First-line Drug Of Choice Research Articles

Carriage of multiple resistance genes by community and hospital isolates of Stenotrophomonas maltophilia resistant to the first line drug of choice in Nigeria

Carriage of multiple resistance genes by community and hospital isolates of Stenotrophomonas maltophilia resistant to the first line drug of choice in Nigeria

Management of Dyslipidemia in Patients with Diabetes Mellitus

Most patients with diabetes mellitus (DM) have dyslipidemia, which is characterized by increased triglycerides, decreased high-density lipoprotein cholesterol, and increased small dense low-density lipoprotein cholesterol (LDL-C). Dyslipidemia is an important modifiable risk factor for cardiovascular disease (CVD). Therefore active management is essential. Despite its increasing prevalence, the proportion of patients with adequately-controlled dyslipidemia is small, and efforts to improve this pattern are required. The Korean Diabetes Association guidelines recommend setting goals by evaluating each patient’s future CVD risk, including the presence or absence of CVD, target organ damage, major cardiovascular risk factors, and the duration of DM. The primary target is an LDL-C level below 55 mg/dL (and a reduction in LDL-C level by 50% or more from baseline), 70 mg/dL, and 100 mg/dL from the highest risk group to the lowest risk group, respectively. Statins are the first-line drug of choice, and if the LDL-C target is not reached by a maximum tolerable dose of statin, combination therapy with ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors is recommended. In hypertriglyceridemia, lifestyle changes including weight loss and abstinence from alcohol are very important, along with glycemic control.

CLOZAPINE INDUCED EXTRAPYRAMIDAL SYMPTOMS FOLLOWING ALCOHOL CONSUMPTION IN PATIENT WITH SCHIZOPHRENIA AND ALCOHOL DEPENDENCE SYNDROME: A CASE REPORT OF SIALORRHEA, ACUTE AKATHISIA AND DYSTONIA

Clozapine (CLZ), a second-generation or atypical antipsychotic, although not recommended as the first-line drug of choice in the treatment of schizophrenia and schizoaffective disorders; however, it is recommended in the treatment of Treatment-Resistant Schizophrenia and in schizophrenic patients to decrease the recurrent risk of suicidal behavior. For the cytochrome P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4, CLZ serves as a substrate. CLZ also exhibits drug-food interaction with alcohol leading to an increase in the risk of seizures and extrapyramidal symptoms. A case of a 36-year-old male patient with a known history of paranoid schizophrenia and alcohol dependence syndrome came with complaints of dystonia and hypersalivation 1 day following the consumption of alcohol after ingestion of tablet CLZ. After clinical pharmacist intervention, the doses were titrated and the patient improved gradually. With this, it can be postulated that the concomitant use of alcohol with CLZ can be a predisposing factor for drug toxicity in the patients and hence patients should be monitored and counseled to abstain from the use of alcohol while on CLZ therapy.

O-094 Management of subfertility in women with PCOS: expectations, problems and solutions

Abstract Polycystic ovarian syndrome (PCOS) is a common cause of subfertility particularly when anovulation is present. In this circumstance efforts are made to induce ovulation through lifestyle modification, medication, or a combination of both. Other patients with PCOS may be ovulatory but require IVF/ICSI for other causes, including male factor or tubal infertility. In all cases, attention needs to be placed on the underlying metabolic, psychological, and reproductive features that may complicate treatment and subsequent pregnancy. Pregnancy itself has a higher chance of complications and these can be reduced by adequate preconception evaluation and intervention. Recently, the international evidence-based guideline for evaluation and treatment of PCOS has been updated (1) and the infertility section subjected to a literature integrity check to exclude publications that did not meet the highest criteria for incorporation into clinical management. A recent individual patient data meta-analysis has also clarified the relative efficacy of fertility treatments (2). The following conclusions are recommended; 1. Letrozole is the first line drug of choice for ovulation induction based on its efficacy and lower multiple pregnancy rate 2. Clomiphene is an effective drug particularly given a long experience of use and its lower cost 3. Metformin may be valuable for some patients particularly if glucose intolerance is present 4. A combination of clomiphene and metformin may be effective, particularly in overweight individuals 5. Gonadotrophins are an effective treatment in experienced clinics which the resources to undergo adequate monitoring 6. Laparoscopic ovarian surgery may assist some patients and is associated with a lower multiple pregnancy rate and may have long term benefits 7. IVF may be safely conducted with appropriate safeguards to reduce ovarian hyperstimulation syndrome in those where ovulation induction has failed. It should be noted that some of these drugs are “off-label” in many countries and are not recommended in several healthcare systems.There are several areas where further information may lead to altered and improved practice: 1. IVF as a first line therapy may be more effective and allow better control of multiple pregnancy rates. 2. In vitro maturation (IVM) with IVF/ICSI shows increasing success with no or minimal FSH use (3). 3. Bariatric surgery is more readily available and may lead to significant weight loss related ovulation. 4. Newer GLP1 receptor agonists show dramatic weight loss and are being evaluated in PCOS. 5. First line gonadotrophin treatment has been advocated by some proponents. 6. Higher dose and longer use of standard oral agents may help in ovulation induction resistant patients. 7. Inositol and myoinositol are being evaluated as safe, low cost, over the counter alternatives. 8. Alternatives to hCG are available for ovulation induction in oral and IVF cycles. 9. Promising pharmacogenomic approaches may allow individualisation of treatment. While the genomic and environmental aetiology of PCOS remains uncertain, the increasing emphasis on evaluation and assessment of effective therapies for subfertility is advancing rapidly.

Protracted bacterial bronchitis: new aspects of the problem based on сlinical recommendation of the Ministry of Health of Russian Federation

In world pediatric practice, protracted bacterial bronchitis is the leading cause of chronic cough in preschool-age children. However, in Russia this nosology is not often diagnosed, and in real clinical practice children are observed for doubtful and ambiguous diagnoses. In 2021, the Russian Ministry of Health updated the clinical guidelines “Bronchitis” for pediatric age category with inclusion of protracted bacterial bronchitis in the list of bronchitis variants with designation of disease criteria: wet cough lasting at least 4 weeks, auscultatory symptoms of bronchitis in the absence of signs of chronic lung and bronchial pathology, cough relief after 2 weeks of therapy with an antibacterial drug active against H. influenzae, S. pneumoniae, M. catarrhalis. The article presents a review of the literature on protracted bacterial bronchitis in the historical aspect, and also reflects the criteria of the disease, epidemiology, etiology, pathogenesis, clinical presentation, methods of examination. Particular attention is paid to the treatment and debatable scientific and practical issues in the study of protracted bacterial bronchitis in the light of the clinical guidelines of the Ministry of Health of the Russian Federation. It is emphasized that the etiotropic treatment of protracted bacterial bronchitis is antibacterial therapy. The effectiveness of antibiotics for this disease has been proven in systematic reviews. Therapy is prescribed empirically. The first-line drugs of choice is oral amoxicillin/clavulanic acid. Preference is given to drugs in the form of dispersible tablets. The duration of therapy remains a subject of scientific debate. According to the clinical guidelines of the Russian Federation Ministry of Health, the course of treatment should not exceed 2 weeks, in case of ineffectiveness and/or relapse of protracted bacterial bronchitis, the course of antibiotic therapy may be prolonged to 4–6 weeks.

Current Trend in Antiviral Therapy for Chronic Hepatitis B.

Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study.

Совместное применение метформина и интраназального инсулина нормализует чувствительность к глюкозе и гормональный статус у крыс с диабетом 2 типа

Metformin is the first-line drug of choice in the treatment of type 2 diabetes mellitus (T2DM). It acts on peripheral tissues as well as different regions of the brain and restores metabolic and hormonal parameters. Insulin administered intranasally (II) enters the brain and normalises the insulin signaling in the central nervous system, including the hypothalamus, which is weakened in T2DM. This improves the central regulation of metabolism, food intake and functions of the endocrine system. We suggested that the combined use of metformin and II should enhance their restorative effect on the metabolic and hormonal parameters in T2DM. The study was conducted on male rats with T2DM2 induced by a high-calorie diet and a low-dose streptozotocin. The male rats with T2DM were administered metformin (4 weeks, 100 mg/kg/day) and II (4 weeks, 0.5 IU/rat/day), separately and together. The aim of the study was to analyse the effect of the treatment on glucose sensitivity and the levels of insulin, leptin, glucagon-like peptide-1 (GLP-1), thyroid hormones and testosterone. Metformin monotherapy improved glucose homeostasis and normalised basal and glucose-stimulated levels of insulin, leptin and GLP-1. Co-administration of metformin with II enhanced the restorative effects of metformin on tissue insulin sensitivity and leptin levels. Metformin and II normalised the levels of thyroid hormones and testosterone, and their combined use caused the activation of the thyroid system, as indicated by an increase in the levels of thyroid hormones. The data obtained indicate the prospects for the combined use of metformin and II for improving metabolic and hormonal parameters. It may also be used to improve the thyroid and androgenic status in patients with T2DM.

Kinase-Inhibitors in Iodine-Refractory Differentiated Thyroid Cancer-Focus on Occurrence, Mechanisms, and Management of Treatment-Related Hypertension.

Differentiated thyroid cancer (DTC) usually has a good prognosis when treated conventionally with thyroidectomy, radioactive iodine (RAI) and thyroid-stimulating hormone suppression, but some tumors develop a resistance to RAI therapy, requiring alternative treatments. Sorafenib, lenvatinib and cabozantinib are multikinase inhibitors (MKIs) approved for the treatment of RAI-refractory DTC. The drugs have been shown to improve progression-free survival (PFS) and overall survival (OS) via the inhibition of different receptor tyrosine kinases (RTKs) that are involved in tumorigenesis and angiogenesis. Both sorafenib and lenvatinib have been approved irrespective of the line of therapy for the treatment of RAI-refractory DTC, whereas cabozantinib has only been approved as a second-line treatment. Adverse effects (AEs) such as hypertension are often seen with MKI treatment, but are generally well manageable. In this review, current clinical studies will be discussed, and the toxicity and safety of sorafenib, lenvatinib and cabozantinib treatment will be evaluated, with a focus on AE hypertension and its treatment options. In short, treatment-emergent hypertension (TE-HTN) occurs with all three drugs, but is usually well manageable and leads only to a few dose modifications or even discontinuations. This is emphasized by the fact that lenvatinib is widely considered the first-line drug of choice, despite its higher rate of TE-HTN.

Efeitos adversos do tratamento com inibidores seletivos da recaptação da serotonina sobre o feto e neonatais de mães com depressão gestacional: Uma revisão crítica

A depressão é um dos transtornos psiquiátricos mais comuns, tendo em vista a alta incidência nesta década, nota-se um predomínio maior de ocorrência em mulheres, destacando o transtorno depressivo maior na gestação. Quando diagnosticada, o tratamento é de acordo o nível da doença, e se tratando de nível moderado a grave inicia-se o tratamento farmacológico com antidepressivos. Os medicamentos mais prescritos são os inibidores seletivos da receptação de Serotonina (ISRS), que tornaram-se fármacos de primeira escolha pela maior segurança em relação aos demais. Entretanto, o tratamento com os ISRS durante a gestação tem implicado em efeitos indesejáveis nos fetos e neonatos. Portanto, o objetivo deste trabalho foi investigar os efeitos adversos sobre o feto/neonatais de gestantes depressivas que passaram por terapêutica com ISRS. Este estudo caracterizou-se em uma revisão crítica, sendo utilizados os bancos de dados da Pubmed/MEDLINE, Scopus e Web of Science, sendo incluídos 35 artigos. Após análise dos estudos, foi constatado que a terapia com ISRS na depressão gestacional aumenta os riscos no feto e neonatos para defeitos congênitos, como: má formação cardíaca, abstinência neonatal, hipertensão pulmonar persistente e possível associação com transtorno do espectro do autismo. Assim, baseado nas evidências científicas o protocolo medicamentoso com ISRS gera efeitos nocivos a criança, no entanto muitas vezes o seu uso na gestação é inevitável. Dessa forma, em situações em que é necessário usar ISRS, a decisão de tal conduta terapêutica deve ser avaliada analisando os riscos da depressão não tratada e a relação risco/benefício do uso dos medicamentos.

Resistance to Fluoroquinolones and Other Antimicrobials in Culture-Positive <i>Salmonella typhi</i> Isolates in Gulbarga, South India

Background: Typhoid fever is a major public health concern in developing countries. The upsurge in the occurrence of bacterial isolates that are resistant to nalidixic acid; with reduced susceptibility to ciprofloxacin in typhoidal Salmonellae constitutes a challenge to the clinician. Methods: In order to better understand the epidemiology of Salmonella infections in South India, Salmonella typhi isolates were screened from various healthcare centers. Salmonella isolates were identified by using standard phenotypic, serological, antibiotic susceptibility and molecular methods. Results: Among a total of 100 S. typhi isolates 9% were found to be multidrug resistant and 30% were nalidixic acid resistant. Isolates with reduced susceptibility to ciprofloxacin displays single base mutations in the gyrA gene. A very low rate of 1% resistance was found to ciprofloxacin. The only one isolate with ciprofloxacin MIC ≥ 4 μg/ml also showed single mutation in the QRDR of the gyrA gene in S. typhi (GenBank accession no. HQ176349-HQ176368). Conclusions: A very low rate of nalidixic acid resistance with reduced susceptibility to ciprofloxacin was observed in comparison to other endemic areas in isolates of S. typhi from Gulbarga, South India, with steadily increasing NAR S. typhi but decreasing MDR isolations over the study period. This is most likely due to an increased use of ciprofloxacin as a first line drug of choice over more traditional antimicrobial agents for the treatment of typhoid fever.

Prevalence and Reinfection Rates of Schistosoma mansoni and Praziquantel Efficacy against the Parasite among Primary School Children in Sanja Town, Northwest Ethiopia.

Background Schistosomiasis is among the most widespread chronic infections in the world. The magnitude of the infection may show variations across different areas with respect to time. Praziquantel is a first line drug of choice for the treatment of schistosomiasis although its low cure rate has been reported in different parts of the world. Thus, an assessment of the magnitude of the diseases, the efficacy of currently available drugs, and reinfection rates is crucial. Objective Our principal objective is to determine the prevalence and reinfection rates of Schistosoma mansoni and to evaluate the efficacy of PZQ against Schistosoma mansoni. Method A school-based cross-sectional study was conducted on Sanja Elementary Schools, Sanja town, northwest Ethiopia. Stool specimens were examined using Kato-Katz method. Schoolchildren who tested positive for intestinal schistosomiasis and fulfilled the inclusion criteria took part in the efficacy and reinfection study. Positive participants were treated with 40 mg/kg of Praziquantel. Cure and egg reduction rates were evaluated three weeks after treatment. The intensity of infection was determined following the WHO's guideline. Moreover, the reinfection rate of those who were cured was evaluated after a six-month posttreatment period. Data were analyzed using SPSS version 20. Results At baseline, 130 (35%) of the 372 schoolchildren were found infected with Schistosoma mansoni. Out of the 130 infected schoolchildren, 112 (86.2%) had moderate infection intensity. Among the S. mansoni positive schoolchildren, 80 were included as study participants for the evaluation of PZQ efficacy, based on the inclusion criteria established by WHO. The cure and egg reduction rates were found to be 90% (72/80) and 99.5%, respectively. Of the seventy-two schoolchildren considered for the determination of reinfection rate, after 6 months of posttreatment, 13.9% were found to be reinfected. Conclusion The schoolchildren in the three primary schools of Sanja are at moderate risk of the infection caused by S. mansoni. Although the therapeutic potency of PZQ at 40 mg/kg was efficient against S. mansoni, a high rate of reinfection was reported in the study site, suggesting the need for integrated schistosomiasis control measures.

The comparison on antihyperglycemic activity between gedong gincu mango leaf (Mangifera indica var. gedong gincu) and metformin in streptozotocin-induced diabetic rats

Pharmacologic treatment is one of important modalities in the comprehensive management in type 2 diabetes mellitus, whereas metformin is the first line drug of choice in initiating oral antihyperglycemic agent. Mangiferin, quersetin, tannins, and flavonoid have blood-glucose lowering properties. They are available in mango leaf. Gedong gincu mango is widely available in Cirebon, West Jawa, Indonesia, but the study enrolling its leaf in antihyperglycemic effect is not provided yet. This study was aimed to compare antihyperglycemic activity between gedong gincu mango leaf (Mangifera indica var. gedong gincu) and metformin on streptozotocin-induced diabetic rats. This study was experimental research with pre- and post-test control group design enrolling 30 wistar streptozotocin-induced rats divided into 5 groups of treatment consists of 1 negative control group, and 4 positive control group using metformin 9mg/200gr and 3 groups given gedong gincu mango leaf extract with doses of 150 (P1), 300 (P2) and 600 (P3) mg/200 gr for 7 days. There is significant decrease in blood glucose level in P1, P2, and P3 (96.24mg/dl, 116.62 mg/dl, and 136.21mg/dl). We concluded that gedong gincu mango leaf has antihyperglycemic activity in dose-dependent response. The 600 mg/200g of it is not inferior to 9mg/200g of metformin in antihyperglycemic activity.

Blastocystis sp., Parasite Associated with Gastrointestinal Disorders: An Overview of its Pathogenesis, Immune Modulation and Therapeutic Strategies.

Blastocystis sp. is a unicellular parasitic microorganism commonly found in the gastrointestinal tracts of humans and animals. It causes symptomatic or asymptomatic infection and its route of transmission is via fecal-oral. High prevalence of Blastocystis infection in developing countries is usually due to poor hygiene practices, exposure to animals infected with the parasite and intake of contaminated water or food. Blastocystis infected individuals often suffer from diarrhea, abdominal pain, nausea, and stomach bloating. Even though pathogenicity of Blastocystis is unclear, it is commonly associated with irritable bowel syndrome. In this review, we have analysed the evidence that shows the association between this microorganism and gastrointestinal disorders. There have been a number of studies which showed that the pathogenicity of Blastocystis is related to its different STs. The pathogenicity is speculated to be due to cysteine proteases formation which stimulates mucosal cells to release interleukin-8 which has been associated with extreme dehydration and gut inflammation. In vitro studies on human colonic epithelial cells revealed that incubation of Blastocystis modulated the host immune response by stimulating the formation of pro-inflammatory cytokines and granulocyte macrophage colonystimulating factor. Metronidazole is found to be the first-line drug of choice. Another treatment option is the combination therapy with trimethoprim/sulfamethoxazole.

Therapeutic effectiveness of oxcarbazepine in intractable trigeminal neuralgia

Trigeminal neuralgia (TN) is one of the ancient neuropathic disorders which torments a significant proportion of the population. Although Carbamazepine is the first line drug of choice in the treatment of this debility, cases falling into the domain of intractable neuralgia fail to respond to maximum tolerable doses of the drug. In such cases, Oxcarbazepine (OXC) may be given more preference owing to the minor risk for drug interactions and its better tolerability in comparison with CBZ. This study was designed to study the therapeutic effectiveness of OXC in intractable TN using Efficacy index of Clinical Global Impressions (CGI) score, also accounting for the adverse effects using Liverpool Adverse Events Profile.

Unusual manifestation of Helicobacter cinaedi infection: a case report of intracranial subdural empyema and bacteremia

BackgroundThere have been various reports concerning Helicobacter cinaedi infections. However, few reports have examined central nervous system infections.Case presentationA 52-year-old man was transferred from the local hospital because of a persistent headache and suspected intracranial subdural empyema. Neurosurgical drainage was performed via burr holes. Gram staining and results from abscess cultures were negative. The blood culture yielded H. cinaedi. He was given an antibiotic regimen consisting of 2 g of ceftriaxone twice a day, but the size of the abscess was not reduced in size at all after 3 weeks of treatment. Neurosurgical drainage was performed again, and the antimicrobial regimen was switched to 2 g of meropenem 3 times a day. The size of the abscess was reduced after 2 weeks of the second drainage and antimicrobial drug change to meropenem. After 4 weeks treatment with meropenem, the patient was discharged, and his symptoms had completely resolved.ConclusionsH. cinaedi infection should be considered in the differential diagnosis of subdural empyema cases for which Gram staining and abscess culture results are negative. Meropenem can be a first-line drug of choice or an effective alternative treatment for H. cinaedi central nervous system infections.

Prescribing practices for systemic agents in the treatment of severe pediatric atopic dermatitis in the US and Canada: The PeDRA TREAT survey

There is a paucity of literature to direct physicians in the prescribing of immunomodulators for patients with severe atopic dermatitis (AD). To survey systemic agent prescribing practices for severe childhood AD among clinicians in the United States and Canada. The TREatment of severe Atopic dermatitis in children Taskforce (TREAT), US&CANADA, a project of the Pediatric Dermatology Research Alliance (PeDRA), developed an online multiple-response survey to assess clinical practice, gather demographic information and details of systemic agent selection, and identify barriers to their use in patients with recalcitrant pediatric AD. In total, 133 of 290 members (45.9%) of the Society for Pediatric Dermatology completed the survey, and 115 of 133 (86.5%) used systemic treatment for severe pediatric AD. First-line drugs of choice were cyclosporine (45.2%), methotrexate (29.6%), and mycophenolate mofetil (13.0%). The most commonly used second-line agents were methotrexate (31.3%) and mycophenolate mofetil (30.4%); azathioprine was the most commonly cited third-line agent. The main factors that discouraged use of systemic agents were side-effect profiles (82.6%) and perceived risks of long-term toxicity (81.7%). Investigation of the sequence of systemic medications or combination systemic therapy was limited. Recall bias may have affected the results. Great variation exists in prescribing practices among American and Canadian physicians using systemic agents for treatment of pediatric AD.

Trigeminal neuralgia: a retrospective multicentre study of 320 Asian patients

This study was performed to obtain the clinicodemographic data regarding patients with trigeminal neuralgia (TN) treated at oral-maxillofacial medicine clinics, as there is a paucity of such information in the Asian setting. Retrospective multicenter study involving clinicodemographic information of 320 patients with TN diagnosed between 2001 and 2012 at eight regional oral-maxillofacial medicine clinics and followed up for at least 6months. Statistical tests were performed to assess the associations among the clinicodemographic factors. TN was mostly diagnosed during the seventh and sixth decades of life, with a median of 58.2years (interquartile range=13.0). Females were more commonly affected (61.6%). TN affected the right side more frequently, and the mandibular branch was most commonly involved (58.5%). Carbamazepine was the first-line drug of choice (87.5%). Asian patients with TN exhibited features similar to those in Caucasian patients except for the increased affliction of the mandibular division.

Effect of in utero exposure to the atypical anti-psychotic risperidone on histopathological features of the rat placenta.

For clinical management of different forms of psychosis, both classical and atypical anti-psychotic drugs (APDs) are available. These drugs are widely prescribed, even during pregnancy considering their minimal extra-pyramidal side effects and teratogenic potential compared to classical APDs. Among AAPDs, risperidone (RIS) is a first-line drug of choice by physicians. The molecular weight of RIS is 410.49g/mol; hence, it can easily cross the placental barrier and enter the foetal bloodstream. It is not known whether or not AAPDs like RIS may affect the developing placenta and foetus adversely. Reports on this issue are limited and sketchy. Therefore, this study has evaluated the effects of maternal exposure to equivalent therapeutic doses of RIS on placental growth, histopathological and cytoarchitectural changes, and to establish a relationship between placental dysfunction and foetal outcomes. Pregnant rats (n=24) were exposed to selected doses (0.8, 1.0 and 2.0mg/kg) of RIS from gestation days 6-21. These dams were sacrificed; their placentas and foetuses were collected, morphometrically examined and further processed for histopathological examination. This study revealed that in utero exposure to equivalent therapeutic doses of RIS during organogenesis-induced placental dystrophy (size and weight), disturbed cytoarchitectural organization (thickness of different placental layers), histopathological lesions (necrosis in trophoblast with disruption of trophoblastic septa and rupturing of maternal-foetal interface) and intrauterine growth restriction of the foetuses. It may be concluded that multifactorial mechanisms might be involved in the dysregulation of structure and function of the placenta and of poor foetal growth and development.

Effect of aspirin resistance with dyslipidemia against VerifyNOW® measurement in Bethesda hospital Yogyakarta

Background : Aspirin is first line drug of choice to prevent ischemic stroke. However, some cases are found occuring of aspirin resistance. Objective : This study was to examine the effect of dyslipidemia on the risk of antiplatelet resistance with VerifyNOW ® at Bethesda Hospital Yogyakarta. Method : This research was observational analysis using a nested casecontrol study design. The subjects were ischemic stroke patients who underwent tests of platelet function by VerifyNOW ® (Accumetrics, San Diego, CA, USA). The Case group was ischemic stroke patients who has history of aspirin resistance. The control group was ischemic stroke patients who response on aspirin therapy. Both groups were analyzed and compared to the state of dyslipidemia. Results : Bivariate analysis on the incidence of aspirin resistance indicate that dyslipidemia had OR = 0.979 (95% CI; 0.378 to 2.531), p = 0.572. Hypercholesterolemia had OR = 0,909 (CI 95%; 0,377-2,190) p = 0,500; hypertrigliceride had OR = 0,838 (CI 95%; 0,331-2,119) p = 0,409; abnormal HDL had OR = 1,468 (CI 95% 0,564-3,817) p = 0,238; abnormal LDL had OR = 0,937 (CI 95% 0,374-2,345) p = 0,500. Patient factors such as age >55 years (p = 0.168) and female gender (p = 0.226) showed a nonsignificant results. Conclusion : Ischemic stroke patients at Bethesda Hospital Yogyakarta who had dyslipidemia were not evident to have a greater risk of aspirin resistance than ischemic stroke patients who did not undergo dyslipidemia.

Metformin targets liver tumor-initiating cells through the PI3K/Akt/mTOR survival pathway

Liver tumor-initiating cells (T-ICs) are thought to be inherently resistant to the cytotoxic effects of chemotherapy, and can self-renewal and maintain tumor-initiating potential. Therefore, effective anticancer research strategies should target the unique properties of T-ICs. In this study, we found that metformin, a first-line drug of choice for the treatment of type 2 diabetes, inhibited liver T-ICs both in vivo and in vitro. Metformin inhibited the formation of hepatospheres and epithelial-specific antigen-positive (ESA, CD133+) cell colonies by hepatocellular carcinoma (HCC) cell lines. Metformin also downregulated the expression of several T-IC-related genes which are involved in the signaling pathways, governing the self-renewal, proliferation and differentiation of T-ICs. Furthermore, the targeting of liver T-ICs by metformin was PI-3-kinase-Akt-mTOR (PI3K/Akt/mTOR)-pathway dependent. The PI3K/Akt/mTOR inhibitor LY294002 and rapamycin abolished the inhibitory effect of metformin on CD133+ cells, and the PI3K/Akt/mTOR stimulator EGF promoted the inhibitory effect of metformin on CD133+ cells. Metformin also dramatically decreased the tumor volume and number of CD133 expressing tumor cells in a xenograft mouse model. Metformin exerted a synergistic effect with cisplatin to target both T-ICs and non-T-ICs, and resulted in the smallest tumor volume and lowest number of CD133 expressing tumor cells. This study indicates that the antidiabetic drug metformin could potentially be used in combination therapy with chemotherapeutic agents to improve the treatment of liver cancer.