Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases.

Background: Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years' follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods: Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results: After 40.3 months' minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50-0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61-0.81). Rates of treatment-related hepatic adverse events (primarily grade 1-2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions: After 3 years' minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration: CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.

Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi.

Limited data address the impact of HIV coinfection on the pharmacokinetics (PK) of antituberculosis drugs in sub-Saharan Africa. A total of 47 Malawian adults underwent rich pharmacokinetic sampling at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 h postdose. Of the subjects, 51% were male, their mean age was 34 years, and 65% were HIV-positive with a mean CD4 count of 268 cells/µl. Antituberculosis drugs were administered as fixed-dose combinations (150 mg rifampin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol) according to recommended weight bands. Plasma drug concentrations were determined by high-performance liquid chromatography (rifampin and pyrazinamide) or liquid chromatography-mass spectrometry (isoniazid and ethambutol). Data were analyzed by noncompartmental methods and analysis of variance of log-transformed summary parameters. The pharmacokinetic parameters were as follows (median [interquartile range]): for rifampin, maximum concentration of drug in plasma (Cmax) of 4.129 µg/ml (2.474 to 5.596 µg/ml), area under the curve from 0 to 24 h (AUC0-∞) of 21.32 µg/ml · h (13.57 to 28.60 µg/ml · h), and half-life of 2.45 h (1.86 to 3.08 h); for isoniazid, Cmax of 3.97 µg/ml (2.979 to 4.544 µg/ml), AUC0-24 of 22.5 (14.75 to 34.59 µg/ml · h), and half-life of 3.93 h (3.18 to 4.73 h); for pyrazinamide, Cmax of 34.21 µg/ml (30.00 to 41.60 µg/ml), AUC0-24 of 386.6 µg/ml · h (320.0 to 463.7 µg/ml · h), and half-life of 6.821 h (5.71 to 8.042 h); and for ethambutol, Cmax of 2.278 µg/ml (1.694 to 3.098 µg/ml), AUC0-24 of 20.41 µg/ml · h (16.18 to 26.27 µg/ml · h), and half-life of 7.507 (6.517 to 8.696 h). The isoniazid PK data analysis suggested that around two-thirds of the participants were slow acetylators. Dose, weight, and weight-adjusted dose were not significant predictors of PK exposure, probably due to weight-banded dosing. In this first pharmacokinetic study of antituberculosis drugs in Malawian adults, measures of pharmacokinetic exposure were comparable with those of other studies for all first-line drugs except for rifampin, for which the Cmax and AUC0-24 values were notably lower. Contrary to some earlier observations, HIV status did not significantly affect the AUC of any of the drugs. Increasing the dose of rifampin might be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in the half-life of isoniazid of 41% (P = 0.022). Possible competitive interactions between isoniazid and sulfamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further.

Pharmacokinetics of anti-TB drugs in Malawian children: reconsidering the role of ethambutol.

BACKGROUND: Current guidelines for dosing of anti-TB drugs in children advocate higher doses for rifampicin and isoniazid despite limited availability of paediatric data on the pharmacokinetics of these drugs, especially from Africa, where the burden of childhood disease remains high. METHODS: Thirty children aged 6 months to 15 years underwent intensive pharmacokinetic sampling for first-line anti-TB drugs at Queen Elizabeth Central Hospital, Blantyre, Malawi. Rifampicin, isoniazid, pyrazinamide and ethambutol were dosed at 10, 5, 25 and 20 mg/kg, respectively. Plasma drug concentrations were determined using sensitive, validated bioanalytical methods and summary pharmacokinetic parameters were estimated using non-compartmental analysis. RESULTS: The median (IQR) Cmax was 2.90 (2.08-3.43), 3.37 (2.55-4.59), 34.60 (32.30-40.90) and 1.20 (0.85-1.68) mg/L while the median (IQR) AUC0-∞ was 16.92 (11.10-22.74), 11.48 (7.35-18.93), 333.50 (279.50-487.2) and 8.65 (5.96-11.47) mg·h/L for rifampicin, isoniazid, pyrazinamide and ethambutol, respectively. For all drugs, pharmacokinetic parameters relating to drug absorption and exposure were lower than those published for adults, though similar to existing paediatric data from sub-Saharan Africa. Weight and/or dose predicted at least one measure of exposure for all drugs. Age-related decreases in CL/F for rifampicin and pyrazinamide and a biphasic elimination pattern of isoniazid were observed. Predicted AUC0 -∞ for rifampicin dosed at 15 mg/kg was comparable to that of adults while the dose required to achieve ethambutol exposure similar to that in adults was 55 mg/kg or higher. CONCLUSIONS: These data support recently revised WHO recommendations for dosing of anti-TB drugs in children, but dosing of ethambutol in children also appears inadequate by comparison with adult pharmacokinetic data.

Unmet needs, quality of life and psychological distress: insights regarding head and neck cancer patients in a rural setting.

OBJECTIVE: This study aimed to evaluate the perceived quality of life, unmet needs and psychological distress in patients with head and neck cancer in a rural setting in New Zealand. METHOD: Patients presenting with head and neck cancer in Northland, New Zealand, were asked to complete questionnaires on quality of life, unmet needs, and anxiety or depression together with a free-text option. RESULTS: About one quarter of respondents (27 per cent) scored high in the anxiety and depression scale, with corresponding diminished quality of life scores and increased needs. Over half of respondents (54 per cent) found it challenging to travel for treatment. Financial difficulties were encountered more frequently with indigenous patients. Rurality alone does not lead to significant differences in quality of life or needs. CONCLUSION: After treatment for head and neck cancer, it is important to monitor and manage patients' psychological distress and ease of access to health services to improve quality of life.

Time course and recovery of arterial blood gases during exacerbations in adults with Cystic Fibrosis.

INTRODUCTION: Hypoxia and hypercapnia are closely linked to morbidity and mortality in patients with Cystic Fibrosis (CF). The aims of this study were to describe the changes in blood gases during and following an acute pulmonary exacerbation in adults with CF. METHODS: We performed a prospective observational study of patients with CF admitted for management of an acute exacerbation. Blood gas and spirometric analysis was performed on admission, throughout the treatment period, and 31 days after discharge (day 45). RESULTS: At presentation, eight of nineteen patients had evidence of either hypoxia (PaO(2)<8 kPa) and/or hypercapnia (PaCO(2)>6.6 kPa). Blood gas parameters stabilized following two weeks of intravenous antibiotic therapy, with little difference evident in between treatment completion and subsequent review following discharge. Hypercapnia reversed in three patients, with persistent hypercapnia evident in two patients. CONCLUSION: In our study group, hypoxemia and hypercapnia were frequently observed at presentation of the acute exacerbation. Blood gases stabilized following two weeks of intravenous antibiotic therapy, with arterial PCO(2) one month following hospital discharge generally similar to that at time of discharge.

Stability of antioxidants in an apple polyphenol-milk model system.

The stability of antioxidants in an apple polyphenol-milk model system was examined. The model system consisted of skim milk fortified with pH-neutralised apple polyphenols (AP, 0-200mg per 100ml milk), with or without ascorbic acid (100mg per 100ml milk). Physical and chemical changes were evaluated after thermal treatment (120°C, 5min) and oxidative storage (20°C and 38°C, up to 12 weeks). Antioxidant capacity was determined using both oxygen radical absorbance capacity (ORAC) assay and ferric reducing antioxidant power (FRAP) assay. Significant antioxidant capacity was detected in the presence of milk. Antioxidant capacity was retained during thermal treatment but decreased slowly during storage. The concentration of ascorbic acid decreased rapidly, and was close to zero after 2-week storage at 38°C or 10-week storage at 20°C. The brownness of the polyphenol-milk system increased over storage duration of 0-12 weeks; this effect was retarded by the addition of ascorbic acid. This high polyphenol-milk has demonstrated good physical stability.

Suboptimal Exposure to Anti-TB Drugs in a TBM/HIV+ Population Is Not Related to Antiretroviral Therapy.

A placebo-controlled trial that compares the outcomes of immediate vs. deferred initiation of antiretroviral therapy in HIV +ve tuberculous meningitis (TBM) patients was conducted in Vietnam in 2011. Here, the pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol were investigated in the presence and absence of anti-HIV treatment in 85 patients. Pharmacokinetic analyses show that HIV therapy has no significant impact on the pharmacokinetics of TB drugs in this cohort. The same population, however, displayed generally low cerebrospinal fluid (CSF) and systemic exposures to rifampicin compared to previously reported HIV -ve cohorts. Elevated CSF concentrations of pyrazinamide, on the other hand, were strongly and independently correlated with increased mortality and neurological toxicity. The findings suggest that the current standard dosing regimens may put the patient at risk of treatment failure from suboptimal rifampicin exposure, and potentially increasing the risk of adverse central nervous system events that are independently correlated with pyrazinamide CSF exposure.

A comparison of HFrEF vs HFpEF's clinical workload and cost in the first year following hospitalization and enrollment in a disease management program.

BACKGROUND: Admission with heart failure (HF) is a milestone in the progression of the disease, often resulting in higher intensity medical care and ensuing readmissions. Whilst there is evidence supporting enrolling patients in a heart failure disease management program (HF-DMP), not all reported HF-DMPs have systematically enrolled patients with HF with preserved ejection fraction (HFpEF) and there is a scarcity of literature differentiating costs based on HF-phenotype. METHODS: 1292 consenting, consecutive patients admitted with a primary diagnosis of HF were enrolled in a hospital based HF-DMP and categorized as HFpEF (EF≥45%) or HFrEF (EF<45%). Hospitalizations, primary care, medications, and DMP workload with associated costs were evaluated assessing DMP clinic-visits, telephonic contact, medication changes over 1year using a mixture of casemix and micro-costing techniques. RESULTS: The total average annual cost per patient was marginally higher in patients with HFrEF €13,011 (12,011, 14,078) than HFpEF, €12,206 (11,009, 13,518). However, emergency non-cardiovascular admission rates and average cost per patient were higher in the HFpEF vs HFrEF group (0.46 vs 0.31 per patient/12months) & €655 (318, 1073) vs €584 (396, 812). In the first 3months of the outpatient HF-DMP the HFrEF population cost more on average €791 (764, 819) vs €693 (660, 728). CONCLUSION: There are greater short-term (3-month) costs of HFrEF versus HFpEF as part of a HF-DMP following an admission. However, long-term (3-12month) costs of HFpEF are greater because of higher non-cardiovascular rehospitalisations. As HFpEF becomes the dominant form of HF, more work is required in HF-DMPs to address prevention of non-cardiovascular rehospitalisations and to integrate hospital based HF-DMPs into primary healthcare structures.

Adherence to oral tamoxifen: a comparison of patient self-report, pill counts, and microelectronic monitoring.

PURPOSE: Recent innovations allow the integration of microelectronics into drug packaging, providing a continuous record of the interactions of the patient with the drug package. We hypothesized that adherence to oral tamoxifen, as measured by a pressure-activated microelectronic monitoring device, would be significantly discrepant from traditional measures of patient adherence, ie, patient self-report (SR) and pill counts (PCs). PATIENTS AND METHODS: Twenty-six patients receiving oral tamoxifen therapy were assessed by patient SR, PCs, and Medication Event Monitoring System (MEMS; Aprex Corp, Fremont, CA) microelectronic monitoring. A microprocessor in the MEMS cap recorded each opening as a presumptive dose, listing the date, time, and duration of opening for later retrieval on a microcomputer. Patients were not informed that their adherence was to be monitored electronically or that PCs would be performed. RESULTS: A total of 2,102 days (70.1 months) of tamoxifen therapy were monitored; patients were monitored for a mean of 2.92 months of tamoxifen therapy. SR adherence to oral tamoxifen was significantly higher than that suggested by either PCs (SR missed doses only v PC, P = .008) or MEMS adherence monitoring (SR missed doses only v MEMS missed doses only, P = .005; SR dosing-interval errors only v MEMS dosing-interval errors only, P < .0001; SR all dosing errors v MEMS all dosing errors, P < .0005). PC data also suggested significantly higher adherence rates than MEMS monitoring. CONCLUSION: Microelectronic adherence monitoring provides both confirmatory and complimentary data regarding adherence behavior, while also allowing for the evaluation of patterns of nonadherence. Patient SRs and PCs likely overestimate the degree to which patients adhere to their tamoxifen regimen.

Attitudes and behaviors on physician-assisted death: a study of Michigan oncologists.

PURPOSE: To ascertain the attitudes of oncologists toward physician-assisted death, ie, physician-assisted suicide and active euthanasia, as well as their experiences with these activities and their opinions toward their legalization. METHODS: A survey was mailed to all practicing 250 oncologists in the state of Michigan, with subsequent development of psychometric scales and their correlation with self-reported behaviors in physician-assisted death. RESULTS: Analysis revealed five distinct, meaningful factors regarding approval or disapproval of physician-assisted death. These factors reflected global attitudes toward physician-assisted death, passive euthanasia, philosophical prohibitions toward physician-assisted death, concerns of legal consequences with physician-assisted death, and attitudes that physician-assisted death could be avoided with better end-of-life care (alpha = .94, .74, .76, .87, and .84, respectively). High levels of therapy withdrawal were reported (81%), with significant reservations toward assisted suicide and active euthanasia, although reported participation in such actions was noteworthy (18% and 4%, respectively). The scales reflecting global and philosophical attitudes correlated with several attitudes and behaviors toward physician-assisted death (P < .001). Legislation that would allow physician-assisted death was favored by 20.8% of respondents. CONCLUSION: Although they have reservations about physician-assisted death, significant numbers of oncologists are willing to consider such actions should they become legal. Given the substantial number of physicians who report that they have already participated in physician-assisted death, these findings may help better understand the attitudes that motivate physician behaviors toward assisted death.

Determination of an optimal dosing schedule for combining Irinophore C™ and temozolomide in an orthotopic model of glioblastoma.

Our laboratory reported that Irinophore C™ (IrC™; a lipid-based nanoparticulate formulation of irinotecan) is effective against an orthotopic model of glioblastoma (GBM) and that treatment with IrC™ was associated with vascular normalization within the tumor. Here, the therapeutic effects of IrC™ when used in combination with temozolomide (TMZ) in concurrent and sequential treatment schedules were tested. It was anticipated that IrC™ engendered vascular normalization would increase the delivery of TMZ to the tumor and that this would be reflected by improved treatment outcomes. The approach compared equally efficacious doses of irinotecan (IRN; 50 mg/kg) and IrC™ (25 mg/kg) in order to determine if there was a unique advantage achieved when combining TMZ with IrC™. The TMZ sensitive U251MG(O) cell line (null expression of O-6-methylguanine-DNA methyltransferase (MGMT)) modified to express the fluorescent protein mKate2 was inoculated orthotopically into NOD.CB17-SCID mice and treatment was initiated 14 days later. Our results demonstrated that IrC™ and TMZ administered concurrently resulted in optimal treatment outcomes, with 50% long term survivors (>180 days) in comparison to 17% long term survivors in animals treated with IRN and TMZ or TMZ alone. Indeed, the different treatments resulted in a 353%, 222% and 280% increase in median survival time (MST) compared to untreated animals for, respectively, IrC™ combined with TMZ, IRN combined with TMZ, and TMZ alone. When TMZ was administered after completion of IRN or IrC™ dosing, an increase in median survival time of 167-174% was observed compared to untreated animals and of 67% and 74%, respectively, when IRN (50 mg/kg) and IrC™ (25mg/kg) were given as single agents. We confirmed in these studies that after completion of the Q7D×3 dosing of IrC™, but not IRN, the tumor-associated vascular was normalized as compared to untreated tumors. Specifically, reductions in the fraction of collagen IV-free CD31 staining (p<0.05) and reductions in tumor vessel diameter were observed in tumors from IrC™-treated animals when compared to tumors from untreated or IRN treated animals. Analysis by transmission electron microscopy of the ultra-structure of tumors from IrC™-treated and untreated animals revealed that tumor-associated vessels from treated animals were smaller, more organized and exhibited a morphology comparable to normal blood vessels. In conclusion, optimal treatment outcomes were achieved when IrC™ and TMZ were administered concurrently, whereas IrC™ followed by TMZ treatment given sequentially did not confer any therapeutic advantage.

A comparison of liposomal formulations of doxorubicin with drug administered in free form: changing toxicity profiles.

The anthracycline antibiotic doxorubicin has wide activity against a number of human neoplasms and is used extensively both as a single agent and in combination regimens. In addition to the use of free, unencapsulated doxorubicin, there are two US Food and Drug Administration approved liposomal formulations of doxorubicin currently available, with several additional liposomal formulations being researched either in the laboratory or in clinical trials. The two approved liposomal formulations of doxorubicin have significantly different lipid compositions and loading techniques, which lead to both unique pharmacokinetic and toxicity profiles, distinct from those of the unencapsulated form. This article discusses the toxicities associated with the free form of doxorubicin, as well as those associated with the two most common liposomal formulations, namely Doxil and Myocet. One of the key toxicity issues linked to the use of free doxorubicin is that of both an acute and a chronic form of cardiomyopathy. This is circumvented by the use of liposomal formulations, as these systems tend to sequester the drug away from organs such as the heart, with greater accumulation in liver, spleen and tumours. However, as will be discussed, the liposomal formulations of doxorubicin are not without their own related toxicities, and, in the case of Doxil, may be associated with the unique toxicity of palmar-plantar erythrodysaesthesia. Overall, the use of liposomal doxorubicin allows for a greater lifetime cumulative dose of doxorubicin to be administered, however acute maximal tolerated doses differ significantly, with that of Myocet being essentially equivalent to free doxorubicin, while higher doses of Doxil may be safely administered. This review highlights the differences in both toxicity and pharmacokinetic properties between free doxorubicin and the different liposomal formulations, as have been determined in pre-clinical and clinical testing against a number of different human neoplasms. The need for further testing of the liposomal formulations prior to the replacement of free doxorubicin with liposomal doxorubicin in any established combination therapy regimens, as well as in combination with the newer therapeutics such as monoclonal antibodies is also discussed.

The ultrastructure of a pheromone-secreting gland in the male scorpion-fly Harpobittacus Australis (Bittacidae: Mecoptera).

The eversible vesicles of the sex pheromone glands consist of three cell types, secreting the cuticle, the duct and the pheromone, respectively. Each pheromone-secreting cell has an end apparatus, bounded by microvilli and lined by a granular mass, that is penetrated by remarkable elongate filaments extending far up into the secretory duct. Vesicles containing secretion or secretion precursors abound. The possible role is discussed of the various organelles in the elaboration and transport of the pheromone.

The structure and development of a surface pattern on the cuticle of the green vegetable bug Nezara viridula.

Adult Nezara possess an area of cuticle on the metathoracic sternite with a surface pattern of minute mushroom-like projections. The surface pattern is formed by two types of cell, one forming projections and the other depressions. The surface pattern is largely determined before epicuticle deposition by deformation of the epidermal surface. This is brought about by interactions between the moulting fluid secretions and the cells. Maintenance of shape of the cells may be associated with the presence of oriented cytoplasmic microtubules. The mushroom area may function as an external reservoir causing retarded evaporation of defensive secretions.

The ultrastructure of the osmeterium and the nature of its secretion in Papilio larvae (lepidoptera).

Two main cell types constitute the defensive osmeterium gland of Papilio larvae. Ellipsoid gland cells have an extensively infolded basal plasma membrane, abundant ribosomes and whorls of smooth endoplasmic reticulum. The apical plasma membrane bears long microvilli extending into a mass of granular material containing electron-lucid cavities. Tangential slits occur in the epicuticle. Tubular arm cells contain heterogeneous, electron-dense inclusions, extensively-branched nuclei and large mitochondria sometimes distended with electron-dense material. The apical plasma membrane bears short microvilli. The inner, dense epicuticle forms a complex ramifying system. The two-phase defensive fluid consists mainly of water, 2-methyl propionic acid, and 2-methyl butyric acid.

Ultrastructure of the copper-accumulating region of the Drosophila larval midgut.

The copper-accumulating region of the midgut is a mosaic of interstitial and cup-shaped, copper-accumulating cells. The cup of each cuprophilic cell is lined with a highly refractile border of long microvilli except in one strain where it is predominantly lamellar. The nucleus lies basally; the basal plasma membrane is fairly extensively infolded. Cytolysomes are abundant and increase in number with increasing copper content of the diet. The interstitial cells bear short, less regular microvilli and have a less electron-dense cytoplasm. The nucleus is apical, the mitochondria-associated basal membrane is very extensively infolded and cytolysomes are less abundant. Virus-like particles present in nuclei of both cell types increase in number with increasing copper concentration.

Vascular access: a role for a renal nurse clinician.

The team approach to the delivery of healthcare is important and has become more so since the boundaries between professional groups have become blurred. Renal replacement therapy requires that patients have adequate access. This could be in the form of an arterio-venous fistula, a graft, or a vascular catheter. Doctors have historically always provided access for patients. Placement of vascular access is a lengthy process often causing long delays and anxiety. Due to the reduction in junior doctors hours and the further demands on senior medical staff, a nurse was nominated and developed the role of vascular access specialist and clinician. Before the development of the nurse clinicians' role, the situation in this centre regarding venous access for haemodialysis was based on an ad hoc arrangement between junior doctors. Historically surgeons and medical staff have always provided vascular access for haemodialysis. However, it was felt that a suitably educated renal nurse would be more suitable to develop this role, and a relevant course, (MSc in Advanced Nursing Practice) had been developed at a nearby university. The access role included the insertion of both short and long-term vascular access catheters. An access referral pathway is now in place, giving a streamlined service. A designated access specialist nurse now inserts vascular access, providing focused individualised care specifically targeted at the renal patients' needs. Because of the success of this role, four more nurses are being supported to undertake the clinical MSc. The aim is to develop other areas of renal provision and to provide a nurse led specialist individualised service in line with the future National Service Framework. The role has also provided scope for nursing career development, giving motivation to experienced clinical nurses who wish to remain clinically involved, improve the care for patients and progress their career.

Hydrogen production by tuning the photonic band gap with the electronic band gap of TiO2.

Tuning the photonic band gap (PBG) to the electronic band gap (EBG) of Au/TiO2 catalysts resulted in considerable enhancement of the photocatalytic water splitting to hydrogen under direct sunlight. Au/TiO2 (PBG-357 nm) photocatalyst exhibited superior photocatalytic performance under both UV and sunlight compared to the Au/TiO2 (PBG-585 nm) photocatalyst and both are higher than Au/TiO2 without the 3 dimensionally ordered macro-porous structure materials. The very high photocatalytic activity is attributed to suppression of a fraction of electron-hole recombination route due to the co-incidence of the PBG with the EBG of TiO2 These materials that maintain their activity with very small amount of sacrificial agents (down to 0.5 vol.% of ethanol) are poised to find direct applications because of their high activity, low cost of the process, simplicity and stability.

Irinophore C™, a lipid-based nanoparticulate formulation of irinotecan, is more effective than free irinotecan when used to treat an orthotopic glioblastoma model.

Given compelling evidences supporting the therapeutic potential of irinotecan (IRN) for patients with glioblastoma (GBM), the present study evaluated the activity of Irinophore C™ (IrC™), a lipid-based nanopharmaceutical formulation of IRN, in GBM. The levels of IRN and SN-38 were determined in plasma and brain after a single intravenous dose of IRN or IrC™ in tumor-free mice. Treatment with IrC™ significantly increased the plasma AUC(0-24h) of the active (lactone) forms of IRN and SN-38 when compared to free drug (760 and 30-fold increase, respectively). Levels of IRN and SN-38 in brain tissue were also increased significantly (compared to IRN treatment) following IrC™ administration. A tolerability study revealed that IrC™ is better tolerated than IRN. The efficacy of IrC™ and IRN was assessed in an orthotopic model of GBM. The therapeutic efficacy of IrC™ given at 25mg/kg weekly was comparable to the efficacy achieved using twice the dose of IRN. At the maximum tolerated dose, IrC™ (100mg/kg) increased the survival time of tumor-bearing mice of 83% compared to untreated animals. Ki67 immunostaining analysis of IrC™-treated tumors revealed a transient increase in cell proliferation after treatment. The results justify further studies evaluating the use of IrC™ for treating GBM.