Dyah Aryani Perwitasari

Anti-emetic drugs in oncology: pharmacology and individualization by pharmacogenetics

Objective Nausea and vomiting are the most distressful side effects of cytotoxic drugs in cancer patients. Antiemetics are commonly used to reduce these side effects. However, the current antiemetic efficacy is about 70–80% in patients treated with highly-emetogenic cytotoxic drugs. One of the potential factors explaining this suboptimal response is variability in genes encoding enzymes and proteins which play a role in metabolism, transport and receptors related to antiemetic drugs. Aim of this review was to describe the pharmacology and pharmacogenetic concepts of of antiemetics in oncology. Method Pharmacogenetic and pharmacology studies of antiemetics in oncology published between January 1997 and February 2010 were searched in PubMed. Furthermore, related textbooks were also used for exploring the pharmacology of antiemetic drugs. The antiemetic drugs which were searched were the 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs), dopamine antagonists, corticosteroids, benzodiazepines, cannabinoids, antihistamines and neurokinin-1 antagonists. Result The 5-HT3RAs are widely used in highly emetogenic chemotherapy in combination with dexamethasone and a neurokinin-1 antagonist, especially in acute phase. However, the dopamine antagonists and benzodiazepines were found more appropriate for use in breakthrough and anticipatory symptoms or in preventing the delayed phase of chemotherapy induced nausea and vomiting. The use of cannabinoids and antihistamines need further investigation. Only six articles on pharmacogenetics of the 5-HT3RAs in highly emetogenic chemotherapy are published. Specifically, these studies investigated the association of the efficacy of 5-HT3RAs and variants in the multi drug resistance 1 (MDR1) gene, 5-HT3A,B and C receptor genes and CYP2D6 gene. The pharmacogenetic studies of the other antiemetics were not found in this review. Conclusion It is concluded that pharmacogenetic studies with antiemetics are sparse. It is too early to implement results of pharmacogenetic association studies of antiemetic drugs in clinical practice: confirmation of early findings is required.

Translation and Validation of EORTC QLQ-C30 into Indonesian Version for Cancer Patients in Indonesia

OBJECTIVE Quality of life studies in Indonesia are still uncommon. This research was aimed to validate the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 in Indonesian version. The standard procedure of forward-backward translation was adhered to in the translation procedures. The validity procedure included reliability, convergent and discriminant validity, known-groups validity, factor analysis and external convergent validity. METHODS Data were collected from cancer patients in the Oncology Department of Sardjito Hospital, Yogyakarta, Indonesia, who were treated with cisplatin at the dosage ≥50 mg/m(2) as monotherapy or in combinations. The Short Form-36 was used to assess the external convergent validity of our translated questionnaire. RESULTS One hundred and twenty-eight patients were recruited from March 2009 to November 2009. The internal consistency with values of >0.70 was observed in the Indonesian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 scales. All items in the questionnaire met the criteria of convergent and discriminant validity, except for items 5. Both of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and the Short Form-36 showed that different diagnoses were associated with a similar impact on quality of life. Factor analysis showed that only the role function and social function loaded onto the second factor together. Correlations between the Indonesian versions of both questionnaires were moderate: between 0.18 and 0.48 for the physical, emotional, social, fatigue and pain domains. CONCLUSIONS The Indonesian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 can be used as a questionnaire to assess quality of life in Indonesian cancer patients with high-emetogenic treatments.

Association of ABCB1, 5-HT3B Receptor and CYP2D6 Genetic Polymorphisms with Ondansetron and Metoclopramide Antiemetic Response in Indonesian Cancer Patients Treated with Highly Emetogenic Chemotherapy

OBJECTIVE Suboptimal treatment of chemotherapy-induced nausea and vomiting and unsatisfactory response to antiemetic drugs cause impairment of cancer patients daily functioning. This study was aimed to investigate the association of selected germline polymorphisms with ondansetron and metoclopramide response in Indonesian cancer patients treated with highly emetogenic chemotherapy. METHODS We enrolled 202 chemotherapy naïve patients treated with cisplatin at a dosage of ≥50 mg/m(2) as monotherapy or as combined chemotherapy. Ondansetron 8 mg and dexamethasone 8 mg intravenously were the standard antiemetic therapy for prevention of acute chemotherapy-induced nausea and vomiting. Metoclopramide 10 mg orally, three times per day as fixed prescription, was given until 5 days after chemotherapy to prevent delayed chemotherapy-induced nausea and vomiting. Primary and secondary outcomes were the occurrence of chemotherapy-induced nausea and vomiting in the acute and delayed phase. The following single-nucleotide polymorphisms were determined in ABCB1: rs1045642, rs2032582 and rs1128503; in 5-HT3B-R: rs45460698, rs4938058 and rs7943062; and in CYP2D6: rs16947 (CYP2D6 2), rs3892097 (CYP2D6 4) and rs1065852 (CYP2D6 10) using Taqman assays. RESULTS During the acute phase, 21.8 and 30.2% patients experienced Grade 3 and 4 nausea and vomiting, respectively, whereas 38.6% patients experienced nausea and/or vomiting in the delayed phase. Carriers of the CTG haplotype of the ABCB1 gene experienced Grade 3 and 4 chemotherapy-induced nausea and vomiting more often than other haplotypes in the delayed phase (P< 0.05). No associations were found with the 5-HT3B receptor haplotypes and CYP2D6-predicted phenotypes. CONCLUSIONS Our study shows that in Indonesian cancer patients treated with highly cytostatic emetogenic, carriership of the CTG haplotype of the ABCB1 gene is related to an increased risk of delayed chemotherapy-induced nausea and vomiting.

Impact of Chemotherapy-Induced Nausea and Vomiting on Quality of Life in Indonesian Patients With Gynecologic Cancer

Background Quality of life (QoL) has become a major outcome in the treatment of patients with cancer. This study is aimed at examining the impact of chemotherapy-induced nausea and vomiting on QoL of patients with gynecologic cancer in Indonesia. Methods Chemotherapy-naive patients with gynecologic cancer, who were treated with cisplatin at a dosage 50 mg/m2 or higher as monotherapy or as part of combination chemotherapy regimens, were recruited in the Oncology Department, Dr. Sardjito Hospital, Yogyakarta, Indonesia. Quality of life was assessed by using the Indonesian version of the European Organization for Research and Treatment for Cancer of Quality of Life Questionnaire and Short Form-36, administered immediately before and on day 5 after chemotherapy administration. Patients used a daily diary to record nausea and vomiting during 5 days after chemotherapy. Results Most (74.9%) of the 179 patients experienced delayed emesis during the 5 days after chemotherapy despite prophylactic use of antiemetics. The delayed nausea and emesis caused significant negative impact on patients’ QoL. Nausea in the delayed phase caused negative effects on patients’ QoL. Conclusions Patients reported a negative impact on the QoL of delayed emesis after chemotherapy. Poor prophylaxis of patients’ nausea and vomiting after chemotherapy interferes with patients’ QoL. Medical and behavioral interventions may help to alleviate the negative consequences of chemotherapeutic treatment in patients with gynecologic cancers treated with suboptimal antiemetics.

Differences in 5-hydroxytryptamine-3B haplotype frequencies between Asians and Caucasians

Background The 5-hydroxytryptamine (5-HT3) receptor is a ligand-operated ion channel with five different receptor subunits (5-HT3A, B, C, D, and E) found in humans. Activation of 5-HT3 receptors influences various effects such as drug-induced emesis and causes behavioral problems such as anxiety, depression and cognitive disorders. To explore interethnic differences in the response to 5-HT3 antagonists, we studied haplotype frequencies in the gene encoding the 5-HT3B receptor in Asians and Caucasians. Methods Three single nucleotide polymorphisms (SNPs) of the 5-HT3B receptor gene, i.e., deletion AAG at the 5′-UTR position, 18792A>G at the intron position, and 46698G>A at the 3′ near gene position, were selected and genotyped in 165 Indonesian cancer patients and 188 Caucasian healthy volunteers. Haplotypes were set with gPlink, whereas the differences in haplotype frequencies between Indonesians and Caucasians were compared using multivariate analysis. Results The haplotype profiles based on the deletion AAG, 18792A>G and 46698G>A were AAGAA, AAGAG, AAGGG, and deletion AG in both Indonesians and Caucasians. The frequency of the AAGAG haplotype was 54.8% in Indonesians and 39.9% in Caucasians (p<0.05). The frequency of the AAGGG haplotype was 14.3% in Indonesians and 29.3% in Caucasians. Moreover, there were significant differences in the frequencies of haplotype pairs between Indonesians and Caucasians (p<0.001). Conclusion Indonesian cancer patients had significantly different AAGAG and AAGGG haplotype frequencies of the gene encoding the 5-HT3B receptor compared to healthy Caucasians. This finding could be useful for understanding interethnic differences in the response to drugs targeting the 5-HT3B receptor in cancer-treatment-related emesis.

Validation of isoniazid for therapeutic drug monitoring in human plasma by high-performance liquid chromatography

Isoniazid is one of anti-tuberculosis agent which can cause hepatotoxicity. However, not all of the TB patients and health providers can recognize early symptoms of antituberculosis-induced hepatotoxicity. Thus, the Therapeutic Drug Monitoring needs to be performed to monitor the hepatotoxicity symptoms. The aim of this study is to establish the validity of the Isoniazid assay method using High-Performance Liquid Chromatography from human plasma. We recruited 6 healthy subjects for this validation study. The validation was performed using Shimadzu HPLC system with a model AT LC20 LC 10AT pump, detector SPD 20A and LC solution software. We used C18 column shim-pack VP-ODS (250 mm x 4.6 mm, id 5 µm) as well as other tools such as centrifuges, vortex, appliance glass (Pyrex IWAKI) and other supporting tools. Chemicals and solvents was used from Merck Germany. Isoniazid standard compounds were obtained from SIGMA. Our study has been approved by National Ethics Committee of Health Research. Our study shows tha...

Validation of pyrazinamide in human plasma using Hplc-Uv for therapeutic drug monitoring

Currently, Indonesia is in the 5th rank of the highest tuberculosis prevalence over the world. The treatment of tuberculosis is going complicated due to the side effect experienced by the patients. The four combination of antituberculosis agent used in minimally 6 months of treatment could stimulate the hepatotoxicity as the one of the dominant side effect in tuberculosis treatment. Thus, it is important to do the Therapeutic Drug Monitoring (TDM) to optimize the tuberculosis treatment. This study is aimed to validate the TDM of pyrazinamide in human plasma using High Performance Liquid Chromatography-UV. We recruited 6 TB patients in the validation of pyrazinamide study. The C18 column shim-pack VP-ODS (250 mm x 4.6 mm, id 5 µm) and aquabidest-acetonitrile as mobile phase were applied in this study. We used Shimadzu HPLC system with a model AT LC20 LC 10AT pump, detector SPD 20A and LC solution software. We performed the analysis for linearity, system appropriateness, accuracy and recovery to develop the validation method. This study has been approved by National Ethics Committee of Health Research. Our study shows that the linearity is good with value of r2> 0.99 and the equation y = 16740.876x - 2953.615. The CV TR and CV peak area for system suitability are 1.46% and 0.29%, respectively. The LoD and LoQ value are 2.532 and 7.672 µg/mL, respectively. The accuracy on the concentration of 1.00, 8.00, 60.00 ug/ml are 108.80 %, 92.57 % and 100.98 %, respectively for intraday accuracy and 103.18 %, 92.44%, and 94.94%, respectively for interday accuracy. Furthermore, the precision on the concentration of 1.00, 8.00, 60.00 ug/ml are 1.17%, 3.57%, 3.32%, respectively for intraday precision and 3.66%, 1.37% and 1.59%, respectively for interday precision. In conclusion, the method which we applied in this study was sensitive and reliable for routine TDM of pyrazinamide.