Pharmacological management of treatment-resistant schizophrenia: advanced use of clozapine

2018 ◽  
Author(s):  
Siobhan Gee ◽  
David Taylor
Keyword(s):  
Older Adults ◽  
Adverse Events ◽  
Plasma Concentrations ◽  
Practical Experience ◽  
Treatment Resistant ◽  
Serious Adverse Events ◽  
Pharmacological Management ◽  
Off Label ◽  
Theoretical Support ◽  
The Uk

Clozapine is licensed in the UK for use in treatment-resistant schizophrenia, treatment-intolerant schizophrenia, or psychosis associated with Parkinson’s disease. As with many drugs, it is also used outside of these licensing parameters for other conditions or clinical situations—often referred to as ‘off-label’ prescribing. These off-label indications have varying degrees of theoretical support, peer-reviewed evidence, and practical experience associated with them. This chapter discusses the use of clozapine for children and adolescents, older adults, and in the treatment of aggression and mood disorders. The use of supramaximal doses of clozapine to achieve therapeutic plasma concentrations is also off-label, although adding interacting medication to reach the same result is not; these contrasting approaches are also debated. Finally, rechallenging with clozapine in patients who have previously had serious adverse events to the drug is also considered.

Tonabersat, a Gap-Junction Modulator: Efficacy and Safety in Two Randomized, Placebo-Controlled, Dose-Ranging Studies of Acute Migraineceph

Cephalalgia ◽  
2009 ◽  
Vol 29 (2_suppl) ◽  
pp. 17-27 ◽  
Author(s):  
SD Silberstein ◽  
J Schoenen ◽  
H Göbel ◽  
HC Diener ◽  
AH Elkind ◽  
...  
Keyword(s):  
Adverse Events ◽  
North American ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Plasma Concentrations ◽  
International Study ◽  
Maximum Plasma ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Dose Ranging

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.

scholarly journals Potentially inappropriate medication use in older adults with mild-moderate Alzheimer’s disease: prevalence and associations with adverse events

2020 ◽  
Vol 49 (4) ◽  
pp. 580-587
Author(s):  
Claire Murphy ◽  
Adam H Dyer ◽  
Brian Lawlor ◽  
Sean P Kennelly ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Adverse Events ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Inappropriate Medication ◽  
Potentially Inappropriate Medication ◽  
Randomised Control Trial ◽  
Vulnerable Group ◽  
Serious Adverse Events

Abstract Aim Potentially inappropriate medication (PIM) use is prevalent in older adults and is associated with adverse events, hospitalisation and mortality. We assessed the patterns and associations of PIM use in older adults with mild-to-moderate Alzheimer’s Disease (AD), who may represent a particularly vulnerable group. Design Analysis of data from NILVad, an 18-month Randomised Control Trial of Nilvadapine in mild-to-moderate AD. The v2 STOPP criteria were applied in duplicate to identify PIM use. Associations between PIM use and adverse events/unscheduled healthcare visits in addition to the associations between PIM use and AD progression were evaluated. Setting and Participants 448 older adults with mild-to-moderate AD from 23 centres in nine European countries. Results Of 448 participants (mean age: 72.56 ± 8.19 years), over half (55.8%) were prescribed a PIM with 30.1% being prescribed 2+ PIMs. The most frequent PIMs were (i) long-term benzodiazepines (11.6% N = 52/448), (ii) selective serotonin reuptake inhibitors without appropriate indication (11.1% N = 50/448), and (iii) Proton-Pump Inhibitors (PPIs) without appropriate indication (10.7% N = 48/448). Increasing number of PIMs was associated with a greater risk of adverse events (IRR 1.17, 1.13–1.19, P < 0.001), serious adverse events (IRR 1.27; 1.17–1.37, P < 0.001), unscheduled hospitalisations (IRR 1.16, 1.03–1.30, P = 0.016) and GP visits (IRR 1.22, 1.15–1.28, P < 0.001). PIM use was not associated with dementia progression. Conclusions and Implications PIM use is highly prevalent in mild-to-moderate AD and is associated with adverse events and unscheduled healthcare utilisation. Further attention to de-prescribing in this vulnerable group is warranted.

Phase 1 Safety and Immunogenicity Study of a Respiratory Syncytial Virus Vaccine With an Adenovirus 26 Vector Encoding Prefusion F (Ad26.RSV.preF) in Adults Aged ≥60 Years

2020 ◽  
Vol 222 (6) ◽  
pp. 979-988 ◽  
Author(s):  
Kristi Williams ◽  
Arangassery Rosemary Bastian ◽  
Robert Allen Feldman ◽  
Edmund Omoruyi ◽  
Els de Paepe ◽  
...  
Keyword(s):  
Older Adults ◽  
Respiratory Syncytial Virus ◽  
Adverse Events ◽  
Immune Responses ◽  
Phase 1 ◽  
Geometric Mean ◽  
High Dose ◽  
Serious Adverse Events ◽  
Syncytial Virus ◽  
Vector Particles

Abstract Background Despite the high disease burden of respiratory syncytial virus (RSV) in older adults, there is no approved vaccine. We evaluated the experimental RSV vaccine, Ad26.RSV.preF, a replication-incompetent adenovirus 26 vector encoding the F protein stabilized in prefusion conformation. Methods This phase 1 clinical trial was performed in healthy adults aged ≥60 years. Seventy-two participants received 1 or 2 intramuscular injections of low-dose (LD; 5 × 1010 vector particles) or high-dose (HD; 1 × 1011 vector particles) Ad26.RSV.preF vaccine or placebo, with approximately 12 months between doses and 2-year follow-up for safety and immunogenicity outcomes. Results Solicited adverse events were reported by 44% of vaccine recipients and were transient and mild or moderate in intensity. No serious adverse events were related to vaccination. After the first vaccination, geometric mean titers for RSV-A2 neutralization increased from baseline (432 for LD and 512 for HD vaccine) to day 29 (1031 for LD and 1617 for HD). Pre-F–specific antibody geometric mean titers and median frequencies of F-specific interferon γ–secreting T cells also increased substantially from baseline. These immune responses were still maintained above baseline levels 2 years after immunization and could be boosted with a second immunization at 1 year. Conclusions Ad26.RSV.preF (LD and HD) had an acceptable safety profile and elicited sustained humoral and cellular immune responses after a single immunization in older adults.

Pharmacokinetics of Tecarfarin and Warfarin in Patients with Severe Chronic Kidney Disease

2017 ◽  
Vol 117 (11) ◽  
pp. 2026-2033 ◽  
Author(s):  
Detlef Albrecht ◽  
Mintu Turakhia ◽  
Daniel Ries ◽  
Thomas Marbury ◽  
William Smith ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Adverse Events ◽  
Plasma Concentrations ◽  
Anticoagulation Therapy ◽  
Serious Adverse Events ◽  
Single Dose Study ◽  
Cyp2c9 Genotype ◽  
The Difference ◽  
Repeated Dosing

AbstractChronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis (n = 13) were matched to healthy volunteers (HVs) (n = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life (t 1/2) increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin's inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy.

The Safety of Acupuncture – Evidence from the Uk

2006 ◽  
Vol 24 (1_suppl) ◽  
pp. 53-57 ◽  
Author(s):  
Adrian White
Keyword(s):  
Adverse Event ◽  
Adverse Events ◽  
Adverse Reactions ◽  
Event Rate ◽  
Adverse Event Rate ◽  
Serious Adverse Events ◽  
Positive Evidence ◽  
Safe Treatment ◽  
Significant Events ◽  
The Uk

Background Patients are attracted to acupuncture partly by its reputation for having low risks. The safety of acupuncture should be established by positive evidence. Methods Two prospective surveys were conducted among different groups of professionals in the UK, including doctors, physiotherapists and practitioners primarily trained in acupuncture. Participants monitored adverse events over a defined period of time, and reported minor and significant events on purpose designed forms. Results A total of 652 acupuncturists reported 6733 adverse reactions including tiredness in 66 229 patients, an adverse event rate of 10.2%. The most common events were tiredness (3%) bleeding or bruising (3%), aggravation of symptoms (2%) and pain at the needling site (1%). There were no serious adverse events. A total of 86 (0.1%) of the treatments was associated with an event that the practitioner judged to be significant though without persistent consequences for the patient's health. Conclusion The risks associated with acupuncture can be classified as negligible, and acupuncture is a very safe treatment in the hands of competent practitioners.

scholarly journals Semi-Recumbent Vibration Exercise in Older Adults: A Pilot Study of Methodology, Feasibility, and Safety

2019 ◽  
Vol 5 ◽  
pp. 233372141988155
Author(s):  
Murad H. Taani ◽  
Ellen Siglinsky ◽  
Jessie Libber ◽  
Diane Krueger ◽  
Neil Binkley ◽  
...  
Keyword(s):  
Older Adults ◽  
Adverse Events ◽  
Physical Function ◽  
Retention Rate ◽  
Functional Decline ◽  
Adherence Rate ◽  
Serious Adverse Events ◽  
Vibration Exercise ◽  
Type Of Exercise ◽  
And Control

Objectives: Older adults with impaired physical function are at risk for further functional decline in part due to limited ability to engage in regular exercise. Effective approaches to exercise in this vulnerable population are needed to improve functional capacity and optimize independence. Methods: Thirty-two residential care apartment complex (RCAC) residents, age ≥70, with low short physical performance battery (SPPB) scores were recruited and randomly assigned to a crossover-design study exploring feasibility and safety of semi-recumbent vibration exercise in older adults living in one RCAC. The primary outcomes were retention and adherence rates and adverse events. Results: The retention rate was 78%. Adherence rate was 79.7% and 78.6% during the vibration and control training sessions, respectively. Thirty-eight adverse events (AEs) occurred. Mild muscle soreness and knee pain were the only AEs related to vibration exercise. No serious adverse events (SAEs) were study-related. Participants were able to increase training intensity and load and rated the training enjoyable. Conclusion: Semi-recumbent vibration exercise was feasible, well tolerated, and safe in RCAC residents with reduced physical function. Future studies need to examine the effect of this type of exercise on physical function, mobility, falls, and quality of life.

scholarly journals Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Nadine G. Rouphael ◽  
Selwyn J. Hurwitz ◽  
Mari Hart ◽  
Allison Beck ◽  
Evan J. Anderson ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Laboratory ◽  
Subcutaneous Tissue ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Plasma Exposure ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Time Curve

ABSTRACT Filociclovir (MBX-400, cyclopropavir) is an antiviral agent with activity against cytomegalovirus (CMV). A phase 1, double-blind, randomized, placebo-controlled (3:1 ratio), single-center, multiple-ascending-dose trial was conducted to assess the safety, tolerability, and pharmacokinetics of filociclovir. Filociclovir (n = 18) or placebo (n = 6) was administered as a daily oral dose (100 mg, 350 mg, or 750 mg) for 7 days to normal healthy adults (ages, 25 to 65 years) who were monitored for 22 days. Safety assessments included clinical, laboratory, and electrocardiogram monitoring. Plasma and urine samplings were used to determine pharmacokinetic parameters. All study product-related adverse events were mild, most commonly gastrointestinal (17%), nervous system (11%), and skin and subcutaneous tissue (11%) disorders. One subject had reversible grade 3 elevation in serum creatinine and bilirubin, which was associated with an ∼1-log increase in plasma filociclovir exposure compared to levels for other subjects in the same (750-mg) cohort. No other serious adverse events were observed. Plasma exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) on days 1 and 7 were similar, suggesting negligible dose accumulation. There was a sublinear increase in plasma exposure with dose, which plateaued at the daily dose of 350 mg. The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro. (This study has been registered at ClinicalTrials.gov under identifier NCT02454699.)

scholarly journals Serious adverse events of older adults in nursing home and community intervention trials

2018 ◽  
Vol 9 ◽  
pp. 77-80 ◽  
Author(s):  
Rupak Datta ◽  
Mark Trentalange ◽  
Peter H. Van Ness ◽  
Joanne M. McGloin ◽  
Jack M. Guralnik ◽  
...  
Keyword(s):  
Older Adults ◽  
Nursing Home ◽  
Adverse Events ◽  
Community Intervention ◽  
Serious Adverse Events ◽  
Intervention Trials

scholarly journals GB0139, an inhaled small molecule inhibitor of galectin-3, in COVID-19 pneumonitis: a randomised, controlled, open-label, phase 2a experimental medicine trial of the safety, pharmacokinetics, and potential therapeutic value

2021 ◽  
Author(s):  
Erin Gaughan ◽  
Tariq Sethi ◽  
Tom Quinn ◽  
Nikhil Hirani ◽  
Andrew Mills ◽  
...  
Keyword(s):  
Adverse Events ◽  
Therapeutic Potential ◽  
Plasma Concentrations ◽  
Experimental Medicine ◽  
Target Engagement ◽  
Serious Adverse Events ◽  
Hospitalised Patients ◽  
Galectin 3 ◽  
Highest Posterior Density ◽  
Inspired Oxygen

Rationale: High galectin-3 levels predict poor outcomes in patients with COVID-19. Galectin-3 activates monocytes and macrophages which are directly implicated in COVID-19 immunopathology and the cytokine storm. GB0139 is a potent thiodigalactoside galectin-3 inhibitor and may reduce the severe effects of the disease. We report safety and pharmacokinetics and pharmacodynamics of the inhaled galectin-3 inhibitor, GB0139, and assess clinical outcomes and key systemic inflammatory biomarkers in hospitalised patients with COVID-19 (ClinicalTrials.gov/EudraCT identifier: NCT04473053/2020-002230-32). Methods: Adults with COVID-19 requiring oxygen, and with pneumonitis on x-ray, were randomised to receive standard of care (SOC; including dexamethasone; n=21) or SOC plus 10 mg GB0139 twice daily for 48 hours, then once daily for ≤14 days (n=20). Results: Patients aged 27–87 years were enrolled from July 2020; the final patient completed the 90-day follow-up in April 2021. GB0139+SOC was well tolerated with no treatment-related serious adverse events reported. Incidences of adverse events were similar between treatment arms (40 with GB0139+SOC vs 35 with SOC). Plasma GB0139 was measurable in all patients after inhaled exposure, with moderate interpatient variability, and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc over days 2–7: p=0·0099 vs SOC). Rate of decline in fraction of inspired oxygen (%) requirement was significantly greater in the GB0139+SOC arm with a posterior mean difference of −1 ·51 (95% highest posterior density: −2·90, −0·189) versus SOC. Plasma levels of biomarkers associated with inflammation, coagulopathy, major organ function and fibrosis showed a downward trend versus SOC. Conclusions: GB0139+SOC was well tolerated and achieved clinically relevant plasma concentrations and target engagement. This, and the reduction in markers associated with inflammatory, coagulation, fibrosis, and reduction in inspired oxygen (%) over SOC alone, indicates the therapeutic potential for inhaled GB0139 in hospitalised patients with COVID-19.

scholarly journals Post-market surveillance to detect adverse events associated with Melody® valve implantation

2016 ◽  
Vol 27 (6) ◽  
pp. 1090-1097 ◽  
Author(s):  
Kevin D. Hill ◽  
Bryan H. Goldstein ◽  
Michael J. Angtuaco ◽  
Patricia Y. Chu ◽  
Gregory A. Fleming
Keyword(s):  
Adverse Events ◽  
Large Scale ◽  
The United States ◽  
Stent Fracture ◽  
Serious Adverse Events ◽  
Market Surveillance ◽  
Off Label ◽  
Post Market Surveillance ◽  
Post Market ◽  
Valve Implantation

AbstractObjectiveThe aim of this study was to describe previously unrecognised or under-recognised adverse events associated with Melody® valve implantation.BackgroundIn rare diseases and conditions, it is typically not feasible to conduct large-scale safety trials before drug or device approval. Therefore, post-market surveillance mechanisms are necessary to detect rare but potentially serious adverse events.MethodsWe reviewed the United States Food and Drug Administration’s Manufacturer and User Facility Device Experience (MAUDE) database and conducted a structured literature review to evaluate adverse events associated with on- and off-label Melody® valve implantation. Adverse events were compared with those described in the prospective Investigational Device Exemption and Post-Market Approval Melody® transcatheter pulmonary valve trials.ResultsWe identified 631 adverse events associated with “on-label” Melody® valve implants and 84 adverse events associated with “off-label” implants. The most frequent “on-label” adverse events were similar to those described in the prospective trials including stent fracture (n=210) and endocarditis (n=104). Previously unrecognised or under-recognised adverse events included stent fragment embolisation (n=5), device erosion (n=4), immediate post-implant severe valvar insufficiency (n=2), and late coronary compression (n=2 cases at 5 days and 3 months after implantation). Under-recognised adverse events associated with off-label implantation included early valve failure due to insufficiency when implanted in the tricuspid position (n=7) and embolisation with percutaneous implantation in the mitral position (n=5).ConclusionPost-market passive surveillance does not demonstrate a high frequency of previously unrecognised serious adverse events with “on-label” Melody® valve implantation. Further study is needed to evaluate safety of “off-label” uses.

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