Primaquine structure activity relationship of methadone

primaquine structure activity relationship of methadone

In amino acid side chain, there are two amino group, for optimum activity, the distance between the two nitrogens of amino acid side chain. A discussion of the structure-activity relationships (SAR) of 8-aminoquinoline antimalarial drugs is thalene analogues of primaquine and quinocide were. Cometta-Morini et al proposed a structure activity relationship for the Methadone has a unique structure compared to other opioids since it.

Despite pre-clinical and clinical safety assessment of drug candidates, DILI is often the reason for drug failure and consequently for post-approval withdrawal from the market Egan et al. Besides the economic costs, the late discovery of hepatotoxicity of drugs may have serious health consequences for humans Howell et al. DILI is a matter of concern since it is the main cause of acute liver injury Vinken, The liver is the most important organ involved in drug toxicity since functionally it lies between the site of absorption and the systemic circulation Russmann et al.

primaquine structure activity relationship of methadone

This unique position in the body means it receives blood from the gastrointestinal tract and the abdominal space before it is pumped into the general circulation.

Thus, when a drug enters the body orally, it is totally or partially absorbed in the gastrointestinal tract and then reaches the liver. In addition, when a drug reaches the general circulation, it is extracted and metabolized by the liver Roberts et al.

Generally, metabolic transformation leads to the formation of molecules that are no longer—or are less—biologically active, so they are excreted more easily from the body; however, in some cases the metabolic activity of the liver produces substances that are more toxic and reactive than their parent compound Williams and Park, DILI is commonly classified as intrinsic or idiosyncratic.

This toxicity is generally dose-dependent and can often be foreseen. Idiosyncratic hepatotoxicity, however, is related to an abnormal reaction to a drug that is not dose-dependent. It generally damages only a limited numbers of people who are hyper-sensitive to a substance, with no specific connection to its pharmacological toxicity.

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Individual variability and susceptibility to injury make it hard to predict Cheng and Dixon, ; Russmann et al. Hepatotoxicity may occur in several ways depending on the different mechanisms of action. For example liver steatosis is caused by abnormal synthesis and elimination of lipids that accumulate in the liver cells interfering with the normal cell activity Tolman and Dalpiaz, ; cholestasis reflects the accumulation of bile acids in the hepatocytes Padda et al.

The hepatic transaminase levels offer a valuable indicator of liver injury. However, they are not always specific and sensitive in recognizing liver diseases provoked by DILI or other causes such as viruses Przybylak and Cronin, The absence of well-defined specific diagnostic biomarkers for the evaluation of hepatotoxicity Padda et al.

Furthermore, DILI is affected by individual factors such as sex, age, race, health, genetic polymorphism and environment Pirmohamed, ; Greene et al. DILI is therefore poorly understood and hard to predict. Early identification of DILI is essential in order primarily to increase drug safety but also to reduce the costs of drug development.

Primaquine - DrugBank

Besides in vitro techniques which anyway are expensive and time-consuming, interest is rising in computational tools for predicting toxicity that can evaluate and screen large numbers of compounds in a limited time and affect the attrition rates of compounds in drug discovery and development phases Muster et al.

Commercial software exists for the prediction of human toxic endpoints such as mutagenicity, carcinogenicity, developmental and reproductive toxicity, skin and eye irritation. However, the prediction of toxicity at organ level is still a challenge on account of the complex intrinsic nature of mechanisms of toxicity and the paucity of reliable in vivo and in vitro data Cheng and Dixon, Despite the objective hurdles to modeling DILI, some in silico tools for the prediction of hepatotoxicity have been developed through most of them are commercial.

The models for in silico assessment of hepatotoxicity have been recently reviewed by Przybylak and Cronin and Chen et al. Among computational models, quantitative structure-activity relationship QSAR and structure-activity relationship SAR are the most used ones. QSAR models quantitatively examine the toxicological activity of a compound starting from its chemical structure, on the principle that similar chemical substances should have similar biological behavior.

  • Introduction
  • Identification
  • Associated Data

SAR focuses on the rule determining the relationship, as a classifier Pery et al. Considering the model structure, in silico models can be divided in two main groups: Besides software, other in silico models based on SAs have been recently described in the literature Egan et al.

This model was built by developing automatically and manually-extracted SAs, which are chemical sub-structures linked to a particular activity or toxicity. The use of human data for building the model means the information provided can be used without the need to extrapolate the results from different species, reducing the uncertainty linked to inter-species variability. Furthermore, this in silico model can be used as alternative to animal testing for screening purposes and will be implemented in the VEGA platform http: Materials and methods Hepatotoxicity data collection The first step was to collect data for modeling.

Few public datasets on DILI are available. We focused on the following data sources since they were easily detectable and downloadable from the web and they were reliable since already used by other authors Chen et al. The first was Fourches et al. These were extracted through a data mining approach based on a combination of lexical and linguistic methods and ontological rules in order to link substances to a series of liver diseases, searching the open literature.

This database contains data from in vitro and in vivo studies and follows a simple classification approach: More details can be found in Fourches et al.

primaquine structure activity relationship of methadone

An in vitro metabolism-linked hemotoxicity assay has been developed. Methemoglobin formation, real-time generation of reactive oxygen intermediates ROIs and depletion of reactive thiols were monitored as multiple biochemical end points for hemotoxicity.


Primaquine alone did not produce any hemotoxicity, while a robust increase was observed in methemoglobin formation and generation of ROIs by primaquine in the presence of human or mouse liver microsomes.

Primaquine caused similar methemoglobin formation in G6PD - and normal human erythrocytes. However, G6PD - erythrocytes suffered higher oxidative stress and depletion of thiols than normal erythrocytes due to primaquine toxicity. The results provide significant insights regarding CYP isoforms contributing to hemotoxicity and may be useful in controlling toxicity of primaquine to increase its therapeutic utility.

Its ability to form dormant liver stages confounds control and elimination efforts. To compare the efficacy and safety of primaquine regimens for radical cure, we undertook a randomized controlled trial in Ethiopia.

timing primaquine treatment: Topics by

Methods and findings Patients with normal glucosephosphate dehydrogenase status with symptomatic P. The primary endpoints were the risk of P. The risk of recurrent P. The corresponding risks were On day 42, the risk was