Metoclopramide: dose-related toxicity and preliminary antiemetic studies in children receiving cancer chemotherapy.

1985 ◽  
Vol 3 (8) ◽  
pp. 1136-1141 ◽  
Author(s):  
J C Allen ◽  
R Gralla ◽  
L Reilly ◽  
M Kellick ◽  
C Young
Keyword(s):  
Older Adults ◽  
Clinical Trials ◽  
Cancer Chemotherapy ◽  
Randomized Clinical Trials ◽  
Dose Range ◽  
Toxicity Study ◽  
Dose Increase ◽  
Younger Adults ◽  
Nonrandomized Trial ◽  
Safe Dose

Prior studies in adults have shown that metoclopramide (MCP), when given in high intravenous (IV) doses (2 mg/kg), is a highly effective antiemetic for chemotherapy-induced vomiting. It is well-tolerated in older adults, but younger adults have an increased disposition to acute extrapyramidal reactions (EPRs). Before studying the efficacy of MCP as an antiemetic in children, we first had to establish the safe dose range. We performed a dose-increase MCP toxicity study in children receiving highly emetic chemotherapy such as cisplatin (120 mg/m2) or cyclophosphamide (greater than 900 mg/m2), beginning with a dose of 0.2 mg/kg and increasing the dose in nine steps to 3 mg/kg. MCP was given every two hours for four doses beginning one-half hour before chemotherapy. To reduce the incidence of EPRs, we added concomitant diphenhydramine. In MCP doses less than 2 mg, toxicity was minimal. In doses greater than or equal to 2 mg, 4/27 (15%) had EPRs and 9/27 (33%) had akathisia. Children who received two consecutive days of MCP had a higher frequency of EPRs. Metoclopramide (2 mg/kg) had promising antiemetic efficacy in a preliminary nonrandomized trial. Chemotherapy-experienced children vomited fewer than five times in 9/21 (43%) trials, and new patients vomited fewer than five times in 7/10 (70%) trials. MCP will become more useful as an antiemetic in children if better measures to prevent EPRs can be developed. Chemotherapy-induced emesis has the same negative implications in children as it does in adults and optimum antiemetic regimens can only be discovered by conducting randomized clinical trials in children.

scholarly journals Unanticipated efficacy of SARS-CoV-2 vaccination in older adults

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Graham Pawelec ◽  
Janet McElhaney
Keyword(s):  
Older Adults ◽  
Clinical Trials ◽  
Infectious Diseases ◽  
Vaccine Efficacy ◽  
Paradigm Shift ◽  
Randomized Clinical Trials ◽  
Senior Citizens ◽  
Older Individuals ◽  
Younger Adults ◽  
The Impact

AbstractThe rapidity with which vaccines against COVID-19 have been developed and tested is unprecedented. As classically the case with randomized clinical trials, many studies excluded older adults. However, given the early realisation that senior citizens were most highly susceptible to COVID, older individuals have been included in licensing trials under these unusual conditions. The recently published results from the Comirnaty Vaccine (BNT162b) trial unexpectedly documented that vaccine efficacy was equally exceptionally high in older and younger adults. These extremely encouraging trial results with a neoantigen vaccine may suggest the beginning of a paradigm shift in our view of the impact of immunosenescence on vaccination against novel infectious diseases.

Phase 1 Clinical Trials of Small Molecules: Evolution and State of the Art

2021 ◽  
Vol 16 ◽  
Author(s):  
John J. Sramek ◽  
Michael F. Murphy ◽  
Sherilyn Adcock ◽  
Jeffrey G. Stark ◽  
Neal R. Cutler
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Healthy Volunteers ◽  
Small Molecules ◽  
Phase 1 ◽  
Dose Range ◽  
Pharmacodynamic Modeling ◽  
Inpatient Setting ◽  
Conducting Phase ◽  
Safe Dose

Background: Phase 1 studies comprise the first exposure of a promising new chemical entity in healthy volunteers or, when appropriate, in patients. To assure a solid foundation for subsequent drug development, this first step must carefully assess the safety and tolerance of a new compound, and often provide some indication of potential effect, so that a safe dose or dose range can be confidently selected for the initial Phase 2 efficacy study in the target patient population. Methods: This review was based on a literature search using both Google Scholar and PubMed, dated back to 1970, using search terms including “healthy volunteers”, “Phase 1”, and “normal volunteers” , and also based on the authors’ own experience conducting Phase 1 clinical trials. This paper reviews the history of Phase 1 studies of small molecules and their rapid evolution, focusing on the critical single and multiple dose studies, their designs, methodology, use of pharmacokinetic and pharmacodynamic modeling, application of potentially helpful biomarkers, study stopping criteria, and novel study designs. Results: We advocate for determining the safe dose range of a new compound by conducting careful dose escalation in a well-staffed inpatient setting, defining the maximally tolerated dose (MTD) by reaching the minimally intolerated dose (MID). The dose immediately below the MID is then defined as the MTD. This is best accomplished by using appropriately screened patients for the target indication, as patients in many CNS indications often tolerate doses differently than healthy non-patients. Biomarkers for safety and pharmacodynamic measures can also assist in further defining a safe and potentially effective dose range for subsequent clinical trial phases. Conclusion: Phase 1 studies can yield critical insights to the pharmacology of a new compound in man and offer perhaps the only development period in which the dose range can be safely and thoroughly explored. Phase 1 studies often contain multiple endpoint objectives, the reconciliation of which can present a dilemma for drug developers and study investigators alike, but which can crucially determine whether a compound can survive to the next step in the drug development process.

scholarly journals Antihypertensive Agents in Older Adults: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

2019 ◽  
Vol 104 (5) ◽  
pp. 1575-1584 ◽  
Author(s):  
Mohammad Hassan Murad ◽  
Laura Larrea-Mantilla ◽  
Abdullah Haddad ◽  
Gabriela Spencer-Bonilla ◽  
Valentina Serrano ◽  
...  
Keyword(s):  
Systematic Review ◽  
Older Adults ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Antihypertensive Agents

Myelotoxicity and Dose Intensity of Chemotherapy: Reporting Practices From Randomized Clinical Trials

2003 ◽  
Vol 1 (3) ◽  
pp. 440-454 ◽  
Author(s):  
David C. Dale ◽  
Gordon C. McCarter ◽  
Jeffrey Crawford ◽  
Gary H. Lyman
Keyword(s):  
Clinical Trials ◽  
Cancer Chemotherapy ◽  
Randomized Clinical Trials ◽  
Early Stage ◽  
Dose Intensity ◽  
Hematologic Toxicity ◽  
Intensity Data ◽  
Reporting Practices ◽  
Standard Procedures ◽  
Treatment Alternatives

Delivery of cancer chemotherapy is often limited by myelotoxicity, primarily neutropenia. As part of an effort to create a model to predict the risk of chemotherapy-induced neutropenia, we reviewed the reports of randomized clinical trials with more than 50 patients per arm in early-stage breast cancer (ESBC) and non-Hodgkin's lymphoma (NHL) published between 1990 and 2000. We observed that no hematologic toxicity data were reported in 39% and 34% of the ESBC and NHL trials, respectively. The remaining trials reported on hematologic toxicity in 16 different ways. When reported, rates of neutropenia, leukopenia, and hematotoxicity varied widely with the same and similar chemotherapy regimens. Dose-intensity data were not reported in 39% and 54% of ESBC and NHL trials, respectively. The majority of the remaining studies reported incomplete dose-intensity data such as percentages of patients completing all cycles or receiving a given percentage of planned dose intensity. Only 28% reported the mean or median relative dose intensity received by patients. Based on this review, we conclude that current practices for reporting chemotherapy treatments are inadequate for describing the risk of chemotherapy to patients or for quantitatively assessing the risk of treatment alternatives. We recommend that standard procedures for documenting and reporting hematologic toxicity and dose intensity in cancer chemotherapy trials be required for publication of chemotherapy trials.

Inclusion of Older Adults in Randomized Clinical Trials for Systemic Medications for Atopic Dermatitis

2020 ◽  
Vol 156 (11) ◽  
pp. 1240
Author(s):  
Megan Lam ◽  
Jie Wei Zhu ◽  
Talha Maqbool ◽  
Gaelen Adam ◽  
Mina Tadrous ◽  
...  
Keyword(s):  
Older Adults ◽  
Clinical Trials ◽  
Atopic Dermatitis ◽  
Randomized Clinical Trials

The special problems of conducting clinical trials in elderly patients

1997 ◽  
Vol 7 (1) ◽  
pp. 1-3 ◽  
Author(s):  
Jacqueline Bene ◽  
Richard Liston
Keyword(s):  
Older Adults ◽  
Clinical Trials ◽  
Clinical Practice ◽  
Elderly Patients ◽  
Patient Care ◽  
Real World ◽  
Younger Adults ◽  
Medical Treatments ◽  
Multiple Pathology ◽  
Complete Exclusion

It is frequently observed that medical treatments are evaluated in patient populations which have characteristics significantly different from those of patients upon whom the treatments will be used once established in clinical practice. The most striking illustration of this has been the almost complete exclusion, until recently, of elderly patients from trials of new medication. Whereas clinical trials include younger adults with a single pathology, the real world of patient care is dominated by older adults with multiple pathology.

scholarly journals Evaluation of the Effectiveness of Digital Technology Interventions to Reduce Loneliness in Older Adults: Systematic Review and Meta-analysis (Preprint)

2020 ◽  
Author(s):  
Syed Ghulam Sarwar Shah ◽  
David Nogueras ◽  
Hugo Cornelis van Woerden ◽  
Vasiliki Kiparoglou
Keyword(s):  
Older Adults ◽  
Clinical Trials ◽  
Digital Technology ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Public Health Issue ◽  
Future Research ◽  
Physical And Mental Health ◽  
Significant Difference

BACKGROUND Loneliness is a serious public health issue, and its burden is increasing in many countries. Loneliness affects social, physical, and mental health, and it is associated with multimorbidity and premature mortality. In addition to social interventions, a range of digital technology interventions (DTIs) are being used to tackle loneliness. However, there is limited evidence on the effectiveness of DTIs in reducing loneliness, especially in adults. The effectiveness of DTIs in reducing loneliness needs to be systematically assessed. OBJECTIVE The objective of this study is to assess the effectiveness of DTIs in reducing loneliness in older adults. METHODS We conducted electronic searches in PubMed, MEDLINE, CINAHL, Embase, and Web of Science for empirical studies published in English from January 1, 2010, to July 31, 2019. The study selection criteria included interventional studies that used any type of DTIs to reduce loneliness in adults (aged ≥18 years) with a minimum intervention duration of 3 months and follow-up measurements at least 3 months after the intervention. Two researchers independently screened articles and extracted data using the PICO (participant, intervention, comparator, and outcome) framework. The primary outcome measure was loneliness. Loneliness scores in both the intervention and control groups at baseline and at follow-up at 3, 4, 6, and 12 months after the intervention were extracted. Data were analyzed via narrative synthesis and meta-analysis using RevMan (The Cochrane Collaboration) software. RESULTS A total of 6 studies were selected from 4939 screened articles. These studies included 1 before and after study and 5 clinical trials (4 randomized clinical trials and 1 quasi-experimental study). All of these studies enrolled a total of 646 participants (men: n=154, 23.8%; women: n=427, 66.1%; no gender information: n=65, 10.1%) with an average age of 73-78 years (SD 6-11). Five clinical trials were included in the meta-analysis, and by using the random effects model, standardized mean differences (SMDs) were calculated for each trial and pooled across studies at the 3-, 4-, and 6-month follow-ups. The overall effect estimates showed no statistically significant difference in the effectiveness of DTIs compared with that of usual care or non-DTIs at follow-up at 3 months (SMD 0.02; 95% CI −0.36 to 0.40; <i>P</i>=.92), 4 months (SMD −1.11; 95% CI −2.60 to 0.38; <i>P</i>=.14), and 6 months (SMD −0.11; 95% CI −0.54 to 0.32; <i>P</i>=.61). The quality of evidence was very low to moderate in these trials. CONCLUSIONS Our meta-analysis shows no evidence supporting the effectiveness of DTIs in reducing loneliness in older adults. Future research may consider randomized controlled trials with larger sample sizes and longer durations for both the interventions and follow-ups. INTERNATIONAL REGISTERED REPORT RR2-10.1136/bmjopen-2019-032455

scholarly journals Subacute Toxicity Study of Nicotinamide Mononucleotide via Oral Administration

2020 ◽  
Vol 11 ◽  
Author(s):  
Yingnan You ◽  
Yang Gao ◽  
Han Wang ◽  
Jingshu Li ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Uric Acid ◽  
Oral Administration ◽  
Dose Range ◽  
Cellular Level ◽  
Toxicity Study ◽  
Beagle Dogs ◽  
Subacute Toxicity ◽  
Nicotinamide Mononucleotide ◽  
Age Related ◽  
Safe Dose

Nicotinamide mononucleotide (NMN), a key precursory metabolite of NAD+, has been shown to elevate the cellular level of NAD+ and ameliorate various age-related diseases. Despite these progresses, systemic evaluation pertaining to the subacute toxicity of NMN remains to be determined. Here, we examine the subacute toxicity of NMN in mice and beagle dogs. Mice were gavaged with a saturated concentration of NMN solution at the maximum intragastric dose once or twice per day for 7 days. Dogs were gavaged twice per day for 14 days. In mice, NMN administrated once per day for 7 days is well tolerated with minimal deleterious effects. Upon higher dosage, we observe slightly increased level of alamine aminotransferase, while other biomarkers remain unchanged. Consistently, administration of NMN in beagle dogs only results in mild increases in creatinine and uric acid. Together, our study highlights the safety of NMN, providing a possible safe dose range for oral administration of NMN.

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