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Law Number 33 of 2014 concerning Guarantees for Halal Products (UUJPH) regulates the obligation of business actors to include non-halal information on products containing haram ingredients. The existence of regulations regarding these obligations in practice are not followed by compliance with business actors, in Indonesia itself the last 4 years have been enlivened by cases of the discovery of pharmaceutical products containing haram ingredients circulating in the Indonesian market without including non-halal information on their packaging. This study aims to determine the responsibility of business actors who do not include non-halal information on pharmaceutical products types of drugs containing Pig DNA according to Law Number 33 of 2014 concerning Guarantees for Halal Products and to determine legal protection for consumers for the distribution of pharmaceutical types of drugs containing Pig DNA without including information that is not halal according to Law Number 33 of 2014 concerning Guarantees for Halal Products. The researcher uses a normative juridical approach with analytical descriptive research specifications and uses secondary data types. The data collection technique used is the method of literature and the method of analysis used is qualitative analysis. The results of this study are that the responsibility of business actors who do not include non-halal information on pharmaceutical products of the type of drugs containing Pig DNA according to Law Number 33 of 2014 concerning Guarantees for Halal Products is absolute responsibility and uses the principle of inverted liability. Legal protection for Muslim consumers for the circulation of pharmaceutical products of the type of drugs containing Pig DNA without including non-halal information according to Law Number 33 of 2014 concerning Guarantees for Halal Products can be carried out through internal and external legal protection. Abstrak. Undang-Undang Nomor 33 Tahun 2014 tentang Jaminan Produk Halal (UUJPH) mengatur mengenai kewajiban pelaku usaha untuk melakukan pencantuman keterangan tidak halal pada produk yang mengandung bahan haram. Adanya peraturan mengenai kewajiban tersebut dalam prakteknya tidak di ikuti dengan patuhnya oleh para pelaku usaha, di Indonesia sendiri belakangan 4 tahun ini diramaikan dengan kasus ditemukannya produk farmasi yang mengandung bahan haram beredar dipasaran Indonesia dengan tanpa mencantumkan keterangan tidak halal didalam kemasannya. Penelitian ini bertujuan untuk mengetahui tanggung jawab pelaku usaha yang tidak mencantumkan keterangan tidak halal pada produk farmasi Jenis obat-obatan yang mengandung DNA Babi menurut Undang-Undang Nomor 33 Tahun 2014 Tentang Jaminan Produk Halal dan untuk mengetahui perlindungan hukum terhadap konsumen atas beredarnya produk farmasi jenis obat-obatan yang mengandung DNA Babi tanpa mencantumkan keterangan tidak halal menurut Undang-Undang Nomor 33 Tahun 2014 Tentang Jaminan Produk Halal. Peneliti menggunakan metode pendekatan yuridis normatif dengan spesifikasi penelitian deskriptif analitis dan menggunakan jenis data sekunder. Teknik pengumpulan data yang digunakan adalah metode kepustakaan serta metode analisis yang digunakan adalah analisis kualitatif. Hasil penelitian ini adalah tanggung jawab pelaku usaha yang tidak mencantumkan keterangan tidak halal pada produk farmasi jenis obat-obatan yang mengandung DNA Babi menurut Undang-Undang Nomor 33 Tahun 2014 Tentang Jaminan Produk Halal adalah tanggung jawab mutlak dan menggunakan prinsip pertanggungjawaban terbalik. Perlindungan hukum terhadap konsumen muslim atas beredarnya produk farmasi jenis obat-obatan yang mengandung DNA Babi tanpa mencantumkan keterangan tidak halal menurut Undang-Undang Nomor 33 Tahun 2014 Tentang Jaminan Produk Halal dapat dilakukan melalui perlindungan hukum secara internal dan eksternal.

Objectives: To determine the antiviral activity of phosphorodiamidate morpholino oligomers (PMO) and peptide-conjugated PMO (PPMO) in AG129 mice infected with dengue 2 virus (DENV-2). Methods: Antisense PMO and PPMO were designed against the 5 0 terminal region (5 0 SL) or the 3 0 -cyclization sequence region (3 0 CS) of DENV genomic RNA and administered to AG129 mice before and/or after infection with DENV-2. In addition, cell culture evaluations designed to determine optimum PPMO length, and pharmacokinetic and toxicity analysis of PPMO were also carried out. Results: Mock-treated AG129 mice lived for 9–17 days following intraperitoneal (ip) infection with 10 4 –10 6 pfu of DENV-2 (strain New Guinea C). Intraperitoneal administration of 5 0 SL or 3 0 CS PPMO before and after DENV infection produced an increase in the average survival time of up to 8 days. Animals receiving only post-infection PPMO treatment did not benefit significantly. Cell culture studies showed that PPMO of 22–24 bases long produced substantially higher DENV titre reductions than did PPMO that were either shorter or longer. Pharmacokinetic and toxicology analysis with noninfected animals showed that nine consecutive once-daily ip treatments of 10 mg/kg PPMO resulted in high concentrations of PPMO in the liver and caused little impact on overall health. Conclusions: The data indicate that PPMO had considerable antiviral efficacy against DENV-2 in the AG129 mouse model and that PPMO treatment early in the course of an infection was critical to extending the survival times of DENV-2-infected mice in the AG129 model system.

Conjugation of arginine-rich cell-penetrating peptide (CPP) to phosphorodiamidate morpholino oligomers (PMO) has been shown to enhance cytosolic and nuclear delivery of PMO. However, the in vivo disposition of CPP-PMO is largely unknown. In this study, we investigated the pharmacokinetics, tissue distribution, stability, and safety profile of an anti-c-myc PMO conjugated to the CPP, (RXR)4 (X = 6-aminohexanoic acid) in rats.The PMO and CPP-PMO were administrated intravenously into rats. The concentrations of the PMO and the CPP-PMO in plasma and tissues were monitored by HPLC. The stability of the CPP portion of the CPP-PMO conjugate in rat plasma and tissue lysates was determined by mass spectrometry. The safety profile of the CPP-PMO was assessed by body weight changes, serum chemistry, and animal behavior.CPP conjugation improved the kinetic behavior of PMO with a 2-fold increase in the estimated elimination half-life, a 4-fold increase in volume of distribution, and increased area under the plasma concentration vs time curve. Consistent with the improved pharmacokinetic profile, conjugation to CPP increased the uptake of PMO in all tissues except brain, varied between organ type with greater uptake enhancement occurring in liver, spleen, and lungs. The CPP-PMO conjugate had greater tissue retention than the corresponding PMO. Mass spectrometry data indicated no observable degradation of the PMO portion, while there was identifiable degradation of the CPP portion. Time-dependent CPP degradation was observed in plasma and tissue lysates, with the degradation in plasma being more rapid. The pattern of degraded products differed between the plasma and lysates. Safety evaluation data showed that the CPP-PMO was well-tolerated at the dose of 15 mg/kg with no apparent signs of toxicity. In contrast, at the dose of 150 mg/kg, adverse events such as lethargy, weight loss, and elevated BUN (p0.01) and serum creatinine (p0.001) levels were recorded. Supplementation with free L-arginine ad libitum showed improved clearance of serum creatinine (p0.05) and BUN (p0.01) at the toxicological dose, suggesting that the CPP caused toxicity in kidney.This study demonstrates that conjugation of CPP to PMO enhances the PMO pharmacokinetic profile, tissue uptake, and subsequent retention. Therefore, when dosed ator = 15 mg/kg, CPP is a promising transporter for enhancing PMO delivery in therapeutic settings.

Plasma pharmacokinetics of ST-246, smallpox therapeutic, was evaluated in mice, rabbits, monkeys and dogs following repeat oral administrations by gavage. The dog showed the lowest Tmax of 0.83 h and the monkey, the highest value of 3.25 h. A 2- to 4-fold greater dose-normalized Cmax was observed for the dog compared to the other species. The mouse showed the highest dose-normalized AUC, which was 2-fold greater than that for the rabbit and monkey both of which by approximation, recorded the lowest value. The Cl/F increased across species from 0.05 L/h for mouse to 42.52 L/h for dog. The mouse showed the lowest VD/F of 0.41 L and the monkey, the highest VD/F of 392.95 L. The calculated extraction ratios were 0.104, 0.363, 0.231 and 0.591 for mouse, rabbit, monkey and dog, respectively. The dog showed the lowest terminal half-life of 3.10 h and the monkey, the highest value of 9.94 h. The simple allometric human VD/F and MLP-corrected Cl/F were 2311.51 L and 51.35 L/h, respectively, with calculated human extraction ratio of 0.153 and terminal half-life of 31.20 h. Overall, a species-specific difference was observed for Cl/F with this parameter increasing across species from mouse to dog. The human MLP-corrected Cl/F, terminal half-life, extraction ratios were in close proximity to the observed estimates. In addition, the first-in-humans (FIH) dose of 485 mg, determined from the MLP-corrected allometry Cl/F, was well within the dose range of 400 mg and 600 mg administered in healthy adult human volunteers.

Therapeutics for the treatment of pathogenic orthopoxvirus infections are being sought. In the absence of patients with disease, animal models of orthopoxvirus disease are essential for evaluation of the efficacies of antiviral drugs and establishment of the appropriate dose and duration of human therapy. Infection of nonhuman primates (NHP) by the intravenous injection of monkeypox virus has been used to evaluate a promising therapeutic drug candidate, ST-246. ST-246 administered at 3 days postinfection (which corresponds to the secondary viremia stage of disease) at four different doses (from 100 mg/kg of body weight down to 3 mg/kg) once a day for 14 days was able to offer NHP 100% protection from a lethal infection with monkeypox virus and reduce the viral load and lesion formation. In NHP, the administration of ST-246 at a dose of 10 mg/kg/day for 14 days resulted in levels of blood exposure comparable to the levels attained in humans administered 400 mg in the fed state. These results suggest that administration of an oral dosage of 400 mg once daily for 14 days will be effective for the prevention or treatment of smallpox or monkeypox infections in humans.

The concept of using antisense oligonucleotides to interfere with gene expression offers a new therapeutic strategy for the treatment of diseases resulting from overexpression or dysfunction of certain genes. Phosphorodiamidate morpholino oligomers (PMOs) represent a neutral class of antisense agents that interfere with target gene expression either by binding and sterically blocking the assembly of translation machinery, resulting in inhibition of translation, or by altering splicing of pre-mRNA. Studies in animal models and human clinical trials have demonstrated a high degree of functional bioavailability in several target organs. Preclinical and clinical studies have shown that PMOs demonstrate improved efficacy, excellent kinetic behavior, biological stability, and a good safety profile. We conclude from the emerging data that PMOs display advantageous pharmaceutical properties in comparison with other antisense strategies.

Androgen-insensitive prostate cancer cells are highly resistant to several chemotherapeutic drugs and are characterized by the appearance of apoptosis-resistant cells. In this study, we identified the critical role of X-linked inhibitor of apoptosis protein (XIAP), a potent antiapoptotic factor, in conferring chemotherapy resistance in an androgen-insensitive DU145 human prostate cancer cell line. Results reveal that DU145 cells were highly resistant to cisplatin, but this resistance was overridden when the cells were treated for a prolonged time (96 hours) with cisplatin (IC(50) = 27.5 to 35.5 micromol/L). A decrease in levels of XIAP and Akt/phospho-Akt and an increase in caspase-3 activity were identified to be key factors in cisplatin sensitivity (40% to 55% decrease in cell viability) at later time points. In contrast, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment caused a 40% to 50% decrease in cell viability within 6 hours (IC(50) = 135 to 145 ng/mL). However, increasing concentrations or prolonged treatment with TRAIL did not change drug potency. A significant increase in caspase-3 activity was observed with TRAIL treatment with no apparent change in XIAP levels. Specific inhibition of XIAP expression using an antisense XIAP phosphorodiamidate morpholino oligomer induced apoptosis and increased caspase-3 activity. Combination of cisplatin with XIAP antisense potentiated cisplatin sensitivity by decreasing the IC(50) from200 micromol/L with cisplatin alone to 9 to 20 micromol/L and decreasing incubation time required for activity from 96 to 24 hours. Similarly, TRAIL in combination with XIAP antisense phosphorodiamidate morpholino oligomer enhanced TRAIL potency by 12- to 13-fold. In conclusion, abrogation of XIAP expression is essential for therapeutic apoptosis and enhanced chemotherapy sensitization in androgen-refractory prostate cancer cells.

Rat selenoprotein W (SeW) promoter activity was investigated using different concentrations of cadmium, copper, and zinc. Two fragments (404 and 1265 bp) of the SeW promoter, containing a single metal response element (MRE), were ligated into the multiple cloning site of a pGL3-Basic reporter plasmid. The constructs were transfected into cultured C6 (rat glial) and L8 (myoblast) cells and promoter activity measured by means of luciferase reporter gene fused to the SeW promoter fragments in the reporter plasmid. With post-transfection exposure of these cell lines to these metals, copper and zinc, but not cadmium, significantly increased promoter activity of the unmutated 1265 bp (not 404 bp) construct (p

Both selenium and green tea have been reported to exhibit antigenotoxic and cancer chemopreventive properties. We compared the antimutagenic activities of regular green tea and selenium-enriched green tea obtained from Hubei Province, China, toward the heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in the Salmonella assay. Selenium-enriched green tea obtained by foliar application of selenite exhibited concentration-dependent inhibition of IQ-induced mutagenesis in the presence of rat liver S9 and was significantly more effective than regular green tea tested under the same conditions. Analytical studies revealed no major differences in the polyphenol or caffeine content between regular green tea and selenium-enriched green tea, but the latter tea contained approximately 60-fold higher concentrations of selenium compared with regular green tea. The only soluble form of selenium was identified as selenite. The antimutagenic effects of certain individual tea constituents, such as epicatechin gallate and catechin, were enhanced by the addition of selenite to the Salmonella assay. Sodium selenite, sodium selenate, seleno-DL-cysteine, seleno-L-methionine, and L-Se-methylselenocysteine were not antimutagenic toward IQ when tested alone, but augmented significantly the inhibitory potency of green tea. The results suggested an enhancing ("coantimutagenic") effect of selenium in combination with green tea in vitro, but in vivo studies are needed to assess whether there is a synergistic effect of tea and selenium to protect against heterocyclic amine-induced mutagenesis and carcinogenesis.