K. Pattichis

The Design and Development of Deferiprone (L1) and Other Iron Chelators for Clinical Use: Targeting Methods and Application Prospects

Iron is essential for all human cells as well as neoplastic cells and invading microbes. Natural and synthetic iron chelators could affect biological processes involving iron and other metal ions in health and disease states. Iron overload is the most common metal toxicity condition worldwide. There are currently two iron chelating drugs, which are mostly used for the treatment of thalassaemia and other conditions of transfusional iron overload. Deferoxamine was until recently the only approved iron chelating drug, which is effective but very expensive and administered parenterally resulting in low compliance. Deferiprone (L1 or 1,2-dimethyl-3-hydroxypyrid-4-one) is the worlds first and only orally active iron chelating drug, which is effective and inexpensive to synthesise thus increasing the prospects of making it available to most thalassaemia patients in third world countries who are not currently receiving any form of chelation therapy. Deferiprone has equivalent iron removal efficacy and comparable toxicity to deferoxamine. There are at least four other known iron chelators, which are currently being developed. Even if successful, these are not expected to become available for clinical use in the next five years and to be as inexpensive as deferiprone. The variation in the chemical, biological, pharmacological, toxicological and other properties of the chelating drugs and experimental chelators provide evidence of the difference in the mode of action of chelators and the need to identify and select molecular structures and substituents based on structure/activity correlations for specific pharmacological activity. Such information may increase the prospects of designing new chelating drugs, which could be targeted and act on different tissues, organs, proteins and iron pools that play important role not only in the treatment of iron overload but also in other diseases of iron and other metal imbalace and toxicity including free radical damage. Chelating drugs could also be designed, which could modify the enzymatic activity of iron and other metal containing enzymes, some of which play a key role in many diseases such as cancer, inflammation and atherosclerosis. Other applications of iron chelating drugs could involve the detoxification of toxic metals with similar metabolic pathways to iron such as Al, Cu, Ga, In, U and Pu.

Histamine, Histamine H2-Receptor Antagonists, Gastric Acid Secretion and Ulcers: An Overview

Histamine, a biogenic amine, is involved in allergic reactions and asthma. The involvement of histamine in peptide ulcers is reviewed here. The discovery, distribution, synthesis, catabolism, and pharmacological effects of histamine are briefly described. Histamine actions are mediated by more than one type of receptor. The discovery, development and mode of action of H2-antagonists is discussed. A brief comparison of the clinical profiles (dosage regimen, metabolism and drug interactions) of the four currently used H2-antagonists (cimetidine, ranitidine, nizatidine and famotidine) is given. Furthermore, due to their ability to bind to cytochrome P-450, these compounds have the potential to interfere with the hepatic clearance of other drugs which are also metabolised by the mixed-function oxidase system in man. Therefore, a brief discussion of their adverse effects and drug interactions is included. Modulation of gastric acid secretion, in particular the role of cAMP and the proton pump, is described. Peptic ulcer is a major disease in the Western world and the aetiology and treatment of peptic ulcer are summarised.

Rapid and efficient purification of cimetropium bromide and mifentidine drug metabolite mixtures derived from microsomal incubates for analysis by mass spectrometry

A comparative study of the use of organic solvent extraction versus Sep-Pak C18 cartridges in the recovery and analysis of phase I (unconjugated) drug metabolites using mass spectrometry is presented. Standard mixtures of putative metabolites of the anticholinergic drug cimetropium bromide and the H2-antagonist mifentidine were purified from inactivated liver microsomal preparations using both methods, and subsequently the recovery of each compound was quantitated. In general, the percentage recovery and degree of purification were greater when using Sep-Pak C18 cartridges compared with organic solvent extraction. Even more efficient recovery was achieved when zinc sulphate precipitation of proteins in the liver microsomal mixtures was carried out prior to analysis. Also, the HPLC-grade solvents used in this study contained a variety of ultraviolet-inactive, hydrophobic components. This leads to problems of suppression in fast atom bombardment mass spectrometric analysis. Using Sep-Pak C18 cartridges directly prior to analysis by fast atom bombardment with single or tandem mass spectrometry leads to far superior mass spectral results compared with organic solvent extraction.

Identification of metabolites derived from the H2-receptor antagonist mifentidine using tandem mass spectrometry

Abstract The in vitro metabolism of mifentidine, a second generation histamine H2-receptor antagonist, is investigated after hepatic microsomal incubation. By employing a combination of both daughter and parent ion scanning tandem mass spectrometry on synthetic standards and the microsomal incubate, it is revealed that mifentidine is metabolised to at least three compounds, namely the amine, formamide and urea metabolites. The detection and characterisation of the three metabolites is carried out with minimal sample purification.

In vitro studies on the metabolic fate of mifentidine, a novel histamine H2-receptor antagonist

SummaryThe in vitro metabolism of mifentidine and several of its metabolites was studied using hepatic microsomes from seven animal species. The effects of potential enzyme inducers, inhibitors and activators were also studied. Mifentidine metabolites identified and characterised were: 4-imidazolylphenylamine (amine), 4-imidazolylphenyl-formamide (formamide), the urea derivative of mifentidine (urea) and the imidazole-hydroxylated derivative of the amine (i-OH-amine), along with three unidentified metabolites, M1, M2 and M3. Evidence for the presence of the amine, formamide, urea and i-OH-amine was obtained by comparison with authentic reference compounds: (i) HPLC retention times; (ii) UV spectra; and (iii) MS spectra of metabolites. The postulated intermediates are: carbinolimine (for formamide, amine, i-OH-amine and urea formation); formamide (for amine and i-OH-amine formation); amine (for i-OH-amine formation), and nitrone (for urea formation). One ‘metabonate’ of mifentidine was also identified, namely the nitro analogue of the amine. A possible prerequisite for the formation of this nitro is the corresponding hydroxylamine or nitroso compound. Cytochromes P450I and P450II were shown to be involved in the in vitro microsomal biotransformation of mifentidine, but the involvement of the flavin monooxygenase system was not proven.