Therapeutic Dosing of Pralidoxime Chloride

1987 ◽  
Vol 21 (7-8) ◽  
pp. 590-593 ◽  
Author(s):  
Dennis F. Thompson ◽  
G. Dail Thompson ◽  
Robert B. Greenwood ◽  
Harold L. Trammel
Keyword(s):  
Clinical Trials ◽  
Serum Concentration ◽  
Toxic Effects ◽  
Organophosphate Poisoning ◽  
Minimal Level ◽  
Animal Data ◽  
Pralidoxime Chloride ◽  
Pharmacokinetic Simulations

Pralidoxime chloride is a useful agent in the treatment of organophosphate poisoning. Poisindex, a widely used poisoning treatment resource, recommends dosing pralidoxime chloride as an intermittent iv infusion every 8–12 hours, whereas other authors have used continuous iv infusion with good results. Available animal data suggest that a serum concentration of 4 μg/ml may be a minimal level to protect against the toxic effects of organophosphates. Pharmacokinetic simulations, based on parameters obtained from healthy nonpoisoned subjects, show that pralidoxime levels fall rapidly to <4 μg/ml within 1.5–2 hours after a 1-g iv bolus. Continuous iv infusion (0.5 g/h) maintains pralidoxime levels >4 μg/ml throughout the length of infusion. We conclude that continuous iv infusion of pralidoxime chloride may be the preferred method of administration in patients with acute organophosphate poisoning. Clinical trials will be necessary to document the effectiveness of this regimen.

scholarly journals Toxicity of Combinations of Kinase Pathway Inhibitors to Normal Human Cells in a Three-Dimensional Culture

2021 ◽  
pp. 247263032110088
Author(s):  
Pouria Rafsanjani Nejad ◽  
Pradip Shahi Thakuri ◽  
Sunil Singh ◽  
Astha Lamichhane ◽  
Jacob Heiss ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Protein Kinase ◽  
Single Agent ◽  
Three Dimensional ◽  
Drug Combinations ◽  
Toxic Effects ◽  
Combination Drug ◽  
Normal Cells ◽  
Colon Cells

Resistance to single-agent chemotherapy and molecularly targeted drugs prevents sustained efficacy of treatments. To address this challenge, combination drug treatments have been used to improve outcomes for patients. Potential toxicity of combination treatments is a major concern, however, and has led to the failure of several clinical trials in different cancers. The use of cell-based models of normal tissues in preclinical studies enables testing and identifying toxic effects of drug combinations and facilitates an informed decision-making process for advancing the treatments to animal models and clinical trials. Recently, we established that combinations of molecular inhibitors of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase–protein kinase B (PI3K/Akt) pathways effectively and synergistically inhibit growth of BRAFmut and KRASmut colorectal tumor spheroids by blocking feedback signaling of downstream kinase pathways. These pathways are important for cell proliferation, however, and their simultaneous inhibition may cause toxicity to normal cells. We used a cellular spheroid model to study toxicities of drug combinations to human bone marrow and colon. Our results indicated that MAPK and PI3K/Akt inhibitors used simultaneously were only moderately toxic to bone marrow cells but significantly more toxic to colon cells. Our molecular analysis of proliferative cell activities and housekeeping proteins further corroborated these results. Overall, our approach to identify toxic effects of combinations of cancer drugs to normal cells in three-dimensional cultures will facilitate more informed treatment selections for subsequent animal studies.

scholarly journals Can prospective systematic reviews of animal studies improve clinical translation?

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Pandora Pound ◽  
Merel Ritskes-Hoitinga
Keyword(s):  
Clinical Trials ◽  
Systematic Reviews ◽  
Animal Studies ◽  
Poor Quality ◽  
Human Studies ◽  
Clinical Knowledge ◽  
Safety And Efficacy ◽  
High Quality Evidence ◽  
Animal Data

AbstractSystematic reviews are powerful tools with the potential to generate high quality evidence. Their application to animal studies has been instrumental in exposing the poor quality of these studies, as well as a catalyst for improvements in study design, conduct and reporting. It has been suggested that prospective systematic reviews of animal studies (i.e. systematic reviews conducted prior to clinical trials) would allow scrutiny of the preclinical evidence, providing valuable information on safety and efficacy, and helping to determine whether clinical trials should proceed. However, while prospective systematic reviews allow valuable scrutiny of the preclinical animal data, they are not necessarily able to reliably predict the safety and efficacy of an intervention when trialled in humans. Consequently, they may not reliably safeguard humans participating in clinical trials and might potentially result in lost opportunities for beneficial clinical treatments. Furthermore, animal and human studies are often conducted concurrently, which not only makes prospective systematic reviews of animal studies impossible, but suggests that animal studies do not inform human studies in the manner presumed. We suggest that this points to a confused attitude regarding animal studies, whereby tradition demands that they precede human studies but practice indicates that their findings are often ignored. We argue that it is time to assess the relative contributions of animal and human research in order to better understand how clinical knowledge is actually produced.

scholarly journals Toxic Effects of Cannabis and Cannabinoids: Animal Data

2005 ◽  
Vol 10 (suppl a) ◽  
pp. 23A-26A ◽  
Author(s):  
Pierre Beaulieu
Keyword(s):  
Acute Toxicity ◽  
Present Article ◽  
Chronic Toxicity ◽  
Toxic Effects ◽  
Acute Administration ◽  
Toxicity Data ◽  
Toxicity Studies ◽  
Animal Data ◽  
Animal Toxicity

The present article reviews the main toxic effects of cannabis and cannabinoids in animals. Toxic effects can be separated into acute and chronic classifications. Acute toxicity studies show that it is virtually impossible to die from acute administration of marijuana or tetrahydrocannabinol, the main psychoactive component of cannabis. Chronic toxicity involves lesions of airway and lung tissues, as well as problems of neurotoxicity, tolerance and dependence, and dysregulations in the immune and hormonal systems. Animal toxicity data, however, are difficult to extrapolate to humans.

Increased morbidity and mortality in acute human organophosphate-poisoned patients treated by oximes: a meta-analysis of clinical trials

2006 ◽  
Vol 25 (3) ◽  
pp. 157-162 ◽  
Author(s):  
Roja Rahimi ◽  
Shekoufeh Nikfar ◽  
Mohammad Abdollahi
Keyword(s):  
Clinical Trials ◽  
Relative Risk ◽  
Meta Analysis ◽  
Clinical Situation ◽  
Morbidity And Mortality ◽  
Organophosphate Poisoning ◽  
High Morbidity ◽  
Inclusion Criteria ◽  
Common Causes ◽  
The Third World

Organophosphates are one of the most common causes of poisoning, especially in the Third world, with high morbidity and mortality. The treatment of this type of poisoning involves the use of atropine and oximes. Atropine has been used successfully in large doses to counteract the muscarinic effects of organophosphate poisoning, but the efficacy of oximes in the management of this poisoning remains under question. In this study, we undertook a meta-analysis by reviewing all clinical trials to evaluate the efficacy of oximes in the management of organophosphate poisoning. The databases of PUBMED, EMBASE, Cochrane, SCOPUS, and the search engine of Google were searched for all clinical trials on the use of oximes in organophosphate poisoning. The inclusion criteria were death, development of intermediate syndrome, and need for ventilation. Six clinical trials met the inclusion criteria and were included in the metaanalysis. The x2 tests for heterogeneity (P–0.25, 0.16, and 0.33, respectively) indicated that the included studies were not significantly heterogeneous and could be combined. A significant relative risk (P–0.0017) for death among oxime-exposed was 2.17 (95% CI of 1.34 / 3.51). The ‘need for ventilation’ in patients who received oxime was higher (P–0.03) than those who did not receive oxime with a relative risk of 1.53 (1.16 / 2.02). The incidence of ‘intermediate syndrome’ for oximeexposed patients was significantly higher (P–0.01) than oxime non-exposed patients with a relative risk of 1.57 (95% CI 1.11 / 2.11). It can be concluded that oximes are not effective in the management of organophosphate-poisoned patients and, surprisingly, they can be dangerous and worsen the patient's clinical situation.

Pralidoxime Continuous Infusion in the Treatment of Organophosphate Poisoning

1997 ◽  
Vol 31 (4) ◽  
pp. 441-444 ◽  
Author(s):  
Gretchen M Tush ◽  
Michael I Anstead
Keyword(s):  
Continuous Infusion ◽  
Metabolic Activation ◽  
Chemical Exposure ◽  
Atropine Sulfate ◽  
Organophosphate Poisoning ◽  
Intensive Care Monitoring ◽  
Unknown Quantity ◽  
Pralidoxime Chloride ◽  
The Stability ◽  
Slow Absorption

Objective To report a case of organophosphate poisoning treated with a continuous infusion of pralidoxime chloride. Case Summary A 27-year-old white man presented with extreme agitation, muscle weakness and fasciculations, and respiratory failure after ingesting an organophosphate pesticide (Dursban, active ingredients chlorpyrifos and xylene) as a suicide attempt. Atropine sulfate and pralidoxime chloride were administered intermittently, ut the patient continued to be extremely agitated and have muscle fasciculations. Subsequently, a continuous intravenous infusion of pralidoxime (8 mg/mL concentration) at 500 mg/h was initiated to help control breakthrough nicotinic symptoms. Therapy with atropine and pralidoxime was continued for approximately 72 hours. Therapy was discontinued due to the predominance of anticholinergic symptoms and the patient's increased awareness. Discussion Severe organophosphate poisoning with nicotinic and/or central manifestations should be treated with pralidoxime in addition to atropine. The rationale supporting the use of pralidoxime as a continuous infusion in this case includes: (1) slow absorption of organophosphate compounds following exposure to large quantities, (2) unknown quantity ingested, (3) delayed nicotinic effects from distribution of lipid-soluble organophosphate and metabolic activation of phosphorothioates such as chlorpyrifos, and (4) intensive care monitoring. There is limited documentation in the literature of continuous infusions of pralidoxime used to treat organophosphate poisoning and the stability of the admixture is unknown. Conclusions A continuous pralidoxime infusion successfully managed the prolonged nicotinic symptoms seen after ingestion of an organophosphate. A continuous infusion of pralidoxime may be particularly useful in cases of organophosphate poisoning when the extent of chemical exposure or quantity of chemical ingested is unknown but potentially toxic and the therapy must be symptomatically managed.

scholarly journals Association of Sex With Toxic Effects, Treatment Adherence, and Oncologic Outcomes in the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trials of Rectal Cancer

JAMA Oncology ◽  
2020 ◽  
Vol 6 (2) ◽  
pp. 294
Author(s):  
Markus Diefenhardt ◽  
Ethan B. Ludmir ◽  
Ralf-Dieter Hofheinz ◽  
Michael Ghadimi ◽  
Bruce D. Minsky ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Clinical Trials ◽  
Treatment Adherence ◽  
Randomized Clinical Trials ◽  
Toxic Effects ◽  
Oncologic Outcomes ◽  
Phase 3

scholarly journals Efficacy of Recommended Prehospital Human Equivalent Doses of Atropine and Pralidoxime Against the Toxic Effects of Carbamate Poisoning in the Hartley Guinea Pig

2016 ◽  
Vol 35 (3) ◽  
pp. 344-357 ◽  
Author(s):  
Matthew K. Brittain ◽  
Kevin G. McGarry ◽  
Robert A. Moyer ◽  
Michael C. Babin ◽  
David A. Jett ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Guinea Pig ◽  
Mechanism Of Action ◽  
Ache Activity ◽  
Nerve Agent ◽  
Organophosphate Poisoning ◽  
Pesticide Poisoning ◽  
Free Base ◽  
Negative Effects ◽  
Pralidoxime Chloride

Purpose: Aldicarb and methomyl are carbamate pesticides commonly implicated in human poisonings. The primary toxic mechanism of action for carbamate poisoning is cholinesterase (ChE) inhibition. As such, it is logical to assume that the currently accepted therapies for organophosphate poisoning (muscarinic antagonist atropine and the oxime acetylcholinesterase reactivator pralidoxime chloride [2-PAM Cl]) could afford therapeutic protection. However, oximes have been shown to be contraindicated for poisoning by some carbamates. Methods: A protective ratio study was conducted in guinea pigs to evaluate the efficacy of atropine and 2-PAM Cl. The ChE activity was determined in both the blood and the cerebral cortex. Results: Coadministration of atropine free base (0.4 mg/kg) and 2-PAM Cl (25.7 mg/kg) demonstrated protective ratios of 2 and 3 against aldicarb and methomyl, respectively, relative to saline. The data reported here show that this protection was primarily mediated by the action of atropine. The reactivator 2-PAM Cl had neither positive nor negative effects on survival. Both blood acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were significantly reduced at 15 minutes postchallenge but gradually returned to normal within 24 hours. Analysis of cerebral cortex showed that BChE, but not AChE, activity was reduced in animals that succumbed prior to 24 hours after challenge. Conclusion: The results suggest that coadministration of atropine and 2-PAM Cl at the currently recommended human equivalent doses for use in the prehospital setting to treat organophosphorus nerve agent and pesticide poisoning would likely also be effective against aldicarb or methomyl poisoning.

scholarly journals Chloroquine and Hydroxychloroquine: how about switching?

2021 ◽  
Vol 4 (4) ◽  
pp. 01-12
Author(s):  
Thiago Santana Novotny ◽  
Mychelle Alves Monteiro ◽  
Patrícia Condé de Lima ◽  
Soraya Mendonça de Ochs ◽  
Fernando Antonio Simas Vaz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Dose Response ◽  
Inflammatory Diseases ◽  
Viable Alternative ◽  
Toxic Effects ◽  
Therapeutic Effects ◽  
Response Curves ◽  
Safety And Efficacy ◽  
Safety Concerns ◽  
Dose Response Curves

Early studies suggesting that chloroquine (CQ) and hydroxychloroquine (HCQ) could benefit coronavirus patients brought these old medicines back to the spotlight. This led to an increase in demand and price, turning their counterfeiting a pharmacovigilance issue worldwide. Meanwhile, lack of evidence on effectiveness and safety concerns have reduced their clinical trials in severe COVID-19 cases. Despite the knowledge that CQ and HCQ toxic effects are stereo specific rather than their therapeutic effects, these drugs are available only as racemates. In this context, this work brings a discussion about chiral switching to their eutomers so that CQ and HCQ distomers would become impurities, what may be a viable alternative to test new dose-response curves. Even if it is proven that the use of pure CQ and HCQ enantiomers are useless against COVID-19, chiral switching would certainly improve safety and efficacy in the treatment of many autoimmune inflammatory diseases, benefiting chronic users of these drugs.

scholarly journals How Safe is the use of Antiseptics and Disinfectants in Children?

2021 ◽  
Vol 5 (3) ◽  
pp. RV6-RV9
Author(s):  
Abdullah Hosseni ◽  
Nirmal Thapa ◽  
Priya T.
Keyword(s):  
Health Care ◽  
Clinical Trials ◽  
Health Care Professionals ◽  
Healthcare Professionals ◽  
Pediatric Patients ◽  
Randomized Clinical Trials ◽  
Research Work ◽  
Toxic Effects ◽  
Safety And Efficacy ◽  
Wide Range

A wide range of antiseptic preparations and disinfectants have been used in varying concentrations and combinations in children but much research work regarding their safety and efficacy is not available. The aim of this review is to expand and broaden the pre-existing guidelines useful to the health care professionals so that antisepsis in the pediatric field can be performed appropriately, and at the same time, guarantee safety for children. Previously published studies were also assessed while writing this review. As per the data, there may be several local and systemic toxic effects related to the use of antiseptics and disinfectants in children. Properly designed large multicenter randomized clinical trials are required to direct the healthcare professionals regarding the most appropriate and safe antiseptic and disinfectant to use in pediatric patients.

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