piperidines and Thromboembolism

The Agency for Healthcare Research and Quality, in partnership with the American College of Surgeons and the Johns Hopkins Medicine Armstrong Institute for Patient Safety and Quality, has developed the Safety Program for Improving Surgical Care and Recovery (ISCR), which is a national effort to disseminate best practices in perioperative care to more than 750 hospitals across multiple procedures in the next 5 years. The program will integrate evidence-based processes central to enhanced recovery and prevention of surgical site infection, venous thromboembolic events, catheter-associated urinary tract infections with socioadaptive interventions to improve surgical outcomes, patient experience, and perioperative safety culture. The objectives of this review are to evaluate the evidence supporting anesthesiology components of colorectal (CR) pathways and to develop an evidence-based CR protocol for implementation. Anesthesiology protocol components were identified through review of existing CR enhanced recovery pathways from several professional associations/societies and expert feedback. These guidelines/recommendations were supplemented by evidence made further literature searches. Anesthesiology protocol components were identified spanning the immediate preoperative, intraoperative, and postoperative phases of care. Components included carbohydrate loading, reduced fasting, multimodal preanesthesia medication, antibiotic prophylaxis, blood transfusion, intraoperative fluid management/goal-directed fluid therapy, normothermia, a standardized intraoperative anesthesia pathway, and standard postoperative multimodal analgesic regimens.

Topics: Anesthesia; Anesthesiology; Anti-Bacterial Agents; Antibiotic Prophylaxis; Carbohydrates; Colorectal Neoplasms; Colorectal Surgery; Evidence-Based Medicine; Fluid Therapy; Humans; Patient Safety; Perioperative Care; Piperidines; Quality of Health Care; Randomized Controlled Trials as Topic; Safety Management; Surgical Procedures, Operative; Thromboembolism; Treatment Outcome; United States; United States Agency for Healthcare Research and Quality; Urinary Tract Infections

Two different Janus kinase (JAK) inhibitors-baricitinib and tofacitinib-are effective and licensed in active rheumatoid arthritis (RA). There have been recent concerns about potential thromboembolic risks with these drugs. Concerns about baricitinib focus on clinical trial findings. Using all publically available data, we estimate thromboembolic risks are approximately five events per 1000 patient years with 4 mg baricitinib daily. Concerns about tofacitinib have been raised by analyses of the Federal Drug Administration Adverse Event Reporting System (FAERs). These show some evidence of increased risks of pulmonary thrombosis, though not pulmonary embolism or venous thrombosis. Observational studies suggest in the general population and non-RA controls there are one to four thromboembolic events per 1000 patient years. In RA, thromboembolic risks increase to three to seven per 1000 patient years. The impact of biologics and disease-modifying anti-rheumatic drugs (DMARDs) on disease risk appears minimal, and the number of thromboembolic events is between four and eight per 1000 patient years. In the short term, full details of thromboembolic events in trials of JAK inhibitors need to be published. As the numbers of thromboembolic events will be small and patients enrolled in trials are not representative of all RA patients who may receive JAK inhibitors, this information is unlikely to provide definitive answers. Consequently, in the longer term, large observational studies are needed to accurately quantify thromboembolic risks attributable to JAK inhibitors and other drugs used to treat RA, and differentiate these from risks attributable to RA itself and its comorbidities.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Clinical Trials as Topic; Humans; Janus Kinase Inhibitors; Piperidines; Purines; Pyrazoles; Pyrimidines; Pyrroles; Risk Factors; Sulfonamides; Thromboembolism

The selective estrogen receptor modulators (SERMs) are substances with estrogenic/anti-estrogen effect that act differently depending on the tissue and composition. Since the discovery that tamoxifen and raloxifene (RLX) had a breast cancer preventive effect, the search for the perfect SERM has been the goal. The evidence that tamoxifen significantly increased the risk of endometrial cancer as compared to placebo made this tissue the center of interest in developing new SERMs. Thus, ospemifen, arzoxifene, lasofoxifene (LFX) and bazedoxifene (BZA) appeared as third-generation SERMs but only BZA reached the stage of clinical use. Both experimental and clinical data available on the effects of RLX or third-generation SERMs reaching clinical stage (LFX and BZA) show either neutrality or anti-estrogenic effects at endometrial level. BZA has shown to be equivalent to vehicle in several experimental conditions and acts as anti-estrogen in models were estrogens (conjugated equine estrogens [CEE] or E2) were co-administered. In a 7 years pivotal study the incidence of endometrial adenocarcinoma has been significantly lower in the BZA than in the placebo group. Moreover, in a clinical trial to evaluate the ability of a combination of BZA and CEE to prevent hot flushes in symptomatic postmenopausal women, doses of 20mg or higher of BZA have significantly decreased the risk of presenting endometrial hyperplasia when co-administered with either 0.650 or 0.450mg of CEE.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation, Preclinical; Endometrial Neoplasms; Endometrium; Estradiol; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Hot Flashes; Humans; Indoles; Menopause; Multicenter Studies as Topic; Organ Specificity; Osteoporosis, Postmenopausal; Piperidines; Pyrrolidines; Rats; Selective Estrogen Receptor Modulators; Tamoxifen; Tetrahydronaphthalenes; Thiophenes; Thromboembolism

Timely and important studies are reviewed and commentaries provided by leading palliative care clinicians. Symptoms, interventions, and treatment-related adverse events addressed in this issue are management of Alzheimer's agitation with donepezil; needle-free lidocaine powder for minor painful procedures; psychostimulants in depression; anticoagulation for cancer-related venous thromboembolism; effect of waiting for acute pain treatment on risk of chronic pain; and an update on severe cutaneous reactions associated with medications.

Topics: Alzheimer Disease; Amphetamines; Anesthetics, Local; Anticoagulants; Antidepressive Agents; Depression; Donepezil; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Indans; Lidocaine; Nootropic Agents; Pain; Palliative Care; Phlebotomy; Piperidines; Prescription Drugs; Psychomotor Agitation; Randomized Controlled Trials as Topic; Sertraline; Stevens-Johnson Syndrome; Thromboembolism

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Anticoagulants; Antineoplastic Agents; Azetidines; Body Weight; Cannabinoid Receptor Antagonists; Cetuximab; Drug Therapy; Ezetimibe; Fondaparinux; Humans; Hypoglycemic Agents; Insulin; Osteoporosis, Postmenopausal; Piperidines; Polysaccharides; Pyrazoles; Rimonabant; Smoking Cessation; Teriparatide; Thromboembolism

To establish the mortality risk and adverse events associated with the use of atypical antipsychotic medications in people with Parkinson disease psychosis (PDP) in a clinically defined trial cohort.. Post hoc analysis of data from a multicenter, open-label extension study of pimavanserin comparing people taking and not taking current antipsychotics.. Primary and secondary care medical centers in the United States, Canada, Europe, and India.. A total of 459 people with PDP enrolled in the extension study. Participants were between ages 30 and 80 years, and had an established diagnosis of idiopathic Parkinson disease and moderate to severe psychosis.. Participants were categorized into 2 groups: those receiving concomitant antipsychotic medications ("concurrent APD") and those who did not take antipsychotic medications at any time during the study ("no APD"). Participants were receiving 40 mg pimavanserin daily in addition to concurrent antipsychotics and Parkinson disease medications.. Safety assessments at 2 weeks; 1, 3, 6, 9, and 12 months; and every 6 months thereafter, including evaluation of adverse events (AEs), vital signs, weight, physical examinations, 12-lead electrocardiograms, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS-II+III, activities of daily living and motor impairment, respectively). Differences between participants taking and not taking current antipsychotics were evaluated using incidence rate ratios (IRRs) with 95% confidence intervals (CIs).. There was significant increase in the mortality rate for participants taking concurrent antipsychotics compared with the group not taking antipsychotic medications (IRR 4.20, 95% CI 2.13-7.96). Participants who received a concurrent antipsychotic were also significantly more likely to experience overall a serious AE (IRR 2.95, 95% CI 2.02-4.24), any antipsychotic-related event (IRR 1.66, 95% CI 1.18-2.29), cognition-related events (IRR 2.70, 95% CI 1.19-5.58), infections (IRR 1.97, 95% CI 1.17-3.16), and edema (IRR 2.61, 95% CI 1.09-5.59). The risk of falls, stroke, sedation, orthostatic hypotension, and thromboembolic events was also increased in these individuals but this was not significant.. This study highlights a significant risk of mortality, and severe AEs in patients with Parkinson disease receiving atypical antipsychotics. This is similar to or greater than the risks seen in people with Alzheimer disease, although with a less clear-cut risk of stroke and a longer delay to increased mortality.

Topics: Accidental Falls; Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Antipsychotic Agents; Drug Therapy, Combination; Edema; Female; Humans; Hypotension, Orthostatic; Infections; Male; Middle Aged; Parkinson Disease; Piperidines; Psychotic Disorders; Stroke; Thromboembolism; Urea

Raloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting.. To determine whether women taking raloxifene have a lower risk of invasive breast cancer.. The Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe.. A total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded.. Raloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets.. New cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review.. Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), but not estrogen receptor-negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7).. Among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene.

Topics: Aged; Breast Neoplasms; Double-Blind Method; Endometrial Neoplasms; Estrogen Antagonists; Estrogens; Female; Follow-Up Studies; Humans; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Raloxifene Hydrochloride; Receptors, Estrogen; Risk; Thromboembolism

Ibrutinib is a novel drug used in haematological malignancies. Its use is associated with an increased risk of atrial fibrillation (AF), which, in turn, exposes patients to embolic risk, including stroke. Reducing this risk requires anticoagulant therapy which is a matter of concern in the context of the increased bleeding risk of patients with haematological malignancies. In this context the presence of thrombocytopenia related to haematological disorder, ibrutinib-anticoagulants and ibrutinib-platelets interactions contribute to the amplification of the problem. The correct assessment of the thrombosis vs. haemorrhage balance represents a significant challenge for the clinician. In this paper we discuss practical issues related to anticoagulation in patients treated with ibrutinib and incident AF.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Atrial Fibrillation; Hematologic Neoplasms; Hemorrhage; Humans; Piperidines; Risk Factors; Stroke; Thromboembolism

The Janus kinase (JAK) inhibitors tofacitinib and baricitinib are new treatments for rheumatic diseases. Recent concerns regarding the risk of thrombosis have led to warnings by competent authorities. We therefore aimed to examine the thromboembolic safety signal for tofacitinib and baricitinib.. Individual case safety reports (ICSRs) for tofacitinib and baricitinib were retrieved from the World Health Organization global database VigiBase in April 2019. Primary outcomes were deep vein thrombosis (DVT) and pulmonary thrombosis (PT) or pulmonary embolism (PE). Patient demographics were summarized and then stratified by outcome. Disproportionality analyses were conducted by estimating the reporting odds ratios (RORs) and 95% confidence intervals (CIs) worldwide, and stratified by either Europe or the US.. In both the tofacitinib (n = 40,017) and baricitinib (n = 2138) ICSRs, patients with reported DVT or PT/PE were older and had higher reporting of prothrombotic medications or antithrombotic treatments, suggesting a pre-existing thromboembolic risk/event. In Europe, tofacitinib was associated with increased reporting for DVT (ROR 2.37, 95% CI 1.23-4.56) and PT/PE (ROR 2.38. 95% CI 1.45-3.89). For baricitinib, a threefold increased reporting odds was observed for DVT (ROR 3.47, 95% CI 2.18-5.52) and PT/PE (ROR 3.44, 95% CI 2.43-4.88) in Europe. In the US, tofacitinib was only associated with an elevated ROR of PT (ROR 2.05, 95% CI 1.45-2.90) and no baricitinib ICSRs were reported.. This study supports the current recommendation for cautious use of tofacitinib in patients with high thromboembolic risk. Moreover, with a similar patient profile and elevated reporting for baricitinib, a potential class effect of JAK inhibitors cannot be ruled out.

Topics: Adverse Drug Reaction Reporting Systems; Arthritis, Rheumatoid; Azetidines; Humans; Janus Kinase Inhibitors; Pharmacovigilance; Piperidines; Purines; Pyrazoles; Pyrimidines; Sulfonamides; Thromboembolism; World Health Organization

Topics: Azetidines; Humans; Janus Kinase Inhibitors; Piperidines; Purines; Pyrazoles; Pyrimidines; Sulfonamides; Thromboembolism; World Health Organization

Tofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within.. This post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years' exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed.. DVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32-0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13-0.41)).

Topics: Adult; Aged; Antirheumatic Agents; Clinical Trials as Topic; Female; Humans; Incidence; Male; Middle Aged; Observational Studies as Topic; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rheumatic Diseases; Thromboembolism

A novel postsynaptic antagonist of N-methyl-D-aspartate (NMDA) receptors, CP-101,606-27 may attenuate the effects of focal ischemia. In current experiments, the authors investigated its neuroprotective effect alone and in combination with recombinant tissue plasminogen activator (rt-PA) in thromboembolic focal cerebral ischemia in rats.. Forty-eight male Wistar rats underwent embolization of the right middle cerebral artery to produce focal cerebral ischemia. After random division into six groups (eight rats in each group), animals received: vehicle; low-dose (LD) CP-101, 606-27, 14.4 mg/kg; high-dose (HD) CP- 101,606-27, 28.8 mg/kg; rt-PA, 10 mg/kg; low-dose combination (LDC) CP- 101,606-27, 14.4 mg/kg plus rt-PA, 10 mg/kg; or high-dose combination (HDC) CP- 101,606-27, 28.8 mg/kg plus rt-PA, 10 mg/kg) 2 hours after induction of embolic stroke. Animals were killed 48 hours after the onset of focal ischemia. Brain infarction volume, neurobehavioral outcome, poststroke seizure activity, poststroke mortality, and intracranial hemorrhage incidence were observed and evaluated. Compared with vehicle-treated animals (39.4 +/- 8.6%) 2 hours posttreatment with CP-101,606-27 or rt-PA or in combination a significant reduction in the percentage of brain infarct volume was seen (LD CP-101,606-27: 20.8 +/- 14.3%, p < 0.05; HD CP-101,606-27: 10.9 +/- 3.2%, p < 0.001; rt-PA: 21.1 +/- 7.3%, p < 0.05; LDC, 18.6 +/- 11.5%, p < 0.05; and HDC: 15.2 +/- 10.1%, p < 0.05; compared with control: 39.4 +/- 8.6%). Combination of CP-101,606-27 with rt-PA did not show a significantly enhanced neuroprotective effect. Except for the control and LDC treatment groups, neurobehavioral outcome was significantly improved 24 hours after embolic stroke in animals in all other active therapeutic groups receiving CP-101,606-27 or rt-PA or in combination. The authors also observed that treatment with HD CP-101,606-27 decreased poststroke seizure activity.. The data in this study suggested that postischemia treatment with CP-101,606-27 is neuroprotective in the current stroke model; however, the authors also note that although rt-PA may offer modest protection when used alone, combination with CP-101,606-27 did not appear to enhance its effects.

Topics: Animals; Brain Infarction; Disease Models, Animal; Drug Therapy, Combination; Male; Nervous System Diseases; Neuroprotective Agents; Piperidines; Plasminogen Activators; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Severity of Illness Index; Stroke; Thromboembolism; Tissue Plasminogen Activator

Although pharmacological agents are frequently used to control ventricular rate or restore sinus rhythm of patients with atrial fibrillation (AF), there are no reports of the relationship between those agents and left atrial appendage (LAA) function. Two cases of a decrease in LAA blood flow velocity caused by negative inotropic agents are presented as an indication that negative inotropic agents are a risk factor for systemic thromboembolism with AF.

Topics: Atenolol; Atrial Fibrillation; Atrial Function, Left; Blood Flow Velocity; Cardiotonic Agents; Echocardiography, Transesophageal; Humans; Male; Middle Aged; Piperidines; Thromboembolism

Topics: Bone Density; Clinical Trials as Topic; Dose-Response Relationship, Drug; Estrogen Antagonists; Female; Half-Life; Humans; Middle Aged; Osteoporosis, Postmenopausal; Piperidines; Raloxifene Hydrochloride; Thromboembolism

The anticoagulant and antithrombotic effects of YM-75466 (N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naph thyl)methyl]sulfamoyl acetic acid monomethanesulfonate), a novel orally-active factor Xa (FXa) inhibitor, and warfarin were compared in mice. Both agents were orally administered in all studies. In ex vivo studies, the peak effects of YM-75466 occurred 1 hr after administration while the peak of warfarin activity occurred 18 hr after administration. At each peak, both YM-75466 and warfarin prolonged coagulation time dose-dependently. The dose response curve of warfarin for prothrombin time was steeper than that of YM-75466. In a thromboplastin-induced thromboembolism model, administration of 30 mg/kg YM-75466 or 3 mg/kg warfarin significantly improved the lethality ratio. In blood loss studies, YM-75466 did not increase blood loss from the tail even at 30 mg/kg, while warfarin markedly increased blood loss at 3 mg/kg. Agents that interfere with warfarin action did not interfere with YM-75466 action. In conclusion, this study shows that YM-75466 has advantages over warfarin: i) rapid onset of anticoagulant activity, ii) wide therapeutic range, iii) little effect on bleeding and iv) lack of drug interaction with agents that interfere with warfarin. These results suggest that YM-75466 may be promising as a novel oral anticoagulant agent.

Topics: Administration, Oral; Analgesics, Non-Narcotic; Animals; Anti-Bacterial Agents; Anticoagulants; Anticonvulsants; Antifibrinolytic Agents; Blood Coagulation; Carbamazepine; Cimetidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Erythromycin; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Male; Mice; Mice, Inbred ICR; Partial Thromboplastin Time; Phenytoin; Piperidines; Prothrombin Time; Rifampin; Sulfonamides; Thromboembolism; Thromboplastin; Vitamin K 1; Warfarin

Topics: Angina, Unstable; Animals; Anticoagulants; Antithrombins; Clinical Trials as Topic; Dalteparin; Enoxaparin; Fibrinolytic Agents; Glycine; Heparin, Low-Molecular-Weight; Humans; In Vitro Techniques; Myocardial Infarction; Nadroparin; Piperidines; Thromboembolism

The effect of administration of pirmenol, an extensively metabolized and plasma protein-bound antiarrhythmic agent, was evaluated in ten patients on chronic warfarin therapy. After a 3-week baseline period and 7 days of placebo administration, patients received 150 mg of oral pirmenol every 12 hours for 14 days. Prothrombin time was determined during the baseline and placebo periods, during pirmenol administration, and 14 days after the last pirmenol dose (washout). There was no significant difference between mean baseline, placebo, pirmenol, and washout prothrombin times. Coadministration of pirmenol does not appear to affect the anticoagulant activity of warfarin.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Drug Interactions; Humans; Middle Aged; Piperidines; Prothrombin Time; Thromboembolism; Warfarin