Structural modifications of the salivary conditioning film upon exposure to sodium bicarbonate: implications for oral lubrication and mouthfeel.

The salivary conditioning film (SCF) that forms on all surfaces in the mouth plays a key role in lubricating the oral cavity. As this film acts as an interface between tongue, enamel and oral mucosa, it is likely that any perturbations to its structure could potentially lead to a change in mouthfeel perception. This is often experienced after exposure to oral hygiene products. For example, consumers that use dentifrice that contain a high concentration of sodium bicarbonate (SB) often report a clean mouth feel after use; an attribute that is clearly desirable for oral hygiene products. However, the mechanisms by which SB interacts with the SCF to alter lubrication in the mouth is unknown. Therefore, saliva and the SCF was exposed to high ionic strength and alkaline solutions to elucidate whether the interactions observed were a direct result of SB, its high alkalinity or its ionic strength. Characteristics including bulk viscosity of saliva and the viscoelasticity of the interfacial salivary films that form at both the air/saliva and hydroxyapatite/saliva interfaces were tested. It was hypothesised that SB interacts with the SCF in two ways. Firstly, the ionic strength of SB shields electrostatic charges of salivary proteins, thus preventing protein crosslinking within the film and secondly; the alkaline pH (≈8.3) of SB reduces the gel-like structure of mucins present in the pellicle by disrupting disulphide bridging of the mucins via the ionization of their cysteine's thiol group, which has an isoelectric point of ≈8.3.

Structural study of Al2O3-Na2O-CaO-P2O5 bioactive glasses as a function of aluminium content.

Calcium phosphate based biomaterials are extensively used in the context of tissue engineering: small changes in composition can lead to significant changes in properties allowing their use in a wide range of applications. Samples of composition (Al(2)O(3))(x)(Na(2)O)(0.11-x)(CaO)(0.445)(P(2)O(5))(0.445), where x = 0, 0.03, 0.05, and 0.08, were prepared by melt quenching. The atomic-scale structure has been studied using neutron diffraction and solid state (27)Al MAS NMR, and these data have been rationalised with the determined density of the final glass product. With increasing aluminium concentration the density increases initially, but beyond about 3 mol. % Al(2)O(3) the density starts to decrease. Neutron diffraction data show a concomitant change in the aluminium speciation, which is confirmed by (27)Al MAS NMR studies. The NMR data reveal that aluminium is present in 4, 5, and 6-fold coordination and that the relative concentrations of these environments change with increasing aluminium concentration. Materials containing aluminium in 6-fold coordination tend to have higher densities than analogous materials with the aluminium found in 4-fold coordination. Thus, the density changes may readily be explained in terms of an increase in the relative concentration of 4-coordinated aluminium at the expense of 6-fold aluminium as the Al(2)O(3) content is increased beyond 3 mol. %.

Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted chemotherapy agent for the treatment of patients with acute myeloid leukemia in first relapse.

The purpose of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin (Mylotarg; Wyeth-Ayerst Laboratories, St. Davids, PA) in patients with acute myeloid leukemia (AML) in first relapse. Gemtuzumab ozogamicin is an antibody-chemotherapeutic conjugate characterized as antibody-targeted chemotherapy, consisting of an engineered human anti-CD33 antibody (hP67.6) linked to a potent cytotoxic agent, N-acetyl-gamma calicheamicin DMH. The pharmacokinetics of gemtuzumab ozogamicin was evaluated in 59 adult AML patients in first relapse, enrolled in a phase II study. Plasma was collected following each dose at specified times, and the pharmacokinetics was characterized by measures of hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. After administration of the first 9 mg/m2 dose of gemtuzumab ozogamicin, the pharmacokinetic parameters (mean +/- SD) of hP67.6 following the first dose were as follows: peak plasma concentration, 2.86 +/- 1.35 mg/L; AUC, 123 +/- 105 mg x h/L; t 1/2, 72.4 +/- 42.0 hours; and clearance, 0.265 +/- 0.229L/h. Increased concentrations were observed after the second dose and are believed to be due to a decrease in clearance by CD33-positive blast cells, a result of the reduced tumor burden following the first dose. The concentration profiles of calicheamicin followed the same time course as hP67.6, evidence that calicheamicin remained conjugated to the antibody and delivered to leukemic cells. No relationship was found between plasma concentration and response at the recommended dose. The pharmacokinetics of gemtuzumab ozogamicin has been characterized in AML patients receiving doses at the proposed therapeutic level.

Impact of age and gender on the pharmacokinetics of gemtuzumab ozogamicin.

STUDY OBJECTIVE: To determine the pharmacokinetic parameters of the components of gemtuzumab ozogamicin and to assess the possible influence of age and gender on the values. DESIGN: Phase II, multicenter, open-label, nonrandomized, parallel study SETTING: Hospitals and outpatient oncology clinics. PATIENTS: Fifty-eight patients with acute myeloid leukemia in first relapse participated. Demographic data included 29 men and 29 women; 34 were younger than 60 years of age (mean age 53+/-16 yrs). INTERVENTION: Patients received gemtuzumab ozogamicin as a single 2-hour infusion of 9 mg/m2. Serial plasma samples were collected over 10 days after the beginning of the infusion. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of components of gemtuzumab ozogamicin (hP67.6 antibody, total and unconjugated calicheamicin derivatives) were measured by validated enzyme-linked immunosorbent assays. Pharmacokinetic parameters were determined by noncompartmental methods and comparisons between groups were made by analysis of variance. No significant differences were seen between men and women or between those over 60 and those less than 60 years of age in maximum concentration, time to maximum concentration, area under the curve, clearance, or volume of distribution for components of gemtuzumab ozogamicin. CONCLUSION: No differences occur in the pharmacokinetics of the components of gemtuzumab ozogamicin (hP67.6 or calicheamicin) based on gender or age.

Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects.

An open-label, single-center, single-dose, parallel-group study was performed in healthy young males and females as well as healthy elderly males to examine the influence of age and gender on the pharmacokinetics of modafinil following administration of a single 200 mg oral dose. Twelve subjects were enrolled in each of the following three groups: young males, young females, and elderly males. Each fasted (overnight) subject received 2 x 100 mg modafinil tablets. Blood and urine samples were collected at various times up to 72 hours postdose for the determination of plasma and urine levels of modafinil as well as the acid and sulfone metabolites. The plasma concentrations of the individual isomers, d- and l-modafinil, were also determined. Pharmacokinetic parameters were determined by noncompartmental methods. Modafinil was well tolerated at a single oral dose of 200 mg. The most commonly reported adverse events were headache, fever, pharyngitis, and asthenia. There were no clinically meaningful differences with respect to the incidence rate of treatment-emergent adverse events among the young female, young male, and old male groups. Modafinil was rapidly absorbed after oral dosing and slowly cleared (t1/2 approximately 11-14 hr) from the body. Modafinil acid was the major urinary metabolite, which accounted for 35% to 60% of the dose. Results from this study indicated that there were age and gender effects on modafinil clearance processes. In this regard, the clearance rate of modafinil in males decreased with age while young females cleared modafinil at a faster rate than young males. Stereospecific pharmacokinetics of modafinil were also demonstrated. The d-modafinil was eliminated three times faster than the l-modafinil.

A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers.

A randomized, double-blind, placebo-controlled, ascending-dose study was conducted to evaluate the pharmacokinetic and safety profiles of increasing modafinil doses (200 mg, 400 mg, 600 mg, 800 mg) administered orally over a 7-day period in normal healthy male volunteers. Eight subjects (six modafinil; two placebo) were randomized to each of the four dose groups. Modafinil or a placebo was administered once daily for 7 days. Serial blood samples were obtained following administration of the day 1 and day 7 doses for characterization of pharmacokinetics, and trough samples were obtained prior to dosing on days 2 through 6 to assess the time to reach the steady state. Pharmacokinetic parameters were calculated using noncompartmental methods. Modafinil steady state was reached after three daily doses. Modafinil pharmacokinetics were dose and time independent over the range of 200 mg to 800 mg. Steady-state pharmacokinetics of modafinil were characterized by a rapid oral absorption rate, a low plasma clearance of approximately 50 mL/min, a volume of distribution of approximately 0.8 L/kg, and a long half-life of approximately 15 hr. Modafinil was primarily eliminated by metabolism. Modafinil acid was the major urinary metabolite. Stereospecific pharmacokinetics of modafinil were demonstrated. The d-modafinil enantiomer was eliminated at a threefold faster rate than 1-modafinil. Modafinil 200 mg, 400 mg, and 600 mg doses were generally well tolerated. The modafinil 800 mg dose panel was discontinued after 3 days of treatment due to the observation of increased blood pressure and pulse rate. The safety data from this study suggest that the maximum tolerable single daily oral modafinil dose, without titration, may be 600 mg.

Single-dose pharmacokinetics of modafinil and methylphenidate given alone or in combination in healthy male volunteers.

Modafinil is a novel wake-promoting agent being developed for treatment of excessive daytime sleepiness associated with narcolepsy. An open, 3 x 3 Latin square, randomized, cross-over study was performed in healthy males to compare the pharmacokinetics of single-dose oral modafinil (200 mg) and methylphenidate (40 mg) administered alone or in combination. Blood samples were obtained for analysis of d- and l-threo-methylphenidate and modafinil and its acid and sulfone metabolites. Pharmacokinetic parameters were determined by noncompartmental methods, but could not be evaluated for modafinil sulfone due to plasma levels that were close to the assay quantitation limit. Although sporadic differences in plasma concentrations were observed between treatments, coadministration of modafinil and methylphenidate did not significantly alter the plasma concentrations of modafinil, modafinil acid, modafinil sulfone, or methylphenidate enantiomers compared with administration of these agents alone. Half-life (t1/2), maximum concentration (Cmax), area under the concentration-time curve (AUC0-infinity), total clearance (Cl/F), and apparent volume of distribution (Vd/F) for modafinil and t1/2, Cmax, and AUC0-infinity for modafinil acid were not affected by concomitant administration of methylphenidate. Small but statistically significant increases in time to Cmax (tmax) were observed for modafinil and modafinil acid after methylphenidate coadministration compared with modafinil alone. Modafinil coadministration did not significantly alter the pharmacokinetics of d- or l-threo-methylphenidate, except for a small decrease in Vd/F of l-threo-methylphenidate. Concomitant methylphenidate may cause a delay in the oral absorption of modafinil, but this delay might not be relevant clinically. Coadministration did not alter the extent of oral absorption and disposition of either agent. Therefore, a pharmacokinetic interaction between modafinil and methylphenidate would be unlikely.

Carbohydrate Content and Enzyme Metabolism in Developing Canola Siliques.

Little biochemical information is available on carbohydrate metabolism in developing canola (Brassica napus L.) silique (pod) wall and seed tissues. This research examines the carbohydrate contents and sucrose (Suc) metabolic enzyme activities in different aged silique wall and seed tissues during oil filling. The silique wall partitioned photosynthate into Suc over starch and predominantly accumulated hexose. The silique wall hexose content and soluble acid invertase activity rapidly fell as embryos progressed from the early- to late-cotyledon developmental stages. A similar trend was not evident for alkaline invertase, Suc synthase (SuSy), and Suc-phosphate synthase. Silique wall SuSy activities were much higher than source leaves at all times and may serve to supply the substrate for secondary cell wall thickening. In young seeds starch was the predominant accumulated carbohydrate over the sampled developmental range. Seed hexose levels dropped as embryos developed from the early- to midcotyledon stage. Hexose and starch were localized to the testa or liquid endosperm, whereas Suc was evenly distributed among seed components. With the switch to oil accumulation, seed SuSy activity increased by 3.6-fold and soluble acid invertase activity decreased by 76%. These data provide valuable baseline knowledge for the genetic manipulation of canola seed carbon partitioning.

Degradation kinetics and mechanisms of moricizine hydrochloride in acidic medium.

The degradation kinetics of moricizine hydrochloride (1) were examined over a pH range of 0.6 to 6.0 at an ionic strength of 0.3 and 60 degrees C. The disappearance of intact 1 was followed by a stability-indicating HPLC assay. The degradation products, which had approximate solubilities of less than 100 micrograms/mL, precipitated in aqueous solution. The precipitate was collected for HPLC analysis and identification of degradation products. Degradation of 1 was catalyzed by acetate and phosphate buffers and was pH dependent, with the pH of the minimum rate constant located between 2.8 and 3.2. At pH 0.6-2.0, 1 degraded via amide hydrolysis to yield first ethyl (10H-phenothiazin-2-yl) carbamate (2), an amide hydrolysis product, which further oxidized in parallel to give ethyl (3-oxo-3H-phenothiazin-2-yl) carbamate (3), ethyl (10H-phenothiazin-2-yl) carbamate S-oxide (4), and diethyl (3,10'-bi-10H-phenothiazine-2,2'-diyl)bis(carbamate) (5), the dimer of the amide hydrolysis product. At pH 2.2-6.0, 1 degraded via a reverse Mannich reaction, to form the reverse Mannich product ethyl [10-(1-oxo-2-propenyl)-10H-phenothiazin-2-yl] carbamate (6), and by parallel reaction via the described amide hydrolysis pathway. The dimer of the amide hydrolysis product was not detectable at pH greater than 2.8. At pH greater than 4.0, the reverse Mannich product was the predominant degradation product. Degradation of 1 was subject to positive and negative kinetic salt effects at pH 1.0 and 4.0, respectively. Arrhenius plots determined at pH 1.0 and 6.0 were linear between 37 and 70 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial revascularization combined with intracoronary infusion of hyperosmolar solution in the early management of postinfarction ventricular septal defect. Report of a case.

A patients is described with postinfarction ventricular septal defect in whom the perforation was successfully closed within 24 hours of septal rupture. This presents the second such case reported in the literature. Adjunctive measures consisting of myocardial revascularization and intracoronary infusion of mannitol were thought to be important in the successful outcome of the operative procedure. The importance of complete preoperative cardiac catheterization with coronary arteriography is stressed. The theoretical role of endothelial and myocardial cellular edema as a cause of depressed myocardial function immediately following an ischemic insult is proposed as a practical consideration in the high mortality associated with this condition. Methods used to prevent or reverse such cell swelling are described. The details of the operation in which viable ventricle myocardium was used to fill the septal defect are presented.