) refractory to conservative approaches.[1–5][1] Despite the established efficacy of EBP, some patients require more than one...

Crop rotation can be used to manipulate residue levels under no-tillage in a rainfed Mediterranean-type environment

Fields with low residue levels (<∼2 t ha−1) are prone to erosion and reduced water conservation in semi-arid environments, and high residue amounts (>∼4 t ha−1) can reduce crop establishment and herbicide efficacy. Furthermore, increasing herbicide resistance in southern Australia has resulted in an increase in non-herbicide control measures like ‘windrow burning’, which reduces residue levels. Therefore, it is important to understand crop residue dynamics in this Mediterranean-type environment and any management factors that can be used to regulate amounts of residue. This paper reports on the residue dynamics in a 12-year experiment (2007–2018) in the Wheatbelt of Western Australia, comparing rotations that included: cereal (cereal/cereal/cereal); diverse (wheat/legume/canola); farmer (wheat/barley/break – legume or fallow); and wheat monoculture. Crop residue was either spread behind the harvester (retain) or windrowed at harvest and burnt before seeding (windrow burn). Residue quantity was measured shortly after harvest (usually in December), prior to seeding (usually April), and around anthesis (September).Crop residue amounts were highest after harvest each year and then declined over the next 12 months, until the next harvest. Residue quantity was greatest following years of high rainfall and good crop growth. Within rotations, residue quantity was highest with retained residue in the cereal rotation and wheat monoculture, averaging 5.0 t ha−1 prior to seeding, which could present management problems at seeding time in some years. Residue amounts were lower in the diverse rotation, and levels declined after wheat (4.5 t ha−1) through to legume and canola residue at 3.8 t ha−1. Lowest residue occurred with windrow burning in the farmer rotation, which included one fallow every three years from 2013, with quantities averaging ∼1 t ha−1. Overall, windrow burning before seeding reduced residue amount by ∼50 % compared with retaining the residue.Retaining all residue in a cereal-dominant rotation produced highest residue quantities in this Mediterranean-type environment, but may lead to problems with crop establishment. Residue quantity was reduced to optimal levels by including legume crops or canola in the rotation, as these residues were more rapidly broken down than cereal residues, whilst maintaining residue retention practices.

Electroconvulsive therapy is associated with lower readmission rates in patients with schizophrenia

BackgroundElectroconvulsive therapy is an important somatic treatment for severe mental disorders with established efficacy and safety. However, data on the relationship between ECT and the readmission rate of patients with schizophrenia are scarce. This study will explore the association between the administration of ECT and readmission rates using a machine learning method. MethodsInpatient medical records from the year of 2016 in one large psychiatric hospital in Beijing, China, were analyzed using a machine learning algorithm to determine the most important variables affecting readmission of patients with schizophrenia. ResultsThe medical records of 2131 inpatients with schizophrenia were reviewed. 1099 patients were followed up within 3 months of their index admission (642 ECT cases and 457 non-ECT cases) and 1032 patients were followed up within 6 months (596 ECT cases and 436 non-ECT cases) after discharge. The 3- and 6-month readmission rates in the ECT group (11.37% and 17.94%, respectively) were significantly lower than that of the patients who did not receive ECT (18.79% and 29.36%, respectively, both p < 0.001). The risk of readmission was significantly associated with male sex, older age, being married, having a lower income, a shorter inpatient length of stay, and receiving specific antipsychotic medications including olanzapine, paliperidone, clozapine, and haloperidol during the index admission. In the ECT group, patients who received 9 or more treatments were significantly less likely to be readmitted. ConclusionReceiving ECT may be associated with a lower risk of readmission in patients with schizophrenia.

Rationale, design, and methods of a two-site randomized controlled trial: Comparative effectiveness of two treatments for posttraumatic stress disorder in veterans

PTSD is associated with serious problems in interpersonal functioning, including higher rates of marital conflict and divorce, disrupted relationships with family and friends, estrangement from others and social isolation. Cognitive behavioral and trauma focused treatments are effective for treating PTSD symptoms, but a substantial proportion of individuals, particularly veterans, with PTSD, do not engage, complete, or fully respond to these treatments, and the effects of these treatments on interpersonal functioning are unknown. There is a critical need for alternative treatments with established efficacy, and for treatments that directly address problems in relationship functioning. Interpersonal Psychotherapy for PTSD (IPT-PTSD) is a promising candidate for such a treatment. This paper describes the rationale, design, and methods of the first randomized controlled equivalence trial comparing IPT-PTSD with a first-line gold standard treatment for PTSD (Prolonged Exposure; PE) in the treatment of PTSD in veterans. Both treatments include up to 12 weekly individual sessions. Assessments were conducted at baseline, following sessions four and eight, end of treatment, and 3 and 6 months post-treatment. Primary hypotheses are that IPT-PTSD will be statistically equivalent to PE in reducing the severity of PTSD symptoms, and superior to PE in improving interpersonal functioning. Secondary hypotheses propose that IPT will be superior to PE in improving overall social adjustment and quality of life, and in reducing suicidal ideation. Findings from this study have the potential to improve treatment options for veterans struggling with PTSD and interpersonal problems.

SGLT2 Inhibitors as Calorie Restriction Mimetics: Insights on Longevity Pathways and Age-Related Diseases.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors induce glycosuria, reduce insulin levels, and promote fatty acid oxidation and ketogenesis. By promoting a nutrient deprivation state, SGLT2 inhibitors upregulate the energy deprivation sensors AMPK and SIRT1, inhibit the nutrient sensors mTOR and insulin/IGF1, and modulate the closely linked hypoxia-inducible factor (HIF)-2α/HIF-1α pathways. Phosphorylation of AMPK and upregulation of adiponectin and PPAR-α favor a reversal of the metabolic syndrome which have been linked to suppression of chronic inflammation. Downregulation of insulin/IGF1 pathways and mTOR signaling from a reduction in glucose and circulating amino acids promote cellular repair mechanisms, including autophagy and proteostasis which confer cellular stress resistance and attenuate cellular senescence. SIRT1, another energy sensor activated by NAD+ in nutrient-deficient states, is reciprocally activated by AMPK, and can deacetylate and activate transcription factors, such as PCG-1α, mitochondrial transcription factor A (TFAM), and nuclear factor E2-related factor (NRF)-2, that regulate mitochondrial biogenesis. FOXO3 transcription factor which target genes in stress resistance, is also activated by AMPK and SIRT1. Modulation of these pathways by SGLT2 inhibitors have been shown to alleviate metabolic diseases, attenuate vascular inflammation and arterial stiffness, improve mitochondrial function and reduce oxidative stress-induced tissue damage. Compared with other calorie restriction mimetics such as metformin, rapamycin, resveratrol, and NAD+ precursors, SGLT2 inhibitors appear to be the most promising in the treatment of aging-related diseases, due to their regulation of multiple longevity pathways that closely resembles that achieved by calorie restriction and their established efficacy in reducing cardiovascular events and all-cause mortality. Evidence is compelling for the role of SGLT2 inhibitors as a calorie restriction mimetic in anti-aging therapeutics.

Evaluation of a Bubble CPAP System for Low Resource Settings.

Despite its established safety, efficacy, and relative simplicity, CPAP treatment is not widely available for newborns and infants in low- and middle-income settings. A novel bubble CPAP system was designed to address the gaps in quality and accessibility of existing CPAP systems by providing blended, humidified, and pressurized gases without the need for electricity, compressed air, or manual power. This was the first study that tested the performance of the system with a simulated patient model. METHODS: In a spontaneously breathing 3-dimensional printed nasal airway model of a preterm neonate, CPAP performance was assessed based on delivered pressure, oxygen level, and humidity at different settings. RESULTS: Preliminary device performance characteristics were within 5% among 3 separate devices. Performance testing showed accurate control of CPAP and oxygen concentration at all settings with the bubble CPAP system. Lung model pressure and oxygen concentration were shown to stay within ±0.5 cm H2O and ±4% of full scale of the device settings, respectively, with relative humidity > 80%. CONCLUSIONS: Performance testing of the bubble CPAP system demonstrated accurate control of CPAP and oxygen concentration with humidity levels suitable for premature newborns on noninvasive support.

Exploring the in-silico approach for assessing the potential of natural compounds as a SARS-CoV-2 main protease inhibitors

The SARS-CoV-2 virus emerged as a major cause of the COVID-19 pandemic in December 2019. Many attempts have been made to block the viral infection by targeting various processes like its entry, uncoating, replication, activating T cells response, and rising antibody titer. Also, many drugs are repurposed like remdesivir, dexamethasone, tocilizumab, hydroxychloroquine based on their established therapeutic efficacy against other viruses in the past. Natural products (NP) consist of a promising candidate and are needed to evaluate those molecules with molecular docking for preliminary screening and in vitro studies. Therefore, in the present study, a total of 12 active constituents from natural products like Ashwagandha, Tinospora cordifolia, Tea, Neem and lemon balm were docked, using the Autodock tool, onto the crystal structure of SARS CoV-2 main protease (PDB ID-5R80), to study their capability to act as main protease (Mpro) COVID-19 inhibitors. All NPs derivatives displayed good binding energies (ΔG) ranging from -8.8 to -5.2 kcal/mol, but berberine, epicatechin, and rosmarinic acid were found most potent, among others. Therefore, good binding energy, drug-likeness, and efficient pharmacokinetics suggest the potential of NPs derivatives as SARS-CoV-2 main protease (Mpro) inhibitors. However, further research is necessary to investigate the ability of these compounds as COVID-19 inhibitors.

Coumarin-Annulated Ferrocenyl 1,3-Oxazine Derivatives Possessing In Vitro Antimalarial and Antitrypanosomal Potency.

A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7 P. falciparum) over the investigated trypanosomiasis causal agent (T. b. brucei 427) with mostly single digit micromolar IC50 values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (11b) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects.

Evaluation of Exercise Interventions and Outcomes After Hip Arthroplasty

Preoperative and postoperative exercise interventions are commonly used in patients with total hip arthroplasty despite a lack of established efficacy. To explore clinical outcomes associated with exercise training before and after hip arthroplasty. PubMed, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, EMBASE, and Google Scholar were searched from their inception to March 2020. Reference lists of included trials and related reviews were also searched. Randomized clinical trials of land-based exercise interventions before or after total hip arthroplasty were included. This systematic review and meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data extraction was independently performed in duplicate. Random-effects meta-analyses with restricted maximum likelihood were performed for pooling the data. The primary prespecified outcome was self-reported physical function. Secondary prespecified outcomes were self-reported pain intensity, quality of life, gait speed, lower body muscle strength, lower body flexibility, anxiety, hospital length of stay, and adverse events. A total of 32 randomized clinical trials with 1753 patients were included in the qualitative synthesis, and 26 studies with 1004 patients were included in the meta-analysis. Compared with usual care or no or minimal intervention, postoperative exercise training was not associated with improved self-reported physical function, with a moderate level of certainty, at 4 weeks (standardized mean difference [SMD], 0.01; 95% CI, -0.18 to 0.20), 12 weeks (SMD, -0.08; 95% CI, -0.23 to 0.07) and 26 weeks (SMD, -0.04; 95% CI, -0.31 to 0.24) postoperatively, and low level of certainty at 1 year after surgical treatment (SMD, 0.01; 95% CI, -0.09 to 0.12). For preoperative exercise interventions, there was no association of exercised training with self-reported physical function compared with the control at the 12-week (SMD, -0.14; 95% CI, -0.61 to 0.32) or 1-year follow-ups (SMD, 0.01; 95% CI, -0.37 to 0.40) with very low certainty, and no association with length of stay (mean difference, -0.21; 95% CI, -0.74 to 0.31) at moderate certainty. Results for postoperative hip muscle strength were rated at very low certainty, with no statistical significance. Meta-analysis could not be performed for other outcomes. This systematic review and meta-analysis found low- to moderate-quality evidence that postoperative exercise interventions were not associated with improved self-reported physical function compared with usual care or no or minimal intervention. Furthermore, there was very low-quality evidence that preoperative exercise programs were not associated with higher self-reported physical function and hospital length of stay compared with usual care or no or minimal intervention.

PET-directed local or systemic therapy intensification in prostate cancer patients with post-prostatectomy biochemical recurrence: A trial of the ECOG-ACRIN Cancer Research Group (EA8191).

TPS267 Background: Radiation therapy (RT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). Fluciclovine-PET/CT imaging is FDA-approved in this setting, with improved accuracy for detection of metastases (mets) not identified with conventional imaging (CIM). Given greater sensitivity and specificity of PET, its findings are being increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for local or systemic treatment intensification of otherwise non-tailored SOC. Earlier detection of mets with molecular imaging has led to increasing use of focally ablative met-directed RT, to delay or enhance systemic therapy through better local control. There is also interest in earlier use of advanced systemic therapy; apalutamide (Apa) is a nonsteroidal antiandrogen with established efficacy in improving overall and radiographic progression-free survival (PFS) for non-metastatic castrate-resistant and metastatic castration-sensitive PC, and potential activity for low-volume mets. This study will evaluate whether pts with PET-detected lesions benefit from such local or systemic treatment intensification approaches. Methods: PC pts with post-RP BCR (PSA&gt;0.5ng/mL; &gt;0.2 if RP within 12 mos), and negative CIM who are candidates for SOC ST (RT to prostate bed and pelvic nodes + STAD) and undergo SOC baseline PET are eligible. The study will initially use 18F-fluciclovine but permit additional radiotracers based on FDA approval and availability. Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic mets). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- met-directed RT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of met-directed RT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified logrank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish 5-year PFS rate of 76.5% in experimental arm from 61.5% in control arm. Secondary endpoints include overall and event-free survival, toxicity, and PET progression. Trial was activated on October 8, 2020; NCT04423211. Acknowledgement: This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180868, U10CA180888, U10CA180821, UG1CA233196, UG1CA233253, UG1CA233277, UG1CA233328, and UG1CA233330. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. government. Clinical trial information: NCT 04423211.

Clinical Pharmacokinetics of Enalapril and Enalaprilat in Pediatric Patients—A Systematic Review

Purpose: Enalapril has an established safety and efficacy in adults and is used in hypertension, heart failure, and renal failure. In pediatric patients, enalapril is labeled for children with hypertension and used off label in children with heart failure. The systematic literature search aims to assess the current knowledge about enalapril and its active metabolite enalaprilat pharmacokinetics in children as a basis for dose delineation for pediatric patients with heart failure.Methods: A systematic literature review was performed in the PubMed database using relevant keywords. Dose normalization of relevant pharmacokinetic parameters of the identified studies was done for comparison between different diseases and pediatric age groups.Results: The literature search has resulted in three pediatric pharmacokinetic studies of enalapril out of which Wells et al. reported about children with hypertension and Nakamura et al., and Llyod et al. presented data for pediatric heart failure patients. The area under the curve values of enalaprilat in hypertensive pediatric patients increased with respect to the age groups and showed maturation of body functions with increasing age. Dose normalized comparison with the heart failure studies revealed that although the pediatric heart failure patients of > 20 days of age showed the area under the curve a similar to that of hypertensive patients, two pediatric patients of very early age (<20 days) were presented with 5–6-fold higher area under the curve values.Conclusion: Data related to the pharmacokinetics of enalapril and enalaprilat in hypertensive patients and few data for young heart failure children are available. Comparison of dose normalized exposition of the active metabolite enalaprilat indicated similarities between heart failure and hypertensive patients and a potentially high exposition of premature patients but substantially more pharmacokinetic studies are required to have reliable and robust enalapril as well as enalaprilat exposures especially in pediatric patients with heart failure as a basis for any dose delineation.

Pharmacogenomics and COVID-19: clinical implications of human genome interactions with repurposed drugs.

The outbreak of Coronavirus disease 2019 (COVID-19) has evolved into an emergent global pandemic. Many drugs without established efficacy are being used to treat COVID-19 patients either as an offlabel/compassionate use or as a clinical trial. Although drug repurposing is an attractive approach with reduced time and cost, there is a need to make predictions on success before the start of therapy. For the optimum use of these repurposed drugs, many factors should be considered such as drug–gene or dug–drug interactions, drug toxicity, and patient co-morbidity. There is limited data on the pharmacogenomics of these agents and this may constitute an obstacle for successful COVID-19 therapy. This article reviewed the available human genome interactions with some promising repurposed drugs for COVID-19 management. These drugs include chloroquine (CQ), hydroxychloroquine (HCQ), azithromycin, lopinavir/ritonavir (LPV/r), atazanavir (ATV), favipiravir (FVP), nevirapine (NVP), efavirenz (EFV), oseltamivir, remdesivir, anakinra, tocilizumab (TCZ), eculizumab, heme oxygenase 1 (HO-1) regulators, renin–angiotensin–aldosterone system (RAAS) inhibitors, ivermectin, and nitazoxanide. Drug-gene variant pairs that may alter the therapeutic outcomes in COVID-19 patients are presented. The major drug variant pairs that associated with variations in clinical efficacy include CQ/HCQ (CYP2C8, CYP2D6, ACE2, and HO-1); azithromycin (ABCB1); LPV/r (SLCO1B1, ABCB1, ABCC2 and CYP3A); NVP (ABCC10); oseltamivir (CES1 and ABCB1); remdesivir (CYP2C8, CYP2D6, CYP3A4, and OATP1B1); anakinra (IL-1a); and TCZ (IL6R and FCGR3A). The major drug variant pairs that associated with variations in adverse effects include CQ/HCQ (G6PD; hemolysis and ABCA4; retinopathy), ATV (MDR1 and UGT1A1*28; hyperbilirubinemia; and APOA5; dyslipidemia), NVP (HLA-DRB1*01, HLA-B*3505 and CYP2B6; skin rash and MDR1; hepatotoxicity), and EFV (CYP2B6; depression and suicidal tendencies).