Pharmacokinetics of reduced-dose indinavir/ritonavir 400/100 mg twice daily in HIV-1-infected Thai patients

OBJECTIVE: To study the pharmacokinetics of indinavir/ ritonavir 400/100 mg twice daily in antiretroviral-naive patients at Srinagarind Hospital in Khon Kaen, Thailand. METHODS: This was a steady-state, open-label pharmacokinetic study of 19 patients. A 12 h pharmacokinetic curve was recorded after an overnight fast. Plasma levels of indinavir and ritonavir were determined by a validated HPLC method. Virological failure was defined according to the most recent US Department of Health and Human Services guidelines as a viral load above 400 copies/ml at week 24. RESULTS: Median baseline values for CD4 and viral load were 13cells/mm3 and 167000 copies/ml, respectively. The median (interquartile ranges) for indinavir AUC, Cmax and Cmin were 18.1 (15.3-23.8) mg/l x h, 4.1 (3.6-4.8) mg/l and 0.17 (0.12-0.30) mg/l, respectively. These values represent 37%, 39% and 24% of the AUC, Cmax and Cmin values found, respectively, for the indinavir/ritonavir 800/100 mg dose in HIV-1-infected Thai patients. Short-term virological response was satisfactory. There were three subjects with an indinavir Cmin. below the target value of 0.10 mg/l, of whom one had virological failure (33%). Among the other 16 subjects with an indinavir Cmin above 0.10 mg/l, there was also one virological failure (6%) (P=0.30). CONCLUSIONS: Indinavir exposure in this reduced-dose regimen of 400 mg with 100 mg ritonavir twice daily was more than dose-proportionally lower than previously observed with the indinavir/ritonavir 800/100 mg twice daily regimen. Therapeutic Cmin levels of indinavir were achieved in >80% of the subjects and short-term virological response was satisfactory in this cohort of patients starting highly active antiretroviral therapy at an advanced disease stage with high baseline viral loads.     

Mechanisms of photoexcitation and photoionization in small water clusters

The mechanisms of photoexcitation and photoionization in small water clusters in gas phase, (H₂O)_n; n = 2–3, are studied using the complete active-space second-order perturbation theory (CASPT2) with the aug-cc-pVDZ basis set. The present study characterizes for the first time the structures and energetics of common transition and intermediate complexes in the photoexcitation and photoionization mechanisms in the lowest singlet-excited state. The ab initio results showed that the photoexcitation of the water monomer by a single photon can directly generate [OH]˙ and [H]˙ in their respective electronic-ground states, and a single photon with approximately the same energy can similarly lead to the photoexcitation and also to the photoionization in the water clusters. The S₀ → S₁ excitation leads to strong polarization of the O–H⋯O H-bond and to the formation of the water dimer radical cation transition state complex [(H₂O)₂]⁺˙, from which [OH]˙, [H]˙, and [H₃O]⁺˙ can be generated. These products are obtained from [(H₂O)₂]⁺˙ by the direct dissociation of the O–H bond upon photoexcitation and by proton transfer and the formation of a metastable charge-separated Rydberg-like H-bond complex ([H₃O]⁺˙⋯[OH]˙) upon photoionization. The proposed mechanisms suggest that in the gas phase, the photoexcitation and photoionization processes are most likely bimolecular reactions, in which all the transition and intermediate charged species are more stabilized than in a unimolecular reaction. The theoretical results provide insights into the photoexcitation and photoionization mechanisms of molecular clusters and can be used as guidelines for further theoretical and experimental studies.

The S₀ → S₁ excitation leads to strong polarization and formation of [(H₂O)₂]⁺˙ from which both photoexcited and photoionized products are generated.     

Synergistic Effect of Forbesione From Garcinia hanburyi in Combination with 5-Fluorouracil on Cholangiocarcinoma

Background: Chemotherapy for advanced cholangiocarcinoma (CCA) is largely ineffective; thus innovative combinations of chemotherapeutic agents and natural compounds represent a promising strategy. This study aimed to investigate the synergistic effects of forbesione combined with 5-fluorouracil (5-FU) in hamster cholangiocarcinoma (Ham-1) cells both in vitro and in vivo. The anti-tumor effects of 5-FU combined with forbesione in vitro were determined using the Sulforhodamine B (SRB) assay and the effects in vivo were assessed in transplanted Ham-1 allograph models. Using ethidium bromide/acridine orange (EB/AO) staining, the morphological changes of apoptotic cells was investigated. The expressions of apoptosis-related molecules after combined treatment with forbesione and 5-FU were determined using real-time RT-PCR and western blot analysis. Forbesione or 5-FU alone inhibited proliferation of Ham-1 cells in a dose-dependent manner and their combination showed a synergistic proliferation inhibitory effect in vitro. In vivo studies, forbesione in combination with 5-FU exhibited greater inhibition of the tumor in the hamster model compared with treatment using either drug alone. Forbesione combined with 5-FU exerted stronger apoptotic induction in Ham-1 cells than did single drug treatment. The combination of drugs strongly suppressed the expression of B-cell lymphoma 2 (Bcl-2) and procaspase-3 while enhancing the expression of p53, Bcl-2-associated X protein (Bax), apoptotic protease activating factor-1 (Apaf-1), caspase-9 and caspase-3, compared with single drug treatments. These results explained the decreased expression of cytokeratin 19 (CK19) positive cells and proliferation cell nuclear antigen (PCNA) positive cells in Ham-1 cell tumor tissues of the treated hamsters. There was no apparent systemic toxicity observed in the treated animals compared with the control groups. Forbesione combined with 5-FU strongly induced apoptosis in Ham-1 cells. The growth inhibitory effect of combined treatment using these two drugs was much greater than treatment with either drug alone, both in vitro and in vivo.     

Rhinacanthin-C Extracted from Rhinacanthus nasutus (L.) Inhibits Cholangiocarcinoma Cell Migration and Invasion by Decreasing MMP-2, uPA,FAK and MAPK Pathways

Cholangiocarcinoma is a malignant tumor with high metastatic and mortality rates. We investigated the effectsof rhinacanthin-C on cell proliferation, migration, invasion and the expression of proteins regulating cancer cellinvasion-regulated proteins in a cholangiocarcinoma (KKU-M156) cell line. Cytotoxicity of rhinacanthin-C wasdetermined by the SRB assay. Using wound-migration, chamber-migration and chamber-invasion assays, we assessedthe effects of rhinacanthin-C against KKU-M156 cells. The activities of matrix metalloproteinases 2 and 9 (MMP-2,MMP-9) and urokinase-type plasminogen activator (uPA) were determined using gelatinase and uPA zymographyassays. The expression of invasion-regulated proteins was investigated using western-blot analysis. After treatmentwith rhinacanthin-C, KKU-M156 cells exhibited antiproliferative effects in a dose-dependent manner with greaterefficacy than in Vero cells: IC50 values were 1.50 and 2.37 μM, respectively. Rhinacanthin-C significantly inhibited cellmigration and invasion of KKU-M156 cells in a dose-dependent manner. Consistent with this observation, treatmentwith rhinacanthin-C was associated with a decrease in the expression levels of FAK, p-FAK, MMP-2, and a decrease inthe levels of p38-, JNK1/2- and ERK1/2-MAPK pathways as well as inhibiting NF-κB/p65 expression and translocationof NF-κB/p65 to the nucleus. We have shown for the first time that the anti-metastatic effects of rhinacanthin-C onKKU-M156 cells are mediated via inhibition of the expression of invasion-regulated proteins. Rhinacanthin-C maydeserve consideration as a potential agent for the treatment of cholangiocarcinoma.     

Implementing Cancer Prevention into Clinical Practice

Cancer prevention has been associated with decreased rates of cancer incidence and increased survival. Cancer prevention, however, can have a greater impact if barriers to implementing cancer prevention into practice are removed and opportunities are both fostered and seized. The purpose of this article is to identify barriers and opportunities to cancer prevention in clinical practice and provide recommendations for the future. A multidisciplinary team participated in “The Future Directions Cancer Prevention and Control: Workforce Implications for Training, Practice and Policy” workshop on October 17–18, 2009 at The University of Texas MD Anderson Cancer Center in Houston, TX. During the meeting, the team discussed barriers and opportunities for the implementation of cancer prevention into clinical practice. Further data were collected from peer-reviewed journals and published government and cancer agencies reports. Several issues were identified: (1) The funding allocated to basic cancer prevention research and application is not optimal and less than that for cancer treatment; (2) participation in cancer prevention behaviors and screening practices are lower than desired, especially among the uninsured; (3) a shortage in healthcare professionals is a major challenge in meeting the future needs of cancer prevention; (4) demands on medical schools to balance increased enrollment, incorporate cancer prevention in an already crowded curriculum, and develop faculty are daunting; and (5) healthcare reforms in 2010 provide both opportunities and additional challenges for cancer prevention. Based on the current state of cancer prevention, we formed six recommendations: (1) additional funding for cancer prevention research with a focus on implementation into practice, (2) improved tracking of cancer prevention research funding and the outcomes associated with it, (3) continued monitoring of cancer prevention services participation with emphasis on closing the gap in health disparities, (4) financial and technical assistance to healthcare professional schools for incorporating cancer prevention into curricula, (5) assessment of the current state of technology in cancer prevention care, and (6) the use of effective multidisciplinary teams in cancer prevention care. Improved delivery of cancer prevention services can have a tremendous impact on cancer incidence and survival rates.     

Outcome of cardiopulmonary resuscitation in a 2300-bed hospital in a developing country

OBJECTIVE: To evaluate the outcome and quality of in-hospital cardiopulmonary resuscitation (CPR), and factors affecting the outcome. SETTING: A 2300-bed university hospital in Thailand. METHOD: A 1-year prospective audit according to the Utstein style. RESULTS: A total of 639 cardiac arrests (370 male, 269 female, age 1 day-96 years, mean+/-S.D.=53.3+/-24.12 years) were included. Four hundred and thirty-three cardiac arrests (67.8%) occurred in non-monitored areas and 200 (31.3%) occurred in monitored areas. Five hundred and thirty-six cardiac arrests (84%) were witnessed. The majority of cardiac arrests occurred in medical patients (68.4%) and surgical patients (21.4%). The most common underlying causes of arrest were respiratory failure (24.7%) and septic shock (23.3%). Initial ECG rhythms were ventricular fibrillation 79 (12.4%), asystole 272 (42.6%) with pulseless electrical activity 225 (35.2%). Most patients received basic life support within 1 min (86.7%) and advanced life support (ALS) within 4 min (92.6%) but only 25% of patients received defibrillation within 3 min. Following resuscitation, 394 (61.7%) achieved restoration of spontaneous circulation and 44 patients (6.9%) survived to discharge. Only 162 post-arrest patients were treated in the critical care area. The initial survival rate was not associated with sex, age and time to ALS, but was significantly related to the monitored area. CONCLUSION: In our setting, survival to discharge is 6.9%. Initial survival rate was strongly associated with being in a monitored area. Defibrillators and the critical care areas were insufficient.