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Biomedical subjects

J Barth

Publications and source records attributed to J Barth.

At least 37 records · Page 2Linked to original sources
PubMed2001

Single-dose and steady-state pharmacokinetic and pharmacodynamic evaluation of therapeutically clinically equivalent doses of inhaled fluticasone propionate and budesonide, given as Diskus or Turbohaler dry-powder inhalers to healthy subjects.

Direct comparisons of the pharmacokinetic (PK) and systemic pharmacodynamic (PD) properties of inhaled corticosteroids after single and multiple dosing in the same subjects are scarce. The objective of this study was to compare thePK/PDproperties of clinically equivalent, single, and multiple doses of dry-powder formulations of inhaled fluticasone propionate (FP 200 and 500 microg via Diskus) and budesonide (BUD, 400 and 1,000 microg via Turbohaler). Fourteen healthy subjects completed a double-blind, double-dummy, randomized, placebo-controlled, five-way crossover study consisting of a single dose administered at 8 a.m. on day 1 followed by 4 days of twice-daily dosing at 8 a.m. and 8 p.m. on days 2 to 5. Serum concentrations of FP and BUD were measured using validated liquid chromatography/ mass spectrometry assays. The 24-hour cumulative cortisol suppression (CCS) in serum was monitored as the pharmacodynamic surrogate marker. Peak serum concentrations following single and multiple dosing were observed 10 to 30 minutes after inhalation for BUD and 30 to 90 minutes afterinhalation of FP with no influence of dose ordosingregimen. After a single dose of 1000 microg BUD and 500 microg FP the median estimates of terminal half-life and mean residence time were 3.5 and 3.9 hours for BUD and 10.1 and 12.0 hours for FP, respectively. Using previously reported intravenous data, the mean absorption times (MAT) were calculated to be around 2 hours and 7 hours for BUD and FP respectively. On average, the area under the curve (A UC) at steady state (day 5) was up to 30% higher for BUD compared to that over a 12-hour period following the first dose on day 1, whereas A UC estimates were 50% to 80% higherforFP at steady state, indicating accumulation. However, the steady-state Cmax values were seven to eight times and AUC values three to four times higher for BUD than for FP. Comparison of active treatment data with placebo showed that CCS after a single dose was not pronounced for any of the doses/drugs studied. On day 5, both doses of BUD caused statistically significant suppression (CCS of 19% for the 400 microg dose and 36% for the 1,000 microg dose). For FP only the high dose had a statistically significant effect on serum cortisol (CCS of 14% for the 200 microg dose and 27% for the 500 microg dose). Compared to BUD, FP has slower pulmonary absorption and slower elimination kinetics. However, following inhalation of therapeutically equipotent, multiple twice-daily doses in healthy subjects, the systemic effects of FP delivered via Diskus on AUC24 serum cortisol were relatively low and similar to those of BUD delivered via Turbohaler.

Administration, Inhalation↗
PubMed2000

The benefit/risk profile of rabeprazole, a new proton-pump inhibitor.

Acid-related diseases such as gastro-oesophageal reflux disease (GORD) and peptic ulcer are a common cause of morbidity and if inadequately treated can lead to serious complications. The proton-pump inhibitor rabeprazole has been extensively evaluated in well-controlled trials in North America and Europe for the acute treatment of erosive or ulcerative GORD and gastric and duodenal ulcers and for the long-term maintenance of GORD healing. The results show that rabeprazole has a favourable benefit/risk profile for each indication. Rabeprazole 10 and 20 mg given once daily in the morning was highly effective in producing and maintaining healing, providing symptom relief, and improving overall well-being. Healing rates for rabeprazole were equivalent to omeprazole in all indications, and superior (GORD healing and duodenal ulcer healing) or equivalent (gastric ulcer healing) to the histamine 2-receptor antagonist ranitidine. Symptom relief provided by rabeprazole was equivalent or superior to comparator drugs. Rabeprazole was well tolerated in both short- and long-term studies. The incidence of treatment-emergent signs and symptoms related to rabeprazole was low, and these were generally mild or moderate in severity. The overall rate of discontinuations due to adverse events was approximately 3%. There were no deaths related to rabeprazole therapy. These findings indicate a favourable benefit/risk profile for each intended use.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Rabeprazole for the prevention of pathologic and symptomatic relapse of erosive or ulcerative gastroesophageal reflux disease. Rebeprazole Study Group.

OBJECTIVE: We evaluated the effectiveness and safety profile of 10 and 20 mg of rabeprazole, a new proton pump inhibitor, once daily versus placebo in preventing endoscopic and symptomatic relapse for up to 1 yr among patients with healed erosive or ulcerative gastroesophageal reflux disease (GERD). METHODS: The 52-wk trial used a multicenter, randomized, double-blind, parallel-group design in which 209 men and women were assigned to 10 or 20 mg of rabeprazole once daily in the morning or placebo. RESULTS: Both rabeprazole doses were significantly superior to placebo in preventing endoscopic relapse (p < 0.001), and 20 mg was significantly more effective than 10 mg (p < 0.04). Both doses were also significantly superior to placebo in reducing the frequency and severity of heartburn relapse (p < 0.001). When adjusted for differences in exposure to study medication, no significant differences were found in the incidence of adverse events. No clinically significant changes were found regarding clinical laboratory parameters, vital signs, electrocardiograms, ophthalmological evaluations, body weight, serum gastrin, and enterochromaffin-like cell histology. CONCLUSIONS: Once-daily therapy with 10 or 20 mg of rabeprazole effectively prevents pathological and symptomatic GERD relapse. The 20-mg dose is significantly more effective than the 10-mg dose in preventing endoscopic recurrence. Treatment was well tolerated, and no clinically significant safety findings emerged. Our findings support rabeprazole's efficacy in preventing GERD recurrence with excellent tolerability and a short-term favorable safety profile.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

[In vitro investigations of the effect of morphine and its metabolites on the phagocytosis of peripheral mononuclear cells].

INTRODUCTION: Reports about an increased incidence of infection with facultative intracellular microorganisms suggest a depression of the macrophage/monocyte system. This explosive increase in oxidative metabolism can be measured by chemiluminescence. The aim of the present study was to investigate the influence of morphine and its metabolites morphine-3 (M-3-G) and 6-glucuronide (M-6-G) on the respiratory burst of the peripheral mononuclear cells (PCM). To explain the mechanism of the effect of morphine the antagonist naloxone was used. Furthermore, the effect was compared with that of bupivacaine and propranolol, known as drugs that stabilize the cell membranes. METHODS: PMC were isolated from the blood of healthy young men by Ficol hypaque centrifugation. Four samples of 2 x 10(5) cells were incubated for at 37 degrees C and 10% CO(2) with either morphine, naloxone, bupivacaine, propranolol, M-3-G or M-6-G. After stimulation with oponised zymosan A, the lucigenin-dependent chemiluminescence was measured (n=8) in a biolumat (Berthold). STATISTICS: Wilcoxon matched pairs (significance level p<0.05). RESULTS: Morphine inhibited the phagocytic activity of PMC only in concentrations >10(-7) mol/l. The metabolites M-3-G and M-6-G were considered to be similar based on tests using n=3. Naloxone itself significantly influences the emission of light solely in the high concentration of 10(-4) mol/l. Naloxone (10(-4) mol/l)+morphine(10(-5) mol/l) caused a greater inhibition than either of the substances alone. In comparison, the decreased chemiluminescence of morphine (10(-6) mol/l) was antagonized by naloxone (10(-5) mol/l). Naloxone in the same concentration was ineffective. The membrane stabilization caused by bupivacaine and propranolol did not change the chemiluminescence activity. CONCLUSION: Morphine had a decreasing effect on the respiratory burst of PCM only in concentrations that the human body reaches where renal clearance is reduced. In this situation the metabolites of morphine accumulate more than morphine itself and seem to have a similar effect. The weakening of phagocytosis might possibly be a direct effect of morphine and its metabolites. These investigations suggest that this phenomenon may be receptor dependent: the effect could be antagonized by naloxone, but naloxone itself caused a depression in high concentrations. In comparison the nonspecific stabilization of the membranes showed no such effect.

English Abstract↗
PubMed1999

A pharmacokinetic/pharmacodynamic approach to predict the cumulative cortisol suppression of inhaled corticosteroids.

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16-21% was predicted for FP 250 micrograms, FLU 500 micrograms, and TCA 1000 micrograms. For multiple dosing, a respective CCS of 28-33% was calculated for FLU 500 micrograms bid, FP 250 micrograms, bid, and TCA 1000 micrograms bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.

Administration, Inhalation↗
PubMed1999

Review article: rabeprazole's profile in patients with gastrointestinal diseases.

The selection of agents to treat patients with acid-related gastrointestinal diseases requires knowledge of their efficacy, tolerability, and ease of dosing among individuals with differing disease severities and other baseline characteristics. The efficacy and favourable benefit-risk profile of rabeprazole, a new proton pump inhibitor, has been demonstrated in controlled clinical trials of patients with gastro-oesophageal reflux disease (GERD), duodenal ulcers, and gastric ulcers. In comparative trials, rabeprazole is at least as effective as omeprazole for the treatment of GERD, duodenal ulcers, and gastric ulcers, and it is superior to histamine2-receptor antagonists for the treatment of GERD and duodenal ulcers. Its once-daily dosing regimen and low potential for interaction with drugs metabolized by the cytochrome P450 system make it a particularly attractive option for the treatment of acid-related diseases among older individuals. Rabeprazole is likely to be a valuable new addition to its class in treating patients with acid-related gastrointestinal diseases given its efficacy in acid suppression, high healing rates, rapid symptom relief, and convenient dosing.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

In vitro correlate of immunity in an animal model of inhalational anthrax

The incidence of anthrax in humans is extremely low. Human vaccine efficacy studies for inhalational anthrax cannot be conducted. The identification of a correlate of protection that predicts vaccine efficacy is crucial for determining the immune status of immunized humans. This surrogate marker of immunity can only be established by using an appropriate animal model. Numerous studies showed that protective antigen (PA) is the principle protective antigen in naturally- or vaccine-induced immunity. However, attempts to correlate the quantity of anti-PA antibodies with protective immunity in the guinea pig model for anthrax and various vaccine formulations have failed. In these studies, we used the licensed anthrax vaccine adsorbed (AVA) in rabbits. Groups of New Zealand white rabbits, 10 or 20 per group, were immunized intramuscularly (two doses, 4 weeks apart) with varying doses of AVA, ranging from a human dose to 1:256 dilution in sterile phosphate-buffered saline (PBS). Control rabbits received PBS/Alhydrogel according to the same schedule. Each rabbit was bled 2 weeks after the second dose, and antibody levels to PA measured by both the quantitative anti-PA IgG ELISA and the toxin-neutralizing antibody (TNA) assay. Rabbits were aerosol-challenged 10 weeks from day 0 with a lethal dose of Ames spores. All the rabbits that received the undiluted and 1:4 dilution of vaccine survived, whereas those receiving the higher dilutions of vaccine (1:16, 1:64 and 1:256) had deaths in their groups. All the controls died. Rabbit survival was compared with the antibody response. Statistical models were used to test for significance of the peak antibody responses to predict survival. Results showed that both the amount of anti-PA IgG and TNA titres present in the sera at the time of the peak antibody response were significant (P < 0.0001) predictors of survival. These results demonstrate that the humoral immune response to AVA can predict protection in the rabbit model of inhalational anthrax.

Journal Article↗
PubMed1999

Field investigations of an outbreak of Ebola hemorrhagic fever, Kikwit, Democratic Republic of the Congo, 1995: arthropod studies.

During the final weeks of a 6-month epidemic of Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo, an extensive collection of arthropods was made in an attempt to learn more of the natural history of the disease. A reconstruction of the activities of the likely primary case, a 42-year-old man who lived in the city, indicated that he probably acquired his infection in a partly forested area 15 km from his home. Collections were made throughout this area, along the route he followed from the city, and at various sites in the city itself. No Ebola virus was isolated, but a description of the collections and the ecotopes involved is given for comparison with future studies of other outbreaks.

Adult↗
PubMed1999

Potential for Central American mosquitoes to transmit epizootic and enzootic strains of Venezuelan equine encephalitis virus.

Experimental studies were undertaken to compare the vector competence of Culex (Melanoconion) taeniopus Dyar and Knab, Culex (Melanoconion) ocossa Dyar and Knab, and Psorophora confinnis (Lynch Arribalzalga) from Central America for epizootic (IAB) and enzootic (IE) strains of Venezuelan equine encephalitis (VEE) virus. Virus infection and dissemination rates were significantly higher in Cx. taeniopus orally exposed to IE as compared to those orally exposed to IAB virus. In contrast, both infection and dissemination rates were similar in Cx. ocossa exposed to either IAB or IE strains of VEE virus. Thus, susceptibility to epizootic and enzootic strains of VEE virus seems to be species specific within the subgenus Culex (Melanoconion). Both species transmitted each strain of VEE virus after intrathoracic inoculation, indicating that a midgut barrier affected vector competence in these species. Psorophora confinnis was equally susceptible to both IAB and IE viruses, but apparently had a salivary gland barrier, as only 1 of 16 mosquitoes with a disseminated infection transmitted VEE virus by bite.

Animals↗
PubMed1998

Rational-emotive behavior therapy and the formation of stimulus equivalence classes.

Stimulus equivalence is a behavioral approach to analyzing the "meaning" of stimulus sets and has an implication for clinical psychology. The formation of three-member (A --> B --> C) stimulus equivalence classes was used to investigate the effects of three different sets of sample and comparison stimuli on emergent behavior. The three stimulus sets were composed of Rational-Emotive Behavior Therapy (REBT)-related words, non-REBT emotionally charged words, and a third category of neutral words composed of flower labels. Sixty-two women and men participated in a modified matching-to-sample experiment. Using a mixed cross-over design, and controlling for serial order effects, participants received conditional training and emergent relationship training in the three stimulus set conditions. Results revealed a significant interaction between the formation of stimulus equivalence classes and stimulus meaning, indicating consistently biased responding in favor of reaching criterion responding more slowly for REBT-related and non-REBT emotionally charged words. Results were examined in the context of an analysis of the importance of stimulus meaning on behavior and the relation of stimulus meaning to behavioral and cognitive theories, with special appraisal given to the influence of fear-related discriminative stimuli on behavior.

Adult↗
PubMed1998

Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration.

OBJECTIVE: To evaluate the pharmacokinetic and systemic pharmacodynamic properties of inhaled fluticasone propionate (FP). METHODS: Single doses of 0.25, 0.5, 1.0 and 3.0 mg FP were administered to groups of six healthy subjects. Serum concentration profiles of FP were monitored over 24 h by means of high-performance liquid chromatography/mass spectrometry (HPLC/MS-MS). Systemic pharmacodynamic effects were evaluated by measuring endogenous serum cortisol and circulating white blood cells, and analyzed with previously developed integrated pharmacokinetic/pharmacodynamic (PK/PD) models. RESULTS: FP showed a dose-independent terminal half-life with a mean (SD) of 6.0 (0.7) h. Maximum serum concentrations occurred 1.0 (0.5) h after administration, ranging from 90 pg.ml(-1) for the 0.25 mg dose to 400 pg.ml(-1) for the 3.0 mg dose. This, together with an estimated mean absorption time of nearly 5 h and a known oral bioavailability of less than 1%, indicates prolonged residence at and slow absorption from the lungs. In the investigated dose range, the cumulative systemic effect was dose-dependent for both markers of pharmacodynamic activity. For doses of 0.25, 0.50, 1.0 and 3.0 mg FP, the PK/PD-based cumulative systemic-effect parameters were 159, 186, 257 and 372% .h for lymphocyte suppression, 107, 186, 202 and 348% .h for granulocyte induction and 23.6%, 33.8%, 51.0% and 73.6% for cortisol reduction, respectively. The time courses of lymphocytes, granulocytes and endogenous cortisol could be sufficiently characterized with the applied PK/PD models. The measured in vivo EC50 values, 30 pg.ml(-1) and 7.3 pg.ml(-1) for white blood cells and cortisol, respectively, were in good agreement with predictions based on the in vitro relative receptor affinity of FP. CONCLUSION: After inhalation, FP follows linear pharmacokinetics and exhibits dose-dependent systemic pharmacodynamic effects that can be described by PK/PD modeling.

Administration, Inhalation↗
PubMed1998

Pharmacokinetics and pharmacodynamics of inhaled corticosteroids.

There are significant differences in the pharmacokinetic properties of inhaled corticosteroids currently used in medical practice. All are rapidly cleared from the body but they show varying levels of oral bioavailability and more importantly variation in the rate of absorption after inhalation. Oral bioavailability is lowest for fluticasone propionate, indicating a low potential for unwanted systemic corticosteroid effects. Mathematical modeling has shown pulmonary residence times to be longest for fluticasone propionate and triamcinolone acetonide but shortest for budesonide and flunisolide. These properties appear to relate to pulmonary solubility, which appears to be the rate-limiting step in the absorption process.

Administration, Inhalation↗
PubMed1998

The high-fat phenotype: is leptin involved in the adaptive response to a high fat (high energy) diet?

OBJECTIVE: To investigate physiological differences which could influence the balance between energy expenditure and energy intake, between habitual high-fat (HF) and low-fat (LF) consumers and the potential for weight gain. SUBJECTS: Ten HF and nine LF consumers, all young, lean males (% energy from fat 45.4 and 31.8, respectively). MEASUREMENTS: Habitual dietary variables (from the food frequency questionnaire, FFQ), body mass index (BMI), % body fat (% BF, measured by impedance), fasting concentrations of plasma leptin, glucose and triglycerides. RESULTS: HF and LF subjects (selected for their fat intake) did not differ significantly in BMI or % BF. HF subjects had significantly higher concentrations of plasma leptin and lower concentrations of plasma glucose than LF subjects. In all subjects, concentrations of fasting plasma leptin correlated significantly with BMI, % BF and fat mass; difference in leptin between groups remained significant when BMI and % BF were used as covariants. Leptin significantly correlated with dietary variables; particularly dietary fat (% energy and g) and inversely with dietary carbohydrate (% energy), but showed no correlation with dietary protein or total energy intake. CONCLUSION: Significant differences in concentrations of fasting plasma leptin have been observed between lean male HF and LF consumers. These findings suggest that the difference in leptin concentrations could be associated with a metabolic adaptation which could help to offset the weight inducing properties of high fat (high energy) diets.

Adaptation, Physiological↗