Antithrombotic and Antiplatelet Drug Toxicity

2021 ◽  
Vol 37 (3) ◽  
pp. 591-604
Author(s):  
David B. Liss ◽  
Michael E. Mullins
Keyword(s):  
Drug Toxicity ◽  
Antiplatelet Drug

The present state of aspirin and clopidogrel resistance

2009 ◽  
Vol 29 (03) ◽  
pp. 285-290 ◽  
Author(s):  
K. E. Guyer
Keyword(s):  
Diagnostic Tests ◽  
Arterial Thrombosis ◽  
Cardiovascular Events ◽  
Treatment Success ◽  
Antiplatelet Agents ◽  
Antiplatelet Drug ◽  
Coronary Syndrome ◽  
Testing Method ◽  
Pharmacological Response ◽  
Platelet Physiology

SummaryAntiplatelet therapy has demonstrated significant clinical benefit in the treatment of acute coronary syndrome. However, as with any treatment strategy it has been unable to prevent all cardiovascular events. This is far from surprising when considering the complexity of arterial thrombosis and more specifically platelet physiology. This lack of treatment success has provoked the introduction of various diagnostic tests and testing platforms with the intent of guiding and optimizing clinical treatment. Such tests have resulted in the generation of clinical data that suggest suboptimal response to antiplatelet agents such as aspirin and clopidogrel.In the case of both aspirin and clopidogrel, this suboptimal response has been termed resistance. Drug resistance would imply a lack of pharmacological response that has not been specifically investigated in many of the clinical studies performed to date. Rather, the term resistance has been used to describe various facets of platelet activation and aggregation relative to the testing method. Many of these measured parameters are not addressed in the therapeutic intent of the antiplatelet drug in question.

A Comparison of the Effect of Decorsin and Two Disintegrins, Albolabrin and Eristostatin, on Platelet Function

1995 ◽  
Vol 74 (05) ◽  
pp. 1316-1322 ◽  
Author(s):  
Mary Ann McLane ◽  
Jagadeesh Gabbeta ◽  
A Koneti Rao ◽  
Lucia Beviglia ◽  
Robert A Lazarus ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Sequence Similarity ◽  
Platelet Aggregation Inhibitors ◽  
Antiplatelet Drug ◽  
Rgd Sequence ◽  
Fibrinogen Receptor ◽  
Activated Platelets

SummaryNaturally-occurring fibrinogen receptor antagonists and platelet aggregation inhibitors that are found in snake venom (disintegrins) and leeches share many common features, including an RGD sequence, high cysteine content, and low molecular weight. There are, however, significant selectivity and potency differences. We compared the effect of three proteins on platelet function: albolabrin, a 7.5 kDa disintegrin, eristostatin, a 5.4 kDa disintegrin in which part of the disintegrin domain is deleted, and decorsin, a 4.5 kDa non-disintegrin derived from the leech Macrobdella decora, which has very little sequence similarity with either disintegrin. Decorsin was about two times less potent than albolabrin and six times less potent than eristostatin in inhibiting ADP- induced human platelet aggregation. It had a different pattern of interaction with glycoprotein IIb/IIIa as compared to the two disintegrins. Decorsin bound with a low affinity to resting platelets (409 nM) and to ADP-activated platelets (270 nM), and with high affinity to thrombin- activated platelets (74 nM). At concentrations up to 685 nM, it did not cause expression of a ligand-induced binding site epitope on the (β3 subunit of the GPIIb/IIIa complex. It did not significantly inhibit isolated GPIIb/IIIa binding to immobilized von Willebrand Factor. At low doses (1.5-3.0 μg/mouse), decorsin protected mice against death from pulmonary thromboembolism, showing an effect similar to eristostatin. This suggested that decorsin is a much more potent inhibitor of platelet aggregation in vivo than in vitro, and it may have potential as an antiplatelet drug.

The d-Enantiomer Form of Indobufen Totally Accounts for the Anti-Cyclooxygenase and Antiplatelet Activity Ex Vivo and for the Increase in Bleeding Time by Indobufen in Man

1992 ◽  
Vol 67 (02) ◽  
pp. 258-263 ◽  
Author(s):  
Raffaele De Caterina ◽  
Rosa Sicari ◽  
An Yan ◽  
Walter Bernini ◽  
Daniela Giannessi ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Plasma Levels ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Random Sequence ◽  
Antiplatelet Agent ◽  
Antiplatelet Drug ◽  
Double Blind

SummaryIndobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean ± S.D., 58.7 ± 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 ±3% for both treatments). At 12 h inhibition was 87 ± 6% for d-indobufen and 88 ± 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs. Maximum inhibitory effect on aggregation was seen in response to collagen 1.5 pg/ml (63 ± 44% for d-indobufen and 81 ± 22% for dl-indobufen) and arachidonic acid 0.5-2 mM (78 ± 34% for d-indobufen and 88 ± 24% for dl-indobufen) at 2 h after each administration. An effect of both treatments on platelet aggregation after 12 h was present only for adrenaline 2 μM (55 ± 41% for d-indobufen and 37 ± 54% for dl-indobufen), collagen 1.5 pg/ml (69 ± 30% for d-indobufen and 51 ± 61% for dl-indobufen), arachidonic acid 0.5-2 mM (56 ± 48% for d-indobufen and 35 ± 49% for dl-indobufen). The extent of inhibition of TX production and the extent of residual platelet aggregation were never significantly different between treatments. Bleeding time prolongation was similar in the two treatment groups without showing a pronounced and long lasting effect (from 7.0 ± 2.0 min to 10.0 ± 3.0 min at 2 h and 8.0 ± 2.0 min at 12 h for d-indobufen; from 6.0 ±1.0 min to 8.5 ± 2.0 min at 2 h and 8.0 ± 1.0 min at 12 h for dl-indobufen). These results demonstrate that the biological activity of dl-indobufen as an antiplatelet agent in vivo is totally accounted for by d-indobufen.

Drug Toxicity

2020 ◽  
Author(s):  
Keyword(s):  
Drug Toxicity

TOXICOLOGICAL PROFILE OF “BIOSOLBI” DRUG

1970 ◽  
pp. 67-69
Author(s):  
E. K. Rakhmatullin ◽  
O. D. Sklyarov
Keyword(s):  
Drug Toxicity ◽  
Probit Analysis ◽  
Laboratory Animals ◽  
Control Group ◽  
Hazard Class ◽  
Water Ingestion ◽  
White Rats ◽  
Poorly Soluble ◽  
And Behavior ◽  
Purebred Dogs

The article presents the results of a study of the "Bisolbi" drug toxicity (powder of light ash color, poorly soluble in water). When it is mixed with water it forms a suspension of particles that settle rapidly. Values of acute drug toxicity were determined on rats. We studied groups of six animals of the same sex, as well as similar control ones. The "Bisolbi" drug was injected to white rats intragastrically, males weighing 310 ... 320 g in doses of 2500 and 2740 mg / kg. Each dose was used in six animals; distilled water (3 ml) was used for the controls. The LD50 was calculated by the probit analysis method proposed by Litchfield and Wilcoxon modified by Z. Roth. When administered orally, an atraumatic metal probe was immersed in the stomach. Within 14 days monitored the overall health status and behavior of animals, the manifestation or absence of symptoms of intoxication; noted the features of feed and water ingestion, assessed the condition of the coat, physiological functions. Then groups of experimental rats were euthanized and pathomorphologically examined. We studied the effect of "Bisolbi" with repeated introduction and on not purebred dogs. Two groups of 3-4 years of age were completed with an average initial body weight of 13.63 ... 15.11 kg. Before use, the additive was thoroughly mixed with feed. The drug was injected during 31 days at a dose of 0.5 g / kg. Dogs of the control group (three) were fed wheat flour. After 15 and 31 days in laboratory animals in order to characterize the general condition in the blood, the amount of protein, urea, glucose, creatinine, cholesterol were determined. Based on studies it was found that the drug daily application by animals, is low toxic and safe, does not provoke the development of pathological reactions. According to the Hodge and Sterner classification "Bisolbi" can be attributed to the 6th class of toxicity - relatively harmless. Accordingto GOST 12.1.007-76 LD50 of the drug is more than 151 mg / kg, but less than 5000 mg / kg it is the 3rd hazard class (moderately hazardous).

Analysis of the Potential Association of Drug-Metabolizing Enzymes CYP2C9*3 and CYP2C19*3 Gene Variations With Type 2 Diabetes: A Case-Control Study

2020 ◽  
Vol 21 (14) ◽  
pp. 1152-1160
Author(s):  
Imadeldin Elfaki ◽  
Rashid Mir ◽  
Faisel Mohammed Abu-Duhier ◽  
Chandan Kumar Jha ◽  
Adel Ibrahim Ahmad Al-Alawy ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Antiplatelet Drug ◽  
Drug Metabolizing Enzymes ◽  
Genotype Distribution ◽  
Nucleotide Polymorphisms ◽  
Metabolizing Enzymes ◽  
Specific Pcr ◽  
Increased Risk ◽  
Different Populations

Background:: Cytochrome P450s (CYPs) are drug-metabolizing enzymes catalyzing the metabolism of about 75% of drug in clinical use. CYP2C9 represents 20% CYP proteins in liver cells and is a crucial member of CYPs superfamily. CYP2C19 metabolizes very important drugs such as antiulcer drug omeprazole, the antiplatelet drug clopidogrel and anticonvulsant mephenytoin. Single nucleotide polymorphisms (SNPs) of CYP genes have been associated with unexpected drug reactions and diseases in different populations. Objective:: We examined the associations of CYP2C9*3 (rs1057910) and CYP2C19*3 (rs4986893) with T2D in Saudi population. Methods:: We used the allele-specific PCR (AS-PCR) and DNA sequencing in 111 cases and 104 controls for rs1057910, and in 119 cases and 110 controls for rs4986893. Results:: It is indicated that the genotype distribution of rs1057910 in cases and controls were not significantly different (P=0.0001). The genotypes of rs1057910 were not associated with type 2 diabetes (T2D) (P>0.05). Whereas the genotype distribution of rs4986893 in cases and controls was significantly different (P=0.049). The AA genotype of rs4986893 may be associated in increased risk to T2D with OR=17.25 (2.06-143.8), RR=6.14(0.96-39.20), P=0.008. Conclusion:: The CYP2C9*3 (rs1057910) may not be associated with T2D, while CYP2C19*3 (rs4986893) is probably associated with T2D. These findings need to be validated in follow-up studies with larger sample sizes and different populations.

scholarly journals Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique

2020 ◽  
Vol 18 (1) ◽  
pp. 681-690
Author(s):  
Hassan A. Alhazmi ◽  
Adnan A. Kadi ◽  
Mohamed W. Attwa ◽  
Waquar Ahsan ◽  
Manal Mohamed Elhassan Taha ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Active Metabolite ◽  
Dose Adjustment ◽  
Internal Standard ◽  
Cardiovascular Complications ◽  
Antiplatelet Drug ◽  
Peak Ratio ◽  
Cytochrome P450 Enzymes ◽  
Time Intervals ◽  
Addictive Substance

AbstractClopidogrel (CLOP) is widely used worldwide for cardiovascular complications. CLOP is highly metabolized in the liver to its active metabolite by cytochrome P450 enzymes. Studies have shown that khat, an addictive substance, is a powerful inhibitor of cytochrome P450 enzymes and can influence the metabolism of drugs that are concomitantly used. Therefore, this study was designed to evaluate the effects of khat on the pharmacokinetics of CLOP in rats. In this study, rats were administered either CLOP alone or CLOP combined with khat and their plasma were obtained at different time intervals and analyzed using the newly developed and validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method using foretinib (FTB) as the internal standard. The corresponding peak area of the analyte versus FTB was used for calculating the peak ratio. The validated LC-MS/MS method resulted in the separation of the well-defined quantifiable peaks of CLOP, FTB, and CLOP metabolite within 7 min. Results showed a significant influence of khat on the peak ratio of CLOP metabolite, which was found to be significantly decreased (P < 0.05) in comparison to CLOP alone, suggesting significant decrease in the conversion of CLOP to its active metabolite due to the inhibition of CYP450 enzymes by khat. Therefore, there might be a need for dose adjustment for regular khat chewers using CLOP.

Present trends in the encapsulation of anticancer drugs

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Xavier Montané ◽  
Karolina Matulewicz ◽  
Karolina Balik ◽  
Paulina Modrakowska ◽  
Marcin Łuczak ◽  
...  
Keyword(s):  
Carbon Nanotubes ◽  
Drug Toxicity ◽  
Recent Progress ◽  
Polymeric Micelles ◽  
Drug Loading ◽  
The Body ◽  
Inorganic Nanoparticles ◽  
Hybrid Nanoparticles ◽  
Traditional Medicines ◽  
Low Solubility

Abstract Different nanomedicine devices that were developed during the recent years can be suitable candidates for their application in the treatment of various deadly diseases such as cancer. From all the explored devices, the nanoencapsulation of several anticancer medicines is a very promising approach to overcome some drawbacks of traditional medicines: administered dose of the drugs, drug toxicity, low solubility of drugs, uncontrolled drug delivery, resistance offered by the physiological barriers in the body to drugs, among others. In this chapter, the most important and recent progress in the encapsulation of anticancer medicines is examined: methods of preparation of distinct nanoparticles (inorganic nanoparticles, dendrimers, biopolymeric nanoparticles, polymeric micelles, liposomes, polymersomes, carbon nanotubes, quantum dots, and hybrid nanoparticles), drug loading and drug release mechanisms. Furthermore, the possible applications in cancer prevention, diagnosis, and cancer therapy of some of these nanoparticles have been highlighted.

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