Pharmacokinetics and relative bioavailability of fentanyl pectin nasal spray 100 - 800 µg in healthy volunteers.

OBJECTIVES: Fentanyl pectin nasal spray (FPNS) is formulated as a solution utilizing PecSys®; pectin based enabling technology (Archimedes). On contact with the nasal mucosa the formulation will gel and modulate fentanyl absorption while limiting nasal drip or runoff. This single-dose volunteer study compared the pharmacokinetics of FPNS 100, 200, 400, and 800 µg doses and assessed bioavailability relative to oral transmucosal fentanyl (OTFC) 200 µg. Safety and dose proportionality were also examined. SUBJECTS AND METHODS: 16, opioid-naïve subjects were dosed on five separate visits under naltrexone block. FPNS doses were administered using a Pfeiffer device delivering 100 µl. Devices were filled with either 1.57 mg/ml (100 and 200 µg dosing) or 6.28 mg/ml fentanyl citrate (400 and 800 µg). Venous blood samples were collected up to 48 h after dosing and plasma fentanyl concentrations measured. RESULTS: Median tmax values for FPNS ranged from 15 to 21 min post-dose and were dose-independent. At 200 µg Cmax values were 2.3-fold higher for FPNS compared with OTFC. Mean relative bioavailability of FPNS to OTFC ranged from 103% to 163%. Dose proportionality for Cmax and AUC0-1 across the FPNS range was statistically confirmed. Drug absorption also increased in a close to dose-proportional manner for AUC0-inf. CONCLUSIONS: FPNS has a shorter tmax, higher Cmax and greater bioavailability than OTFC and is well tolerated. The dose proportionality of Cmax and AUC0-1 was demonstrated. It is concluded that the pharmacokinetic profile of FPNS suggests this product is suitable for clinical investigation in breakthrough pain in cancer patients.

Pharmacokinetic comparisons of three nasal fentanyl formulations; pectin, chitosan and chitosan-poloxamer 188.

OBJECTIVES: To optimize the absorption profile and reduce C(max), three new fentanyl nasal spray formulations have been developed: fentanyl pectin (FPNS), fentanyl chitosan (FChNS) and fentanyl in chitosan-poloxamer 188 (FChPNS). The venous pharmacokinetic profiles and tolerability of these formulations were assessed and compared with oral transmucosal fentanyl citrate (OTFC) lozenge. SUBJECTS AND METHODS: This randomized, open-label, crossover study was conducted in opioid-naïve, healthy adult volunteers. Subjects were dosed under naltrexone blockade on four occasions with three nasal sprays (100 microg in 100 microl) and OTFC 200 microg. Fentanyl venous plasma concentrations were measured up to 24 h post-dose. Tolerability was assessed by clinical nasal assessments and a nasal reactogenicity questionnaire. RESULTS: 18 subjects were enrolled and completed the study. The mean dose-normalized AUC(0-infinity) for each nasal formulation was significantly higher (p < 0.05) compared with OTFC. Bioavailability compared with OTFC was significantly greater for all nasal fentanyl formulations (FPNS 132.4%, FChNS 154.1%, FChPNS 122.3%). Median tmax (FPNS 0.33 h, FChNS 0.17 h, FChPNS 0.26 h) were significantly (p < 0.001) reduced (OTFC 1.5 h) and mean C(max) significantly increased with all nasal formulations compared with OTFC. Nasal reactogenicity symptom incidence was lowest for the FPNS formulation (FPNS 2, FChNS 28 and FChPNS 45). CONCLUSIONS: All nasal formulations demonstrated significantly increased systemic exposure and reduced times to peak plasma values compared with OTFC. The FPNS formulation exhibited the most favorable nasal and general tolerability profiles. It appears suitable for further investigation in breakthrough cancer pain management.

An assessment of the utility of the yeast GreenScreen assay in pharmaceutical screening.

In this paper we describe an initial reproducibility study of 12 proprietary compounds followed by the assessment of 51 marketed pharmaceuticals and, lastly, a summary of the data so far from 2698 proprietary compounds from the Johnson & Johnson (J&J) compound library, in the yeast GreenScreen assay (GSA). In this assay, a reporter system in the yeast cells employs the DNA damage inducible promoter of the RAD54 gene, fused to the extremely stable green fluorescent protein (GFP). The assay proved to be very robust, the Excel templates provided by Gentronix with the assay interfaced well with in-house J&J systems with little adaptation, the assay was very rapid to perform and used very little compound. The results confirm previous work which suggests that the yeast GSA detects different classes of genotoxic compounds to the Ames assay and as a result can help screen out important genotoxic compounds at the pre-regulatory test phase that are missed by Ames-test-based screens alone. A combination of SAR evaluation of genotoxicity plus an Ames-test-based screen and the GSA provides a powerful pre-regulatory test battery to aid in the selection of successful drug candidates.

Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson's disease.

During a program to investigate the biochemical basis of side effects associated with the antimalarial drug mefloquine, the authors made the unexpected discovery that the (-)-(R,S)-enantiomer of the drug is a potent adenosine A2A receptor antagonist. Although the compound was ineffective in in vivo animal models of central adenosine receptor function, it provided a unique nonxanthine adenosine A2A receptor antagonist lead structure and encouraged the initiation of a medicinal chemistry program to develop novel adenosine A2A antagonists for the management of Parkinson's disease (PD). The authors have synthesized and screened more than 2,000 chemically diverse and novel adenosine A(2A antagonists. Early examples from two distinct chemical series are the thieno[3,2-dy]pyrimidine VER-6623 and the purine compounds VER-6947 and VER-7835, which have high affinity at adenosine A2A receptors (K(i) values 1.4, 1.1, and 1.7 nmol/L, respectively) and act as competitive antagonists. In particular, VER-6947 and VER-7835 demonstrate potent in vivo activity reversing the locomotor deficit caused by the D2 receptor antagonist haloperidol, with minimum effective doses comparable with that of KW6002 (0.3 to 1 mg/kg). In conclusion, the authors have discovered potent, selective, and in vivo active nonxanthine adenosine A2A antagonists that have considerable promise as a new therapy for PD.

Adaptation of pregnant ewes to an exclusive onion diet.

A diet consisting entirely of cull onions fed to pregnant ewes produced Heinz body hemolytic anemia in all sheep after 21 d. After 28 d of daily consumption of 20 kg of onions/ewe, the anemia stabilized, and for the remaining 74 d the packed cell volume increased in the majority of sheep, although it did not return to normal. Compared to control ewes fed an alfalfa and grain diet, the onion-fed ewes had comparable body condition scores and fleece weights. There was no significant difference (alpha = 0.05) in pregnancy or lambing rate, number of lambs born/ewe exposed, or number of lambs born/ewe lambing. Greater numbers of sulfate-reducing bacteria (Desulfovibrio spp) and more ruminal hydrogen sulfide were present in onion-fed sheep compared to controls. Although an average 27% reduction in packed cell volume and Heinz body anemia developed in the onion-fed ewes, on the basis of this study it appears that pregnant ewes may be fed a pure onion diet with minimal detrimental effects. This adaptation to a pure onion diet is in part likely due to the apparent ability of the sheep's rumen to quickly develop a population of sulfate-reducing bacteria that decrease the toxicity of onion disulfides.

Selenium bioaccumulation by the water boatman Trichocorixa reticulata (Guerin-Meneville).

The input of selenium from subsurface agricultural drainage into surface water systems can result in the accumulation of toxic concentrations of selenium in aquatic food chains. Elevated selenium concentrations in aquatic systems is a significant environmental problem in many areas of the United States. A laboratory investigation was conducted to determine the dominant route of selenium bioaccumulation by the corixid Trichocorixa reticulata, an important food chain organism. The roles of waterborne and foodborne exposure in selenium bioaccumulation were examined using 48-h bioassays. Waterborne selenium concentrations ranged from 0 to 1,000 microgram Se/L as selenate. A mixture of two species of blue-green algae cultured in media with selenium concentrations ranging from 0 to 1,000 microgram Se/L as selenate was used as a corixid diet in the foodborne treatments. Corixids exposed to waterborne selenate did not accumulate selenium above control concentrations. Corixids fed algae exposed to >/=100 microgram Se/L as selenate had significantly higher selenium concentrations than control organisms. These data suggest that corixids may be effectively isolated from the water and selenium accumulation is solely through dietary exposure.

Dietary calcium, protein, and phosphorus are related to bone mineral density and content in young women.

BACKGROUND: Dietary factors have been implicated in modifying bone health, although the results remain controversial, particularly in young women. OBJECTIVE: The objective of the study was to determine relations of selected dietary factors and anthropometric measurements to bone mineral density (BMD) of the spine, femoral neck, trochanter, Ward's triangle, radius, and total body and the bone mineral content (BMC) of the spine, radius, and total body. DESIGN: The study was a cross-sectional analysis of 215 women aged 18-31 y. RESULTS: Weight, height, and lean mass were correlated with bone mineral measures at every site (r = 0.17-0.78). Postmenarcheal age (years since onset of menses) was positively correlated with total-body BMD and BMC, radius BMD and BMC, and spine BMC, and negatively correlated with Ward's triangle BMD. Radius BMD was correlated with protein, calcium, and phosphorus intakes, and spine BMD and BMC were correlated with energy, protein, calcium, and phosphorus intakes. These correlations remained significant when postmenarcheal age, lean mass, and fat mass were controlled. A pattern emerged in multiple regression analyses that showed a complex relation among calcium, protein or phosphorus, and the calcium-protein or calcium-phosphorus ratio and spine or total-body BMC and BMD. All 3 variables (calcium, protein or phosphorus, and calcium-protein or calcium-phosphorus ratio) were required in the model for significance. CONCLUSIONS: Anthropometric measures were predictors of bone mass. A single ratio of calcium to phosphorus or protein did not optimize bone mass across the range of calcium intakes.

Multicenter trial of fluticasone propionate aqueous nasal spray in ragweed allergic rhinitis.

A 4-week multicenter, double-blind, placebo-controlled, parallel-group trial was carried out with 416 adults with ragweed allergic rhinitis to compare 200 micrograms of fluticasone propionate once daily and 100 micrograms of fluticasone propionate twice daily with placebo. Compared with placebo, both groups receiving fluticasone propionate had greater number of symptom free days (P < .01), lower median symptom scores (P < .01), and greater number of days not requiring rescue medications (P < .001). No significant differences for individual symptoms were found between the two fluticasone propionate groups except that those taking the twice daily dosage used less antihistamine (P < .01) and had greater number of days free of rescue medications (P < .05). Adverse events were comparable between the three groups. These results indicate that topical intranasal fluticasone propionate 200 micrograms once daily and 100 micrograms twice daily are both efficacious and well tolerated.

Ecotoxicology of selenium in freshwater systems.

The toxicology, environmental impacts and risk assessment of Se in freshwater systems are a high priority for research and regulatory agencies. However, understanding Se in freshwater systems is a challenging endeavor. The accurate risk assessment and determination of a water-quality criterion for any freshwater ecosystem are difficult for many reasons. First, the understanding of the structure and energy dynamics in ecosystems is limited. Second, knowledge of Se cycling and transformations in aquatic ecosystems is rudimentary. Third, the role of various environmental factors affecting its bioaccumulation, biotransformation, and toxicology in aquatic ecosystems is largely unknown. Fourth, the extrapolation and use of existing data in commonly used formulas for risk assessment and calculations of water quality criteria is difficult because of the demonstrated species differences in the bioaccumulation, metabolism, and tolerance of Se. There are many aspects of Se ecotoxicology that need to be addressed to develop more accurate environmental risk assessments and determine appropriate water-quality criteria to protect aquatic ecosystems. Studies evaluating the biochemical speciation of Se in aquatic ecosystems, and determination of the role of microbial communities in its cycling, bioaccumulation, transformation, transfer, and toxicity in aquatic systems, appear to be priorities for future research. These would include a broad exploration of Se effects on ecosystems, e.g., exposure regime, direct and indirect biologic effects, and ecosystem level effects. There are, however, ecological uncertainties that tend to confound such endeavors, e.g., insufficient data, extrapolation issues, and environmental stochasticity (Harwell and Harwell 1989). There are several concepts concerning the ecotoxicology of Se that can be stated. Elevated concentrations have degraded many freshwater ecosystems throughout the United States, and additional systems are expected to be affected as anthropogenic activities increasingly mobilize Se into aquatic systems. Se is a very toxic essential trace element. Toxic threshold concentrations in water, dietary items, and tissues are only 2-5 times normal background concentrations. Toxicity in freshwater ecosystems is the result of bioaccumulation, biotransformation, and cycling of Se in aquatic food chains. Thus, environmental risk assessment and development of effective water-quality criteria to protect freshwater ecosystems become formidable tasks.

The toxicity and bioaccumulation of selenate, selenite and seleno-L-methionine in the cyanobacterium Anabaena flos-aquae.

A laboratory investigation was conducted to study the toxicity and bioaccumulation of seleno-L-methionine, selenate and selenite in the cyanobacterium Anabaena flos-aquae. The first sub-lethal effects of seleno-L-methionine, selenite and selenate occurred at 0.1, 3.0, and 3.0 mg/L, respectively with a decrease in chlorophyll a concentration (P less than 0.0001). Selenium bioconcentration factors (BCF) were in the order of seleno-L-methionine, selenite, and selenate. Significant decreases in intracellular selenium concentration were observed at both the no effect (NOEL) and low effect levels (LOEL) at each oxidation state tested in the given experiment (p less than 0.0001). Mechanisms for the assimilation, toxicity and regulation of selenium are presented.

Effects of elevated foodborne selenium on growth and reproduction of the fathead minnow (Pimephales promelas).

Several field studies of selenium-contaminated lakes and reservoirs have indicated the possibility of selenium-induced reproductive failure in important populations of fish. These investigators have hypothesized that bioaccumulation of selenium through the food chain led to fish selenium levels high enough to elicit toxic responses. The present investigation was designed to determine the effects of elevated foodborne selenium on the fathead minnow (Pimephales promelas). Fish were fed a diet spiked with a mixture of inorganic (selenite and selenate) and organic (seleno-L-methionine) selenium and effects on growth and reproduction were determined. Growth was significantly inhibited at the highest selenium treatment levels evaluated (20 and 30 ppm Se). There were no significant treatment effects on any of the reproductive parameters measured. Reasons for the disparity between selenium-induced reproductive impairment observed in other species and apparent lack of impairment in fathead minnows may involve reduced bioaccumulation of selenium by minnows due to differences in gut morphology and physiology.

Metabolic changes due to experimentally induced rupture of the bovine urinary bladder.

Metabolic changes were studied in the serum, saliva and peritoneal fluid of 5 healthy yearling feedlot steers after experimentally induced urinary bladder rupture. There were statistically significant decreases in serum, saliva and peritoneal fluid sodium and chloride values and significant increases in serum, saliva and peritoneal fluid urea nitrogen, creatinine and phosphorus values. Serum calcium, pH, bicarbonate, and base excess decreased significantly. Potassium did not change significantly in serum but did increase significantly in the saliva. The hemogram and peritoneal fluid analysis failed to provide clinicopathologic evidence of peritonitis. The average time of death or euthanasia after bladder rupture was 13.6 days with a range of 8-21 days. No single biochemical parameter could be identified which would allow prediction of the approaching time of death or duration of the disease process. There was no peritonitis at necropsy indicating that urine was not irritating to the bovine peritoneal cavity. Extracellular replacement fluid with or without sodium bicarbonate supplementation appeared to be the fluid of choice for correction of fluid and electrolyte imbalances in steers with ruptured urinary bladders. The ratio between serum and peritoneal fluid creatinine concentrations appears to be valuable for the clinical diagnosis of ruptured urinary bladders in steers.

The early detection of colorectal cancer.

A review of the American Cancer Society's statistics for colorectal cancer indicates that there has been little improvements in the survival rate for this disease in the past 25 years. Although there have been advances in surgical techniques, radiation therapy, and chemotherapy, the key to improved survival rates is earlier diagnosis. A significant percentage of patients continues to present with regional or distal metastasis at the time of their initial diagnosis. Both proctosigmoidoscopy and guaiac impregnated filter slide paper methods have been productive in diagnosing this disease at an earlier stage. The "Hemoccult" test, however, is inexpensive, can be used on a routine basis, is easier for patients to perform themselves, and is aesthetically pleasing. It represents a significant cost savings compared to proctosigmoidoscopy and should be advocated for routine use in all patients over 40 years of age. Although there continues to be a role for local and regional mass screening programs, significant improvements in colorectal survival rates cannot be expected until routine application of this type of screening is practiced.

Disodium cromoglycate in ragweed-allergic rhinitis.

This study was designed to test the effectiveness of disodium cromoglycate when compared to placebo in a double-blind study in patients with ragweed allergic rhinitis. Patients were selected on the basis of a clinical history and a 4+ reaction to the intradermal injection of water-soluble ragweed, 0.02 c.c. of 500 PNU/c.c. Active agent/placebo groups were selected at random and were on the drug for approximately 8 wk, commencing 1 wk prior to the onset of the ragweed pollen season. Patient response was evaluated using patient diary cards, number of antihistamine tablets taken, and patient interviews. In the Toronto study, of 17 patients on the active drug, 15 were graded as improved, compared to only 6 of 21 placebo-treated patients who were improved. However, in the Hamilton study, results were less impressive. Nonetheless, it appears that intranasal insufflation of disodium cromoglycate was more effective in reducing ragweed hay fever symptoms than placebo.