The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison.

BACKGROUND: Circadian variation in renal toxicity of aminoglycosides has been demonstrated in animal and human studies. People with CF are frequently prescribed aminoglycosides. Altered pharmacokinetics of aminoglycosides are predictive of toxicity. AIM: To investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission. METHODS: Children (age 5-18years) with CF scheduled for tobramycin therapy were randomly allocated to receive tobramycin at 0800 or 2000h. Serum tobramycin levels were drawn at 1h and between 3.5 and 5h post-infusion between days 5 and 9 of therapy. Melatonin levels were measured serially at intervals from 1800h in the evening until 1200h on the next day. Circadian rhythm was categorised as normal when dim light melatonin onset was demonstrated between 1800 and 2200h and/or peak melatonin levels were observed during the night. Weight and spirometry were measured at the start and end of the therapy. Urinary biomarkers of kidney toxicity (KIM1, NAG, NGAL, IL-18 and CysC) were assayed at the start and end of the course of tobramycin. RESULTS: Eighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 was greater in the evening dosage group compared to the morning group (mean difference, 0.73ng/mg; 95% CI, 0.14 to 1.32; p=0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%). CONCLUSIONS: Renal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels (ClinicalTrials.gov NCT01207245).

Development and evaluation of a sublingual tablet based on recombinant Bet v 1 in birch pollen-allergic patients.

BACKGROUND: Sublingual immunotherapy (SLIT) applied to type I respiratory allergies is commonly performed with natural allergen extracts. Herein, we developed a sublingual tablet made of pharmaceutical-grade recombinant Bet v 1.0101 (rBet v 1) and investigated its clinical safety and efficacy in birch pollen (BP)-allergic patients. METHODS: Following expression in Escherichia coli and purification, rBet v 1 was characterized using chromatography, capillary electrophoresis, circular dichroism, mass spectrometry and crystallography. Safety and efficacy of rBet v 1 formulated as a sublingual tablet were assessed in a multicentre, double-blind, placebo-controlled study conducted in 483 patients with BP-induced rhinoconjunctivitis. RESULTS: In-depth characterization confirmed the intact product structure and high purity of GMP-grade rBet v 1. The crystal structure resolved at 1.2 Å documented the natural conformation of the molecule. Native or oxidized forms of rBet v 1 did not induce the production of any proinflammatory cytokine by blood dendritic cells or mononuclear cells. Bet v 1 tablets were well tolerated by patients, consistent with the known safety profile of SLIT. The average adjusted symptom scores were significantly decreased relative to placebo in patients receiving once daily for 5 months rBet v 1 tablets, with a mean difference of 17.0-17.7% relative to the group treated with placebo (P < 0.025), without any influence of the dose in the range (12.5-50 µg) tested. CONCLUSION: Recombinant Bet v 1 has been produced as a well-characterized pharmaceutical-grade biological drug. Sublingual administration of rBet v 1 tablets is safe and efficacious in patients with BP allergic rhinoconjunctivitis.

Water soaking and exogenous enzyme treatment of plant-based diets: effect on growth performance, whole-body composition, and digestive enzyme activities of rohu, Labeo rohita (Hamilton), fingerlings.

A 2 × 2 × 2 factorial experiment was conducted to delineate the main effect of water soaking of plant ingredients, phytase, cellulase, and their interactions on the growth and digestive enzyme activities of Labeo rohita fingerlings. Two basal diets were prepared using water-soaked (S) or unsoaked (US) plant-based ingredients. Feed of US ingredients was supplemented with phytase (U kg(-1)) and cellulase (%) at the level of 0, 0 (C(us)); 500, 0 (T(1)); 0, 0.2 (T(2)); 500, 0.2 (T(3)), and feed of S ingredients at 0, 0 (C(s)); 500, 0 (T(4)); 0, 0.2 (T(5)), and 500, 0.2 (T(6)), respectively. Three hundred and sixty fingerlings were randomly distributed into eight treatments, each with three replicates. Soaking of the ingredients for 24 h significantly reduced the tannin content. However, feeding of S diets did not improve the fish growth. Highest performance was recorded in the T(3) group. A significant interaction between dietary phytase and cellulase was observed for apparent net protein utilization. Tissue crude protein, ether extract, and ash content of the fingerlings were observed highest in the T(3) group. Activities of amylase, protease, and lipase were recorded highest in the T(3) group. Results suggested that soaking of plant-based ingredients reduces tannin content; however, growth and digestive enzyme activities of group fed soaked diet were not improved, possibly due to leaching of soluble nutrients. Probably, a shorter duration soaking may be effective in reducing tannin content and avoiding nutrients leaching.

Role of biological therapies in the development of personalized medicine.

Development of personalized medicine involves integration of several biotechnologies. This editorial stresses the important role that biological therapies such as cell and gene therapies, recombinant proteins and vaccines play in personalization of treatment. Cell-based therapies, particularly vaccines made from the patient's own tumor cells, were the first therapeutic vaccines for cancer. Adoptive cell therapy is an immunotherapy based on ex vivo expansion of autologous T lymphocytes and subsequent administration to cancer patients. Stem cells as well as genetic modification of cells has been used for in vivo production of therapeutic substances best suited for individual patients. Besides cell therapy, RNAi has been used for personalized therapy of cancer. Monoclonal antibodies, designed to bind specifically to receptors in certain tumors, are also personalized medicines.

In vitro and in situ antiyeast activity of Gracilaria changii methanol extract against Candida albicans.

BACKGROUND AND OBJECTIVES: The Gracilaria (G.) sp are widely used in the traditional medicine in Malaysia. The methanol extract of Gracilaria changii B.M. Xia & I.A. Abbott (Gracilariaciae) was evaluated for antiyeast activity against Candida albicans (Berkhout). MATERIALS AND METHODS: The antiyeast activities were studied by using disc diffusion method and broth dilution method. The effect of the extract on the growth profile of the yeast was also examined via time-kill assay. In addition, the in situ antiyeast activity was studied by microscopic observations using scanning electron microscopy (SEM), transmission electron microscopy (TEM) to determine the major alterations in the microstructure of Candida (C.) albicans. RESULTS AND DISCUSSION: The extract showed a favourable antimicrobial activity against C albicans with a minimum inhibitory concentration (MIC) value of 1.56 mg/mL. The main abnormalities noted from the SEM and TEM studies were the internal shrinkage of cell, disorganization within the cell cytoplasm and complete collapse of the yeast cells after 36 h of exposure to the extract. The time-kill assay suggested that the G. changii extract significantly inhibited C. albicans growth and it also exhibited prolonged antiyeast activity against the C albicans. CONCLUSION: The extract has shown in vitro fungicidal properties against C. albicans and should be investigated for its therapeutic potential.

Effects of Vernonia cinerea less methanol extract on growth and morphogenesis of Candida albicans.

BACKGROUND AND OBJECTIVES: Vernonia (V.) cinerea Less (Asteraceae) have many therapeutic uses in the practice of traditional medicine. The methanol extract of V cinerea, was screened for antiyeast activity against pathogenic yeast Candida albicans. MATERIALS AND METHODS: The antimicrobial activities were studied by using disc diffusion method and broth dilution method. The effect of the extract on the growth profile of the yeast was also examined via time-kill assay. In addition to the fungicidal effects study, microscopic observations using Scanning (SEM) electron microscopy, Transmission (TEM) electron microscopy and light microscopy (LM) were done to determine the major alterations in the microstructure of Candida (C) albicans. RESULTS AND DISCUSSION: The extract showed a favorable antimicrobial activity against C. albicans with a minimum inhibitory concentration (MIC) value of 1.56 mg/mL. Time-kill assay suggested that Vernonia cinerea extract had completely inhibited Candida albicans growth and also exhibited prolonged antiyeast activity. The main abnormalities notes from these microscopic observations were the alterations in morphology and complete collapse of the yeast cells after 36 h of exposure to the extract. CONCLUSION: The extract of Vernonia cinerea may be an effective agent to treat the Candida albicans infection.

Toxicity study of Vernonia cinerea.

The methanol extract of Vernonia cinerea Less (Asteraceae), which exhibited antimicrobial activity, was tested for toxicity. In an acute toxicity study using mice, the median lethal dose (LD(50)) of the extract was greater than 2000 mg/kg, and we found no pathological changes in macroscopic examination by necropsy of mice treated with extract. As well as the oral acute toxicity study, the brine shrimp lethality test was also done. Brine shrimp test LC(50) values were 3.87 mg/mL (6 h) and 2.72 mg/mL (24 h), exhibiting no significant toxicity result. In conclusion, the methanol extract of V. cinerea did not produce toxic effects in mice and brine shrimp.

Molecular variability of group 1 and 5 grass pollen allergens between Pooideae species: implications for immunotherapy.

BACKGROUND: Differences between major allergens from distinct grass species remain to be investigated, both in terms of structure and antigenicity. METHODS: Group 1 and 5 allergens purified from five common Pooideae species were analysed by mass spectrometry (MS). Major histocompatibility complex (MHC) class II-restricted T cell epitopes were identified using predictive algorithms and human leucocyte antigen (HLA)-binding assays. CD4+ T cell reactivity and IgE binding were assessed based on the induction of CD154 expression in peripheral blood mononuclear cells and using competitive ELISA assays, respectively. RESULTS: MS analysis of group 5 pollen allergens reveals considerable intra- and inter-species variability in amino acid sequence, with 30-50 predominant isoforms found for each species. Differences in the amino acid sequence as well as N- and O-glycosylation contribute to the variability of group 1 allergens, yielding 5-10 main isoforms, depending on the species. Out of 14 MHC class II-restricted T cell epitopes identified within group 1, only one is conserved among the five grass species. Significant differences in binding affinities for HLA-DR molecules result in variable CD4+ T cell recognition of group 1 and 5 allergens purified from the various species. Up to 38% and 85% of patients exhibit seric IgE responses to species-restricted (or semi-restricted) epitopes associated with group 1 or 5 allergens, respectively. CONCLUSION: Major pollen allergens from distinct grass species bear both shared and species-restricted T and B cell immune epitopes. When compared with single extracts, a five grass pollen extract is thus more suitable for specific immunotherapy, as it contains a broader repertoire of the IgE epitopes to which patients are sensitized.

Antimicrobial Activity of Emilia sonchifolia DC., Tridax procumbens L. and Vernonia cinerea L. of Asteracea Family: Potential as Food Preservatives

Chemical preservatives have been used in the food industry for many years. However, with increased health concerns, consumers prefer additive-free products or food preservatives based on natural products. This study evaluated antimicrobial activities of extracts from Emilia sonchifolia L. (Common name: lilac tassel flower), Tridax procumbens L. (Common name: tridax daisy) and Vernonia cinerea L. (Common name: Sahadevi), belonging to the Asteracea family, to explore their potential for use against general food spoilage and human pathogens so that new food preservatives may be developed. Three methanol extracts of these plants were tested in vitro against 20 bacterial species, 3 yeast species, and 12 filamentous fungi by the agar diffusion and broth dilution methods. The V. cinerea extract was found to be most effective against all of the tested organisms and the methanol fraction showed the most significant (p < 0.05) antimicrobial activity among all the soluble fractions tested. The minimum inhibitory concentrations (MICs) of extracts determined by the broth dilution method ranged from 1.56 to 100.00mg/mL. The MIC of methanol fraction was the lowest in comparison to the other four extracts. The study findings indicate that bioactive natural products from these plants may be isolated for further testing as leads in the development of new pharmaceuticals in food preservation as well as natural plant-based medicine.

Nanomedicine: application of nanobiotechnology in medical practice.

Nanomedicine is the application of nanobiotechnologies to medicine. This article starts with the basics of nanobiotechnology, followed by its applications in molecular diagnostics, nanodiagnostics, and improvements in the discovery, design and delivery of drugs, including nanopharmaceuticals. It will improve biological therapies such as vaccination, cell therapy and gene therapy. Nanobiotechnology forms the basis of many new devices being developed for medicine and surgery such as nanorobots. It has applications in practically every branch of medicine and examples are presented of those concerning cancer (nanooncology), neurological disorders (nanoneurology), cardiovascular disorders (nanocardiology), diseases of bones and joints (nanoorthopedics), diseases of the eye (nanoophthalmology), and infectious diseases. Safety issues of in vivo use of nanomaterials are also discussed. Nanobiotechnology will facilitate the integration of diagnostics with therapeutics and facilitate the development of personalized medicine, i.e. prescription of specific therapeutics best suited for an individual. Many of the developments have already started and within a decade a definite impact will be felt in the practice of medicine.

Stability and delivery of RNA via the gastrointestinal tract.

Oral RNA has been used in the past as a nutritional supplement as well as a therapeutic agent for several disorders. It is difficult to validate any of the therapeutic claims in the absence of scientific studies and in view of the instability of orally administered RNA. Absorption from the gastrointestinal tract remains questionable. Most of the current efforts in relation to oral RNA are devoted to oral administration of siRNA for therapeutic purposes. A hypothesis is presented of the usefulness of RNA as a nutraceutical. After review of the available literature, role of mRNA in the body, and various routes of administration, suggestions are made for possible methods to improve delivery of RNA and to study its pharmacokinetics. There is commercial potential for such a product if absorption by oral route can be verified as it is easy to administer and can be produced at lower cost than intravenous preparations.

Use of nanoparticles for drug delivery in glioblastoma multiforme.

Treatment of glioblastoma multiforme (GBM), a primary malignant tumor of the brain, is one of the most challenging problems as no currently available treatment is curative. Surgery remains the basic treatment in which the bulk of the tumor is removed and the peripheral infiltrating part is the target of supplementary treatments. The currently available anticancer therapeutics have less than optimal usefulness for GBM, mainly owing to delivery problems to the tumor, including those due to blood-brain barrier. Several new therapies in development for GBM will require innovative methods of delivery besides the current practice of direct introduction of drugs and devices into the tumor. Nanobiotechnology, particularly nanoparticles, is making a significant contribution to the improvement of drug delivery in cancer and many of these technologies can be applied to GBM. Nanobiotechnology can provide a platform for combination of diagnostics, therapeutics, and its delivery to the tumor with subsequent monitoring of response. These technologies are reviewed and the prospects of improvement of therapeutic delivery to the brain are excellent during the next 5 years. Curing of GBM, however, depends on discovery of an anticancer agent that will destroy GBM completely.

Improvement in suction catheter efficiency and safety in arterial operations.

The Blood Shield is a new device which has been developed to attach easily to the tip of a conventional suction catheter. Two experiments were performed to determine if the Blood Shield could limit the degree of splash which occurs during vascular graft flushing and whether it could increase the efficiency of a standard suction tip in collecting shed blood for autotransfusion. The results of the experiments indicate that the Blood Shield, when added to a conventional suction catheter, diminishes the amount of spray which may occur during anastomotic flushing. Secondly, it more effectively collects blood from a flushed anastomosis or arteriotomy in comparison with a suction catheter alone.

The protective action of essential oils of onion and garlic in cholesterol-fed rabbits.

The effects of the essential oils of onion and garlic have been investigated in cholesterol-fed rabbits and have been compared with the effects of clofibrate. The marked rise in serum cholesterol and blood coagulability that followed 3 months of cholesterol feeding (0.2 g/kg/day) was significantly reduced by the essential oils of both onion and garlic. Fibrinolytic activity was actually increased even above the normal control levels. The essential oils of onion and garlic (equivalent to 1 g/kg/day of raw bulbs) proved more effective than clofibrate in the usual clinical dose of 33 mg/kg/day. Garlic was even more effective than onion. Cholesterol feeding increased the average lipid content of aorta from 5.95 to 13.75 mg/100 mg dry weight. With addition of clofibrate, onion or garlic the values were 7.79, 6.23 and 5.28 mg/100 ml, respectively. Thus it can be seen that the essential oils effectively prevent lipid acculation in the rabbit oarta.