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1.
Preanalytical Challenges During Capillary Fingerstick Sampling Preclude Its Widespread Use in Adult Hospitalized Patients.
Jankowski, CA, Casapao, AM, Siller, S, Isache, C, Cani, KV, Claudio, AM, Brown, M, Milstid, B, Feldhammer, M
American journal of clinical pathology. 2021;(3):412-417
Abstract
OBJECTIVES Patient compliance with laboratory testing is one of the most underrecognized challenges in developing a treatment plan for acute and chronically ill patients. The ability to offer alternatives to standard venipuncture blood draws would greatly increase a laboratory's ability to provide testing to patients and health care providers. METHODS We performed a prospective observational study on paired venous and fingerstick capillary blood samples from admitted patients undergoing vancomycin therapy. Paired specimens were analyzed for vancomycin and a basic metabolic panel (BMP: calcium, carbon dioxide, chloride, potassium, sodium, creatinine, glucose, serum urea nitrogen) on the core laboratory's automated chemistry and immunochemistry platforms. RESULTS A total of 59 paired fingerstick and venous blood specimens from 56 unique inpatients were analyzed. Paired samples were comparable for all the analytes tested with the exception of bicarbonate and potassium, which were significantly different among the capillary sample group. Patients required multiple fingers be lanced in 15% of cases to obtain sufficient blood to carry out the testing. Capillary sample rejection rates due to insufficient volumes were as high as 30% in the initial 30 patients enrolled in the study. CONCLUSIONS Vancomycin and the BMP, with the exception of potassium and bicarbonate, were determined to be analytically comparable. However, significant preanalytical issues should preclude laboratories and providers from more widespread adoption of fingerstick-derived capillary blood as an alternative sampling method except in the most extenuating of circumstances.
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Discovery and development of trastuzumab deruxtecan and safety management for patients with HER2-positive gastric cancer.
Shitara, K, Baba, E, Fujitani, K, Oki, E, Fujii, S, Yamaguchi, K
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2021;(4):780-789
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Abstract
Approximately 12-15% of gastric cancers (GCs) are human epidermal growth factor receptor-2 (HER2)-positive (HER2 immunohistochemistry 3 + or 2 + /in situ hybridization + [ERBB2/CEP17 ≥ 2.0]). While the anti-HER2 monoclonal antibody trastuzumab, in combination with chemotherapy, is the standard treatment for HER2-positive GC, other HER2-targeted therapies have not demonstrated survival benefits in patients with GC, despite showing efficacy in patients with HER2-positive breast cancer. This indicates that there are unique challenges to the use of currently available HER2-targeted therapies for the treatment of HER2-positive GC. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 human monoclonal IgG1 antibody with the same amino acid sequence as trastuzumab, an enzymatically cleavable peptide-based linker, and DXd, a novel topoisomerase I inhibitor, as its released payload. T-DXd has a high drug-antibody ratio (approximately 8) and a demonstrated bystander antitumor effect. It has demonstrated significant efficacy when compared with standard therapies and is approved as third- or later-line treatment for HER2-positive GC in Japan and second- or later-line treatment in the US. T-DXd treatment is associated with gastrointestinal and hematological adverse events, and a risk of interstitial lung disease (ILD), with the ILD risk being higher in Japan than in countries other than Japan. However, most adverse events, including ILD, can be managed with proactive monitoring and T-DXd dose modification, and initiation of adequate treatment. In this review, we summarize the discovery and development of T-DXd and provide guidance for T-DXd safety management, including ILD monitoring, for patients with HER2-positive GC.
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Safety and disease monitoring biomarkers in Duchenne muscular dystrophy: results from a Phase II trial.
Wagner, KR, Guglieri, M, Ramaiah, SK, Charnas, L, Marraffino, S, Binks, M, Vaidya, VS, Palmer, J, Goldstein, R, Muntoni, F
Biomarkers in medicine. 2021;(15):1389-1396
Abstract
Aim: Evaluate the utility of glutamate dehydrogenase (GLDH) and cardiac troponin I as safety biomarkers, and creatine kinase and muscle injury panel as muscle health biomarkers in Duchenne muscular dystrophy. Patients & methods: Data were collected during a Phase II trial of domagrozumab. Results: GLDH was a more specific biomarker for liver injury than alanine aminotransferase. Cardiac troponin I elevations were variable and not sustained, limiting its applicability as a biomarker. Muscle injury panel biomarkers were no more informative than creatine kinase as a muscle health biomarker. Conclusion: Results support the use of GLDH as a specific biomarker for liver injury in patients with Duchenne muscular dystrophy. Clinical trial registration: ClinicalTrials.gov, NCT02310763.
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Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial.
Gomes Freitas, C, Walsh, M, Coutinho, EL, Vincenzo de Paola, AA, Atallah, ÁN
PloS one. 2021;(4):e0248567
Abstract
OBJECTIVES To determine whether the generic and branded warfarins used as anticoagulants in Brazil are therapeutic equivalents based on their international normalized ratio (INR) results. METHODS This crossover randomized controlled trial had four periods. We used the branded Marevan and two generic versions of warfarin sodium tablets, manufactured by União Química and Teuto laboratories, all purchased from retail drugstores. Eligible participants were outpatients from an anticoagulation clinic at a university hospital in São Paulo, Brazil. They had atrial fibrillation or flutter and had been using warfarin for at least 2 months with an INR therapeutic range of 2.0-3.0. Randomization was by numbered, opaque, sealed envelopes. Healthcare personnel and outcome assessors were blinded to treatments, but patients were not. The primary outcome was the variability in the INR (ΔINR) and secondary outcomes included mean INR. We accepted formulations as equivalent if the 95% confidence interval (CI) of the comparison of ΔINR between branded and generic formulations was within the limit of ±0.49. RESULTS One hundred patients were recruited and randomized to six sequences of treatment (four sequences with n = 17 and two sequences with n = 16). União Química generic warfarin had equivalent variability in the INR to Marevan (ΔINR +0.09 [95% CI -0.29 to +0.46], n = 84). Comparison between Teuto generic warfarin and Marevan was inconclusive (ΔINR +0.29 [95% CI -0.09 to +0.68], n = 84). CONCLUSIONS Marevan and União Química warfarin had equivalent therapeutic effectiveness and both could be confidently used for anticoagulation. The comparison between Marevan and TW was inconclusive and does not warrant a statement of equivalence. Our methods are especially important for comparing generic and branded drugs that raise concerns and may be subject of future investigations by regulatory agents. TRIAL REGISTRATION ClinicalTrials.gov NCT02017197.
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Usefulness of daily folic acid supplementation during methotrexate treatment of Japanese patients with rheumatoid arthritis.
Sasaki, K, Tsuji, T, Kimoto, Y, Yanagihara, Y, Masuguchi, K, Chikamori, A, Watanabe, H, Murakami, T, Oryoji, D, Hashimoto, M, et al
Modern rheumatology. 2021;(1):108-113
Abstract
OBJECTIVES We investigated the effect of daily folic acid supplementation on methotrexate (MTX) toxicity and efficacy in Japanese patients with rheumatoid arthritis (RA). METHODS We followed 19 patients treated with MTX who switched from taking weekly 5 mg folic acid supplementation (weekly regimen) to 1.25 mg daily (daily regimen). White blood cell (WBC) and platelet (PLT) counts, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels were collected for 24 weeks following the change. RESULTS We observed no significant changes in WBC or PLT counts. AST and ALT levels, which had exceeded the upper limits of their normal ranges at the beginning of the study, were improved significantly at weeks 4 and 8, no subsequent deterioration in liver function was found. Further, no significant changes in ESR and CRP levels were observed. CONCLUSION Our data indicate that supplementing 1.25 mg of folic acid daily rather than 5 mg weekly reduces toxicity caused by MTX without affecting its efficacy.
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Therapeutic Drug Monitoring of HIV Antiretroviral Drugs in Pregnancy: A Narrative Review.
O'Kelly, B, Murtagh, R, Lambert, JS
Therapeutic drug monitoring. 2020;(2):229-244
Abstract
To date, therapeutic drug monitoring (TDM) has played an important role in the management of pregnant HIV patients on highly active antiretroviral therapy. Historically, in pregnant women living with HIV, the third agent in triple therapy has been either non-nucleoside reverse transcriptase inhibitors or protease inhibitors (PIs). PIs have been the preferred agents because of their robustness from the perspective of viral resistance and the dominant drug class for the management of HIV during pregnancy for the previous decade. As with many drugs used during pregnancy, pharmacokinetic changes decrease exposure to these agents as the pregnancy progresses. This can lead to viral escape at the time of pregnancy and ultimately increase the risk of mother-to-child transmission (MTCT) of HIV. TDM has been well-established for this class of highly active antiretroviral therapy, and appropriate dose adjustment studies have been performed. At present, there is a shift from the traditional treatment paradigm in pregnancy to a new drug class, integrase strand transfer inhibitors (INSTIs). Although INSTIs are affected by pharmacokinetic changes during pregnancy, they do not harbor the same issues with viral escape as seen with PIs at birth and in general eliminate the need for boosting with additional agents like ritonavir (r) and cobicistat (c) [bar elvitegravir (EVG)] that can lead to interactions with treatment of other common infections in HIV, including tuberculosis. Furthermore, INSTIs are the most successful medication for rapidly reducing the viral load (VL) in HIV patients, a useful factor where VL may be unknown, or in late presenters. These merits make INSTIs the best choice in pregnancy, although their use has been hindered in recent years by a report of neural tube defects from a large African study with dolutegravir (DTG). New data from Botswana and Brazil indicate that this risk is less significant than previously reported, necessitating further data to shed light on this critical issue. Current international guidelines including DHHS, EACS, WHO, and BHIVA (for patients with VLs >100,000 copies/mL or late presenters) now recommend INSTIs as first-line agents. The role of TDM in INSTIs shifts to cases of insufficient viral suppression with standard adherence measures, cases of drug-drug interactions, or cases where EVG/c is continued throughout pregnancy, and thus remains an important aspect of HIV care in pregnancy.
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Neuroleptic malignant syndrome: evaluation of drug safety data from the AMSP program during 1993-2015.
Schneider, M, Regente, J, Greiner, T, Lensky, S, Bleich, S, Toto, S, Grohmann, R, Stübner, S, Heinze, M
European archives of psychiatry and clinical neuroscience. 2020;(1):23-33
Abstract
Neuroleptic malignant syndrome (NMS) is a rare, but severe adverse drug reaction of drugs with anti-dopaminergic properties. The main symptoms are fever and rigor. In addition, other symptoms such as creatine kinase elevation, alteration of consciousness and various neurological symptoms may occur. A total of 52 NMS cases have been documented in the drug safety program 'Arzneimittelsicherheit in der Psychiatrie' from 1993 to 2015. We calculated incidences and analyzed imputed substances and additional risk factors to study the impact of changing therapy regimes. The overall incidence was 0.16‰. High-potency first-generation antipsychotics (FGAs) had the highest incidences, e.g. flupentixol with 0.61‰. Second-generation antipsychotics (SGAs) had lower incidences. Low-potency FGAs had very low incidences, comparable to SGAs, but in contrast to SGAs, had not been imputed alone in any case of NMS. Preexisting organic pathologies of the central nervous system, lithium treatment, infection/exsiccosis and the withdrawal of medication with anticholinergic properties or alcohol were found to be additional risk factors. With the increasing use of SGAs, one should always be aware of the risk of NMS. Better suited diagnostic criteria for 'atypical NMS' would lead to a better understanding and, therefore, to improved treatment possibilities.
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Fasting Status and Circadian Variation Must be Considered When Performing AUC-based Therapeutic Drug Monitoring of Tacrolimus in Renal Transplant Recipients.
Gustavsen, MT, Midtvedt, K, Robertsen, I, Woillard, JB, Debord, J, Klaasen, RA, Vethe, NT, Bergan, S, Åsberg, A
Clinical and translational science. 2020;(6):1327-1335
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Abstract
Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC-guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice-daily tacrolimus in a real-life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting-state and under real-life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting-conditions: 45% higher peak-concentration and 20% higher AUC following the morning dose. In the real-life nonfasting setting, the PK-profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting-state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real-life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting-state, whereas flatter PK-profiles and no circadian variation was present in a real-life, nonfasting setting.
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Study of the safety of oral Triphala aqueous extract on healthy volunteers.
Phetkate, P, Kummalue, T, Rinthong, PO, Kietinun, S, Sriyakul, K
Journal of integrative medicine. 2020;(1):35-40
Abstract
BACKGROUND Triphala extract is a well known medicinal herbal formula which is usually prescribed by Thai traditional doctors to adjust the physiological functions of the body. Previous studies have reported that Triphala has antioxidant, anti-inflammatory, antihypercholesterolemia and anticancer properties. Though this herbal recipe is commonly used in Thailand, its human safety, especially in the oral form, has not been studied. We therefore conducted a clinical trial (Phase I). OBJECTIVE This study evaluated the safety of administering the aqueous extract of Triphala to healthy volunteers at 2500 mg/d. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS An open-label, single-arm trial was conducted at Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand, between July 2017 and July 2018. The study enrolled 10 male and 10 female healthy volunteers; all were given Triphala (water extract; five capsules of 500 mg each) orally, once a day, at bedtime, for four consecutive weeks. MAIN OUTCOME MEASURES Signs and symptoms, physical examinations, hematology and blood chemistry were assessed at the beginning of the trial and every week thereafter, for four consecutive weeks. After finishing the trial, on day 28, all volunteers were invited to a follow-up session on day 35 to evaluate the safety of the herbal recipe using the same measurements. RESULTS At the oral dose of 2500 mg/d, Triphala had no serious adverse effects in healthy volunteers. Moreover, it was found to have significantly improved the volunteers' high-density lipoprotein cholesterol (HDL-C) levels on day 35 and also reduced their blood sugar levels on days 14 and 35. CONCLUSIONS We conclude that aqueous extract of Triphala is safe for healthy volunteers and that it elevates HDL-C levels and lowers blood sugar. Further clinical study should investigate its effects on HDL-C and blood sugar levels among the dyslipidemic and prediabetic groups. TRIAL REGISTRATION This trial was registered in the Thai Clinical Trial Registry with the identifier TCTR20180423002.
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Cov-hep study: heparin in standard anticoagulation based on citrate for continuous veno-venous hemodialysis in patients with COVID-19: a structured summary of a study protocol for a randomized controlled trial.
Lins, PRG, de Albuquerque, CCC, Assis, CF, Rodrigues, BCD, E Siqueira Campos, BP, de Oliveira Valle, E, Cabrera, CPS, de Oliveira Gois, J, Segura, GC, Strufaldi, FL, et al
Trials. 2020;(1):920
Abstract
OBJECTIVES The primary objective is to test if heparin added to a standard regional anticoagulation protocol based on citrate is able to reduce dialysis circuit losses by clotting without increasing the risk of thrombocytopenia or bleeding, in patients with COVID-19 with acute kidney injury requiring dialysis. TRIAL DESIGN Randomized, parallel-group, open-label trial, with two arms (ratio 1:1) comparing different continuous renal replacement therapy anticoagulation strategies. PARTICIPANTS Eligibility conditions: All ICU patients of University of Sao Paulo General Hospital (Hospital das Clínicas), Brazil will be screened for eligibility conditions. Adults (> 18 years old) with confirmed COVID-19 and acute kidney injury requiring dialysis with agreement between ICU and nephrology teams for the introduction of renal continuous replacement therapy in daily ICU rounds. Continuous renal replacement therapy will be prescribed by consulting nephrologists based on standard clinical guidelines, including acute kidney injury with hemodynamic instability plus hyperkalemia, severe acidosis, volume overload, respiratory distress, multiorgan failure or some combination of these factors. DATA COLLECTION Patients demographics and associated clinical data and comorbidities will be recorded at ICU entry. Demographic information will include the patient's age, sex, and admission dates. Clinical data comprise comorbidities, APACHE 2, SAPS 3, need for mechanical ventilation, and use of vasopressor drugs. Physiological data collected by the day of CRRT start will be vital signs, the arterial oxygen tension/fraction of inspired oxygen (PaO2/FiO2) index, and serum creatinine, blood urea nitrogen, bilirubin, hemoglobin, hematocrit, platelets, white blood cell count levels and Peak D-dimer levels. Patients will be analyzed for the first 72h of CRRT, and they will be evaluated regarding clinical variables, filter patency and any adverse events that could be related to the anticoagulation choice, as bleeding (mild or major) or low platelets counts (<100.000 ui/uL) during treatment period. Mild and major bleeding will be defined by hemorrhagic event without clinical impact or hemoglobin (Hb) fall lesser than 1g/dL and hemorrhagic event with clinical impact or Hb fall higher than 1g/dL, respectively. EXCLUSION CRITERIA Hypersensitivity to any of the substances going to be used in the study (Citric acid dextrosol 2.2% and unfractionated heparin); Previous diagnosis of coagulopathy or thrombophilia; Contraindication to the use of unfractionated heparin; Risk of citrate poisoning - (Lactate> 30 mg/dL, international normalized ratio > 2.5, Total bilirubin> 15 mg/dL); Pregnancy; Patients unlikely to survive for more than 24 hours. The trial is being undertaken at the University of Sao Paulo General Hospital (Hospital das Clinicas), Brazil. INTERVENTION AND COMPARATOR Group A (control) - Patients on continuous renal replacement therapy (blood flow 150 ml/min, dose of 30 mL/Kg/h) receiving anticoagulation with sodium citrate at 4 mmol/L Group B (experiment): Patients on continuous hemodialysis (blood flow 150 mL/min, dose of 30 mL/Kg/h) receiving anticoagulation with sodium citrate at 4 mmol/L associated with unfractionated heparin at 10 U/Kg/h. MAIN OUTCOMES The percentage of clotted dialyzers within 72 hours in each of the studied groups (Primary outcome) Secondary outcomes: Number of dialyzers used in the first 72 hours of dialysis protocol, Mortality in the first 72 h of dialysis protocol, Bleeding events (Major or minor) in the first 72 h of dialysis protocol, Thrombocytopenia (less than 50.000 platelets) proportion in the first 72 h of dialysis protocol, Dialysis efficiency (Urea sieving) - variation in urea sieving between the first, second and third days of dialysis protocol, Continuous renal replacement therapy pressures (Arterial, Venous, dialysate and pre-filter pressure) in the first 72 h of dialysis protocol, in-hospital mortality. RANDOMIZATION RedCap→ randomization - 2 blocks randomization by D-dimer level (5000ng/dL cut-off) and catheter site (Right Internal Jugular versus other sites) with 1:1 allocation ratio. BLINDING (MASKING): No blinding - Open label format NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Total number of patients 90 (45 per group) TRIAL STATUS Trial version 2.0 - ongoing recruitment. First recruitment: June 29, 2020 Estimated date for last recruitment: December 31, 2020 TRIAL REGISTRATION Responsible Party: University of Sao Paulo General Hospital (Hospital das Clinicas) ClinicalTrials.gov Identifier: NCT04487990 , registered July 27, 2020, ReBec www.ensaiosclinicos.gov.br/rg/RBR-45kf9p/ Other Study ID Numbers: U1111-1252-0194 FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1) In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.