A study on influencers of total sales revenue of generic pharmaceutical companies in Indonesia

This paper empirically examines the influence of firms’ one-year lagged of total new products (t-1), one-year lagged profitability (t-1), and market share of new products to firms’ amount of sales revenue in pharmaceutical generic companies in Indonesia. The data used in this study was panel dataset, gathered from six large pharmaceutical generic companies in Indonesia, during the period 2006 to 2010. The regression analysis method uses fixed effect models, with generalized least squares (GLS) method. The result shows that firms’ one-year lagged of total new product (t-1), one-year lagged profitability (t-1), and market share of new products to be positive and affect significantly the firms’ sales revenue in the pharmaceutical generic companies in Indonesia.Pharmaceutical Generic Companies, Profitability, New Generic Product, Market Share, Sales Revenue

MOLECULAR ANALYSIS OF GENE EXPRESSION RELATED TO THE EFFECTS OF DLBS3233 TREATMENT IN DIFFERENTIATION OF 3T3-L1 PRE-ADIPOCYTE

Objective: DLBS3233 is a standardized extract combination containing Lagerstroemia speciosa and Cinnamomum burmannii. The effect of DLBS3233 on adipocyte differentiation was examined in this study.Methods: 3T3-L1 pre-adipocyte was used to investigate gene expression using the real-time reverse transcription polymerase chain reaction (RT-PCR) method. Oil red-O staining for detecting lipid formation was also carried out in this experiment.Results: DLBS3233 caused cell differentiation of 3T3-L1 pre-adipocytes into adipocytes which were indicated by positive results on staining cells with oil red-O on day 6 of the differentiation process. Analysis of gene expressions associated with adipogenesis (C/EBP-α, PPAR-γ, C/EBP-δ, FASn and adiponectin) showed an increase compared to control. In this study, DLBS3233 at a concentration of 5 μg/ml exhibited better differentiation effect than DLBS3233 at a concentration of 10 μg/ml.Conclusion: DLBS3233 can stimulate differentiation of 3T3-L1 pre-adipocytes into adipocytes.Keywords: DLBS3233, Adipogenesis, Gene expression analysis, Real-time RT-PC

Induction of cyclo-oxygenase-2 mRNA by prostaglandin E2 in human prostatic carcinoma cells.

Prostaglandins are synthesized from arachidonic acid by the enzyme cyclo-oxygenase. There are two isoforms of cyclooxygenases: COX-1 (a constitutive form) and COX-2 (an inducible form). COX-2 has recently been categorized as an immediate-early gene and is associated with cellular growth and differentiation. The purpose of this study was to investigate the effects of exogenous dimethylprostaglandin E2 (dmPGE2) on prostate cancer cell growth. Results of these experiments demonstrate that administration of dmPGE2 to growing PC-3 cells significantly increased cellular proliferation (as measured by the cell number), total DNA content and endogenous PGE2 concentration. DmPGE2 also increased the steady-state mRNA levels of its own inducible synthesizing enzyme, COX-2, as well as cellular growth to levels similar to those seen with fetal calf serum and phorbol ester. The same results were observed in other human cancer cell types, such as the androgen-dependent LNCaP cells, breast cancer MDA-MB-134 cells and human colorectal carcinoma DiFi cells. In PC-3 cells, the dmPGE2 regulation of the COX-2 mRNA levels was both time dependent, with maximum stimulation seen 2 h after addition, and dose dependent on dmPGE2 concentration, with maximum stimulation seen at 5 microg ml(-1). The non-steroidal anti-inflammatory drug flurbiprofen (5 microM), in the presence of exogenous dmPGE2, inhibited the up-regulation of COX-2 mRNA and PC-3 cell growth. Taken together, these data suggest that PGE2 has a specific role in the maintenance of human cancer cell growth and that the activation of COX-2 expression depends primarily upon newly synthesized PGE2, perhaps resulting from changes in local cellular PGE2 concentrations

SOLID-STATE PROPERTIES AND SOLUBILITY STUDIES OF NOVEL PHARMACEUTICAL COCRYSTAL OF ITRACONAZOLE

Objective: Pharmaceutical cocrystal is a promising method to improve the solubility of active pharmaceutical ingredients (APIs). Itraconazole (ITZ) is a BCS class II antifungal drug with poor aqueous solubility, therefore an attempt was made to improve the solubility of ITZ using cocrystallization technique. In this work, six novel pharmaceutical cocrystals of ITZ with various coformers, including 4-hydroxybenzoic acid (4HBA), trans-cinnamic acid (TCA), suberic acid (SUB), sebacic acid (SBC), 1-hydroxy-2-naphthoic acid (1H2N), and benzamide (BZD) were prepared.Methods: ITZ cocrystals was prepared by solvent evaporation process. The cocrystals produced were characterized using powder x-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and fourier transform infrared (FTIR) spectroscopy. Solubility analysis was performed to evaluate the cocrystals.Results: PXRD and DSC analysis revealed that the pattern of all ITZ cocrystals was distinguishable from the individual compounds which indicates the formation of new phase. The solubility of ITZ and its cocrystals from highest to lowest after 24 h in 0.1 N HCl solution (pH 1.2) follows the order ITZ-TCA (1.97-fold), ITZ-SBC (1.09-fold), ITZ, ITZ-1H2N (0.58-fold) and ITZ-4HBA (0.46-fold).Conclusion: This study demonstrates that the selection of coformers has pronounced an impact on the physicochemical properties of ITZ. Based on this study, it can be concluded that cocrystallization offers a valuable way to improve the solubility of ITZ

HEMOSTASIS PROFILE AND CLINICAL OUTCOME OF ACUTE ISCHEMIC STROKE PATIENTS TREATED WITH ORAL LUMBROKINASE DLBS1033: A COMPARATIVE STUDY VERSUS ASPIRIN AND CLOPIDOGREL

Objectives: This clinical study was conducted to determine the hemostasis profile and clinical outcome of acute ischemic stroke patients treated withDLBS1033 in comparison with aspirin or clopidogrel. DLBS1033 is a proprietary bioactive protein fraction derived from the earthworms (Lumbricusrubellus) that possesses both fibrinolytic and antithrombotic properties.Methods: This was a 3-arm, parallel, randomized, controlled, open-label, blinded-evaluation study involving 126 acute ischemic stroke patients. Eachsubject received any of the following study medication within 96 hrs after the stroke onset: Aspirin 80 mg daily (Group 1), or clopidogrel 75 mg dail(Group 2), DLBS1033 490 mg 3 times daily (Group 3), for 90 days. Hemostasis parameters evaluated were prothrombin time (PT), activated partialthromboplastin time (aPTT), and international normalized ratio (INR), while the clinical outcomes were measured using Gadjah Mada Stroke Scale(SSGM) and Barthel index (BI).Results: Baseline characteristics, including the hemostasis and clinical profiles, were comparable between groups. At the end of the study, PT, aPTTand INR values were not significantly different between groups, which were all within the normal ranges. There was a significant improvement of BIas well as SSGM from baseline in each group. The improvement size of BI was found similar between groups (p=0.098). However, a significantly betterimprovement of SSGM was observed in those received DLBS1033 (6.98±4.90; p=0.001 vs. aspirin [3.74±3.66], p=0.006 vs. clopidogrel [4.26±4.21]).Conclusion: It was concluded that DLBS1033 provided a safe hemostasis profile (PT, aPTT, and INR) comparable to that of aspirin or clopidogrel inischemic stroke patients. Treatment with DLBS1033 improved clinical outcomes indicated by the BI and SSGM, and the improvement size of SSGM waseven better than that of aspirin or clopidogrel treatment.Keywords: Acute ischemic stroke, Barthel index, DLBS1033, Hemostasis, Gadjah Mada Stroke Scale, Oral lumbrokinase

ANTI-INFLAMMATION EFFECTS OF BIOACTIVE FRACTION DLBS0533 CONTAINING PHALERIA MACROCARPA AND NIGELLA SATIVA ON ANIMAL MODEL

Objective:  DLBS0533 extract is a bioactive fraction obtained from combination of Phaleria macrocarpa and Nigella sativa. This present study aims to observe its potentially anti-inflammatory activities using carragenaan-induced paw edema in mice as animal model.Methods:  Mice were divided into control, positive control and dose groups. Diclofenac potassium was used as a positive control. Treatment DLBS0533 was given at dose 39, 78 and 156 mg/kg body weight (b. w.). Edema thickness was examined for 6 hours.Results:  Reduction in edema is shown in 27.26%; 30.71% and 32.72% at dose of 39, 78 and 156 mg/kg b. w., respectively. Comparation between dose groups and positive control group show that dose 156 mg/kg b. w. did not give significantly different. Therefore, dose 39 and 78 mg/kg b. w. also gave anti-inflammatory activities proved by reduction in edema.Conclusions:  Taken together, DLBS0533 potentially have anti-inflammatory activities.Â

PROCESSING PARACETAMOL-5-NITROISOPHTHALIC ACID COCRYSTAL USING SUPERCRITICAL CO2 AS AN ANTI-SOLVENT

Objective: A new method of cocrystallization based on the use of supercritical carbon dioxide (CO2) as an anti-solvent was explored. In the present study, we investigate and analyze paracetamol (PCA)-5-nitroisophthalic acid (5NIP) cocrystal produced using supercritical anti-solvent (SAS) process. Methods: PCA-5NIP cocrystals prepared by SAS cocrystallization were compared to those produced using traditional solvent evaporation by rapid evaporation (RE) process. The cocrystals produced were characterized using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), polarized light microscopy (PLM), Fourier Transform Infrared (FTIR) spectroscopy, particle size analysis and scanning electron microscopy (SEM). Results: The products obtained from SAS and RE process exhibited identical PXRD spectra and were distinguishable from the individual compounds, indicating the formation of a new phase. DSC analysis revealed that PCA-5NIP cocrystals from each method possess similar melting point which lies between the melting points of the parent compounds. Cocrystal particles with a mean diameter of 4.66 µm were produced from SAS process, which was smaller than those produced by traditional solvent evaporation method with a mean diameter of 38.09 μm. Conclusion: This study demonstrates the ability of SAS process to produce the submicron size of PCA-5NIP cocrystal with altered physicochemical properties in a single step process

BIOACTIVE FRACTION DLBS2411 FROM CINNAMOMUM BURMANNII, (NEES AND T. NEES) BLUME AS COLON AND GASTROPROTECTOR BY STIMULATING MUC5AC AND CYCLOOXYGENASE-2 GENE EXPRESSION

Objective: Mucus therapy is one of the therapies for gastric ulcer management aside from proton pump inhibitor (PPI) and H2-blocker medication. Bioactive fraction DLBS2411 which comes from Cinnamomum burmannii has been identified as a gastric acid anti-secretory agent by inhibiting the activity of hydrogen-potassium adenosine triphosphate (H+/K+ATPase). The study was aimed to evaluate the effect of DLBS2411 as a neuroprotective agent in gastric and colon by investigating its regulation on mucus related pathway.Methods: Total RNA was extracted from gastric and colon cells followed by quantitative real-time polymerase chain reaction (qPCR) analysis for mucus synthesis and mucosal blood flow gene expression. Protein expression of prostaglandin E2 (PGE2) and phosphorylation of IĸB kinase subunit alpha (IKKα) was analyzed with enzyme-linked immunosorbent assay (ELISA) kit and western blot. Measurement of nitric oxide (NO), which is related to mucosal blood flow, was also analyzed.Results: Treatment of DLBS2411 elevated phosphorylation of IKKα and activated nuclear factor-КB (NF-κB) which in turn stimulated mucus synthesis and mucosal blood flow. High level of NF-κB increased mucus synthesis pathway by promoting cyclooxygenase-2 (COX-2) and PGE2 expression, which increased the MUC5AC gene. Activation of NF-κB also increased production of NO, which stimulated mucosal blood flow.Conclusion: DLBS2411 is a promising candidate for gastric and colon mucus protection by increasing mucus synthesis and stimulating mucosal blood flow.Â

DLBS1033, A Protein Extract from Lumbricus rubellus, Possesses Antithrombotic and Thrombolytic Activities

The medicinal value of earthworm has been widely known since the history of Asian ancient medicine. This present study aims to determine the mechanism of action and effect of a standardized extract of Lumbricus rubellus named as DLBS1033. The fibrinogen degradation, antiplatelet aggregation, and ex vivo antithrombotic assay using human blood were performed to study antithrombotic activity. Fibrin plate and clot lysis assay were also done to examine thrombolytic properties. DLBS1033 was found to possess fibrinogenolytic activity on α-, β-, and γ-chain of fibrinogen. It also induced antiplatelet aggregation and prolonged blood clotting time, which further confirmed its antithrombotic properties. In addition, thrombolytic properties of DLBS1033 were shown with its fast and long-acting fibrinolytic activity, as well as its effective blood clot lysis activities. In conclusion, DLBS1033 conferred antithrombotic and thrombolytic action which could be used as a safe and promising oral thrombolytic drug

Factors affecting productivity of research-based pharmaceutical companies following mergers and acquisitions

This paper analyzes the impact of mergers and acquisitions (M&A) activities in research-based pharmaceutical companies, specifically the impact of R&D expenditure, profitability, and sales revenue on firms’ productivity, R&D intensity, in pharmaceutical industries following M&A activities. The model was estimated using annual data, gathered from seven large research-based pharmaceutical companies pre and post-M&A, during the period 2003 until 2010. The regression analysis method uses a fixed effect method with generalized least square (GLS) analysis. The result further shows that following M&A activities, firms’ one-year lagged R&D expenditure (t-1) and lagged profitability (t-1) to be positive in increasing significantly the firms’ amount of R&D intensity in research-based pharmaceutical industries, while, surprisingly firms’ one-year lagged sales revenue (t-1) have a negative impact in increasing significantly the firms’ amount of R&D intensity in research-based pharmaceutical industries