Retrospective dosimetry of Iodine-131 exposures using Iodine-129 and Caesium-137 inventories in soils--A critical evaluation of the consequences of the Chernobyl accident in parts of Northern Ukraine.

The radiation exposure of thyroid glands due to (131)I as a consequence of the Chernobyl accident was investigated retrospectively based on (129)I and (137)Cs inventories in soils in Northern Ukraine. To this end, soil samples from 60 settlements were investigated for (129)I, (127)I, and (137)Cs by AMS, ICP-MS and gamma-spectrometry, respectively. Sampling was performed between 2004 und 2007. In those parts of Northern Ukraine investigated here the (129)I and (137)Cs inventories are well correlated, the variability of the individual (129)I/(137)Cs ratios being, however, high. Both the (129)I and (137)Cs inventories in the individual 5 samples for each settlement allowed estimating the uncertainties of the inventories due to the variability of the radionuclide deposition and consequently of the retrospective dosimetry. Thyroid equivalent doses were calculated from the (129)I and the (137)Cs inventories using aggregated dose coefficients for 5-year old and 10-year-old children as well as for adults. The highest thyroid equivalent doses (calculated from (129)I inventories) were calculated for Wladimirowka with 30 Gy for 5-years-old children and 7 Gy for adults. In 35 settlements of contamination zone II the geometric mean of the thyroid equivalent doses was 2.0 Gy for 5-years-old children with a geometric standard deviation (GSD) of 3.0. For adults the geometric mean was 0.47 Gy also with a GSD of 3.0. In more than 25 settlements of contamination zone III the geometric means were 0.82 Gy for 5-years old children with a GSD of 1.8 and 0.21 Gy for adults (GSD 1.8). For 45 settlements, the results of the retrospective dosimetry could be compared with thyroid equivalent doses calculated using time-integrated (131)I activities of thyroids which were measured in 1986. Thus, a critical evaluation of the results was possible which demonstrated the general feasibility of the method, but also the associated uncertainties and limitations.

Vertically transmitted symbiont reduces host fitness along temperature gradient.

Parasites with exclusive vertical transmission from host parent to offspring are an evolutionary puzzle. With parasite fitness entirely linked to host reproduction, any fitness cost for infected hosts risks their selective elimination. Environmental conditions likely influence parasite impact and thereby the success of purely vertical transmission strategies. We tested for temperature-dependent virulence of Caedibacter taeniospiralis, a vertically transmitted bacterial symbiont of the protozoan Paramecium tetraurelia. We compared growth of infected and cured host populations at five temperatures (16­32 °C). Infection reduced host density at all temperatures, with a peak of −30% at 28 °C. These patterns were largely consistent across five infected Paramecium strains. Similar to Wolbachia symbionts, C. taeniospiralis may compensate fitness costs by conferring to the host a 'killer trait', targeting uninfected competitors. Considerable loss of infection at 32 °C suggests that killer efficacy is not universal and that limited heat tolerance restricts the conditions for persistence of C. taeniospiralis.

Iodine-129, iodine-127 and caesium-137 in the environment: soils from Germany and Chile.

Soil profiles from Bavaria in southern Germany and from Chile were analysed for (129)I by accelerator mass spectrometry (AMS), for (127)I by inductively coupled plasma mass spectrometry (ICP-MS), and for (137)Cs by gamma-spectrometry. The mean deposition density of (137)Cs in soils from Bavaria was (41×1.5(±1)) kBq m(-2) (geometric mean and geometric standard deviation), originating mostly from the Chernobyl fall-out. The deposition density of (129)I in these soils was (109×1.5(±1)) mBq m(-2). The dominant sources of (129)I in Bavaria are, however, the reprocessing plants La Hague and Sellafield and not the Chernobyl fall-out. The (129)I/(127)I isotopic ratios of the Bavarian soils were between 10(-7) and 10(-10), i.e. 10(2)-10(5) times higher than the ratios observed for the samples from Chile. The (129)I integral deposition densities in Chile, Easter Island and Antarctica were between 0.3 mBq m(-2) and 2 mBq m(-2). In these soils, the observed (129)I/(127)I ratios were about 10(-12). The soils from Chile allow the determination of the (129)I fall-out from the atmospheric nuclear weapons explosions undisturbed from contaminations due to releases from reprocessing plants. An upper limit of the integral (129)I deposition density of the atmospheric nuclear weapons explosions on the Southern Hemisphere (27°S) is about 1 mBq m(-2). Finally, the dependence of the migration behaviour of (137)Cs, (127)I and of (129)I on the soil properties is discussed. It turns out that there is a distinctly different behaviour of (127)I, (129)I, and (137)Cs in the soils exhibiting different sorption mechanisms for old and recent iodine as well as for (137)Cs.

Iodine-129 and iodine-127 in European seawaters and in precipitation from Northern Germany.

In order to obtain a comprehensive survey on the consequences of the marine (129)I discharges from the European reprocessing plants La Hague and Sellafield, the distribution of (129)I and (127)I in surface waters of the North Sea, the English Channel, the Irish Sea, and the Northeast Atlantic was studied using accelerator mass spectrometry for (129)I and ICP-MS for (127)I. Samples of seawater were taken in the German Bight in May, September, and November 2005 and in the entire North Sea and the English Channel in August 2005. Further samples were obtained from the Irish Sea in June and August 2006 and from Arctic waters between Spitsbergen and Southern Norway in September 2005. (129)I is a conservative tracer in seawater. The concentrations of (127)I are relatively constant with exceptions of coastal areas with high biological activity and of areas influenced by influx from rivers and the Baltic Sea. The variability of the (129)I/(127)I isotopic ratios is exclusively determined by admixture of (129)I released from the reprocessing facilities Sellafield and La Hague to the seawater. The (129)I/(127)I ratios were between 4 × 10(-9)and 3 × 10(-6): at least 3 orders of magnitude higher than the natural equilibrium isotopic ratio 1.5 × 10(-12). (129)I/(127)I ratios of a few times 10(-10) were only found in seawater from the Indian Ocean and from the Pacific at Hawaii. Comparison of the results obtained for seawater with those of a measurement of airborne iodine species and with iodine isotopes in precipitation in Northern Germany demonstrates the transfer of (129)I and (127)I from the sea into the atmosphere and the dominating role of the marine discharges for the atmospheric fallout of (129)I in Western Europe. The results are discussed with the goal to estimate the relevance of the marine discharges for the contamination of the continental areas.

Thorough QT study of the effect of fesoterodine on cardiac repolarization.

OBJECTIVE: Fesoterodine 4 mg and 8 mg once daily are indicated for the treatment of overactive bladder. A thorough QT study was conducted to investigate the effects of fesoterodine on cardiac repolarization. MATERIALS AND METHODS: In this parallel-group study, subjects were randomly assigned to receive double-blind fesoterodine 4 mg, fesoterodine 28 mg, or placebo or open-label moxifloxacin 400 mg (positive control) for 3 days. Electrocardiograms (ECGs) were obtained on Days -1 (baseline), 1, and 3. The primary analysis was the time-averaged changes from baseline for Fridericia's-corrected QT interval (QTcF) on Day 3. RESULTS: Among 261 subjects randomized to fesoterodine 4 mg (n = 64), fesoterodine 28 mg (n = 68), placebo (n = 65), or moxifloxacin 400 mg (n = 64), 256 completed the trial. The least squares mean changes in QTcF from baseline were 21.1, 20.5, 18.5, and 31.3 ms (maximum), and -5.1, -4.2, -5.2, and 7.6 ms (time-averaged at Day 3) for placebo, fesoterodine 4 mg, fesoterodine 28 mg, and moxifloxacin, respectively. The lower limit of the 95% confidence interval exceeded 5 ms for moxifloxacin. CONCLUSIONS: The results indicate that fesoterodine is not associated with QTc prolongation or other ECG abnormalities at either therapeutic or supratherapeutic doses.

The design and development of fesoterodine as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine.

This review highlights the design and development of fesoterodine (Toviaz) as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), which is also the active metabolite of tolterodine, for the treatment of overactive bladder (OAB). Tolterodine and 5-HMT are both potent antimuscarinic agents. A prodrug approach was necessary for systemic bioavailability of 5-HMT after oral administration. Fesoterodine was selected amongst a series of ester analogues of 5-HMT to develop an advanced OAB treatment with an optimum biopharmaceutics profile, while maintaining a pharmacological link to tolterodine. While tolterodine and 5-HMT have similar antimuscarinic activity, the logD value, a determinant of lipophilicity and permeability across biological interfaces such as the gut wall and blood-brain barrier, is considerably lower for 5-HMT (0.74) versus tolterodine (1.83). In contrast to the cytochrome P450 (CYP) 2D6-mediated metabolism of tolterodine, 5-HMT formation from fesoterodine occurs via ubiquitous nonspecific esterases. Consequently, treatment with fesoterodine results in consistent, genotype-independent exposure to a singular active moiety (5-HMT); treatment with tolterodine results in CYP2D6 genotype-dependent exposure to varying proportions of two active moieties (5-HMT and tolterodine). At least partially due to the avoidance of variations in pharmacokinetic exposures observed with tolterodine, it was possible to develop fesoterodine with the flexibility of two efficacious and well-tolerated dosage regimens of 4 and 8 mg daily.

Influence of age, gender, and race on pharmacokinetics, pharmacodynamics, and safety of fesoterodine.

OBJECTIVE: Fesoterodine, a new antimuscarinic agent for overactive bladder, undergoes immediate and extensive hydrolysis by nonspecific esterases to 5-hydroxymethyl tolterodine (5-HMT), the metabolite principally responsible for its antimuscarinic activity. Formation of 5-HMT does not require cytochrome P450 (CYP)-mediated metabolism, but its further metabolism and inactivation involves CYP3A4 and CYP2D6 isoenzymes. Subject age, gender, and race can play a key role in inter-subject variability in pharmacokinetics and thus efficacy and safety of drugs. This article examines the effects of age, gender, and race on the pharmacokinetics and pharmacodynamics of fesoterodine. METHODS: Data from two randomized, double-blind, placebo-controlled, parallel-group trials in healthy subjects are presented: Study 1 investigated the effects of race (white vs. black men) and Study 2 investigated the effects of age (young vs. old men) and gender (elderly men vs. elderly women) on the pharmacokinetics and pharmacodynamics of single doses of fesoterodine 8 mg. In both studies, the primary endpoints were area under the concentration-time curve up to the last sample (AUC0-tz) and maximum concentration (Cmax) of 5-HMT in plasma. Pharmacodynamic variables included spontaneous salivary secretion (Studies 1 and 2) and residual urine volume (Study 2 only). The two studies included 5 groups of 16 subjects each (randomized 3 : 1 to fesoterodine or placebo): white men aged 18 - 45 years, black men aged 18 - 45 years (Study 1); young white men aged 18 - 40 years, elderly white men aged > 65 years, and elderly white women aged > 65 years (Study 2). RESULTS: There were no clinically meaningful differences in the primary endpoints between white and black subjects or between young white men, elderly white men, and elderly white women. Mean AUC0-tz was 70.7 ng/ml x h in whites and 64.1 ng/ml x h in blacks; mean Cmax was 6.1 and 5.5 ng/ml in whites and blacks, respectively. Mean AUC0-tz in young white men, elderly white men, and elderly white women was 49, 48, and 54 ng/ml x h, respectively; mean Cmax in young white men, elderly white men, and elderly white women was 4.1, 3.8, and 4.6 ng/ml, respectively. Consistent with the anticholinergic pharmacology of fesoterodine, declines in salivary volume were observed in both studies, and elevations in residual urinary volume were observed, especially in elderly subjects, in Study 2. Fesoterodine was well tolerated, with common adverse events such as headache and dry mouth recognized as antimuscarinic class effects. CONCLUSIONS: Subject demographics, such as age, gender, and race, do not have a clinically meaningful effect on 5-HMT pharmacokinetics or pharmacodynamics after single-dose administration of fesoterodine 8 mg; thus, no dosage adjustment is required for fesoterodine based on age, gender, or race.

Influence of food on the pharmacokinetic profile of fesoterodine.

OBJECTIVE: Fesoterodine is a new, once-daily, oral, antimuscarinic agent indicated for the treatment of overactive bladder. It undergoes rapid and extensive metabolism by plasma esterases to form its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). The sustained-release formulation of fesoterodine delivers 5-HMT with linear, dose-proportional pharmacokinetics (PK) suitable for once-daily dosing. This study was designed for the definitive assessment of the effect of food on 5-HMT PK using the commercial formulation of fesoterodine. METHODS: In this randomized, open-label, single-dose, 2-way, crossover study, fesoterodine 8 mg was administered orally to healthy subjects in either a fed (after a high-fat, high-calorie breakfast) or fasted state. Blood samples for PK were drawn up to 36 hours after dosing. Primary endpoints for food effect assessment were area under the concentration-versus-time curve up to the last sample (AUC(0-tz)), and maximum plasma concentration (C(max)) for 5-HMT. Adverse events, vital signs, hematology, clinical chemistry, and electrocardiograms were monitored for safety assessment. RESULTS: A total of 16 healthy male subjects enrolled and completed the study. Mean values of both primary PK parameters of 5-HMT (AUC(0-tz) and C(max)) were approximately 19% higher after fesoterodine administration in the fed versus the fasted state. The upper limits of the corresponding 90% confidence intervals for the "fed/fasted" ratios of AUC(0-tz) (104%, 137%) and C(max) (94%, 149%) were not included in the prespecified acceptance range (80%, 125%) for concluding "no food effect." Secondary PK variables, (i.e. time to maximum plasma concentration terminal elimination half-life and mean residence time), did not differ markedly between the fed and fasted states. Fesoterodine was well tolerated, and adverse events were mild, with no apparent difference in frequency between fed and fasted states. CONCLUSIONS: The hypothesis of "no food effect" could not be statistically confirmed; however, only modest increases of approximately 19% were observed for C(max) and AUC(0-tz) of 5-HMT. This magnitude of PK effects is unlikely to be of clinical relevance based on Phase 2 and 3 clinical experience with fesoterodine, supporting its administration without regard to meals.

Accumulation of (137)Cs in Brazilian soils and its transfer to plants under different climatic conditions.

The spatial distribution and behaviour of the global fallout (137)Cs in the tropical, subtropical and equatorial soil-plant systems were investigated at several upland sites in Brazil selected according to their climate characteristics, and to the agricultural importance. To determine the (137)Cs deposition density, undisturbed soil profiles were taken from 23 environments situated between the latitudes of 02 degrees N and 30 degrees S. Sampling sites located along to the equator exhibited (137)Cs deposition densities with an average value of 219Bqm(-2). Extremely low deposition densities of 1.3Bqm(-2) were found in the Amazon region. In contrast, the southern part of Brazil, located between latitudes of 20 degrees S and 34 degrees S, exhibited considerably higher deposition densities ranging from 140Bqm(-2) to 1620Bqm(-2). To examine the (137)Cs soil-to-plant transfer in the Brazilian agricultural products, 29 mainly tropical plant species, and corresponding soil samples were collected at 43 sampling locations in nine federal states of Brazil. Values of the (137)Cs concentration factor plant/soil exhibited a large range from 0.020 (beans) to 6.2 (cassava). Samples of some plant species originated from different collecting areas showed different concentration factors. The (137)Cs content of some plants collected was not measurable due to a very low (137)Cs concentration level found in the upper layers of the incremental soils. Globally, the soil-to-plant transfer of (137)Cs can be described by a logarithmic normal distribution with a geometric mean of 0.3 and a geometric standard deviation of 3.9.

Vardenafil increases penile rigidity and tumescence in men with erectile dysfunction after a single oral dose.

OBJECTIVES: To evaluate the effect of two doses of vardenafil hydrochloride on penile rigidity and tumescence while determining the pharmacokinetics. METHODS: Twenty-one patients with erectile dysfunction completed three oral single-dose regimens (placebo, 20 and 40 mg vardenafil) in a randomized, placebo-controlled, 3-way cross-over study. Penile rigidity and tumescence were measured at the base and tip with a Rigiscan for up to 2 h after dosing. The period included three 20-min repeated episodes of visual sexual stimulation. Blood samples were taken periodically up to 24 h after dosing. RESULTS: After 20 and 40 mg vardenafil, the mean duration of >60% rigidity of the base of the penis was greater than after placebo by 42.9 min (95% Cl 29.3-56.4) and by 49.3 min (95% Cl 35.7-62.9), respectively (p<0.001), and greater than after placebo by 34.6 min (95% Cl 22.1-47.1) for both doses at the tip. Additionally, significantly greater rigidity activity units and tumescence activity units were found for both doses compared with placebo (p<0.001). The plasma concentrations of vardenafil increased rapidly, with a median t(max) of about 40 min and a mean t1/2 of 4.4-4.8 h. Relative bioavailability was slightly higher for the 40-mg dose than for the 20-mg dose. The treatments were well tolerated, although slightly more adverse events, primarily headache, flushing and nasal congestion, were seen with the 40-mg dose compared with placebo. CONCLUSION: The findings confirm that vardenafil was able to generate stronger erections of longer duration than placebo under conditions of visual sexual stimulation in patients with erectile dysfunction. The pharmacokinetic, pharmacodynamic and tolerability profiles support vardenafil hydrochloride as a strong candidate for further testing as a treatment for erectile dysfunction.

Effect of probenecid on the kinetics of a single oral 400mg dose of moxifloxacin in healthy male volunteers.

OBJECTIVE: To investigate the effect of oral probenecid on the pharmacokinetics of oral moxifloxacin in healthy adult male volunteers. DESIGN AND SETTING: This was a nonblinded, randomised, 2-way crossover study. PATIENTS AND PARTICIPANTS: 12 male Caucasian volunteers (mean age 33.7 years) participated in the study. METHODS: A single oral dose of moxifloxacin 400mg was administered after an overnight fast with or without a 2-day course of probenecid 500mg twice daily starting at 1 hour before the moxifloxacin dose. There was a washout phase of at least 1 week between the 2 treatments. Samples of plasma and urine were taken according to predefined sampling schedules and the concentrations of moxifloxacin were determined with a validated high performance liquid chromatography assay with fluorescence detection. Noncompartmental pharmacokinetic data were calculated. RESULTS: Pharmacokinetic results with and without probenecid were virtually identical except for a slight delay in absorption with probenecid, indicated by a very slightly increased time to maximum concentration and a decreased maximum concentration (approximately 10%), which was not clinically relevant. Probenecid had no significant influence on the renal elimination of moxifloxacin, suggesting urinary excretion by glomerular filtration and partial tubular reabsorption. Safety and tolerability were good, with no clinically relevant drug-related adverse events or changes in laboratory parameters. CONCLUSION: Dosage adjustments for moxifloxacin are not necessary when it is administered together with probenecid.

Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study.

The pharmacodynamic effect on penile rigidity and tumescence and the pharmacokinetic properties of single oral doses of 10 and 20 mg vardenafil, a new PDE5-inhibitor, were investigated in 21 erectile dysfunction patients. Patients were evaluated with RigiScan on three occasions in a randomized, placebo-controlled, double-blind crossover fashion, while receiving visual sexual stimulation. Relative to placebo, a single dose of 10 mg vardenafil led to a mean increase in the duration of >60% penile rigidity of 24.4 min (95% CI: 7.4 to 41.3) at the base and of 24.8 min (8.5 to 41.1) at the tip. For the 20-mg dose, the increase in duration of > 60% penile rigidity relative to placebo was 37.2 min (20.2 to 54.1) at the base and 28.7 min (12.7 to 44.7) at the tip. Single doses of 10 and 20 mg vardenafil led to a rapid rise in the plasma concentrations of vardenafil, with a median tmax of 0.9 h and 0.7 h and a geometric mean Cmax of 9.1 microg/l (geometric SD = 1.63) and 20.9 microg/l (geometric SD = 1.83), respectively. In the post-absorptive phase, the concentrations declined with an average terminal t 1/2 of 4.2 h (geometric SD = 1.27) and 3.9 h (geometric SD = 1.31). The systemic exposure of vardenafil expressed as AUC normalized for dose and body weight was dose-proportional (associated 90% CI: -4 to 30%) as well as Cmax (associated 90% CI: -12 to 33%). The treatments were well tolerated. There was a small, clinically irrelevant reduction in blood pressure with a small compensatory rise in heart rate. There were no electrocardiographic effects or relevant changes of the safety laboratory screens. The observed pro-erectile properties, pharmacokinetic characteristics and safety profile make vardenafil a suitable candidate for further evaluation in the treatment of erectile dysfunction.

The role of allopurinol and deferoxamine in preventing pressure ulcers in pigs.

Ischemia and reperfusion may be important in the pathogenesis of pressure ulcers. On the basis of this hypothesis, the effects of intermittent pressure and the anti-free radical agents allopurinol and deferoxamine were studied in a pig model in which a pressure of 150 mmHg was applied intermittently to the scapulae. Cutaneous blood flow, transcutaneous oxygen tension, skin and muscle damage, and muscle levels of adenosine triphosphate were quantified. A control group of pigs (n = 6) was untreated, the allopurinol group (n = 6) received oral allopurinol beginning 2 days before the experiment, and the deferoxamine group (n = 6) received an intramuscular injection of deferoxamine 2 hours before the experiment. Pressure (150 mmHg) was applied to the scapulae for 210 minutes, and it was relieved for 30 minutes. This 4-hour cycle was repeated continuously for 48 hours, and it resulted in pressure injuries in all animals. Allopurinol and deferoxamine improved cutaneous blood flow and tissue oxygenation, but only deferoxamine could significantly reduce cutaneous and skeletal muscle necrosis (p < 0.001). This study suggests a future role for anti-free radical agents in the reduction of pressure-induced injury.

PCR-SSCP analysis of human adrenocortical adenomas: absence of K-ras gene mutations.

Little is known about the pathogenesis and etiology of benign tumors of the adrenal cortex. A variety of cellular oncogenes and tumor suppressor genes has been studied so far. The role of K-ras in this process is not yet clearly understood. Recent findings suggest a strong influence of mutated K-ras in the pathogenesis of adrenal adenomas (Lin et al., 1998). Therefore we studied 40 human adrenal tumors for mutations in the coding region of the cellular proto-oncogene K-ras by PCR-SSCP (Single-strand conformation polymorphism) analysis. We did not identify any activating mutation in the coding region of the K-ras gene. We conclude that activating mutations of the K-ras gene are not a major cause for the development of adrenal adenomas, if at all.

The effect of food and time of administration on the pharmacokinetic and pharmacodynamic profile of metrifonate.

OBJECTIVE: Metrifonate--via its pharmacologically active metabolite DDVP--is an inhibitor of cholinesterase effective in the treatment of Alzheimer's disease. Two separate studies were performed to investigate the influence of food and time of administration, respectively, on the concentration vs. time profiles of metrifonate and DDVP and cholinesterase inhibition. METHODS: In study I, a single dose of metrifonate 50 mg tablet was administered either in the fasting condition or within 5 min after completion of an American breakfast. In study II, a single dose of metrifonate 80 mg tablet was given either at 8:00 a.m. after overnight fasting, 7:00 p.m. (7 h after lunch) or 10:00 p.m. (4 h after dinner). Both studies were performed in a non-blind, randomized, single-centre, cross-over design in healthy Caucasian volunteers. AUC and Cmax of metrifonate and DDVP as primary parameters were compared between treatments by ANOVA and acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition vs. time profiles were assessed. RESULTS: In study I a high-fat/high-calorie breakfast had no effect on the AUC of DDVP, while its Cmax was decreased to 56% and tmax was prolonged, compared to the fasting condition. The effects on metrifonate were similar. In study II bioequivalence was shown for AUC and Cmax of DDVP when comparing administration of metrifonate at 8:00 a.m. and 7:00 p.m. Administration at 10:00 p.m. also had no effect on AUC of DDVP while a reduction in rate of absorption was observed. In both studies the equivalence in AUC of DDVP was paralleled by equivalent effects on BChE inhibition. Following single metrifonate administration little inhibition of AChE was observed. Metrifonate was well tolerated. CONCLUSIONS: Delayed gastric emptying is likely to cause the reduced rate of absorption of metrifonate with food. In view of unchanged bioavailability of its active metabolite, this food effect is considered to be without clinical relevance and metrifonate can be administered with or without food. The decrease in rate of absorption following administration of the drug at 10:00 p.m. is either a protracted food effect or an effect of time. As the bioavailability of DDVP as well as pharmacodynamic profiles were independent of the time of administration it is concluded that metrifonate can be taken in the morning or evening without compromising its safety or efficacy.

Mohs micrographic surgery for fungal soft tissue infections.

BACKGROUND: Invasive fungal infections of the integument are relatively rare. In the immunocompromised patient, however, they may show an extremely aggressive biological behavior despite high dosed topical or systemic antifungal therapy. As the fungal tissue invasion usually reaches well beyond the area of clinical necrosis or other visible changes, standard surgical excision often proves to be inadequate, resulting in the need for repeated relatively wide excisions with the resulting substantial loss of initially healthy tissues. OBJECTIVE: To present the use of Mohs surgery as a safe and effective treatment modality for invasive fungal infections in a patient with a zygomycetes infection of his scalp. RESULTS: The micrographic excision of the highly aggressive fungal infection, the acute postoperative course, and the delayed reconstruction with a split-thickness skin graft were all well tolerated without complications. CONCLUSION: Mohs micrographic excision deserves serious consideration in the treatment of aggressive localized fungal infections.

Multimodality evaluation of pressure relief surfaces.

Multimodality evaluation of six different support surfaces was performed measuring interface pressure, transcutaneous oxygen tension, and blood flow in pressure ulcer-prone areas on healthy subjects. Interface pressure was measured with a flexible force-sensing resistor array. The interface pressure distribution patterns of 10 healthy male volunteers were measured in the supine and lateral positions using a pressure sensor (force sensing resistor) array. Transcutaneous oxygen (TcPO2) and laser Doppler flowmeter probes were placed over the sacrum, the right trochanter, and the right ischium. Data were recorded for 15 minutes each with the subject in the supine and lateral decubitus positions. Statistically significant differences (p < 0.05) between the various surfaces could be observed for blood flow and pressure measurements, especially in the lateral position over the trochanter and for the TcPO2 measurements in the supine position over the sacrum. We conclude that measuring interface pressure, transcutaneous oxygen tension, and blood flow allows a more thorough evaluation of the physiologic effects of special support surfaces than any single technique. Future studies on patients will assess algorithms for using these measurement techniques to predict the efficacy of various support surfaces in minimizing pressure ulceration.

The effect of omeprazole pre- and cotreatment on cerivastatin absorption and metabolism in man.

OBJECTIVE: Cerivastatin, a novel HMG-CoA reductase inhibitor, is exclusively cleared via cytochrome P450-mediated biotransformation and subsequent biliary and renal excretion of the metabolites. The presented study was performed to determine the influence of the gastric acid secretion inhibitor omeprazole on bioavailability and pharmacokinetics of cerivastatin. METHOD: In a controlled, randomized, non-blind two-way crossover study single oral doses of 0.3 mg cerivastatin were administered in 12 healthy male subjects under fasting conditions either alone or together with 20 mg omeprazole following a 4-day pretreatment with oral 20 mg omeprazole once daily. RESULTS: The mean AUC and Cmax ratios (combination treatment versus monotherapy) including 90% confidence intervals were 1.00 (0.92 - 1.09) and 0.94 (0.80 - 1.16) for cerivastatin. Similar results were obtained for the metabolites of cerivastatin and for omeprazole. CONCLUSION: No metabolic inhibitory interaction was noted for either cerivastatin or its major active metabolites, nor for omeprazole, respectively. In addition, the change in gastric pH as consequence of the inhibition of gastric acid secretion exerted by omeprazole had no influence on cerivastatin absorption.

Comparison of supine and lateral positioning on various clinically used support surfaces.

In this study, interface pressures, transcutaneous oxygen tension (TcPO2), and blood flow were compared with the classic pressure ulcer-prone areas in the supine and lateral position on six different high- and low-air-loss support surfaces. Interface pressures were substantially higher in the lateral decubitus than in the supine position. Consistent with this, mean TcPO2 and blood flow readings over the trochanter in the lateral position were lower than over the sacrum and ischium in the supine position. With weighting, the average TcPO2 readings decreased from 78.6 mmHg to 11.9 mmHg on the trochanter and from 65.4 mmHg to 45.7 mmHg on the sacrum and ischium. In parallel, average laser Doppler readings decreased from 2.3 to 0.7 laser Doppler flow units over the trochanter, but did not change significantly over the sacrum and ischium. These data support the clinical suggestion that the lateral decubitus position should not be maintained for long periods of time, not even on many special support surfaces.

Lack of drug-drug interaction between cerivastatin and nifedipine.

Cerivastatin is a novel, potent HMG-CoA reductase inhibitor. It is primarily cleared via demethylation and hydroxylation with involvement of cytochrome P450 (CYP) 3A4 and subsequent biliary and renal excretion of the metabolites. Both cerivastatin and the dihydropyridine calcium antagonist nifedipine, which is primarily metabolized by CYP 3A4, are used concomitantly in the prevention and therapy of coronary heart disease. To study the drug-drug interaction potential, the mutual effects of cerivastatin and nifedipine were investigated in a controlled, randomized, non-blind 3-way crossover study in healthy male subjects. Single oral doses of 0.3 mg cerivastatin or of 60 mg nifedipine were administered either alone or concomitantly under fasting conditions. The mean AUC- and Cmax ratios (combination treatment versus monotherapy) including 90% confidence intervals were 1.04 (0.98 - 1.10) and 1.00 (0.93 - 1.07) for cerivastatin, and 0.98 (0.73 - 1.32) and 0.95 (0.80 - 1. 13) for nifedipine, respectively. Our results indicate that no mutual drug-drug interaction between cerivastatin and nifedipine occurs.