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Clinical Pharmacokinetics Apr 2023Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to...
BACKGROUND AND OBJECTIVE
Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to treat myelofibrosis, polycythemia vera and steroid-refractory graft-versus-host disease in the setting of allogeneic stem-cell transplantation. This review describes the pharmacokinetics and pharmacodynamics of ruxolitinib.
METHODS
Pubmed, EMBASE, Cochrane Library and web of Science were searched from the time of database inception to march 15, 2021 and was repeated on November 16, 2021. Articles not written in English, animal or in vitro studies, letters to the editor, case reports, where ruxolitinib was not used for hematological diseases or not available as full text were excluded.
RESULTS
Ruxolitinib is well absorbed, has 95% bio-availability, and is bound to albumin for 97%. Ruxolitinib pharmacokinetics can be described with a two-compartment model and linear elimination. Volume of distribution differs between men and women, likely related to bodyweight differences. Metabolism is mainly hepatic via CYP3A4 and can be altered by CYP3A4 inducers and inhibitors. The major metabolites of ruxolitinib are pharmacologically active. The main route of elimination of ruxolitinib metabolites is renal. Liver and renal dysfunction affect some of the pharmacokinetic variables and require dose reductions. Model-informed precision dosing might be a way to further optimize and individualize ruxolitinib treatment, but is not yet advised for routine care due to lack of information on target concentrations.
CONCLUSION
Further research is needed to explain the interindividual variability of the ruxolitinib pharmacokinetic variables and to optimize individual treatment.
Topics: Animals; Humans; Female; Janus Kinases; Protein Kinase Inhibitors; Pyrazoles; Nitriles
PubMed: 37000342
DOI: 10.1007/s40262-023-01225-7 -
Sexual Medicine Reviews Jan 2021Testosterone prescriptions have increased dramatically in recent years, largely because of changes in expert guidelines. Concerns have been raised that testosterone... (Review)
Review
INTRODUCTION
Testosterone prescriptions have increased dramatically in recent years, largely because of changes in expert guidelines. Concerns have been raised that testosterone therapy (TTh) may be associated with an increased incidence of conditions such as cardiovascular (CV) disease, thromboembolic events, obstructive sleep apnea (OSA), benign prostatic hyperplasia (BPH), and prostate cancer (PCa) and also may be a beneficial therapy in the management of prediabetes. As such, considerable debate remains regarding which hypogonadal populations are appropriate candidates for TTh.
OBJECTIVES
This systematic review aims to affirm or refute, using the most current evidence, the published concerns surrounding TTh and its potential increased risk of conditions such as CV disease, thromboembolic events, OSA, urolithiasis, BPH, and PCa, as well as its role as a potential tool for managing prediabetes.
METHODS
A systematic review of literature surrounding TTh and its impact on increasing risk for the adverse conditions mentioned previously was performed. 62 publications were selected for inclusion based on their relevance to the effects and risks of TTh. Evidence is current through December 2019.
RESULTS
Evidence demonstrates that positive associations exist between TTh and OSA, erythrocytosis, as well as urolithiasis. TTh may potentially be used to treat hypogonadal men with prediabetes. While low testosterone is positively correlated with adverse CV events, TTh in hypogonadal men either has no effect or decreases such risk. TTh is likely not associated with increased risk of PCa incidence or recurrence.
CONCLUSIONS
Despite historical beliefs that TTh increases the risk of CV disease, thromboembolic events, BPH, and PCa, recent evidence suggests that TTh conveys less risk than previously perceived. While caution should continue to be exercised, evidence suggests that TTh is a reasonable treatment option in many hypogonadal men who were previously excluded from TTh based on risk factors and prior health histories. Twitchell DK, Pastuszak AW, Khera M. Controversies in Testosterone Therapy. Sex Med Rev 2021;9:149-159.
Topics: Hormone Replacement Therapy; Humans; Hypogonadism; Male; Polycythemia; Prostatic Neoplasms; Testosterone
PubMed: 33309270
DOI: 10.1016/j.sxmr.2020.09.004 -
Journal of Oncology Pharmacy Practice :... Sep 2022To provide up to date guidance, practice recommendations and highlight barriers to medication adherence in the long-term management of chronic myeloproliferative...
PURPOSE
To provide up to date guidance, practice recommendations and highlight barriers to medication adherence in the long-term management of chronic myeloproliferative neoplasms (MPNs).
AIM
Current drug therapy for MPN is not curative and has not been shown to prolong survival. The main indication for treatment is the prevention of thrombosis and medication adherence remains a challenge in this group of patients. Identifying potentially modifiable barriers to medication adherence including primary nonadherence and non-persistent adherence enables timely interventions to be put in place and improve overall medication adherence.
METHODS
A systematic review of peer-reviewed literature and expert opinions was performed using electronic databases (PubMed, EMBASE, MEDLINE, and Web of Science) that were searched for articles reporting MPN and medication adherence. Discussions A case vignette is discussed throughout the article and expert opinion with international peer reviewed guidelines that are authored to support clinical decision making at the point of care were utilised. The evidence base was combined with more practical/clinical (data based) insight from real world clinical practice. Adoption of a broad range of digital health care activities and services in the health care system (telehealth applications) by the advanced practice providers (Non-Medical Prescribers-NMPs) in MPN clinics included medication prescribing and management, oral drug compliance and adherence evaluations, interventions, chronic care management, counselling and patient education on treatments.
CONCLUSION
Current drug therapy for MPN is neither curative nor has it been shown to prolong survival, and medication adherence remains a challenge in this group of patients. The longevity of the patients' disease course may contribute to the high risk of non-adherence in this patient cohort. Poor adherence to long-term therapies severely compromises the effectiveness of treatment. Adherence interventions should be tailored to the needs of the patient in order to achieve maximum impact. Interventions aimed at improving adherence provide the best experience and outcome for the patient and their families and can have a profound impact on the quality of life and mitigation of disease consequences.
Topics: Humans; Medication Adherence; Myeloproliferative Disorders; Neoplasms; Quality of Life; Thrombosis
PubMed: 35296179
DOI: 10.1177/10781552221082293 -
Lupus Aug 2021Antiphospholipid syndrome (APS) and myeloproliferative neoplasms (MPN) are associated with an increased risk of thrombosis. The optimal management of patients with...
Antiphospholipid syndrome (APS) and myeloproliferative neoplasms (MPN) are associated with an increased risk of thrombosis. The optimal management of patients with coexistent APS and MPN has not been defined. A single centre and systematic literature review of patients with coexistent APS and MPN was performed. Cases were divided into two groups based on whether they met international consensus criteria for APS. Of the 12 studies identified, eight were excluded (leaving five of a total 54 patients), as although antiphospholipid antibodies (aPL) were documented, the diagnosis of APS was not conclusively demonstrated. Another ten patients with definite APS were identified at our centre. Fifteen patients (ten females, five males) were therefore included in this analysis (eleven definite APS and four highly likely), median age 44 (range: 13-71) years. Nine had polycythaemia vera and six, essential thrombocythaemia. Thirteen of the 15 patients (86.7%) had thrombotic APS (seven with initial venous events and six arterial) and two (13.3%) had obstetric APS. Nine patients were single-positive, and six double-positive for aPL. None were triple aPL-positive. Four patients at our centre had recurrent thrombotic/obstetric events, including while on anticoagulation/antiplatelet treatment.
Topics: Adolescent; Adult; Aged; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Cohort Studies; Female; Humans; Male; Middle Aged; Polycythemia Vera; Pregnancy; Recurrence; Thrombocytosis; Thrombosis; Young Adult
PubMed: 34192956
DOI: 10.1177/09612033211021154 -
Hematology (Amsterdam, Netherlands) Dec 2023Polycythemia vera (PV) is classically thought to be associated with low erythropoietin (EPO) levels. Here, we present a review of the utility of using EPO levels in...
OBJECTIVES
Polycythemia vera (PV) is classically thought to be associated with low erythropoietin (EPO) levels. Here, we present a review of the utility of using EPO levels in diagnosing polycythemia.
METHODS
We conducted a systematic literature review of the Medline data through Pubmed and Google Scholar. We included the articles which described confirmed PV associated with elevated EPO level. Our search strategy included the following terms in Pubmed (((polycythemia vera[MeSH Terms]) OR (jak2 protein tyrosine kinase[MeSH Terms])) OR (Myeloproliferative Disorders[MeSH Terms])) AND (Erythropoietin[MeSH Terms]), and 'polycythemia vera with erythropoietin' in Google Scholar.
RESULTS
Our research yielded four cases of PV with elevated EPO levels. The most common symptom was a headache. Thrombotic phenomena happened in a single case in the form of Budd-Chiari syndrome. The mean Hb level was 20.2 gm/dl, and the EPO level was 213 mlU/mL.
DISCUSSION
Although PV is usually associated with low EPO levels, high levels do not exclude this diagnosis. Workup should include testing for JAK2 mutation and bone marrow biopsy in the presence of suggestive signs and symptoms. Novel biomarkers are also being proposed to aid in the diagnosis.
CONCLUSION
Although elevated EPO levels suggest secondary causes of polycythemia, cases where elevated EPO levels were associated with an underlying PV are reported in the literature, and we have summarized a review of them. Workup for polycythemia should include JAK2 mutation testing if signs and symptoms suggest PV even if EPO is elevated.
Topics: Humans; Polycythemia; Polycythemia Vera; Janus Kinase 2; Bone Marrow; Erythropoietin
PubMed: 37843428
DOI: 10.1080/16078454.2023.2269510 -
Ultrasound in Obstetrics & Gynecology :... Dec 2022To ascertain maternal and perinatal outcomes of monochorionic twin pregnancies complicated by twin-twin transfusion syndrome (TTTS) treated with the Solomon technique... (Meta-Analysis)
Meta-Analysis Review
Solomon technique vs selective fetoscopic laser photocoagulation for twin-twin transfusion syndrome: systematic review and meta-analysis of maternal and perinatal outcomes.
OBJECTIVE
To ascertain maternal and perinatal outcomes of monochorionic twin pregnancies complicated by twin-twin transfusion syndrome (TTTS) treated with the Solomon technique compared with selective fetoscopic laser photocoagulation (SFLP) of placental anastomoses.
METHODS
MEDLINE, EMBASE and The Cochrane Library were searched to identify relevant studies. The outcomes observed were perinatal loss and survival, preterm prelabor rupture of membranes (PPROM), preterm birth (PTB), gestational age (GA) at delivery, interval between laser treatment and delivery, maternal bleeding, septostomy or chorioamniotic separation, placental abruption, twin anemia-polycythemia sequence (TAPS), recurrence of TTTS, neonatal morbidity and neurological morbidity. Random-effects head-to-head meta-analyses were used to analyze the data. Pooled odds ratios (OR) and mean differences (MD) and their 95% CIs were calculated.
RESULTS
Nine studies were included in the systematic review. There was generally no difference in the main maternal and pregnancy characteristics between pregnancies treated using the Solomon technique and those treated using SFLP of placental anastomoses. The risks of fetal loss (pooled OR, 0.69 (95% CI, 0.50-0.95); P = 0.023), neonatal death (pooled OR, 0.37 (95% CI, 0.16-0.84); P = 0.018) and perinatal loss (pooled OR, 0.56 (95% CI, 0.38-0.83); P = 0.004) were significantly lower in pregnancies treated using the Solomon technique than in those treated with SFLP. Likewise, pregnancies treated using the Solomon technique had a significantly higher chance of survival of at least one twin (pooled OR, 2.31 (95% CI, 1.03-5.19); P = 0.004) and double survival (pooled OR, 2.18 (95% CI, 1.29-3.70); P = 0.001). There was no difference in the risk of PPROM (P = 0.603), PPROM within 10 days from laser surgery (P = 0.982), PTB (P = 0.207), maternal bleeding (P = 0.219), septostomy or chorioamniotic separation (P = 0.224) or chorioamnionitis (P = 0.135) between the two groups, while the risk of placental abruption was higher in pregnancies treated using the Solomon technique (pooled OR, 2.90 (95% CI, 1.55-5.44); P = 0.001). In the Solomon technique group, pregnancies delivered at a significantly earlier GA than did those treated with SFLP (pooled MD, -0.625 weeks (95% CI, -0.90 to -0.35 weeks); P < 0.001), while there was no difference in the interval between laser treatment and delivery (P = 0.589). The rate of recurrence of TTTS was significantly lower in pregnancies undergoing the Solomon technique (pooled OR, 0.43 (95% CI, 0.22-0.81); P < 0.001), while there was no difference in the risk of TAPS between the two groups (P = 0.792). Finally, there was no difference in the overall risk of neonatal morbidity (P = 0.382) or neurological morbidity (P = 0.247) between the two groups.
CONCLUSIONS
Monochorionic twin pregnancies complicated by TTTS undergoing laser treatment using the Solomon technique had a significantly higher survival rate and lower recurrence rate of TTTS but were associated with an increased risk of placental abruption and earlier GA at delivery compared to those treated with SFLP. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Abruptio Placentae; Anemia; Fetofetal Transfusion; Fetoscopy; Gestational Age; Laser Coagulation; Laser Therapy; Lasers; Placenta; Polycythemia; Pregnancy, Twin; Premature Birth
PubMed: 36240516
DOI: 10.1002/uog.26095 -
Laryngoscope Investigative... Apr 2022The aim of this systematic review and meta-analysis was to investigate the association between obstructive sleep apnea (OSA) and erythrocytosis. (Review)
Review
OBJECTIVE
The aim of this systematic review and meta-analysis was to investigate the association between obstructive sleep apnea (OSA) and erythrocytosis.
METHODS
The PubMed, Web of Science, and Cochrane Library databases were searched for articles examining hematocrit values in patients with OSA and control individuals published till September 1, 2021. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated, and subgroup analyses were performed.
RESULTS
Eleven eligible studies with a total of 4608 patients with OSA were included in this meta-analysis. Pooled outcomes revealed that hematocrit values were significantly higher in patients with OSA than in controls (SMD, 0.19; 95% CI, 0.08-0.29; < .01). When studies were stratified by disease severity, the significant differences in hematocrit values between patients and controls were only observed in the severe OSA group (SMD, 0.34; 95% CI, 0.08-0.59; < .01), but not in the mild and moderate OSA groups. In subgroup analyses according to sex and publication year, significant differences in hematocrit values between patients and controls remained stable in studies with only female patients (SMD, 0.25; 95% CI, 0.12-0.38; < .01) and in studies published after 2012 (SMD, 0.17; 95% CI, 0.06-0.28, < .01).
CONCLUSION
Our meta-analysis revealed that the hematocrit value was significantly increased in patients with OSA, particularly in severe patients, compared with that in controls. However, the elevation was modest, and the hematocrit value is expected to be within the normal range in patients with OSA. These data suggest that OSA leads to slight increases in hematocrit but does not cause clinically significant erythrocytosis.
PubMed: 35434329
DOI: 10.1002/lio2.751 -
Heart, Lung & Circulation Mar 2022Polycythaemia vera (PV) is a condition that may potentially put patients undergoing cardiac surgery at an increased risk of bleeding and thrombosis; however, there is... (Review)
Review
OBJECTIVES
Polycythaemia vera (PV) is a condition that may potentially put patients undergoing cardiac surgery at an increased risk of bleeding and thrombosis; however, there is currently a paucity of literature regarding the management of these patients. We aim to examine the literature in this systematic review to indicate the interventions that may be considered to minimise complications.
METHODS
We conducted a literature search using keywords and MeSH terms to identify articles discussing PV and cardiac surgery. The studies were identified and qualitatively analysed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol.
RESULTS
In total, 10 case reports representing 11 patients were identified for this systematic review and were included in qualitative analysis. 63.6% of patients had preoperative intermittent phlebotomy, and the majority of patients received postoperative therapy that involved one antiplatelet agent and one anticoagulant. Generous perioperative fluid management, phlebotomy, preservation of core body temperature, early extubation, monitoring of myocardial ischaemia, infarction and vascular events, intense chest physiotherapy and patient mobilisation are important to consider to reduce the risk of complications arising from surgery.
CONCLUSION
These considerations should be systematically discussed in a multidisciplinary team, where the acute surgical need can be balanced appropriately against the risk of haemorrhage and thrombosis.
Topics: Anticoagulants; Coronary Artery Bypass; Humans; Platelet Aggregation Inhibitors; Polycythemia Vera; Thrombosis
PubMed: 34794873
DOI: 10.1016/j.hlc.2021.10.012 -
Leukemia Jun 2021Data on the efficacy and safety of interferon (IFN)-α for the treatment of essential thrombocythemia (ET) and polycythemia vera (PV) are inconsistent. We conducted a... (Meta-Analysis)
Meta-Analysis
Data on the efficacy and safety of interferon (IFN)-α for the treatment of essential thrombocythemia (ET) and polycythemia vera (PV) are inconsistent. We conducted a systematic review and meta-analysis and searched MEDLINE and EMBASE via Ovid, Scopus, COCHRANE registry of clinical trials, and Web of Science from inception through 03/2019 for studies of pegylated IFN (peg-IFN) and non-pegylated IFN (non-peg-IFN) in PV and ET patients. Random-effects models were used to pool response rates for the primary outcome of overall response rate (ORR) defined as a composite of complete response, partial response, complete hematologic response (CHR) and partial hematologic response. Peg-IFN and non-peg-IFN were compared by meta-regression analyses. In total, 44 studies with 1359 patients (730 ET, 629 PV) were included. ORR were 80.6% (95% confidence interval: 76.6-84.1%, CHR: 59.0% [51.5%-66.1%]) and 76.7% (67.4-84.0%; CHR: 48.5% [37.8-59.4%]) for ET and PV patients, respectively. In meta-regression analyses results did not differ significantly for non-peg-IFN vs. peg-IFN. Annualized rates of thromboembolic complications and treatment discontinuation due to adverse events were low at 1.2% and 8.8% for ET and 0.5% and 6.5% for PV patients, respectively. Both peg-IFN and non-peg-IFN can be effective and safe long-term treatments for ET and PV.
Topics: Antiviral Agents; Humans; Interferon-alpha; Polycythemia Vera; Thrombocythemia, Essential
PubMed: 32868875
DOI: 10.1038/s41375-020-01020-4 -
African Journal of Reproductive Health Nov 2023We compare the hematocrit, hemoglobin, need for transfusion, recurrent phototherapy, serum bilirubin level, and serum ferritin at different time frames for the umbilical... (Meta-Analysis)
Meta-Analysis
Comparing the safety and effectiveness of various umbilical cord milking techniques and delayed cord clamping in full-term and preterm infants: A systematic review and meta-analysis.
We compare the hematocrit, hemoglobin, need for transfusion, recurrent phototherapy, serum bilirubin level, and serum ferritin at different time frames for the umbilical cord milking (UCM) and delayed cord clamping (DCC) in both full-term and preterm infants. A comprehensive search through various databases aimed to compare UCM and DCC studies until May 2nd, 2023. Cochrane and NIH tools assessed RCTs and cohorts, respectively. Meta-analysis employed Review Manager 5.4 software, calculating MD and RR with 95% CIs for continuous and dichotomous data. We included 20 studies with a total of 5189 infants. Regarding preterm infants, hematocrit level showed no significant difference between intact Umbilical Cord Milking (iUCM) compared to DCC (MD = -0.24, 95% CI [-1.11, 0.64]). Moreover, Neonatal death incidence was significantly higher with the UCM technique in comparison to DCC (RR = 1.28, 95% CI [1.01 to 1.62]). Regarding term and late preterm infants, Hematocrit level showed no significant difference between the iUCM or cUCM techniques compared to DCC (MD = 0.21, 95% CI [-1.28 to 1.69]), (MD = 0.96, 95% CI [-1.02 to 2.95]), respectively. UCM led to a higher risk of neonatal death in preterm infants compared to DCC. However, the incidence of polycythemia was lower in the UCM group. Additionally, UCM was associated with higher rates of severe IVH events. Based on these findings, DCC may be preferred due to its lower incidence of severe IVH and neonatal death.
Topics: Infant; Pregnancy; Female; Infant, Newborn; Humans; Infant, Premature; Umbilical Cord Clamping; Perinatal Death; Umbilical Cord; Hematocrit
PubMed: 38053339
DOI: 10.29063/ajrh2023/v27i11.11