Clinically relevant drug interactions between anticancer drugs and psychotropic agents.

Drug interactions are commonly seen in the treatment of cancer patients. Psychotropics are often indicated for these patients since they may also suffer from pre-existing psychological disorders or experience insomnia and anxiety associated with cancer therapy. Thus, the risk of anticancer drug (ACD)-psychotropic drug-drug interactions (DDIs) is high. Drug interactions were compiled from the British National Formulary (53rd edn), Lexi-Comp's Drug Information Handbook (15th edn), Micromedex (v5.1), Hansten & Horn's Drug Interactions (2000) and Drug Interaction Facts (2008 edn). Product information of the individual drugs, as well as documented literature on ACD-psychotropic interactions from PubMed and other databases was also incorporated. This paper identifies clinically important ACD-psychotropic DDIs that are frequently observed. Pharmacokinetic DDIs were observed for tyrosine kinase inhibitors, corticosteroids and antimicrotubule agents due to their inhibitory or inductive effects on cytochrome P450 isoenzymes. Pharmacodynamic DDIs were identified for thalidomide with central nervous system depressants, procarbazine with antidepressants, myelosuppressive ACDs with clozapine and anthracyclines with QT-prolonging psychotropics. Clinicians should be vigilant when psychotropics are prescribed concurrently with ACDs. Close monitoring of plasma drug levels should be carried out to avoid toxicity in the patient, as well as to ensure adequate chemotherapeutic and psychotropic coverage.

6-Shogaol, an active constituent of ginger, inhibits breast cancer cell invasion by reducing matrix metalloproteinase-9 expression via blockade of nuclear factor-κB activation.

BACKGROUND AND PURPOSE: Shogaols are reported to possess anti-inflammatory and anticancer activities. However, the antimetastatic potential of shogaols remains unexplored. This study was performed to assess the effects of shogaols against breast cancer cell invasion and to investigate the underlying mechanisms. EXPERIMENTAL APPROACH: The anti-invasive effect of a series of shogaols was initially evaluated on MDA-MB-231 breast cancer cells using the matrigel invasion assay. The suppressive effects of 6-shogaol on phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 (MMP-9) gelatinolytic activity and nuclear factor-κB (NF-κB) activation were further determined. KEY RESULTS: Shogaols (6-, 8- and 10-shogaol) inhibited PMA-stimulated MDA-MB-231 cell invasion with an accompanying decrease in MMP-9 secretion. 6-Shogaol was identified to display the greatest anti-invasive effect in association with a dose-dependent reduction in MMP-9 gene activation, protein expression and secretion. The NF-κB transcriptional activity was decreased by 6-shogaol; an effect mediated by inhibition of IκB phosphorylation and degradation that subsequently led to suppression of NF-κB p65 phosphorylation and nuclear translocation. In addition, 6-shogaol was found to inhibit JNK activation with no resulting reduction in activator protein-1 transcriptional activity. By using specific inhibitors, it was demonstrated that ERK and NF-κB signalling, but not JNK and p38 signalling, were involved in PMA-stimulated MMP-9 activation. CONCLUSIONS AND IMPLICATIONS: 6-Shogaol is a potent inhibitor of MDA-MB-231 cell invasion, and the molecular mechanism involves at least in part the down-regulation of MMP-9 transcription by targeting the NF-κB activation cascade. This class of naturally occurring small molecules thus have potential for clinical use as antimetastatic treatments.

Advice-giving on self-medication: perspectives of community pharmacists and consumers in Singapore.

BACKGROUND: In Singapore, community pharmacists provide an advice-giving service to consumers who seek self-medication for minor ailments management. This service has not been studied formally from the perspectives of pharmacists and consumers. OBJECTIVES: The study aimed to identify (i) the approach taken by pharmacists in providing advice for self-medication and (ii) consumers' behaviour in self-treatment and their perception of the advice-giving role of the community pharmacist. METHOD: The pharmacists and consumers were surveyed independently using two structured questionnaires. RESULTS AND DISCUSSION: All community pharmacists who participated in the survey were confident in providing advice on self-medication. However, none of them recorded the consultations and only 17.5% of them had documented their general physician referrals. Most consumers (66.3%) would self-medicate and only consult a professional when the desired outcome was not achieved. Less than 10% of consumers would approach the pharmacists as the first option for advice. More than half of the pharmacists felt that the advice they rendered deserved a fee whereas only 28.4% of the consumers were willing to pay. Both parties thought the fee should not be more than S5 dollars (US3 dollars). CONCLUSION: Generally, there is congruence in the perspectives on self-medication between the advice-giving pharmacist and the consumer. The consumers still lack awareness that pharmacists can help them to self-medicate more safely and effectively. Therefore, more effort in public education is warranted. The current state of poor documentation of the advisory function of community pharmacists should be improved.

Combinatorial mixture synthesis and biological evaluation of dihydrophenyl triazine antifolates.

The traditional 'one-pot' three component synthesis was adapted successfully for combinatorial mixtures synthesis of dihydrophenyl triazines, which are nonclassical, dihydrofolate reductase (DHFR) inhibitors. Each library was designed to comprise eight reaction mixture pots and in every pot there were three dihydrophenyl triazines. A total of three libraries were synthesized and the final number of compounds harvested was 64. The products precipitated out of the reaction mixture and could be collected easily and cleansed by washing. Solid supports and further purification processes were not required. The reactions were monitored by TLC and a HPLC method was developed to determine the number of products in each pot. All 24 pots were screened for inhibitory activity against the rat liver DHFR. Two pots showed good inhibitory activity and the products in them were individually synthesized, characterized and biologically tested again. One lead compound was identified amongst all the compounds synthesized, and would be further optimized.

Pharmacist-operated drug information centres in Singapore.

OBJECTIVE: Relatively little is known about the organized drug information centres (DICs) in Asia. Here we evaluate the four pharmacist-operated DICs in Singapore and compare them with published information on DICs located in Australia, the U.K. and the U.S., and with established guidelines for quality assurance of DICs. METHODS: A prospective survey was conducted in 1996 in which two sets of questionnaires were developed and distributed to the DIC pharmacists to elicit information on the DIC as well as the DIC pharmacists. In addition, the enquiry records received by the DICs over the period 1 April to 31 July 1996 were collated for evaluation. RESULTS: All the pharmacist-operated DICs in Singapore were well equipped with facilities for information retrieval, storage and dissemination, and they had adequate literature resources comparable with DICs in Australia, the U.K. and the U.S. They also complied with many of the DIC guidelines compiled by The Society of Hospital Pharmacists of Australia, except for the institution of formal quality assurance programmes, which was lacking in all centres. The professional activities of the local DIC pharmacists were also similar to their counterparts in Australia, the U.K. and U.S., but the job scope could be expanded to include other activities that are gaining impetus among other DIC pharmacists. Postgraduate professional training of pharmacists was inadequate compared with the specialist training received by DIC pharmacists in the U.S. A total of 2517 enquiries were collated for evaluation. Physicians were the major class (47-57%) of enquirers in the local hospitals. The classes of questions received by the DICs were not different from those received by DICs elsewhere, although the DICs in the hospitals received a preponderance of questions on dose (20-25%) and product availability (13-16%). More than 60% of enquiries received by the DICs in the hospitals were answered within 5 min, while about 80% of the enquiries required reference to not more than one literature resource. CONCLUSIONS: The pharmacist-operated DICs in Singapore have comparable standards to established DICs in Australia, the U.K. and U.S., while the workload and activities of the local DIC pharmacists are similar to their counterparts in these countries. It is recommended that the DICs institute formal quality assurance programmes and expand the training and job scope of the DIC pharmacists.

Prolonged retention of cross-linked trypsin in calcium alginate microspheres.

Trypsin microencapsulated in a calcium alginate matrix was lost quickly through diffusion when the microspheres were placed in an aqueous medium. This problem was overcome by first reacting trypsin with glutaraldehyde to form cross-linkages and then incorporating the enzyme in the alginate microspheres. The performance of the cross-linked trypsin remained optimal at pH 8 while it was found to be more heat-stable and remained highly active even at 80 degrees C. Esters and amides of L-arginine were preferentially hydrolysed by the enzyme indicating that cross-linking did not adversely affect the conformation of the active site. There was a suppression in enzymatic activity when the microspheres were placed in reaction media with an increasing concentration of organic solvent such as ethanol, acetonitrile or isopropanol. However, when returned to a totally aqueous environment, the enzyme resumed its initial tryptic capability. Such a microencapsulated form of cross-linked enzyme may find application in enzyme replacement therapy, optical resolution of racemic compounds as well as organic synthesis in an aqueous-organic environment.

Deviation of the ratio of drugs in a two-component mixture encapsulated in cellulose phthalate microspheres.

Microspheres were formed when a solution of cellulose phthalate was extruded into 30% glacial acetic acid solution. Sulphonamides entrapped in such microspheres leached into the hardening solution because they dissolved freely in the acetic acid solution. This resulted in poor loading efficiency of the sulphonamides in the microspheres. When mixtures of sulphaguanidine and sulphathiazole in various drug ratios were microencapsulated by this method, the observed drug ratios were found to be markedly changed. This was attributed to the difference in solubility of the two sulphonamides in acid such that their extent of diffusion into the hardening solution was not similar. NSAIDS such as ibuprofen and mefenamic acid which are acidic and more hydrophobic in nature are less soluble in acetic acid. These drugs were retained better in the microspheres during the hardening process and the loading efficiency was consequently improved. In cases where mixture of the NSAIDS were encapsulated, the drug ratios showed little deviation from the theoretical values. This study shows that loading of the CAP microspheres is dependent on the solubility of the drugs in acetic acid. When more than one drug is required to be microencapsulated, the drug ratio may change if the drugs have different solubility in acetic acid.

Enzyme-based high-performance liquid chromatography supports as probes of enzyme activity and inhibition: the immobilization of trypsin and alpha-chymotrypsin on an immobilized artificial membrane high-performance liquid chromatography support.

Immobilized artificial membrane (IAM) HPLC supports have been used to immobilize the enzymes alpha-chymotrypsin and trypsin. The enzymes were trapped in hydrophobic cavities on the support and were not covalently attached to the IAM surface. The resulting IAM-enzyme supports retained the hydrolytic activity of the immobilized enzymes: the IAM-trypsin support catalyzed the hydrolysis of N alpha-benzoyl-DL-arginine-p-nitroanilide (BAPNA), and the IAM-alpha-chymotrypsin support (IAM-ACHT) catalyzed the hydrolysis of a number of substrates, including tryptophan methyl ester. The activities of both supports were decreased by known enzyme inhibitors and the activity of the IAM-ACHT was affected by changes in pH and temperature. When a substrate was chromatographed on an IAM-ACHT HPLC, the hydrolytic activity of the immobilized enzyme could be determined from the resulting substrate/product ratios. These data were obtained either directly from the IAM-ACHT chromatogram or from the chromatogram produced by a coupled column system. The results of this study indicate that IAM-immobilized alpha-chymotrypsin and trypsin can be used as chromatographic probes for the qualitative determination of enzyme/substrate and enzyme/inhibitor interactions.