Dose-proportional pharmacokinetics of a methylphenidate extended-release capsule

OBJECTIVE: To assess the dose-proportionality of the 10 mg, 20 mg and 30 mg methylphenidate extended-release (MPH ER) capsule formulations in healthy adults. MATERIALS: Metadate CD (methylphenidate HCl, USP) extended-release capsules (10, 20 and 30 mg) were obtained from Celltech Manufacturing Inc. (Rochester, NY, USA). METHODS: This was a single-center, single-dose, fasted, randomized, open-label, 3-way crossover study with a 1-week washout period between doses, in 24 healthy male and female subjects, aged 21-40 years. MPH plasma concentration-time data were used to calculate the pharmacokinetic parameters for each treatment. The 20 mg capsule, the first FDA-approved dosage strength, was used as reference treatment. RESULTS: Twenty-three subjects completed all 3 study periods. Regardless of the dose, MPH ER capsules exhibited similar PK profiles as evidenced by a biphasic absorption profile, consisting of a sharp initial increase followed by a second increase in MPH plasma levels, all occurring at the same times. All 90% confidence intervals for the 10:20 mg and 30:20 mg dose-normalized geometric mean ratios were within the 80-125% FDA limits for bioequivalence. This was true for Cmax (maximum observed concentration), AUC(0-last) (area under the plasma concentration curve from time 0 to the last measurable time point) and AUC(0-inf) (area under the plasma concentration curve from time 0 to infinity). Adverse events were mild and the number and types of adverse events experienced by subjects did not differ among the 3 dosages. CONCLUSION: Data collected from this study demonstrate the dose proportionality of the new 10 mg and 30 mg dosage strengths of MPH ER capsules with the 20 mg capsule. The availability and predictability of these dosage strengths should facilitate dose titration of ADHD patients.     

IgG antibodies against microorganisms and atopic disease in Danish adults: the Copenhagen Allergy Study

BACKGROUND: Seropositivity to food-borne and orofecal microorganisms (hepatitis A virus, Helicobacter pylori, and Toxoplasma gondii ), which are considered to be markers of poor hygiene, has been reported to be associated with a lower prevalence of atopy. In contrast, colonization of the gut with Clostridium difficile, a potential intestinal bacterial pathogen, in early childhood may be associated with a higher prevalence of atopy. OBJECTIVE: The objective of this study was to investigate the association between atopy and exposure to 2 groups of food-borne and orofecal microorganisms: (1) markers of a poor hygiene and (2) intestinal bacterial pathogens. METHODS: A cross-sectional population-based study of 15- to 69-year-olds living in Copenhagen, Denmark, was carried out in 1990 to 1991. Atopy was defined as a positive test result for specific IgE to at least 1 of 6 inhalant allergens. Exposure to microorganisms was assessed as IgG seropositivity to microorganisms. RESULTS: Seropositivity to 2 or 3 markers of poor hygiene (hepatitis A virus, H pylori, and T gondii ) was associated with a lower prevalence of atopy (adjusted odds ratio, 0.5; 95% CI, 0.3 to 0.8). In contrast, seropositivity to 2 or 3 intestinal bacterial pathogens (C difficile, Campylobacter jejuni, and Yersinia enterocolitica ) was associated with a higher prevalence of atopy (adjusted odds ratio, 1.7; 95% CI, 1.2 to 2.6). CONCLUSION: Exposure to markers of poor hygiene was associated with a lower prevalence of atopy, whereas exposure to intestinal bacterial pathogens was associated with a higher prevalence of atopy. These findings raise the hypothesis that different groups of food-borne and orofecal microorganisms may have different effects on the risk of atopy.     

Three-dimensional navigator coronary MRA with the aid of a blood pool agent in pigs: improved image quality with inclusion of the contrast agent first-pass

PURPOSE: To evaluate the effect of including the first-pass of a blood pool agent (BPA) on the image quality of three-dimensional navigator coronary MRA. MATERIALS AND METHODS: A pig model was used to perform: 1) T1 simulation of the BPA, based on actual blood samples, and 2) BPA-enhanced three-dimensional navigator coronary MRA, with or without inclusion of the first-pass of the BPA. The acquisitions with inclusion of the first-pass were timed with the use of a test bolus. The acquisitions without first-pass were started one minute after bolus injection (steady-state). A gradient echo acquisition technique with centric k-space sampling was applied. Comparison of both acquisitions was based on determination of contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and vessel length. RESULTS: T1 simulation shows a distinct T1 reduction during first-pass (to a level below 50 msec), increasing to 190 msec during steady-state. Images obtained with first-pass inclusion showed improved CNR (8.6 +/- 1.7 vs. 4.5 +/- 1.8), SNR (11.9 +/- 1.6 vs. 7.4 +/- 2.0), and vessel length (99.2 +/- 10.9 mm vs. 60.5 +/- 21.8 mm) as compared to the acquisitions during steady-state only (all: P< 0.05). CONCLUSION: The image quality of three-dimensional navigator coronary MRA combined with a gadolinium BPA in pigs is improved when starting the image acquisition during first-pass of the bolus.     

Toward comparability of coronary magnetic resonance angiography: proposal for a standardized quantitative assessment

A method is proposed for the quantitative assessment of coronary magnetic resonance angiography (MRA) acquisitions. The method is based on four parameters: signal-to-noise ratio (SNR); contrast-to-noise ratio (CNR); vessel length; and vessel-edge definition. A pig model (n=7) was used to illustrate the proposed quantitative analysis method. Three-dimensional gradient-echo coronary MRA was performed with and without exogenous contrast enhancement using a gadolinium-based blood-pool contrast agent (Vistarem, Guerbet, Aulnay-Sous-Bois, France). The acquired images could be well differentiated based on the four parameters. The SNR was calculated as 9.0±1.4 vs 10.4±2.1, the CNR as 6.2±0.8 vs 8.2±0.9, the vessel length as 48.2±11.6 vs 86.5±13.8 mm, and the vessel-edge definition as 4.9±1.5 vs 7.7±3.4. Different coronary MRA techniques can be evaluated objectively with the combined use of SNR, CNR, vessel length, and vessel-edge parameters.     

Mycobacterium tuberculosis Beijing genotype

Molecular epidemiologic studies of strains of Mycobacterium tuberculosis are currently conducted worldwide. The genetically distinct Beijing family of strains has been associated with large outbreaks of tuberculosis, increased virulence, and multidrug resistance. However, in this first population-based search for Beijing strains in the Danish DNA fingerprint database, analysis of 97% of all culture-positive tuberculosis patients in 1992 to 2001 showed that 2.5% of 3,844 patients, 1.0% of Danish-born patients, and 3.6% of immigrants (from 85 countries) had Beijing strains. No Beijing strains were found among 201 strains from Danish-born patients sampled in the 1960s, and no evidence of an increase in Beijing strains was found over time. The true prevalence of Beijing strains worldwide is unknown because only a fraction of global strains have been analyzed.     

Three-dimensional quantification of color-marked occlusal paths on anatomically oriented casts

STATEMENT OF PROBLEM: The analysis of occlusal contacts on mounted diagnostic casts is an important task in prosthetic diagnostics. However, it is still restricted mainly to qualitative aspects because existing measuring techniques fail to provide 3-dimensional data for more than a few single points in acceptable time. PURPOSE: The aim of this study was to develop a method for quantifying occlusal contacts and paths by using anatomically oriented diagnostic casts and to design the method to allow fast acquisition of digital 3-dimensional coordinates. MATERIAL AND METHODS: Plaster casts with color-marked contacts were digitized optically with a profilometric system based on the fringe projection technique. Digital camera images taken simultaneously were used to define the contact areas by marking them either manually or automatically with the help of image-processing routines. Three-dimensional coordinates were determined by finding the corresponding points within the profilometric data set. RESULTS: Color-marked contact areas on diagnostic casts were successfully digitized with a computer-controlled, automatic setup in approximately 30 seconds. The accuracy of the acquired 3-dimensional data was estimated to be better than 60 microm in lateral and 30 microm in height resolution. The data set was visualized and evaluated in a skull related coordinate system. SUMMARY: This study verified the use of a new tool to quantify color-marked occlusal contacts on diagnostic casts in terms of spatial coordinates. The resulting digital data may be stored easily and analyzed numerically as well as visualized 3-dimensionally with computer graphic equipment. Because the anatomic orientation of the casts is maintained throughout the measurement process, it is possible to compare the data with electronically registered condyle paths and therefore to investigate, for example, their relation to the corresponding guidance paths of the frontal teeth and the canines in dynamic occlusion.     

Perennial rhinitis: an analysis of skin testing, serum IgE, and blood and smear eosinophilia in 201 patients

Allergen skin testing, eosinophil counting in blood and nasal smear and serum IgE determination were performed in patients with simple perennial rhinitis, and in patients with rhinitis and asthma. The results were compared with those obtained in normal controls. As a positive skin test was demonstrated in 40% of patients with simple rhinitis and in 88% of patients with rhinitis and asthma, skin testing is considered relevant in all patients with perennial rhinitis. While blood eosinophil count and serum IgE level were elevated in a fair proportion of asthmatic patients, only a few subjects with simple perennial rhinitis had an elevated level, and the diagnostic values of these tests is questionable. On the other hand, examination of a nasal smear for eosinophils could usually separate the patients from the controls. The study emphasizes the importance of making a distinction between simple perennial rhinitis and perennial rhinitis associated with other symptoms and diseases.     

A system model for closed-circuit inhalation anesthesia. I. Computer study.

Developing a custom computer program to simulate the uptake, distribution, and elimination of inhalational anesthetics allows the anesthesiologist to address specific problems, but extensive skills are required to translate the involved processes first into a set of mathematical equations and then into a satisfactory computer program. The first step is often facilitated by solutions offered in the literature. The second step demands computer proficiency that is often not available, but this problem can be obviated by means of a special-purpose simulation language (SPSL). We therefore constructed a model for closed-circuit inhalation anesthesia with the aid of the block-structured SPSL TUTSIM. Noticeable differences with previous models are that the linear, 14-compartment basic model does not assume a constant alveolar concentration and mimics circulation times through the use of blood pools. Advanced features of the SPSL were used to develop variants of the basic model to simulate feedback-controlled isoflurane administration, nitrous oxide uptake, and the impact of a nonlinearity by incorporating the effect of enflurane on cardiac output. Two variants were concatenated to form a multiple model showing the concentration and second-gas effects. The model was capable of reproducing the anesthetic uptake from previous experimental studies for nitrous oxide. After its validation for other anesthetic agents, the model can be used for clinical, teaching, and research purposes. The SPSL freed the authors from the problems associated with computer programming and allowed them to concentrate on the structure of the model.