• Toxicological Research
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• 제20권3호
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• pp.263-272
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• 2004

This study was to investigate single and repeated-dose toxicities of DFA IV, a new candidate of nutraceutical which has preventive effect on anemia and osteoporosis. In single-dose oral toxicity study, the test article were administered once by gavage to rats at dose level of 0, 2,000 and 5,000 mg/kg. No dead animal, abnormal sign and abnormal necropsy finding was found in control and treated groups. Thus the approximate lethal dose of DFA IV was considered to be higher than 5,000 mg/kg in rats. In four week repeated dose oral toxicity study, the test article was administered once daily by gavage to rats at dose levels of 0, 500, 1,000 and 2,000 mg/kg. No abnormality was observed in mortality, clinical findings, body weight changes, food and water consumptions, opthalmoscopic findings, hematological findings, necropsy findings, organ weights and histopathological findings. In urinalysis, specific gravity was increased in 2,000 mg/kg groups of male rats. In serum biochemical analysis, creatine phosphokinase was increased in all treatment groups of male rats. These increases in urine specific gravity and serum creatine phosphokinase activity were not accompanied with related signs such as histopathological changes or clinical findings. In conclusion, four week repeated oral dose of DFA IV to rats did not cause apparent toxicological change at the dose of 500, 1,000 or 2000 mg/kg body weight. Thus it is suggested that no-observed-adverse-effect level (NOAEL) of DFA IV in rats would be 2,000 mg/kg/day body weight.

• Asian Pacific Journal of Cancer Prevention
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• 제13권7호
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• pp.3159-3163
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• 2012

Background: For cervical cancer the epidemiological profile is poorly known in Morocco and no data is available concerning the direct medical costs. The purpose of this work is to estimate the direct cost of medical management of invasive cervical cancer during the first year after diagnosis in Morocco. Methods: The estimation of direct costs of medical management of invasive cervical cancer during the first year after diagnosis in Morocco is based on the estimation of individual cost in each stage which covers diagnosis, treatment and follow-up during first year. The cost was estimated per patient and whole cycle-set using the costs for each drug and procedure as indicated by the Moroccan National Agency for Health Insurance. Extrapolation of the results to the whole country was used to calculate the total annual cost of cervical cancer treatments in Morocco. Results: Overall approximately 1,978 new cases of cervical cancer occur each year in Morocco. The majority (82.96%) of these cases were diagnosed at a late stage (stageII or more). The cost of one case of cervical cancer depends on stage of diagnosis, the lowest cost is $382 for stageCis followed by the cost of stageIA1 for young women (< 40 years) which is $2,952. The highest cost is for stageIV, which is $7,827. The total cost of cervical cancer care for one year after diagnosis is estimated at $13,589,360. The share allocated to treatment is the most important part of the global care budget with an annual sum of $13,027,609 whereas other cost components are represented as follows: $435,694 for annual follow-up activity and $126,057 for diagnosis and preclinical staging. Conclusion: This study provides health decision-makers with a first estimate of costs and the opportunity to achieve the optimal use of available data to estimate the needs of health facilities in Morocco.

• 생물정신의학
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• 제7권1호
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• pp.14-20
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• 2000

Recently atypical antipsychotics have been used as first line agent in the treatment of schizophrenia, and also played a significant role in the treatment of many kinds of psychiatric disorders. The pharmacokinetic and pharmacodynamic properties of these newer antipsychotics are well known through preclinical and early clinical trials. However, it is important to note the limitations of the results due to its relatively short experience. Clozapine is eliminated principally by the hepatic P450 1A2 and 3A4 cytochrome enzymes. 1A2 inducers such as carbamazepine and smoking can reduce its half-life, while 1A2 inhibitors such as SSRIs, especially fluvoxamine can increase its duration of action. Carbamazepine should be avoided in a patient on clozapine because of carbamazepine's potential effects on bone marrow. Benzodiazepines tend to increase the chances of sedation, delirium and respiratory depression. Risperidone is metabolized to 9-hydroxyriperidone by the hepatic P450 2D6 cytochrome enzymes. Fluoxetine and paroxetine, 2D6 inhibitors interfere with metabolism, but 9-hydroxyrisperidone has similar biological activity as parental drug, so it has little affect on the outcome. Olanzapine shows minimal capacity to inhibit cytochrome P450 isoenzymes and shows minimal chance of drug interaction. It is eliminated principally by the hepatic P450 1A2 and 2D6 cytochrome enzymes.

• 한국자원식물학회:학술대회논문집
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• 한국자원식물학회 2000년도 The 7th International Symposium
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• pp.116-122
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• 2000

The molecular modification of antiepileptic drugs and direct synthesis of new drugs with the predetermined antiepileptic properties are perspective. New neurochemical attacking to solve the problem including prevention and inhibition of seizures seems to be related to ginsenosides and ginseng polypeptides. The main study based on the severity of febrile convulsions of rat pups has been done from the earlier investigations of antiepileptical action of ginsenosides between KGTRI and MSU (Chepurnov, Park et al., 1995) with different kinds of experimental models of epilepsy. From the cultured cell line DAN25 of ginseng root, the extracts of ginsenosides made in "BIOKHIMMASH" were studied by the project of preclinical anticonvulsant screening (Stables, Kupferberg, 1997). The inhibition of severity of convulsions, decrease of seizures threshold, decrease of audiogenic seizures in rats of different strains and normalization of cerebral blood flow (measured by hydrogen test) were demonstrated in rats after i.c.v., intraperitoneally and orally administration, respectively. The antiepileptical effects by the combination of compounds from ginseng; were compared with the iuluence of Rg1, Rb1, Rc and with the well known antiepileptical drugs such as carbamazepine, valproic acid. The base for the research is obtained by using the WAG/Rij strain (Luijtelaar, Coenen, Kuznetcova), an excellent genetic model for human generalized absence epilepsy. The improving action of gensinosides was effectively demonstrated on the model of electrical kindling of amygdala of WAG/Rij rats with genetically determined absences, and the influences of ginsenosides on the slow wave discharges have also been being investigated. The different characteristics of a kindling process exerted in the sex-different region of the amygdala and demonstrated that the level of sex steroids and content of neurosteroids in amygdaloid tissue can modify the development of seizures. The chemical structures of ginsenosides not only have some principal differences from well-known antiepileptical drugs but the Plant Pharmacology gives us unique possibility to develop new class of antiepileptic drugs and to improve its biological activity.

• 약학회지
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• 제59권2호
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• pp.59-65
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• 2015

KR-67500, trans-4-(2-(4-methyl-1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetamido)adamantane-1-carboxamide, is a novel $11{\beta}$-HSD1 inhibitor with its therapeutic effects of its anti-diabetic, anti-adipogenic and anti-osteoporotic activity. This study was performed to evaluate in vitro and in vivo pharmacokinetic properties of KR-67500 as a new drug candidate. KR-67500 was stable and highly bound to proteins in rat plasma. The microsomal stabilities of KR-67500 in human and rat liver were high. The inhibitory effect of KR-67500 for five cytochrome P450 enzymes was low. Preclinical pharmacokinetic studies have been carried out with intravenous or oral administrations of KR-67500 (10 mg/kg) to male rats and monkey. KR-67500 showed low clearance (0.68 l/h/kg) and high oral bioavailability (102%) in male rats. These results suggest that KR-67500 has good drug-like pharmacokinetic properties with a low first-pass effect and high bioavailability for an oral therapeutic agent of diabetes and osteoporosis.

• 대한한의학방제학회지
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• 제31권3호
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• pp.171-182
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• 2023

Objectives : Saposhnikoviae Radix (SR) and Glehniae Radix (GR) have been frequently used in traditional medicine to treat diseases related to 'wind' syndrome, but there have been cases where it has been mixed in a state where the plant of origin is not clear. In this study, to select materials for conducting preclinical cerebral infarction research, the network pharmacology analysis method was used to select suitable medicinal materials for the study. Methods : In this study, a Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) based network pharmacology analysis method was used, and oral bioavailability (OB), drug likeness (DL), Caco-2 and BBB permeability were utilized to select compounds with potential activity. For the values of each variable used in this study, OB ≥ 20%, DL ≥ 0.18, Caco-2 ≥ 0, and BBB ≥ -0.3 were applied, then networks of bioactive compounds, target proteins, and target diseases was constructed. STRING database was used to construct a protein-protein interaction network. Results : It was confirmed that SR rather than GR has various target proteins and target diseases based on network pharmacological analysis using TCMSP database. And it was analyzed that the bioactive compounds only in SR act more on neurovascular diseases, and both drugs are expected to be effectively used for cardiovascular diseases. Conclusions : In our future study, SR will be used in an ischemic stroke mouse model, and the mechanism of action will be explored focusing on apoptosis and cell proliferation.

• The Plant Pathology Journal
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• 제39권5호
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• pp.430-448
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• 2023

Recently, strategies for controlling Fusarium oxysporum f. sp. lycopersici (Fol), the causal agent of Fusarium wilt of tomato, focus on using effective biocontrol agents. In this study, an analysis of the biocontrol and plant growth promoting (PGP) attributes of 11 isolates of loamy soil Bacillus spp. has been conducted. Among them, the isolates B.PNR1 and B.PNR2 inhibited the mycelial growth of Fol by inducing abnormal fungal cell wall structures and cell wall collapse. Moreover, broad-spectrum activity against four other plant pathogenic fungi, F. oxysporum f. sp. cubense race 1 (Foc), Sclerotium rolfsii, Colletotrichum musae, and C. gloeosporioides were noted for these isolates. These two Bacillus isolates produced indole acetic acid, phosphate solubilization enzymes, and amylolytic and cellulolytic enzymes. In the pot experiment, the culture filtrate from B.PNR1 showed greater inhibition of the fungal pathogens and significantly promoted the growth of tomato plants more than those of the other treatments. Isolate B.PNR1, the best biocontrol and PGP, was identified as Bacillus stercoris by its 16S rRNA gene sequence and whole genome sequencing analysis (WGS). The WGS, through genome mining, confirmed that the B.PNR1 genome contained genes/gene cluster of a nonribosomal peptide synthetase/polyketide synthase, such as fengycin, surfactin, bacillaene, subtilosin A, bacilysin, and bacillibactin, which are involved in antagonistic and PGP activities. Therefore, our finding demonstrates the effectiveness of B. stercoris strain B.PNR1 as an antagonist and for plant growth promotion, highlighting the use of this microorganism as a biocontrol agent against the Fusarium wilt pathogen and PGP abilities in tomatoes.

• Journal of Genetic Medicine
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• 제20권1호
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• pp.6-14
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• 2023

Fabry disease (FD), a rare X-linked lysosomal storage disorder, is caused by mutations in the α-galactosidase A gene gene encoding α-galactosidase A (α-Gal A). The functional deficiency of α-Gal A results in progressive accumulation of neutral glycosphingolipids, causing multi-organ damages including cardiac, renal, cerebrovascular systems. The current treatment is comprised of enzyme replacement therapy (ERT), oral pharmacological chaperone therapy and adjunctive supportive therapy. ERT has been introduced 20 years ago, changing the outcome of FD patients with proven effectiveness. However, FD patients have many unmet needs. ERT needs a life-long intravenous therapy, inefficient bio-distribution, and generation of anti-drug antibodies. Migalastat, a pharmacological chaperone, augmenting α-Gal A enzyme activity only in patients with mutations amenable to the therapy, is now available for clinical practice. Furthermore, these therapies should be initiated before the organ damage becomes irreversible. Development of novel drugs aim at improving the clinical effectiveness and convenience of therapy. Clinical trial of next generation ERT is underway. Polyethylene glycolylated enzyme has a longer half-life and potentially reduced antigenicity, compared with standard preparations with longer dosing interval. Moss-derived enzyme has a higher affinity for mannose receptors, and seems to have more efficient access to podocytes of kidney which is relatively resistant to reach by conventional ERT. Substrate reduction therapy is currently under clinical trial. Gene therapy has now been started in several clinical trials using in vivo and ex vivo technologies. Early results are emerging. Other strategic approaches at preclinical research level are stem cell-based therapy with genome editing and systemic mRNA therapy.

• 동의생리병리학회지
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• 제38권1호
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• pp.22-26
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• 2024

The purpose of this study was to identify the applicability, main compounds, and target genes of Cnidii Fructus (CF) in the treatment of gastritis using network pharmacology. The compounds in CF were searched in Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and a database of medicinal materials and chemical compounds in Northeast Asian traditional medicine (TM-MC). The target gene information of the compounds was collected from pubchem and cross-compared with the gastritis-related target gene information collected from Genecard to derive the target genes. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed on the derived target genes. Afterwards, network analysis between compounds and disease target genes was performed using cytoscape. We identified 121 active compounds and 139 target genes associated with gastritis. Pathways derived from the GO biological process and KEGG pathway DB primarily focus on target genes related to inflammation (IL-6, IL-8, TNF production, NF-κB transcription factor activity, and NF-κB signaling pathway) and cell death (PI3K-Akt, FoxO). Major targets for CF treatment of gastritis include TP53, TNF, BCL2, EGFR, NFKB1, ABCB1, PPARG, PTGS2, IL6, IL1B, and SOD1, along with major compounds such as coumarin, osthol, hexadecanoic acid, oleic acid, linoleic acid, and stigmasterol. This study provided CF's applicability for gastritis, related compounds, and target information. Evaluating CF's effectiveness in a preclinical gastritis model suggests its potential use in clinical practice for digestive system diseases.

• 한국식품영양과학회지
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• 제34권7호
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• pp.959-967
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• 2005

생식 제품이 납중독 흰쥐의 피해경감에 미치는 영향을 규명하기 위하여 12mg의 납을 매일 1회 쥐에게 경구 투여하면서 생식제품이 $12.5\%,\;25\%,\;50\%$ 함유된 식이로 6주간 사육 후 체중 증가율 및 사료 효율, 혈액학적 검사, 간 조직의 과산화지질함량, SOD활성, GSH 함량과 간 및 신장 조직내 납 함량을 측정하였다. 체중 증가율과 사료 효율은 납 투여시 대조군과 비교하여 유의적으로 감소되는 것으로 나타났고(p<0.05), 생식의 급여는 체중과 식이효율을 다소 증가시키는 경향을 보였으며, 특히 $12.5\%$ 생식 섭취군에서는 식이 효율이 납 단독 투여군과 비교하여 유의적으로 증가되는 것으로 나타났다(p<0.05). 납에 의한 혈액학적 독성 증상으로 납 단독 투여군에서는 RBC를 제외한 HGB, HCT, MCV, MCH, RDW에서 유의적인 손상이 나타났으며(p<0.05), HCT의 경우 $50\%$ 생식 섭취군에서 유의적으로 증가되는 것으로 나타났고(p<0.05), MCV, MCH, RDW의 경우 $25\%$와 $50\%$ 생식 급여 시 납에 의한 손상이 완화되는 것으로 나타났다(p<0.05). 그러나 HGB의 경우 생식 농도에 따른 수치 증가는 관찰되었지만 유의 차는 나타나지 않았다. 또한 납 투여로 간조직 의 과산화지 질 생성이 다소 증가되는 것이 관찰되었으며, $12.5\%$와 $50\%$ 생식 섭취군에서 과산화지질 생성이 유의적으로 감소되는 것으로 타나났다(p<0.05). 그러나 납 투여에 따른 SOD활성 변화는 관찰되지 않았으나 생식은 SOD활성을 다소 증가시키는 경향을 보였다 뿐만 아니라 납 단독 투여는 항산화 및 해독 작용 관련 물질인 GSH 수준을 유의적(p<0.05)으로 증가시켜주는 것에 반해 생식의 섭취는 증가된 GSH의 함량을 농도 의존적으로 낮추는 것으로 나타났다(P<0.05). 또한 생식은 간과 신장 조직에서의 납 축적을 억제시켜 간 조직의 경우 $25\%$와 $50\%$ 생식군에서 유의적인 감소 효과가 있었고, 신장 조직에서는 $25\%$ 생식군에서 유의적인 감소 효과가 있었다(p<0.05). 이상의 연구 결과에 의하면 생식의 섭취는 납중독으로 발생되는 혈액학적 및 산화적 손상을 완화시켜 주고, 조직에서의 납축적을 억제시켜 주는 것으로 나타나 생식은 납중독에 의한 피해를 경감시켜줄 수 있는 해독 기능을 갖는 것으로 사료된다. 그러나 본 연구는 생식의 유효성을 평가하기 위한 기초 자료 일환으로 동물실험 수준에서 평가된 연구로서 인체에 적용하기는 아직 무리가 있으며, 향후 용량 설정에 대한 연구 및 임상단계에서 효능을 평가하기 위한 다각적인 연구가 더 필요할 것으로 여겨지고, 이와 함께 후속 연구를 통한 생식의 납 해독 기전이 규명되어야 할 것이다.