Drug and Alcohol Rehabilitation: Gatifloxacin Induces S and G(2)-Phase Cell Cycle Arrest in Pancreatic Cancer Cells via P21/p27/p53.

Gatifloxacin Induces S and G(2)-Phase Cell Cycle Arrest in Pancreatic Cancer Cells via p21/p27/p53.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(10): e47796
Yadav V, Sultana S, Yadav J, Saini N

Pancreatic cancer, despite being the most dreadful among gastrointestinal cancers, is poorly diagnosed, and further, the situation has been aggravated owing to acquired drug resistance against the single known drug therapy. While previous studies have highlighted the growth inhibitory effects of older generation fluoroquinolones, the current study aims to evaluate the growth inhibitory effects of newer generation fluoroquinolone, Gatifloxacin, on pancreatic cancer cell lines MIA PaCa-2 and Panc-1 as well as to elucidate the underlying molecular mechanisms. Herein, we report that Gatifloxacin suppresses the proliferation of MIA PaCa-2 and Panc-1 cells by causing S and G(2)-phase cell cycle arrest without induction of apoptosis. Blockade in S-phase of the cell cycle was associated with increased TGF-?1 expression and translocation of Smad3-4 complex to the nucleus with subsequent activation of p21 in MIA PaCa-2 cells, whereas TGF-? signalling attenuated Panc-1 cells showed S-phase arrest by direct activation of p27. However, Gatifloxacin mediated G(2)-phase cell cycle arrest was found to be p53 dependent in both the cell lines. Our study is of interest because fluoroquinolones have the ability to penetrate pancreatic tissue which can be very effective in combating pancreatic cancers that are usually associated with loss or downregulation of CDK inhibitors p21/p27 as well as mutational inactivation of p53. Additionally, Gatifloxacin was also found to synergize the effect of Gemcitabine, the only known drug against pancreatic cancer, as well as the broad spectrum anticancer drug cisplatin. Taken together our results suggest that Gatifloxacin possesses anticancer activities against pancreatic cancer and is a promising candidate to be repositioned from broad spectrum antibiotics to anticancer agent.
HubMed – drug

 

Access to Artemisinin-Combination Therapy (ACT) and other Anti-Malarials: National Policy and Markets in Sierra Leone.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(10): e47733
Amuasi JH, Diap G, Nguah SB, Karikari P, Boakye I, Jambai A, Lahai WK, Louie KS, Kiechel JR

Malaria remains the leading burden of disease in post-conflict Sierra Leone. To overcome the challenge of anti-malarial drug resistance and improve effective treatment, Sierra Leone adopted artemisinin-combination therapy artesunate-amodiaquine (AS+AQ) as first-line treatment for uncomplicated P. falciparum malaria. Other national policy anti-malarials include artemether-lumefantrine (AL) as an alternative to AS+AQ, quinine and artemether for treatment of complicated malaria; and sulphadoxine-pyrimethamine (SP) for intermittent preventive treatment (IPTp). This study was conducted to evaluate access to national policy recommended anti-malarials. A cross-sectional survey of 127 medicine outlets (public, private and NGO) was conducted in urban and rural areas. The availability on the day of the survey, median prices, and affordability policy and available non-policy anti-malarials were calculated. Anti-malarials were stocked in 79% of all outlets surveyed. AS+AQ was widely available in public medicine outlets; AL was only available in the private and NGO sectors. Quinine was available in nearly two-thirds of public and NGO outlets and over one-third of private outlets. SP was widely available in all outlets. Non-policy anti-malarials were predominantly available in the private outlets. AS+AQ in the public sector was widely offered for free. Among the anti-malarials sold at a cost, the same median price of a course of AS+AQ (US$ 1.56), quinine tablets (US$ 0.63), were found in both the public and private sectors. Quinine injection had a median cost of US$ 0.31 in the public sector and US$ 0.47 in the private sector, while SP had a median cost of US$ 0.31 in the public sector compared to US$ 0.63 in the private sector. Non-policy anti-malarials were more affordable than first-line AS+AQ in all sectors. A course of AS+AQ was affordable at nearly two days’ worth of wages in both the public and private sectors.
HubMed – drug

 

Effects of berberine and hwangryunhaedok-tang on oral bioavailability and pharmacokinetics of ciprofloxacin in rats.

Filed under: Drug and Alcohol Rehabilitation

Evid Based Complement Alternat Med. 2012; 2012: 673132
Hwang YH, Cho WK, Jang D, Ha JH, Jung K, Yun HI, Ma JY

Hwangryunhaedok-Tang (HR) and berberine-containing single herbs are used to treat bacterial infection and inflammatory diseases in eastern Asia. The combination of berberine-containing herbal medicines and ciprofloxacin can be an excellent antibacterial chemotherapy against multidrug resistance bacteria. To evaluate the pretreatment effect of berberine and HR, vehicle, berberine (25 and 50?mg/kg/day), and HR (1.4?g/kg/day) were daily administered to rats for five consecutive days. On day 6, ciprofloxacin was administered (10?mg/kg, i.v. and 20?mg/kg, p.o.) to rats. To assess cotreatment effect of berberine and ciprofloxacin, berberine (50?mg/kg) and ciprofloxacin (20?mg/kg) were coadministered by single oral gavage. Pharmacokinetic data were estimated by noncompartmental model. Compared with ciprofloxacin alone (control group), coadministration of berberine (50?mg/kg) and ciprofloxacin significantly decreased C(max) of ciprofloxacin (P < 0.05). In addition, the pretreatment of berberine (50?mg/kg/day) and HR (1.4?g/kg/day) significantly decreased C(max) and AUC(0??), compared with control group (P < 0.05). The oral bioavailability of ciprofloxacin was reduced by cotreatment of berberine and pretreatment of berberine and HR. Our results suggest that the expression of P-glycoprotein and organic anion and/or organic cation transporters (OAT/OCT) could take a role in reduced oral bioavailability of ciprofloxacin by berberine and HR. HubMed – drug

 

Impact of Temozolomide on Immune Response during Malignant Glioma Chemotherapy.

Filed under: Drug and Alcohol Rehabilitation

Clin Dev Immunol. 2012; 2012: 831090
Sengupta S, Marrinan J, Frishman C, Sampath P

Malignant glioma, or glioblastoma, is the most common and lethal form of brain tumor with a median survival time of 15 months. The established therapeutic regimen includes a tripartite therapy of surgical resection followed by radiation and temozolomide (TMZ) chemotherapy, concurrently with radiation and then as an adjuvant. TMZ, a DNA alkylating agent, is the most successful antiglioma drug and has added several months to the life expectancy of malignant glioma patients. However, TMZ is also responsible for inducing lymphopenia and myelosuppression in malignant glioma patients undergoing chemotherapy. Although TMZ-induced lymphopenia has been attributed to facilitate antitumor vaccination studies by inducing passive immune response, in general lymphopenic conditions have been associated with poor immune surveillance leading to opportunistic infections in glioma patients, as well as disrupting active antiglioma immune response by depleting both T and NK cells. Deletion of O6-methylguanine-DNA-methyltransferase (MGMT) activity, a DNA repair enzyme, by temozolomide has been determined to be the cause of lymphopenia. Drug-resistant mutation of the MGMT protein has been shown to render chemoprotection against TMZ. The immune modulating role of TMZ during glioma chemotherapy and possible mechanisms to establish a strong TMZ-resistant immune response have been discussed.
HubMed – drug

 

Enterovirus infection in Korean children and anti-enteroviral potential candidate agents.

Filed under: Drug and Alcohol Rehabilitation

Korean J Pediatr. 2012 Oct; 55(10): 359-66
Park KS, Choi YJ, Park JS

Although most enterovirus infections are not serious enough to be life threatening, several enteroviruses such as enterovirus 71 are responsible for severe, potentially life-threatening disease. The epidemic patterns of enteroviruses occur regularly during the year, but they may change due to environmental shifts induced by climate change due to global warming. Therefore, enterovirus epidemiological studies should be performed continuously as a basis for anti-viral studies. A great number of synthesized antiviral compounds that work against enteroviruses have been developed but only a few have demonstrated effectiveness in vivo. No proven effective antiviral agents are available for enterovirus disease therapy. The development of a new antiviral drug is a difficult task due to poor selective toxicity and cost. To overcome these limitations, one approach is to accelerate the availability of other existing antiviral drugs approved for antiviral effect against enteroviruses, and the other way is to screen traditional medicinal plants.
HubMed – drug

 

 

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