Melatonin effect on hypoxia inducible factor-1α and clinical response in patients with oral squamous cell carcinoma receiving neoadjuvant chemotherapy: A randomized controlled trial.

CONTEXT: Chemoresistance is a major issue in patients with locally advanced oral squamous cell carcinoma (OSCC). In this study, we evaluated the effectiveness of melatonin in conjunction with neoadjuvant chemotherapy (NC) on hypoxia-inducible factor-1α (HIF-1α) expression and clinical response in locally advanced OSCC patients. AIMS: To study the effects of melatonin on HIF-1α expression and its effect on the clinical response of patients with locally advanced OSCC. SETTINGS AND DESIGN: A randomized controlled trial was conducted, wherein patients were recruited from several hospitals in Jakarta, Indonesia. Patients were randomized into two groups using computerized block randomization. SUBJECTS AND METHODS: Both groups were given NC, with treatment group receiving melatonin. Outcomes measured in this study were HIF-1α expression from tissue samples and clinical response based on the RECIST 1.1 criteria. Twenty-five patients completed the study protocol and were included in the data analysis. STATISTICAL ANALYSIS USED: Shapiro-Wilk test was used to test the data normality. For data with normal distribution, we conducted an independent t-test to compare between the two groups. Data with abnormal distribution were analyzed using Mann-Whitney U-test. The mean difference between the two groups was analyzed using Shapiro-Wilk normality test. RESULTS: Our study showed a significant decrease in HIF-1α expression in the melatonin group compared to the placebo group (P < 0.05, relative risk 3.08). However, the degree of reduction of HIF-1α expression in the melatonin group did not differ significantly (P = 0.301). CONCLUSIONS: Our study showed that melatonin administered at 20 mg/day could reduce the expression of HIF-1α and residual tumor percentage, but did not affect the clinical response in OSCC patients.

A Double-blind, Randomized Controlled Trial of Ciplukan (Physalis angulata Linn) Extract on Skin Fibrosis, Inflammatory, Immunology, and Fibrosis Biomarkers in Scleroderma Patients.

BACKGROUND: scleroderma is an autoimmune disease characterized by organ fibrosis, resistant to standard treatment. It is suspected the addition of Physalis angulata Linn. (Ciplukan) extract as adjuvant therapy can improve the scleroderma skin fibrosis. The aim at this study is to evaluate the effect of ciplukan extract as adjuvant on scleroderma skin fibrosis in standard therapy, based on modified Rodnan skin scale (MRSS), inflammatory biomarkers, immunology and serum fibrosis. METHODS: double-blind, randomized clinical trial was performed in scleroderma patients with stable disease at Cipto Mangunkusumo hospital and Hasan Sadikin hospital during November 2015-March 2017 who met the selection criteria and continued to receive standard therapy. The subjects were randomly allocated into two groups: the study group received the ciplukan  extract 3 x 250 mg / day for 12 weeks and the placebo group. Examination of MRSS, ESR, P1NP, BAFF and sCD40L was performed every 4 weeks until the end of the study. RESULTS: fifty-nine subjects completed the study. They consisted of 29 subjects of the treatment group and 30 of the placebo group, with an average age of 41 (SD 9) years, the proportion of women: male = 9 : 1. There was a significant improvement of skin fibrosis in the study group with a highly significant decrease in MRSS (35.9% VS 6.3%, p <0.001) and a relative decrease in P1NP levels (17.8% VS 0.7%, p = 0.002). No decrease in ESR, BAFF and sCD40L levels in both groups. There was a weak but significant positive correlation between MRSS with P1NP levels (r = 0.236, p = 0.036). CONCLUSION: Ciplukan extract with dose 3 x 250 mg for 12 weeks as adjuvant on scleroderma standard therapy alleviates skin fibrosis significantly based on MRSS and P1NP levels.

Optimal Amikacin Levels for Patients with Sepsis in Intensive Care Unit of Cipto Mangunkusumo Hospital, Jakarta, Indonesia.

BACKGROUND: Amikacin is one of the antibiotics of choice for sepsis and septic shock. Pharmacokinetic of amikacin can be influenced by septic condition with subsequent effect on its pharmacodynamic. At Cipto Mangunkusumo Hospital (RSCM), Jakarta, adult patients in the ICU were given standard amikacin dose of 1 g/day, however the achievement of optimal plasma level had never been evaluated. This study aimed to evaluate whether the optimal plasma level of amikacin was achieved with the use of standard dose in septic conditions. METHODS: all septic patients admitted to the intensive care unit of a national tertiary hospital receiving standard dose of 1g/day IV amikacin during May-September 2015 were included in this study. Information of minimum inhibitory concentration MIC was obtained from microbial culture. Cmax of amikacin was measured 30 minutes after administration and optimal level was calculated. Optimal amikacin level was considered achieved when Cmax/MIC ratio >8. RESULTS: average Cmax achieved for all patients was 86.4 (43.5-238) µg/mL with 87% patients had Cmax of >64 µg/mL.MIC data were available for 7 of 23 patients. MICs for identified pathogens were 0.75 - >256 µg/mL (K. pneumonia), 0.75 - >256 µg/mL(A. baumanii), 1.5 - >256 µg/mL (P. aeruginosa)and 0.75 - 16 µg/mL(E. coli). Four out of seven patients achieved optimal amikacin level. CONCLUSION: despite high Cmax, only half of the patients achieved optimal amikacin level with highly variable Cmax. This study suggests that measurement of Cmax and MIC are important to optimize septic patients management.

Randomized trial of primaquine hypnozoitocidal efficacy when administered with artemisinin-combined blood schizontocides for radical cure of Plasmodium vivax in Indonesia.

BACKGROUND: Safety and efficacy of primaquine against repeated attacks of Plasmodium vivax depends upon co-administered blood schizontocidal therapy in radical cure. We assessed primaquine (PQ) as hypnozoitocide when administered with dihydroartemisinin-piperaquine (Eurartesim®, DHA-PP) or artesunate-pyronaridine (Pyramax®, AS-PYR) to affirm its good tolerability and efficacy. A third arm, artesunate followed by primaquine, was not intended as therapy for practice, but addressed a hypothesis concerning primaquine efficacy without co-administration of blood schizontocide. METHODS: During March to July 2013, an open-label, randomized trial enrolled Indonesian soldiers with vivax malaria at Sragen, Central Java, after six months duty in malarious Papua, Indonesia. No malaria transmission occurred at the study site and P. vivax recurrences in the 12 months following therapy were classified as relapses. A historic relapse control derived from a cohort of soldiers who served in the same area of Papua was applied to estimate risk of relapse among randomized treatment groups. Those were: 1) AS followed 2d later by PQ (0.5 mg/kg daily for 14d); 2) co-formulated AS-PYR concurrent with the same regimen of PQ; or 3) co-formulated DHA-PP concurrent with the same regimen of PQ. RESULTS: Among 532 soldiers, 219 had vivax malaria during the four months following repatriation to Java; 180 of these were otherwise healthy and G6PD-normal and enrolled in the trial. Subjects in all treatment groups tolerated the therapies well without untoward events and cleared parasitemia within three days. First relapse appeared at day 39 post-enrollment, and the last at day 270. Therapeutic efficacy of PQ against relapse by incidence density analysis was 92 % (95 %CI = 83-97 %), 94 %(95 %CI = 86-97 %), and 95 %(95 %CI = 88-98 %) when combined with AS, AS-PYR, or DHA-PP, respectively. CONCLUSIONS: This trial offers evidence of good tolerability and efficacy of PQ against P. vivax relapse when administered concurrently with DHA-PP or AS-PYR. These offer alternative partner drugs for radical cure with primaquine. The AS arm demonstrated efficacy with a total dose of 7 mg/kg PQ without concurrently administered blood schizontocide, another option when primaquine therapy is removed in time from the treatment of the acute malaria or applied presumptively without an attack. TRIAL REGISTRATION: Current Controlled Trials ISRCTN82366390, assigned 20 March 2013.

Opioid Use in Cancer Pain Management in Indonesia: a Call For Attention.

Severe pain is a major problem for cancer patients, and pain management often requires the use of opioids. Indonesia is one of the countries where the use of opioids for cancer patients is extremely low, and this calls for attention, as many cancer patients in the country undergo unnecessary suffering as the consequence of this opioid underuse. The inability to assess pain correctly, failure to determine the correct dose, fear of addiction, overly tight regulation, all contribute to the failure to implement rational use of opioids for cancer patients. Breakthrough pain, a problem which requires special attention not only because it is commonly found but also requires proper knowledge to handle them. These hurdles are discussed in the present review, in order to bring a better understanding about the correct use of opioids in severe cancer pain. Some examples where opiods are used inappropriately in cancer pain management are also discussed.

Prothrombotic Effect of Anti-beta-2 Glycoprotein-1 Antibodies on the Expression of Tissue Factor, Thrombomodulin, and Plasminogen Activator Inhibitor-1 in Endothelial Cells.

AIM: to analyse the effects of immunoglobulin(Ig)G and IgM anti-beta-2 glycoprotein-1 (anti-2GP1) on the expression of tissue factor (TF), thrombomodulin (TM), and plasminogen activator inhibitor-1(PAI-1) of endothelial cells in the messenger RNA level. METHODS: laboratory experimental study in human umbilical vein endothelial cells (HUVEC) was done at Cipto Mangunkusumo Hospital/Faculty of Medicine, Universitas Indonesia. Samples are purified IgG anti-2GP1 from six antiphospholipid syndrome (APS) patients serum and IgM anti-2GP1 from six APS patients serum. For controls, purified IgG from six normal human serum (IgM-NHS) and purified IgM from six normal human serum (IgM-NHS) were used. HUVEC were treated with purified IgG anti-2GP1, IgM anti-2GP1, IgG-NHS, IgM-NHS for four hours of incubation. We measured TF, TM, and PAI-1 of HUVEC in mRNA relative expression levels (before and after treatment) by real time reverse transcription polymerase chain reaction. RESULTS: the mean value of TF, TM, and PAI-1 mRNA levels in HUVEC after treated with IgG anti-2GP1 compared to Ig-NHS were 3.14 (0.93)-, 0.31 (0.13)-, 5.33 (2.75)-fold respectively. In other hand, after treated with IgM anti-2GP1 compared to IgM-NHS, mRNA levels of TF, TM, and PAI-1 were 4.33 (1.98)-, 0.33 (0.22)-, 5.47 (2.64)-fold respectively. Before and after treatment with IgG anti-2GP1 showed significant differences of TF mRNA levels {1.09 (0.76) versus 3.14 (0.93), p=0.003}, TM mRNA levels {0.91 (0.11) versus 0.31(0.13), p=0.001}, and PAI-1 mRNA levels 0.93 (0.13) versus 5.33 (2.75), p=0.013}. Before and after treatment with IgM anti-2GP1 showed significant differences of TF mRNA levels {1.03 (0.11) versus 4.33 (1.98), p=0.008}, TM mRNA levels {0.93 (0.08) versus 0.33 (0.22, p=0.003}, and PAI-1 mRNA levels {1.02 (0.10) versus 5.47 (2.64), p=0.01}. CONCLUSION: IgG anti-2GP1 and IgM anti-2GP1 increased TF and PAI-1 mRNA levels. However, IgG anti-2GP1 and IgM anti-2GP1 decreased TM mRNA levels. It proved that the mechanism of thrombosis in APS occurs through coagulation activation, reduction of fibrinolysis activity, and reduction of anticoagulant activity.

NUDT15 Polymorphism and Its Association With Mercaptopurine Hematotoxicity in Acute Lymphoblastic Leukemia in Indonesian Children.

BACKGROUND/AIM: Hematotoxicity is a life-threatening condition that has become the major cause of drug discontinuation in patients with acute lymphoblastic leukemia (ALL). The nudix hydrolase 15 (NUDT15) gene polymorphism (c.415C>T) is reported to have an association with the hematotoxicity of 6-mercaptopurine (6-MP) as maintenance therapy in patients with ALL. However, the prevalence of this genetic polymorphism in the Indonesian population is unknown. This study aimed to assess the frequency of NUDT15 polymorphism among Indonesian pediatric patients with ALL and its association with the hematotoxicity of 6-MP. PATIENTS AND METHODS: A total of 101 stored DNA samples from pediatric patients with ALL receiving 6-MP treatment were used for genetic testing. Direct sequencing was conducted to determine the NUDT15 c.415C>T genotype. Chi-square or Fisher's exact test were employed to examine the association between the NUDT15 c.415C>T genotype and hematotoxicity. RESULTS: All (100%) of the DNA samples from patients with ALL treated with 6-MP exhibited a homozygous variant of the NUDT15 c.415C>T genotype, 70.3% of which showed hematotoxicity to some extent. We found no significant differences in NUDT15 gene polymorphism among patients with ALL with different states of hematotoxicity. CONCLUSION: The observed high frequency of NUDT15 c.415C>T in our study population might explain the elevated prevalence of 6-MP-associated hematotoxicity in pediatric patients with ALL within the Indonesian population. Our study provides new insight regarding the NUDT15 gene polymorphism and its relation to hematotoxicity. Further studies are required to determine the necessity of adjusting the initial dose of 6-MP for Indonesian pediatric patients with ALL.

Granulocyte Colony-stimulating Factor Improves Innate Immunity in Pediatric Pretransplant Patients.

Background: Children with decompensated cirrhosis (DC) awaiting LT suffer from infection linked to high pediatric end-stage liver disease (PELD) scores and mortality. Granulocyte colony-stimulating factor (G-CSF) therapy has shown promising results in adult DC. Our study investigated G-CSF as an optimizing treatment for pre-transplant DC, exploring its effect on cytokine activity. Methods: An open-label, randomized controlled trial included DC patients aged 3 months-12 years. The intervention group (n=26) received 12 G-CSF courses injected subcutaneously (5 µg/kg/day) plus DC standard medical treatment (SMT). The control group (n = 24) received SMT. We obtained PELD scores, tumor necrosis factor (TNF)-α, interleukin (IL)-10, hepatocyte growth factor (HGF), CD34+ mobilization, liver function, leukocyte and neutrophil counts. Infection and side effects were documented. Results: There was no significant difference in PELD scores between the groups after 3 months G-CSF treatment. Decreased TNF-α (p < 0.001) and increased IL-10 and HGF (p = 0.003 for both markers) were shown 1 month following G-CSF treatment. Alanine aminotransferase (ALT) levels improved significantly (p = 0.038). Significant increase in leucocyte and neutrophil counts (p < 0.001) and a lower incidence of sepsis (p = 0.04) were shown after intervention. There was no significant difference in survival (p = 0.372). Conclusion: Following 3 months of G-CSF treatment, PELD scores did not show significant improvement. G-CSF reversed the cytokine profiles in DC, resulting in reduced TNF-α and increased IL-10. HGF significantly improved, indicating hepatic regeneration. Significantly decreased occurrence of sepsis following G-CSF treatment indicated improved clinical outcome.

Circulating miR-10b, soluble urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 as predictors of non-small cell lung cancer progression and treatment response.

BACKGROUND: Despite advances in lung cancer treatment, most lung cancers are diagnosed at an advanced stage. Expression of microRNA10b (miR-10b) and fibrinolytic activity, as reflected by soluble urokinase-type plasminogen activator receptor (suPAR) and plasminogen activator inhibitor 1 (PAI-1), are promising biomarker candidates. OBJECTIVE: To assess the expression of miR-10b, and serum levels of suPAR and PAI-1 in advanced stage non-small cell lung cancer (NSCLC) patients, and their correlation with progression, treatment response and prognosis. METHODS: The present prospective cohort and survival study was conducted at Dharmais National Cancer Hospital and included advanced stage NSCLC patients diagnosed between March 2015 and September 2016. Expression of miR-10b was quantified using qRT-PCR. Levels of suPAR and PAI-1 were assayed using ELISA. Treatment response was evaluated using the RECIST 1.1 criteria. Patients were followed up until death or at least 1 year after treatment. RESULTS: Among the 40 patients enrolled, 25 completed at least four cycles of chemotherapy and 15 patients died during treatment. Absolute miR-10b expression ⩾ 592,145 copies/µL or miR-10b fold change ⩾ 0.066 were protective for progressive disease and poor treatment response, whereas suPAR levels ⩾ 4,237 pg/mL was a risk factor for progressive disease and poor response. PAI-1 levels > 4.6 ng/mL was a protective factor for poor response. Multivariate analysis revealed suPAR as an independent risk factor for progression (ORa⁢d⁢j, 13.265; 95% confidence intervals (CI), 2.26577.701; P= 0.006) and poor response (ORa⁢d⁢j, 15.609; 95% CI, 2.221-109.704; P= 0.006), whereas PAI-1 was an independent protective factor of poor response (ORa⁢d⁢j, 0.127; 95% CI, 0.019-0.843; P= 0.033). CONCLUSIONS: Since miR-10b cannot be used as an independent risk factor for NSCLC progression and treatment response, we developed a model to predict progression using suPAR levels and treatment response using suPAR and PAI-1 levels. Further studies are needed to validate this model.

Randomized, open-label trial of primaquine against vivax malaria relapse in Indonesia.

Radical cure of Plasmodium vivax infection applies blood schizontocidal therapy against the acute attack and hypnozoitocidal therapy against later relapse. Chloroquine and primaquine have been used for 60 years in this manner. Resistance to chloroquine by the parasite now requires partnering other blood schizontocides with primaquine. However, the safety and efficacy of primaquine against relapse when combined with other drugs have not been demonstrated. This randomized, open-label, and relapse-controlled trial estimated the efficacy of primaquine against relapse when administered with quinine or dihydroartemisinin-piperaquine for treatment of the acute infection. Among 650 soldiers who had returned to their malaria-free base in Java, Indonesia, after 12 months in malarious Papua, Indonesia, 143 with acute P. vivax malaria were eligible for study. One hundred sixteen enrolled subjects were randomized to these treatments: artesunate (200-mg dose followed by 100 mg/day for 6 days), quinine (1.8 g/day for 7 days) plus concurrent primaquine (30 mg/day for 14 days), or dihydroartemisinin (120 mg) plus piperaquine (960 mg) daily for 3 days followed 25 days later by primaquine (30 mg/day for 14 days). Follow-up was for 12 months. One hundred thirteen subjects were analyzable. Relapse occurred in 32 of 41 (78%) subjects administered artesunate alone (2.71 attacks/person-year), 7 of 36 (19%) administered quinine plus primaquine (0.23 attack/person-year), and 2 of 36 (6%) administered dihydroartemisinin-piperaquine plus primaquine (0.06 attack/person-year). The efficacy of primaquine against relapse was 92% (95% confidence interval [CI] = 81% to 96%) for quinine plus primaquine and 98% (95% CI = 91% to 99%) for dihydroartemisinin-piperaquine plus primaquine. Antirelapse therapy with primaquine begun a month after treatment of the acute attack with dihydroartemisinin-piperaquine proved safe and highly efficacious against relapse by P. vivax acquired in Papua, Indonesia.

Lack of a relationship between the serum concentration of aminoglycosides and ototoxicity in neonates.

INTRODUCTION: Gentamicin and the other aminoglycosides are toxic antibiotics, but they are urgently needed to treat newborns with neonatal sepsis. Aminoglycosides are well known for their nephrotoxicity and ototoxicity. The aminoglycoside dosage currently applied in Indonesia is derived from studies done in Caucasian populations. The safety and efficacy of this dosage regimen, however, has never been evaluated to date. The pharmacokinetic profile of drugs may vary between populations and this may be influenced by genetic factors, lifestyle, drug interactions, etc. The detection of aminoglycoside toxicity in newborns is usually problematic. The present study aims to know the proportion of ototoxicity in newborns in the Cipto Mangunkusumo Hospital treated with gentamicin or amikacin in relation to their trough serum concentration. METHODS: The serum level of gentamicin and amikacin were quantified using Liquid Chromatography Tandem Mass Spectrometry (LC-MSMS), and is assumed to be safe if the trough serum concentrations are < 2 mcg/ml and effective if it is between 5 - 12 mcg/ml. For amikacin the desired trough serum concentrations are < 10 mcg/ml and the peak is between 20 - 30 mcg/ml. The hearing function was assessed by Distortion Product Otoacoustic Emission (DPOAE) instrument. This study is registered with the www.clinicaltrials.gov NCT01624324. CONCLUSION: Our study indicated that there was no relationship between aminoglycosides serum trough concentration and ototoxicity in neonates with neonatal sepsis.

Multidrug Resistance-1 C3435T Polymorphism and Carbamazepine Plasma Level in Indonesian Temporal Lobe Epilepsy Patients.

BACKGROUND: Temporal lobe epilepsy (TLE) has the highest probability of becoming resistant. One of the causes was Polymorphism in multidrug resistant-1 (MDR1) C3435T. In Dr. Cipto Mangunkusumo Hospital, potential drug-resistant epilepsy prevalence was 84.51%; 66.6% of them used carbamazepine (CBZ) as antiseizure medication. This comparative cross-sectional study aimed to investigate MDR1 C3435T polymorphism and CBZ plasma level (plCBZ) in Indonesian TLE patients. METHODS: TLE patient was selected consecutively; divided into drug-responsive (DRV) and drugresistant (DRE) groups. Healthy subjects were included as a control for the gene polymorphism comparison. MDR1 was identified using the restriction fragment length polymorphism PCR technique; C allele at 159 and 57bp while T allele at 216bp. High-performance liquid chromatography was used to determine plCBZ. RESULTS: There were 86 subjects; 61 in the study group and 25 controls. The genotype distribution between them was 0.58 vs 0.42, x2=0.54, p=0.000. In the study group, CBZ within therapeutic doses (dCBZ) had outreached the therapeutic plCBZ and found similar in all genotypes. DRE criteria were found in 37 subjects. Distribution of C and T in DRV was 0.63 vs 0.37, x2=10.4; and DRE 0.55 vs 0.45 x2=6.17 (p=0.019). In Tukey's multiple comparison post hoc test, CT in DRV had significantly lower dCBZ (330,36 ± 174,91 mg) and plCBZ (7.15 ± 2.64 mcg/mL) compared to all genotypes in DRE. Whereas mean dCBZ was around 800mg and plCBZ outreached the toxic level; TT was the highest. CONCLUSION: The genotype MDR1 distribution was similar in the normal population and DRE. Therapeutic plCBZ was achieved using the low dose. CT genotype responds to lower dCBZ, while TT genotype outreached the highest toxic plCBZ.

The role of the glucocorticoid receptor and its impact on steroid response in moderate-severe COVID-19 patients.

The effect of corticosteroid therapy in COVID-19 patients is mediated by its suppressive effect on the regulations of inflammatory response. However, its clinical outcome is often unpredictable. This study aimed to explore the role of glucocorticoid receptors in corticosteroid response in Moderate-Severe COVID-19 patients. In this cross-sectional study, we attempted to find the relationship between the expression of the glucocorticoid receptor (encoded by NR3C1), the variation of glucocorticoid receptors isoform, and the mutations of glucocorticoid receptors exon with clinical response to corticosteroids. In addition, the relationship between glucocorticoid receptors expression and the expression of IκBα (encoded by NFKBIA) and glucocorticoid-induced leucine zipper protein (GILZ; encoded by TSC22D3) as steroid pathways was also evaluated. Thirty-four COVID-19 patients were studied. Blood was drawn before and on day 5 of corticosteroid treatment. Glucocorticoid receptors expression, isoform, and mutation were determined by RNA sequencing from white blood cells. Based on the improvement of clinical and oxygen status, patients were classified into responder and non-responder groups. Of thirty-four patients, 23 (67.6%) showed excellent responses to corticosteroids, and 11 (32.4%) were non-responders. The NR3C1 gene expression was significantly higher in the responsive group at baseline and after five days of glucocorticoid treatment. Isoform variant and mutation of glucocorticoid receptors did not correlate with clinical response. The expression of IκBα and GILZ correlated positively with glucocorticoid receptors expression. This study elucidates the relationship between glucocorticoid receptor expression with therapeutic responses to corticosteroids in moderate-severe COVID-19.

Urinary 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin-F1α in healthy post-menopausal and pre-menopausal women receiving aspirin 100 mg.

The prevalence of cardiovascular diseases in women increases sharply after menopause. In postmenopausal women, thromboxane production increases while prostacyclin decreases. Low dose aspirin reduces the production of both thromboxane and prostacyclin. The present study was an open-label clinical trial with two parallel groups of 15 premenopausal women and 15 postmenopausal women. Twenty-four hours urine was collected from each subject before and after aspirin 100 mg daily for 7 days. The concentration of thromboxane and prostacyclin was measured as their metabolites (11-dehydro-thromboxane B(2) and 2,3-dinor-6-keto-prostaglandin-F(1α)) in urine using enzyme immunoassay methods. This study showed that aspirin significantly reduced thromboxane in both groups with significantly larger percentage reduction in postmenopausal women compared to premenopausal women (73.32 vs. 61.13%, p = 0.021). This study also showed that aspirin reduced prostacyclin significantly in both groups, but the percentage reduction between the groups was not significantly different. The decrease in the ratio of 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) should be compared to assess aspirin efficacy as an antithrombotic. Calculation of the ratio of 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) before aspirin consumption was higher in postmenopausal women than in premenopausal women. The decrease in 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) ratio by aspirin was greater in postmenopausal women than in premenopausal women (1.91 vs. 0.17; p = 0.022). It was concluded that aspirin reduced thromboxane and prostacyclin significantly in each group with significant 11-dTXB(2) percentage reduction between groups and non-significant 2,3-dinor-6-keto-PGF(1α) percentage reduction between groups, but reduced the 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) ratio much larger in postmenopausal women compared to that in premenopausal women.

Co-administration of ritonavir and primaquine decreases plasma concentration of primaquine: single- and multiple-dose study in the rats.

AIM: to explore the effects of ritonavir and primaquine combination given as a single-dose or multiple-dose compared to ritonavir alone on ritonavir plasma concentration in the rats. METHODS: in single-dose study, 30 male Spraque Dawley rats were randomly allocated to receive primaquine 12.5 mg/kgBW or primaquine 12.5 mg/kgBW + ritonavir 10 mg/kgBW or primaquine 12.5 mg/kgBW + ketokonazole 10 mg/kgBW. Ketokonazole was used as positive control for inhibitor of primaquine metabolism. In the multiple-dose study, thirty Spraque Dawley male rats were randomly allocated to receive primaquine 12.5 mg/kgBW/day or primaquine 12.5 mg/kgBW/day + ritonavir 10 mg/kgBW/day or primaquine 12.5 mg/kgBW/day + rifampicin 100 mg/kgBW/day. Rifampicin was used as a positive control for inducer of primaquine metabolism. RESULTS: in the single-dose study, ketokonazole increases the area under the plasma concentration (AUC) of primaquine (h45.8%, p<0.000), while the ritonavir decreases the AUC of primaquine (i64.6%, p<0.000). Multiple-dose study shows that both rifampicin and ritonavir decreases the AUC of primaquine by 60.2% (p<0.000) and 67.7% (p<0.000), respectively. CONCLUSION: concomitant administration of primaquine and ritonavir decreases the AUC of ritonavir. This effect could result in the insufficient concentration of primaquine as anti-relapse therapy in malaria caused by Plasmodium vivax, which might lead to treatment failure with primaquine.

Current status of phase I clinical trials in Asia: an academic perspectives.

Clinical trials increasingly occured in Asia during the past years as pharmaceutical industries embraced globalization in the clinical research fields. The trend is true with phase III clinical trials but not for early stage/phase I clinical trials in Asian countries is still under-represented. The conduct of phase I clinical trials is considered more sophisticated and difficult than the later stage clinical trials. There are continuing concerns from the pharmaceutical industries about the capacity of Asian countries in conducting this type of clinical trials. We highlighted several problems concerning the ethical and scientific issues, the implementation of ICH-GCP and local regulations, investigators and clinical trial subjects. The purpose of this paper is to give some perspectives addressing the problems in conducting phase I clinical trials. Improving collaboration and capacity building among the Asian countries is a solution that we proposed in order to increase the quality and quantity of phase I clinical trials in Asian countries.

Increased vegetable intake improves glycaemic control in adults with type 2 diabetes mellitus: a clustered randomised clinical trial among Indonesian white-collar workers.

Dietary patterns high in fibre and green leafy vegetables have shown an inverse association with lower risks of type 2 diabetes mellitus and improved glycaemic control. The study aimed to investigate the effects of increased vegetable intake and conventional diabetes diet on glycaemic control among type 2 diabetic patients. White-collar workers from one telecommunication company with type 2 diabetes were assigned to two treatment groups by cluster randomisation. Individuals with known type 2 diabetes and poor glycaemic control (HbA1c ≥8 g%) were eligible and a total of 84 subjects were recruited. Subjects in the intervention group (n 41) were offered to attend seminars and intensive coaching weekly to encourage them to increase raw vegetable intake. The control group (n 40) followed the conventional diet according to the guidelines of the Indonesian Society of Endocrinology. Glycated haemoglobin (HbA1c), plasma lipids, blood pressure, vegetable intake and anthropometric measurements were assessed at baseline and end line of 12 weeks intervention. A regression analysis was conducted using differences in HbA1C between baseline and 12 weeks as the dependent variable. Student's t test was conducted for the changes of biochemical indicators from baseline to end line during the period of 12 weeks intervention. Glycaemic control improved in the intervention group and mean HbA1C, fasting blood glucose and post-prandial blood glucose in the intervention group decreased significantly along with body weight, waist circumference and total cholesterol. The finding suggested that the intervention which emphasised raw vegetable intake contributed to improved glycaemic control among Indonesian adults with type 2 diabetes mellitus.

Effectiveness of Cimetidine as Adjuvant Therapy in the Treatment of Acute-Extrinsic Atopic Dermatitis: A Double-Blind Randomized Controlled Trial.

INTRODUCTION: Acute extrinsic atopic dermatitis (AD) requires long-term treatment. Cimetidine could be used as an adjuvant therapy for acute-extrinsic AD due to immunomodulatory effects. This study aims to assess the effectiveness of cimetidine as an adjuvant to standard treatment in acute extrinsic AD. METHODS: This is a double-blind randomized controlled trial involving 26 AD patients aged 12-60 years from 2017 to 2020. Effectiveness of cimetidine was assessed by comparing SCORing Atopic Dermatitis (SCORAD) and objective SCORAD changes in both groups at week 2, 4, 6, and 8. Serum levels of immunoglobulin E (IgE), interferon (IFN)-γ, interleukin (IL)-12, and IL-4 were also documented. RESULTS: Significant differences were observed in SCORAD changes at week 2, 4, 6, and 8 (p = 0.004; p = 0.001; p < 0.001; and p < 0.001 respectively), objective SCORAD changes at week 2, 4, 6, and 8 (p = 0.004, p = 0.001, p < 0.001, and p < 0.001 respectively), and IgE level changes at week 8 (p = 0.002) between the two groups. However, there were no significant changes in IFN-γ, IL-12, and IL-4 levels between the two groups. CONCLUSION: Cimetidine is a safe and effective adjuvant therapy for acute-extrinsic AD. TRIAL REGISTRATION: NCT04018131.

The role of clopidogrel resistance-related genetic and epigenetic factors in major adverse cardiovascular events among patients with acute coronary syndrome after percutaneous coronary intervention.

Despite patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) and receiving clopidogrel therapy, some patients still experience major adverse cardiovascular events (MACEs). Clopidogrel resistance, which may be regulated by genetic and epigenetic factors, may play a role in MACEs. This study aimed to determine the association between genetic (CYP2C19 and P2Y12 polymorphisms) and epigenetic (DNA methylation of CYP2C19 and P2Y12 and miRNA-26a expression) factors and their effects on MACEs among post-PCI patients. Post-PCI patients who received a standard dosage of clopidogrel at Harapan Kita Hospital between September 2018 and June 2020 were included in this study. MACEs were observed in patients within 1 year after PCI. Platelet aggregation was assessed using light transmission aggregometry (LTA). DNA methylation of CYP2C19 and P2Y12 was assessed using the bisulfite conversion method. CYP2C19 and P2Y12 polymorphisms and miRNA-26a expression were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). Among a total of 201 subjects, 49.8% were clopidogrel-resistant, and 14.9% experienced MACEs within 1 year after PCI (death was 7.5%). Hypomethylation of CYP2C19 (p = 0.037) and miRNA-26a upregulation (p = 0.020) were associated with clopidogrel resistance. CYP2C19*2/*3 polymorphisms (p = 0.047) were associated with MACEs in 1 year. This study demonstrated that hypomethylation of CYP2C19 and miRNA-26a upregulation increased the risk of clopidogrel resistance in post-PCI patients, but there was no correlation between clopidogrel resistance and MACEs. However, CYP2C19*2/*3 polymorphisms were the factors that predicted MACEs within 1 year.

Therapeutic drug monitoring: focus on conditions in Indonesia.

It has been long recognized that large inter-individual variability is commonly observed in response to drug administration. The large response variability of certain drugs with narrow margin of safety may induce toxicity. To avoid this and to optimize the result of drug treatment, therapeutic drug monitoring (TDM) service has been routinely applied in hospitals in well-developed countries. For certain drugs, the TDM service has been shown beneficial and cost-effective. In Indonesia, the TDM has not yet been implemented. There are three problems that hamper the implementation of TDM here, i.e. cost, the limited expertise to provide interpretation for result of drug assay, and the lack of communication with the clinicians. Today the patient safety issue is considered of paramount importance in the health care service in all hospitals. Therefore, it is now the time to commence the TDM service in Indonesia. This can be started with a pilot project in a large hospital, followed by the others. To avoid unnecesary wasting of funds, TDM should be limited for drugs which toxicity is not readily observed clinically.