Concomitant oral potassium chloride and anticholinergic therapy is associated with upper gastrointestinal bleeding: A cohort study.

AIM: To determine whether oral potassium chloride (KCI) therapy with concomitant anticholinergic exposure among hospitalized patients is associated with an excess risk for upper gastrointestinal bleeding (UGIB). METHODS: A retrospective controlled study among hospitalized patients between January 2007 and April 2019 who were treated with oral KCI. Patients were divided into two groups: with or without concomitant exposure to agents with anticholinergic activity. Outcome was defined as any UGIB. RESULTS: The final sample included 13 728 subjects who received oral KCI treatment, of them 3542 (25.8%) had at least one documented overlap with an anticholinergic agent. Mean age was 67.6 (±17.2) and 6893 (50.2%) were females. Median KCI dose was 2.4 g (interquartile range [IQR] 1.2-5.4, n = 9416) with the majority (90.4%) being treated with the wax-matrix form (Slow-K). Twenty-six (0.2%) patients experienced an UGIB event. Univariate analysis demonstrated a significantly higher rate of UGIB among patients concomitantly treated with oral KCI and anticholinergics (0.3%) compared to those without anticholinergic exposure (0.1%, P = 0.018), with median 7 days (IQR 3-16.8) from first KCI dose to bleeding event. Multivariate analysis demonstrated that concomitant anticholinergic exposure (Odds Ratio 2.48, 95% Confidence Interval 1.11-6.51, P = 0.022) and anticoagulation treatment among patients with hemato-oncologic disease (OR 6.61, 95% CI 1.96-22.25, P = 0.002) were significantly associated with UGIB. CONCLUSION: Hospitalized patients treated concomitantly with oral KCI and anticholinergic agents have significantly increased risk for UGIB.

Pregnancy outcomes following gestational exposure to papaverine: An observational comparative study.

AIMS: Papaverine is indicated for abdominal pain of various aetiologies. However, data on maternal and foetal safety following gestational exposure are lacking. The aim was to examine whether first trimester exposure to papaverine is associated with increased risk for major malformation and whether gestational exposure at any stage is associated with increased risk for preterm delivery, lower birthweight, small for gestational age, caesarean section (CS), lower Apgar score and perinatal death. METHODS: A retrospective comparative study consisted of pregnant women treated with papaverine between February 2010 and October 2019 at a large tertiary center. The control group comprised of livebirth deliveries randomly selected from the institutional obstetric database. RESULTS: The study group consisted of 498 pregnancies, which resulted in 537/544 (98.7%) live births, of whom 46/537 (8.6%) were exposed during the first trimester. The control group consisted of 498 pregnancies and 514 live births. Rate of major malformations did not differ between study group (2/46, 4.3%) and control (25/315, 4.9%, P = .67). Papaverine exposure was associated with higher rate of preterm delivery (22.3 vs. 10.3%, P < .001), CS (35.9 vs. 24.1%, P < .001) and lower birth weight (3207 vs. 3246 g, P = .02). Adjustment for treatment indication demonstrated that these remained significant only when given for obstetrical/surgical aetiologies. Comparable rates were observed for the remaining outcomes. CONCLUSIONS: Short-term gestational exposure to papaverine adjusted for indication was not associated with preterm deliveries, CS, lower birthweight, small for gestational age or perinatal death. Rate of major malformations among 46 first trimester exposures was comparable to controls.

Clinically significant incidental QTc prolongation is subject to within-individual variability.

BACKGROUND: Prolonged QTc interval observed in daily practice is often deemed to be drug induced and might result in drug discontinuation, with possible therapeutic consequences. However, whether clinically significant prolonged QTc may be due to within-individual variability occurs has yet to be described. METHODS: A retrospective cohort study documenting within-individual QTc variability in subjects attending annual routine medical evaluation. At each visit, QT interval was measured and corrected for heart rate using Bazett and three other commonly used formulae. Outcome measures were rates of ΔQTc ≥60 msec, absolute QTc ≥500 msec and QTc ≥25% from baseline. RESULTS: A total of 188 subjects [54 (29%)] females were recruited. Mean age at first ECG was 54 ± 12.8 years with mean time interval of 12.2 ± 1.1 months between measurements. Mean Bazett QTc was higher compared to the other 3 formulae: 412 ± 20 vs. 400 ± 16 msec. Using Bazett formula, 18/188 (9.6%) and 5/188 (2.7%) subjects showed at least one measurement with ΔQTc ≥60 msec and QTc ≥500 msec, respectively. Of the former, 5/18 (27.8%) showed QTc ≥25% prolongation. In multivariate analysis, QTc ≥500 msec was significantly associated with number of measurements (HR: 5.01, 95%CI: 1.21-20.78, p = .026) with no effect of other known confounders. Lower rates were demonstrated with the other three formulae. CONCLUSION: In clinical practice, significant prolonged QTc may be attributed to within-individual variability, particularly when adjusting the QT interval with Bazett correction. This should be taken into consideration when decisions on changing current drug regimens are to be made.

High tacrolimus trough level variability is associated with rejections after heart transplant.

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability.

Adverse Drug Event Rate in Israeli Hospitals: Validation of an International Trigger Tool and an International Comparison Study.

BACKGROUND: Adverse drug events (ADEs) are a major cause of morbidity and mortality worldwide. Hence, identifying and monitoring ADEs is of utmost importance. The Trigger Tool introduced by the Institute of Healthcare Improvement in the United States has been used in various countries worldwide, but has yet to be validated in Israel. OBJECTIVES: To validate the international Trigger Tool in Israel and to compare the results with those generated in various countries. METHODS: A retrospective descriptive correlative analysis surveying four general hospitals in Israel from different geographical regions was conducted. Patient medical charts (n=960) were screened for 17 established triggers and confirmed for the presence of an ADE. Trigger incidence was compared to the actual ADE rate. Further comparison among countries was conducted using published literature describing Trigger Tool validation in various countries. RESULTS: A total of 421 triggers in 279 hospitalizations were identified, of which 75 ADEs in 72 hospitalizations (7.5%) were confirmed. In addition, two ADEs were identified by chart review only. Mean positive predictive value was 17.81% and overall sensitivity was 97%. We found 1.54 ADEs for every 100 hospitalization days, 7.8 ADEs per 100 admissions, and 1.81 ADEs for every 1000 doses of medication. Of the 77 ADEs identified, 22.7% were defined as preventable. CONCLUSIONS: Our results support the Trigger Tool validity in Israel as a standardized method. Further studies should evaluate between hospital and region differences in ADE rate, in particular for the preventable events.

Immune-mediated syndromes following intravenous bisphosphonate therapy.

OBJECTIVES: Intravenous (IV) infusion of aminobisphosphonates (ABP) induces cytokine release by peripheral blood Vγ9δ2 T cells, resulting in an immediate short-term inflammatory response in up to 50% of patients. We evaluated possible long-term pro-inflammatory effects of IV ABP. METHODS: Retrospective case-series study from one rheumatology specialist's clinic. 2261 electronic charts were reviewed for administration of 'zoledronate' or different brand names of zoledronic acid, and relevant clinical data was retrieved for patients who had received the infusion. RESULTS: Thirteen patients had recieved zoledronate. In six, new-onset or exacerbation of a previous inflammatory/autoimmune disorder was diagnosed within 3 months following infusion. Of these, one patient developed new-onset rheumatoid arthritis (RA), two polymyalgia rheumatica (PMR), two suffered a flare of Crohn's disease-related and aromatase inhibitor-induced arthralgias, and one patient acquired autoimmune hemophilia. Pre-existing malignancy and immediate inflammatory response following zoledronate were more frequent in patients experiencing new or worsening immunologic manifestations (3/6 vs. 0/7, and 5/6 vs. 2/7, respectively). CONCLUSIONS: Intravenous ABP may trigger induction of persistent autoimmune syndromes, especially when accompanied by an immediate adverse reaction or pre-existing malignancy.

Optimizing Anti-TNF-α Therapy: Serum Levels of Infliximab and Adalimumab Are Associated With Mucosal Healing in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: It is not clear what serum levels of anti-tumor necrosis factor are associated with reduced intestinal inflammation in patients with inflammatory bowel disease (IBD). We aimed to identify serum levels of infliximab and adalimumab associated with mucosal healing in patients with IBD and to evaluate the putative gain in control of inflammation by incremental increases in drug levels. METHODS: We performed a retrospective cross-sectional study of 145 patients with IBD treated with infliximab (n = 78) or adalimumab (n = 67) at a medical center in Israel from 2009 through 2014. We collected data from colonoscopy examinations; mucosal healing was defined as simple endoscopic score of <3 or a Mayo score ≤1. These data were compared with serum levels of anti-tumor necrosis factor agents, clinical scores, and levels of C-reactive protein. RESULTS: Median serum levels of infliximab and adalimumab were significantly higher in patients with mucosal healing than patients with active disease (based on endoscopy) (for infliximab, 4.3 vs 1.7 µg/mL, P = .0002; for adalimumab, 6.2 vs 3.1 µg/mL, P = .01). Levels of infliximab above 5 µg/mL (area under the curve = 0.75; P < .0001) and levels of adalimumab above 7.1 µg/mL (area under the curve = 0.7; P = .004) identified patients with mucosal healing with 85% specificity. Increasing levels of infliximab beyond 8 µg/mL produced only minimal increases in the rate of mucosal healing, whereas the association between higher level of adalimumab and increased rate of mucosal healing reached a plateau at 12 µg/mL. In patients with measurable levels of infliximab >3 µg/mL, the presence of antibodies to infliximab was associated with a lower rate of mucosal healing compared with patients with similar drug level without antibodies (16% vs 50%, respectively; P = .003). CONCLUSIONS: In a retrospective study, we found significant association between serum levels of anti-tumor necrosis factor agents and level of mucosal healing. We propose that serum levels of 6-10 µg/mL for infliximab and 8-12 µg/mL for adalimumab are required to achieve mucosal healing in 80%-90% of patients with IBD, and that this could be considered as a "therapeutic window." Exceeding these levels produces only a negligible gain in proportion of patients with mucosal healing.

Anti-fibrotic characteristics of Vγ9+ γδ T cells in systemic sclerosis.

OBJECTIVES: γδ T cells of the Vγ9Vδ2 subtype secrete anti-fibrotic cytokines upon isopentenyl pyrophosphate (IPP) stimulation. In this study, we sought to compare IPP and Zoledronate, an up-regulator of IPP, effects on proliferation and cytokine secretion of Vγ9+ T cells from systemic sclerosis (SSc) patients and healthy controls (HCs). We also examined the effect of IPP-triggered peripheral blood mononuclear cells (PBMC) on fibroblast procolla- gen secretion. METHODS: PBMC from SSc patients and HCs were stimulated by increasing concentrations of Zoledronate, with or without IPP, and Vγ9+ T cell percentages were calculated using FACScan analysis. Subsequently, PBMC were cultured with IPP or toxic shock syndrome toxin-1 (TSST-1), and contents of the anti-fibrotic cytokines tumour necrosis factor (TNF)-α and interferon (IFN)-γ were measured by ELISA kits. Finally, supernatants of IPP-triggered Vγ9+ T cells from SSc patients were added to fibroblast cultures, and relative intensities of procollagen α1 chains were determined by densinometry. RESULTS: Higher concentrations of Zoledronate were required for maximal proliferation of Vγ9+ T cells in 9 SSc patients compared to 9 HCs, irrespective of exogenous IPP. When compared to stimulation by TSST-1, a non-Vγ9+ selective reagent, secretion of the anti-fibrotic cytokines TNF-α and IFN-γ in response to IPP was relatively diminished in SSc but not in HCs. Reduction of procollagen secretion by fibroblasts cultured with supernatants of IPP-stimulated PBMC was observed only in some SSc patients. CONCLUSIONS: Activated Vγ9+ T cells could act as anti-fibrotic mediators in SSc, although decreased responsiveness to IPP may play a role in the pathological fibrosis of this disease.

Implementation of a clinical decision support system for computerized drug prescription entries in a large tertiary care hospital.

BACKGROUND: Prescription errors are common in hospitalized patients and result in significant morbidity, mortality and costs. Electronic prescriptions with computerized physician order entry systems (CPOE) and integrated computerized decision support systems (CDSS providing online alerts) reduce prescription errors by approximately 50%. However, the introduction of CDSS is often met by opposition due to the flood of alerts, and most prescribers eventually ignore even crucial alerts ("alert fatigue"). OBJECTIVES: To describe the implementation and customization of a commercial CDSS (SafeRx) for electronic prescribing in Internal Medicine departments at a tertiary care center, with the purpose of improving comprehensibility and substantially reducing the number of alerts to minimize alert fatigue. METHODS: A multidisciplinary expert committee was authorized by the hospital administration to customize the CDSS according to the needs of six internal medicine departments at Sheba Medical Center. We assessed volume of prescriptions and alert types during the period February-August 2012 using the statistical functions provided by the CDSS. RESULTS: A mean of 339 +/- 13 patients per month per department received 11.2 +/- 0.5 prescriptions per patient, 30.1% of which triggered one or more CDSS alerts, most commonly drug-drug interactions (43.2%) and dosing alerts (38.3%). The review committee silenced or modified 3981 alerts, enhancing comprehensibility, and providing dosing instructions adjusted to the patient's renal function and recommendations for follow-up. CONCLUSIONS: The large volume of drug prescriptions in internal medicine departments is associated with a significant rate of potential prescription errors. To ensure its effectiveness and minimize alert fatigue, continuous customization of the CDSS to the specific needs of particular departments is required.

A Gastroenterologist's guide to drug interactions of small molecules for inflammatory bowel disease.

Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few interactions with other medications, the pharmacokinetics of small molecule drugs are complex and may be influenced by a myriad of drug-drug interactions (DDI) as well as by patient characteristics and food intake. This review aims to provide a concise practical guide to small molecule drug interactions for the use of IBD physicians. It starts with a brief overview of the main metabolizing enzymes and transporters involved in drug interactions and the Food and Drug Administration's (FDA) approach to determining drug-interaction hazard thresholds. It is then followed by a more detailed review of the pharmacokinetics of five novel small molecules approved in IBD: Tofacitinib, Upadacitinib, Filgotinib, Ozanimod, and Etrasimod, including their known interactions and specific warnings. This review will also inform readers on challenges in determining the actual magnitude of interactions and their clinical relevance, including the arbitrary nature of some hazard thresholds, the inference of the impact on metabolizing enzymes and transporters from single-drug assays which may not reflect poly-pharmaceutical regimens, and other challenges in this field which the IBD physician needs to be cognizant of. In practice, before administering a small molecule drug, it is advisable to evaluate any potential interactions with other medications the patient is receiving. An increased awareness by health care professionals and patients, may reduce the possible risks associated with DDI of small molecule IBD drugs.

"Body packers" in Israel: a case series.

BACKGROUND: "Body packers" swallow multiple packets filled with illicit drugs, mainly cocaine, in order to smuggle them across international borders. In recent years, an increasing number of body packers have been hospitalized after their detention by the police upon arrival in Israel. OBJECTIVES: To characterize the clinical features and outcomes of body packers hospitalized at the Sheba Medical Center. METHODS: We conducted a retrospective case series of body packers hospitalized between January 2010 and October 2012 in our medical center. Electronic medical records and imaging files were reviewed to extract clinical, laboratory and radiological data as well as details on medical treatments. RESULTS: We identified 23 body packers (mean age 38 +/- 10 years), 20 of whom smuggled cocaine from South America. The number of packets transported ranged from 1 to 242 (median 42) and duration of hospitalization from 1 to 14 days (median 2). Two subjects required surgical intervention. All others were treated conservatively by polyethylene glycol-electrolyte lavage solution, laxatives, or watchful waiting. Ten patients underwent a urinary screen for illicit drugs, 7 of whom tested positive for cocaine and 2 for cannabinoids. Abdominal X-rays were performed in all patients at admission, and 14 had follow-up imaging, including abdominal CT scans without contrast media in 8. CONCLUSIONS: The main treatment goals for body packers are the rapid excretion of drug packets and early detection of complications, i.e., drug intoxication and bowel obstruction. We suggest the use of a structured treatment approach for the in-hospital management of body packers.

Muscle pain and serum creatine kinase are not associated with low serum 25(OH) vitamin D levels in patients receiving statins.

OBJECTIVE: Vitamin D deficiency has been associated in some studies with nonspecific musculoskeletal pain and, more specifically, with statin-induced myalgia, which was ameliorated by high-dose vitamin D supplements. Our objective was to explore the association between vitamin D status and statin-induced myalgia and elevation of serum creatine kinase (CK). DESIGN: Retrospective cohort study, based on the electronic database of a health maintenance organization. PATIENTS: Six thousand eight hundred and eight patients (71·5% women) to whom statins were dispensed during 2008 and who had ≥1 CK and 25-hydroxy vitamin D (25OHD) levels measured during statin exposure. Of these, 376 patients (5·5%) had switched from a first-line statin to atorvastatin because of muscle pain (n = 220) or other reasons (n = 156). Measurements; In the entire cohort, we compared serum CK levels among serum 25OHD quartiles. In addition, we compared CK and 25OHD levels among patients with myalgia, other switchers and nonswitchers. RESULTS: The median 25OHD level in the entire cohort was 21·8 ng/ml [interquartile range (IQR), 16·3-27·4]. CK levels were marginally lower in patients in the lowest 25OHD quartile [median CK (IQR) in 25OHD quartiles 1-4, 87 (61-130), 90 (65-131), 91 (65-132) and 91 (67-131) IU/ml, respectively; P = 0·007]. 25OHD levels in statin switchers were similar to those in nonswitchers; moreover, there were no differences in 25OHD among switchers with muscle pain and other switchers. CONCLUSION: Our findings do not support an association between low 25OHD levels and statin-induced myalgia or CK elevation.

Effects of imatinib on glycemic and lipid profiles: a retrospective cohort study.

Despite a favorable effect of imatinib on glucose metabolism in animal models, human reports are inconsistent. We retrospectively studied the long-term effect of imatinib on fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), LDL-cholesterol (LDL), and triglycerides (TGs) in a large HMO cohort of patients initiating therapy. In patients with diabetes (n = 118), significant reductions in HbA1c (0.53%, IQR 0.09, 1.19; p < .001) and FPG (10.2 mg/dL, IQR -3.5, 32.2; p < .001), independent of demographics and of glucose-lowering drugs utilization, were observed during the first year of imatinib treatment. Significant reductions in LDL (17.8 mg/dL, IQR -1.3, 34.0; p < .001) and TG (25.0 mg/dL, IQR -2.3, 58.3; p < .001), also independent of demographics and of statin utilization, were evident in the entire cohort (n = 611) during the first imatinib year. All reductions persisted during the second treatment year. To conclude, imatinib is associated with durable metabolic benefits, which may guide TKI choice in patients with cardiovascular co-morbidities.

Linearity and stability of intravenous busulfan pharmacokinetics and the role of glutathione in busulfan elimination.

High-dose busulfan (Bu) is frequently used in preparative myeloablative conditioning (MAC) regimens for patients undergoing hematopoietic stem cell transplantation (HSCT). MAC and reduced-intensity conditioning (RIC) protocols for i.v. Bu infusion have been developed to achieve reliable systemic exposure while minimizing toxicity and treatment failure (relapse). The objectives of the present study were to (1) compare the pharmacokinetics (PK) of i.v. Bu in different dosing protocols, (2) compare intrasubject variability of Bu PK over repeated administrations; (3) examine the effect of concomitant administration of fludarabine on Bu PK, and (4) examine the effect of plasma concentrations of glutathione (GSH), the cosubstrate in Bu metabolism, on Bu clearance. We studied Bu PK twice in each of 46 HSCT patients (after the first and then after the middle dose of the treatment cycle) receiving one of 4 dosing protocols, 2 MAC (cumulative dose, 12.8 mg/kg) and 2 RIC (cumulative dose, 6.4 mg/kg), with daily doses administered either as an individual infusion (3.2 mg/kg) or as 4 infusions of 0.8 mg/kg each. Blood samples were obtained for 6-24 hours after dosing for measurement of Bu plasma concentrations. PK parameters were estimated using compartmental analyses. In a subgroup of patients (n = 14), GSH blood concentrations were determined before Bu administration. Dose- and weight-corrected Bu PK parameters (clearance, 0.173 ± 0.051 L/hour · kg; volume of distribution, 0.71 ± 0.17 L/kg; half-life time, 3.0 ± 0.7 hours) did not differ among treatment protocols (all P >.14) and remained stable between the first and mid-cycle doses. Fludarabine did not affect Bu PK. Blood GSH concentrations before Bu dosing were positively correlated with Bu clearance (adjusted R(2) = 0.45; P = .009). Our data indicate that Bu PK parameters are linear, stable, and predictable in different i.v. protocols and are unaffected by coadministration of fludarabine. Differences in whole blood GSH might contribute to variability in Bu clearance.

Potent CYP2D6 Inhibiting drugs do not increase relapse rate in early breast cancer patients treated with adjuvant tamoxifen.

Endoxifen, the most active metabolite of the prodrug tamoxifen, is produced by cytochrome P450 CYP2D6. Breast cancer patients treated with tamoxifen who have reduced CYP2D6 activity, related to either genetic variation or drug inhibition, may have inferior outcomes. To assess the effect of concomitant CYP2D6 inhibiting drug use on clinical outcomes of breast cancer patients treated with adjuvant tamoxifen. We conducted a retrospective database analysis. Women with non-metastatic estrogen receptor positive tumors who had completed adjuvant tamoxifen therapy for 2 years, without treatment with adjuvant aromatase inhibitors or early relapse, were included. Patients were classified as users of CYP2D6 inhibitors if they purchased strong CYP2D6 inhibiting drugs for ≥ 4 consecutive months during tamoxifen treatment. Tumors were classified as "high risk" if adjuvant chemotherapy was prescribed. Primary endpoint was disease free (DFS) and secondary endpoint was overall survival (OS). 902 patients treated with tamoxifen (median duration, 4.9 years) were followed for a median period of 5.9 years. Fifty-nine (6.5%) patients were users of CYP2D6 inhibitors (median duration, 23 months). DFS at 3 years (corresponding to 5 years after tamoxifen initiation) did not differ between users and non-users of CYP2D6 inhibiting drugs (92.7 vs. 93.0%, respectively; adjusted P = 0.44). OS at 3 years was lower in the patients using CYP2D6 inhibiting drugs: 89.4 vs. 93.8%, but after adjustment for age and comorbidities this difference was not significant (P = 0.20). Overall recurrence rates did not differ between users and non-users of CYP2D6 inhibiting drugs (11.8 vs. 19.0% respectively, P = 0.23). Concomitant prolonged therapy with strong CYP2D6 inhibiting drugs does not affect adversely DFS and recurrence rates in tamoxifen-treated early breast cancer patients.

Caffeine citrate for apnea of prematurity-One dose does not fit all a prospective study.

BACKGROUND: Caffeine citrate is the most frequently used medication in preterm neonates for the prevention of apnea of prematurity. There is no accepted consensus regarding the optimal caffeine citrate dosing. In this study, we evaluate clinical responses of premature neonates to standard-dose caffeine citrate treatment. METHODS: A prospective observational study conducted at the NICU at Sheba Medical Center (3/2016-2/2017). The study population included preterm neonates born at a gestational age (GA) < 33 weeks and treated with caffeine citrate according to the local NICU protocol. RESULTS: The study cohort included 66 preterm neonates of GA < 33 weeks. Thirty infants were defined as responders and 36 as nonresponders to 7.5 mg/kg caffeine citrate treatment, and they required a further dose increase to 10 mg/kg. Infants in the nonresponders group were born at earlier GA than responders (29 vs. 31 weeks, respectively, P = 0.004). The nonresponders required a significantly longer hospital stay (56 vs. 46 days, P = 0.014), and longer supplemental oxygen support (18 vs 2 days, P = 0.008). CONCLUSIONS: Caffeine citrate initiation at higher doses is safe and does not require routine serum levels monitoring. It might be more effective for controlling apnea of prematurity in preterm neonates born ≤29 weeks of gestation.

Warfarin and vitamin K intake in the era of pharmacogenetics.

The considerable variability in the warfarin dose-response relationship between individuals, is explained mainly by genetic variation in its major metabolic (CYP2C9) and target (VKORC1) enzymes. Despite the predominance of pharmacogenetics, environmental factors also affect the pharmacokinetics and pharmacodynamics of warfarin, and are often overlooked. Among these factors, dietary and supplemental vitamin K consumption is a controllable contributor to within-, and between-patient variability of warfarin sensitivity. In this commentary we review the current role of vitamin K in warfarin anticoagulation therapy, with emphasis on the following: 1 The effect of dietary and supplemental vitamin K on warfarin anticoagulation, beyond the impact of genetic variability in CYP2C9 and VKORC1. We deal separately with the effects of vitamin K on warfarin dose requirements during the induction of therapy, as opposed to its effect on stability of anticoagulation control during maintenance therapy. 2 The role of vitamin K supplementation in warfarin treated patients with vitamin K deficiency as well as in patients with unstable warfarin anticoagulation, and 3 The role of therapeutic vitamin K in cases of warfarin over-anticoagulation.

Uninterrupted direct oral anticoagulant treatment during acute illness: Impact on clinical outcomes.

BACKGROUND: Uninterrupted drug therapy during acute illness is often associated with pharmacokinetic and pharmacodynamic variations. Among warfarin treated patients, these changes are reflected in the INR. However, in the case of direct oral anticoagulants (DOACs), given that routine laboratory monitoring is not recommended, these changes may result in unforeseen thromboembolic or bleeding events. OBJECTIVES: To determine the rate of thromboembolic (TEE) and bleeding events associated with uninterrupted DOAC compared to warfarin treatment during acute illness. METHODS: A retrospective cohort study of patients treated with DOACs or warfarin, both at steady state, who were hospitalized for acute illness. Primary outcome was any TEE or major bleeding requiring re-hospitalization within one month from discharge. Secondary outcome was a composite of major bleeding and clinically relevant non-major bleeding (CRNMB) events. RESULTS: A total of 410 patients continued oral anticoagulant treatment during their hospitalization, of whom 191 (46.6%) were on DOACs and 219 (53.4%) on warfarin, with a total of 18 (4.4%) events. Rates of TEE and major bleeding events did not differ between DOACs and warfarin treated patients (0.9% vs. 0.5% and 0.5% vs. 1%, respectively). Similarly, rate of secondary outcome was comparable between DOACs (4.7%) and warfarin (2.7%, p = 0.29). Sub-analyses demonstrated significantly higher rates among rivaroxaban (10.4%) treated patients compared to warfarin (p = 0.03). CONCLUSION: Uninterrupted treatment with DOACs during acute illness is not associated with increased risk for re-hospitalizations due to bleeding or thromboembolic events compared to warfarin. Our results suggest a higher bleeding rate among rivaroxaban treated patients at high bleeding risk.