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ABSTRACT: 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.
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.
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).
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.
The International journal of biological markers 11/2011; 27(1):34-8. · 1.48 Impact Factor
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ABSTRACT: 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.
Chemotherapy-naive patients with gynecologic cancer, who were treated with cisplatin at a dosage 50 mg/m 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.
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.
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.
International Journal of Gynecological Cancer 11/2011; 22(1):139-45. · 1.65 Impact Factor
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ABSTRACT: Suboptimal treatment of chemotherapy-induced nausea and vomiting and unsatisfactory response to antiemetic drugs cause impairment of cancer patient's 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.
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.
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.
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.
Japanese Journal of Clinical Oncology 08/2011; 41(10):1168-76. · 1.78 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
International journal of clinical pharmacy. 02/2011; 33(1):33-43.
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ABSTRACT: Potential new targets for antimalarial chemotherapy include parasite proteases, which are required for several cellular functions during the Plasmodium falciparum life cycle. Four new derivatives of N-alkyl and N-benzyl-1,10-phenanthroline have been synthesized. Those are (1)-N-methyl-1,10-phenanthrolinium sulfate, (1)-N-ethyl-1,10-phenanthrolinium sulfate, (1)-N-benzyl-1,10-phenanthrolinium chloride, and (1)-N-benzyl-1,10-phenanthrolinium iodide. Those compounds had potential antiplasmodial activity with IC(50) values from 260.42 to 465.38 nM. Cysteine proteinase inhibitor E64 was used to investigate the mechanism of action of N-alkyl and N-benzyl-1,10-phenanthroline derivatives. A modified fixed-ratio isobologram method was used to study the in vitro interactions between the new compounds with either E64 or chloroquine. The interaction between N-alkyl and N-benzyl-1,10-phenanthroline derivatives and E64 was additive as well as their interactions with chloroquine were also additive. Antimalarial mechanism of chloroquine is mainly on the inhibition of hemozoin formation. As the interaction of chloroquine and E64 was additive, the results indicated that these new compounds had a mechanism of action by inhibiting Plasmodium proteases.
Malaria research and treatment. 01/2010; 2010:540786.
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ABSTRACT: An indole alkaloid with aspidospemane structure possessing a potential antiplasmodial activity, vincadifformine, has been isolated from Aspidosperma pyrifolium Mart. Moreover, 10 derivatives were prepared from the vincadifformine. The study was conducted to evaluate the in vitro antiplasmodial and cytotoxic activity of the vincadifformine and their semisynthetic derivatives. The in vitro antiplasmodial activity was evaluated on Plasmodium falciparum chloroquine-resistant (FcM ) and –sensitive (Nigerian) strains after 24-h and 72-h incubation, 29 while cytotoxic activity was estimated on Hela cells and Cytotoxicity Index (CI = IC on HeLa cells/IC on FcM strain) 50 50 29 was calculated to evaluate the safety of tested compounds. Experiment results showed that two compounds (4 and 8) exhibited good antiplasmodial activities in comparison with parent compound, vincadifformine and other tested compounds with IC ranging from 5.3 to 12.8 μM on FcM strain and 11.4 to 24.0 μM on Nigerian strain. In addition, 50 29 the CI of two compounds were also lower after 24-h incubation (CI, 2.0 and 4.8) than that of after 72-h incubation (CI, 9.5 and 11.5). Further study will be conducted to evaluate quantitative structure-activity relationship (QSAR) in order to design new antimalarial drugs.
Indonesian Journal of Biotechnology; Vol 11, No 1 (2006): Indonesian Journal of Biotechnology-June 2006; pp. 878-883.
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ABSTRACT: Actinomycetes have been the most prolific producer of various kinds of antifungal metabolites, and many of them are described as being produced by polyketide synthetases (pks). We present strain of Actinomycetes producing anticandida isolated from rhizosphere plant for amplification of PKS-I genes. The isolate was obtained from Wanagama I Forest UGM Yogyakarta. Gene of seven isolates, from total of 173 isolates, were amplified using degenerate primer to detect the presence of PKS genes. One strain that is named Streptomyces sp. GMR-22 was partialy identified as anticandida producing actinomycete. The strain shown the strongest activity against Candida albicans. Based on bioautography assay, one spot active with Rf 0.57 was appeared as bright yellow by cerrium sulphate but it was and not visible on UV and lights.
Indonesian Journal of Biotechnology; Vol 15, No 1 (2010): Indonesian Journal of Biotechnology-June 2010; pp. 1-8.
