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PubMed2006

Evaluation of Calvert's formula for dosage adjustment of carboplatin in Japanese patients with hormone refractory prostate cancer.

For hormone refractory prostate carcinoma, a combination therapy of paclitaxel and carboplatin is used to expect life extension. We investigated the pharmacokinetics of carboplatin in Japanese prostate cancer patients (n=10, 55-72 years), and evaluated the usefulness of Calvert's formula in the individualized dosing adjustment. They were intravenously administered carboplatin (area under the free plasma concentration versus time curve (AUC)=5 mg.min/ml), following the intravenous administration of paclitaxel (175 mg/m(2)). The dosage of carboplatin for each patient was determined with Calvert's formula using individual creatinine clearance values. Plasma concentration of total platinum was measured sequentially and the pharmacokinetic parameters of carboplatin were determined in each patient. Plasma concentration of total carboplatin after intravenous infusion well fitted the two-compartment model. Carboplatin clearance was 62.0+/-12.7 ml/min (mean+/-S.D.), and linearly related to the individual creatinine clearance (r(2)=0.64, p<0.01). The actual AUC for total carboplatin was 8.20+/-1.11 mg.min/ml, and its inter-individual variability was decreased to 65% of that in carboplatin clearance, indicating the effectiveness of Calvert's formula for dosage adjustment of carboplatin. Leucopenia of grade 4 according to the National Cancer Institute's Common Toxicity Criteria was found in one patient, but no patient demonstrated thrombocytopenia. In conclusion, determining carboplatin dosage based on Calvert's formula decreased the inter-individual variability in the actual AUC compared with that in the carboplatin clearance, and a target AUC of 5 mg.min/ml of carboplatin was comparatively safe for Japanese patients with prostate cancer.

Aged↗
PubMed2005

The uterine biophysical profile scoring validity.

OBJECTIVE: To determine the applicability of uterine biophysical profile (UBP) scoring with chances of pregnancy in a spontaneous cycle in a cohort of females with unexplained infertility. DESIGN: Observational study. PLACE AND DURATION OF STUDY: A secondary level private hospital, from June 2003 to June 2004. PATIENTS AND METHODS: The study subjects included 26 infertile females in the third decade of life primarily referred for follicle maturation monitoring by ultrasound with patent tubes and normal utero-ovarian morphology. Male factor infertility was also excluded. The UBP was determined by applying the uterine scoring system for reproduction (USSR). A score of 17 or above, out of a perfect score of 20, was hypothesized to be favorable for pregnancy. Frequency of pregnancy was correlated with the cumulative score as well as individual variable. Significance of correlation was taken at p<0.05. RESULTS: None of the patients showed a perfect score of 20. A score of 17 was noted in 06 patients out of whom 04 conceived (pregnancy rate=66.6%). A score of 15 or less was observed in 20 patients, none of whom conceived (p=0.001). No significant correlation was found with any of the individual variables including the endometrium and myometrium characteristics, as well as the uterine artery flow. Myometrium contraction was the most technically difficult parameter to be observed. CONCLUSION: In this small cohort of patients, an ultrasonographically assessed uterine score of 17 or above was significantly associated with chances of pregnancy in the similar spontaneous cycle.

Adult↗
PubMed1984

The representation of the visual field in parvicellular and magnocellular layers of the lateral geniculate nucleus in the macaque monkey.

Two-dimensional maps of individual layers of the dorsal lateral geniculate nucleus (LGN) in the macaque monkey were constructed and used as a basis for comparing laminar size, shape, and topographic organization. Topographical data from the electrophysiological investigation of the LGN by Malpeli and Baker ('75) were displayed on maps of all six layers. As known from previous studies, there is a significant over-representation of central vision in the LGN. Unexpectedly, though, the visual representation is anisotropic over portions of most LGN layers. That is, the linear magnification factor (millimeters along the laminar surface per degree of visual field) is not equal for all directions from a given point in the visual field. Moreover, the visual representations in the parvicellular and magnocellular divisions of the LGN differ both in their emphasis on central vision and in their anisotropies. To determine the degree of individual variability, laminar maps were prepared from the LGN of seven other hemispheres. The shapes of laminar maps varied considerably between LGNs, from nearly circular to highly elliptical, but the surface area was relatively constant for each layer. Topographical organization, determined by mapping the optic disc representation on the LGN laminae and by labeling from anterograde and retrograde tracer injections in striate cortex, showed significant individual variability. Interestingly, the visual representations in the LGN and striate cortex are topologically inverted with respect to one another. This indicates that the establishment of geniculocortical connections involves a systematic crossing-over of fibers. Information on cell densities and magnification factors in striate cortex obtained from other studies was compared to the results of the present study in order to estimate ratios of cortical neurons to LGN neurons at different eccentricities. The total number of cortical neurons per LGN neuron is about 130 on average, but it extends over approximately a tenfold range, from less than 100 in the far periphery to nearly 1,000 in the fovea. The estimated number of cells in layers 4A and 4C beta per parvicellular layer neuron is smaller and extends over a slightly narrower range, from 30 to 240, whereas the number of layer 4C alpha neurons per magnocellular neuron varies more widely, from about 45 to 7,000.

Animals↗
PubMed1979

Respiration in conscious dogs at rest and during exercise.

25 mongrel dogs (average b.w. 24.6 kg) were studied on several occasions at rest and during treadmill exercise of up to 10 mph (15% incline). Minute ventilation (VE), oxygen consumption (VO2), carbon dioxide production (VCO2), tidal volume (VT) and respiratory frequency (f) were determined at rest and at each level of exercise. Individual variability in resting VO2 was considerable (71--695 ml/min). Most often the dogs panted, with VE's above 25 liters/min and f's above 100 min-1. The averate VE/VO2 was 109 at rest. VO2 was linearly related to VE (VO2 = 9.17 VE + 66.9; r = 0.80). Differences in resting VE were largely due to differences in f (f = 3.57 VE + 21.2; r = 0.82). Considerable individual variability in VO2 for a given work load was also observed during exercise. Some dogs showed significant differences in VO2 from experiment to experiment while running at a given treadmill speed. These differences were largely related to the levels of VE. VE/VO2 decreased to 50. We found a leveling off of VO2 (at about 60 ml/min/kg) at treadmill speeds of 5 mph, suggesting that the maximal VO2 in dogs is less than previously reported.

Animals↗
PubMed2002

Pulmonary hypertensive response to endotoxin in cellulose-primed and unprimed broiler chickens.

Previous studies indicate that individual broilers vary widely in their pulmonary vascular responsiveness to i.v. injections of endotoxin. This individual variability may reflect differences acquired during previous respiratory challenges or genetic variability that may be associated with susceptibility to pulmonary hypertension syndrome (ascites). In the present study, we compared the endotoxin responses of 4- to 5- wk-old control broilers (unprimed) and broilers in which the pulmonary vasculature had been immunologically challenged 48 h previously by an i.v. injection of cellulose micro-particles (primed). The injected cellulose micro-particles are carried in the venous blood to the lungs, where they become trapped in the pulmonary vasculature and initiate acute focal inflammatory responses within the surrounding lung parenchyma. Physiological variables (respiratory rate, heart rate, pulmonary and systemic arterial pressures) were evaluated prior to and following the i.v. administration of 1 mg of Salmonella typhimurium endotoxin. Prior to endotoxin injection, the respiratory rate was higher in primed than in unprimed broilers; however, the heart rate, pulmonary arterial pressure, and systemic arterial pressure did not differ between groups. Broilers in both groups exhibited similar ranges of individual variability in their endotoxin responses. The overall time of onset, magnitude, and duration of the pulmonary hypertensive responses were similar for both groups. Accordingly, the initiation of a preexisting inflammatory response within the lung parenchyma did not alter the timing, amplitude, or variability of the subsequent pulmonary hypertensive response to endotoxin in broilers.

Animals↗
PubMed1993

Profound hearing loss in the cat following the single co-administration of kanamycin and ethacrynic acid.

Co-administration of kanamycin (KA) with the loop diuretic ethacrynic acid (EA) has previously been shown to produce a rapid and profound hearing loss in guinea pigs. In the present study we describe a modified technique for developing a profound hearing loss in cats. By monitoring the animal's hearing status during the intravenous infusion of EA the technique minimizes the effects of individual variability to the drug regime. Seven cats received a subcutaneous injection of KA (300 mg/kg) followed by intravenous infusion of EA (1 mg/min). Click-evoked auditory brainstem responses (ABRs) were recorded to monitor the animal's hearing during the infusion. When the ABR thresholds rose rapidly to levels in excess of 90 dB SPL the infusion of EA was stopped. This occurred at EA doses of 10-25 mg/kg, indicating considerable individual variability to the deafening procedure. However, there was a strong negative correlation (r = -0.93) between the EA dose and body weight which accounted for much of this variability. Subsequent ABR monitoring showed that this profound hearing loss was both bilateral and permanent. Significantly, blood urea and creatinine levels, monitored for periods of up to three days after the procedure, remained within the normal range. Furthermore, there was no clinical evidence of renal dysfunction as indicated by weight loss or oliguria. Cochlear histopathology, examined after a two months to three year survival period, showed an absence of all inner and outer hair cells in the majority of cochleas. The extent of loss of spiral ganglion cells was dependent on their distance from the round window and the period of survival following the deafening procedure. Clearly, the degeneration of spiral ganglion cells continued for several years following the initial insult. Finally, we observed no evidence of renal histopathology. In conclusion, the co-administration of KA and EA produces a profound hearing loss in cats without evidence of renal impairment. Monitoring the animal's hearing status during the procedure ensures that the dose of EA can be optimised for individual animals. Moreover, it may be possible to adapt this procedure to produce animal models with controlled high frequency hearing losses.

Animals↗
PubMed1987

Individual variations in energy utilized for biomechanical processes and molecular mobility account for diverse susceptibility to obesity.

To explain why subjects vary in body fat content despite similar nutrient intake and physical activity, a hypothesis is proposed invoking individual variability in the potentially vast quantities of energy utilizable for such biomechanical functions as cellular motility processes, and for protein mobility. The collective term "biomechanical-mobile" activity is introduced. The hypothesis explains variation without differences in external energy losses. After utilization for indispensable metabolic needs and the variable "biomechanical-mobile" activity, excess energy is mainly transduced to anabolic processes, and eventually stored as chemical energy, mostly as adipocyte triglycerides. At one extreme, are subjects with the least degrees of "biomechanical-mobile" activity, the consequently largest surfeits of energy for chemical storage, and thus the greatest susceptibility to massive obesity. The converse applies to inordinate leanness. Between the extremes, the almost infinite individual variability is due to a "continuous" distribution of "biomechanical-mobile" activity inversely related to the quantity remaining for chemical storage. While the extremes may result from mutations, the intervening continuum is ascribed to genetic polymorphism and to novel endocrine-neural mechanisms. In addition, such environmental influences as diet and drugs might modulate "biomechanical-mobile" activity. This hypothesis is extrapolated to all living systems.

Adipose Tissue↗
PubMed2000

Determinants of the acetate recovery factor: implications for estimation of [13C]substrate oxidation.

When using (13)C or (14)C tracers to study substrate metabolism, an acetate correction factor should be applied to correct for loss of label in the exchange pathways of the tricarboxylic acid cycle. We have shown recently that the [(13)C]acetate recovery factor has a high inter-individual variability and should therefore be determined in every subject. In the present study we examined the factors that might explain some of the variability between subjects in acetate recovery factor. Data were pooled from four different studies with identical protocols, in which the acetate recovery factor was measured, prior to an intervention, to correct plasma fatty acid oxidation rates. Acetate recovery was measured after 2 h of [1, 2-(13)C]acetate infusion at rest followed by 1 h of cycling exercise at 40-50% of maximal oxygen uptake. Inter-individual variance in acetate recovery was 12.0% at rest and 16.1% during exercise. Stepwise regression revealed that, at rest, 37.1% of the acetate recovery could be accounted for by basal metabolic rate adjusted for fat-free mass, percentage body fat and respiratory quotient (RQ). During exercise, 69.1% of the variance in acetate recovery could be accounted for by energy expenditure adjusted for fat-free mass, % body fat and RQ. In conclusion, we show that the acetate recovery factor has a high inter-individual variability, both at rest and during exercise, which can partly be accounted for by metabolic rate, RQ and % body fat. These data indicate that the acetate recovery factor needs to be determined in every subject, under similar conditions as used for the tracer-derived determination of substrate oxidation. Failure to do this might result in large under- or over-estimation of plasma substrate oxidation, and hence to artificial differences between groups.

Acetic Acid↗
PubMed1995

[Regression towards the mean and repeated echocardiographic measurements of the left ventricular mass].

The selection of a group of patients based on a high value of a clinical or biological parameter leads to the finding of a tendency to a reduction of this value when remeasured, known as "regression towards the mean". The amplitude of this phenomenon is greater when the selected subjects are far from normal values and the intra-individual variability of the parameter under consideration is very high. Measurement of left ventricular mass is very affected by this statistical phenomenon. The authors undertook a prospective study to analyse the components of variability of repeated echocardiographic measurements of left ventricular mass and to quantify the expected effect of regression towards the mean in the follow-up of patients with left ventricular hypertrophy. Twenty-five randomly chosen subjects underwent 2 echocardiographic examinations at 2 week intervals: at each visit, the patient had two recordings and each recording was measured twice by the same "blinded" operator. Variance analysis showed intra-individual variability represented 30% of total variability, comprising only 2% for the measurements and 28% for the recordings and the visits. The importance of regression towards the mean was calculated with respect to the initial value of the left ventricular mass index: for example, when the left ventricular mass index was 150 g/m2, a spontaneous regression of 18 g/m2 can be expected at the next measurement. This phenomenon should be taken into consideration in the interpretation of longitudinal echocardiographic studies.

Adolescent↗
PubMed2006

[Pharmacogenetic testing: utility in drug development and in routine clinical practice].

Pharmacogenetic tests can identify the role of genetic factors in the inter-individual variability of drug responsiveness. This variability can involve three systems, namely drug-metabolizing enzymes, transmembrane drug transporters, and drug effctor sites (receptors, enzymes, ion, channels, etc.). At present, pharmacogenetic testing is rarely used in clinical practice. A rapid survey of the four laboratories conducting such tests for Paris hospitals shows that about 750 tests were done during a 12-months period in 2004-2005, and that most focused on allelic variants of drug-metabolizing enzymes. Three other European laboratories perform between 25, and 7.000 tests per year. However, the number of pharmacogenetic tests is set to grow rapidely in the near future. The role of genetic factors in adverse drug reactions (ADR) has not yet been the subject of a systematic study. Drug-drug interactions that inhibit or induce certain enzyme activities are a major cause of adverse reactions, but they have not been exhaustively studied Pharmacogenetic and pharmacogenomic tools are increasingly used in the drug development process. This should result in the discovery of new therapeutic targets and in a better understanding of factors governing drug efficacy and tolerability. DNA samples are already collected systematically in many phase II and III clinical trials, and registration agencies such as the FDA are establishing guidelines for the submission of pharmacogenetic data on new drugs. These efforts, together with DNA samples collection during post-registration pharmacoepidemiological studies, should help to understand inter-individual variability in drug efficacy and tolerability. They may also result in the identification of new drug targets and will help to tailor therapy to the individual patient.

Clinical Medicine↗
PubMedDate not supplied

[Renal differential aging processes and ofloxacin pharmacokinetics in the elderly].

Ageing generates an important inter- and intra-individual variability in drug pharmacokinetics. The increasing frequency of ofloxacin adverse effects in elderly patients results from increased ofloxacin plasma levels about two or threefold over normal concentrations. A retrospective study of ofloxacin population pharmacokinetics in 17 elderly patients (83.6 +/- 6.8 years) shows the existence of three subgroups according to ofloxacin total clearance [group 1: 1.44 l/h, group 2: 4.37 l/h and group 3: 15.08 l/h] reflecting the important inter-individual variability. No correlation between this clearance and creatinine clearance, nor between this clearance and age, could be established, showing the limits of traditional drug monitoring in the elderly. Ofloxacin pharmacokinetic parameters estimated by the non-parametric software NPEM2 in the 17 elderly patients (absorption rate constant, Ka: 2.668 +/- 1.256 h-1; apparent volume of distribution related to weight, Vs: 1.272 +/- 0.778 l/kg; elimination rate constant, Ks: 0.265 +/- 0.247 10(-3) min/ml/h) are clearly different from those estimated in young adults. These results show the limits of classic drug monitoring in the elderly, and also the interest of adaptive control of a drug regimen.

Aged↗
PubMed1996

Reproducibility of the growth hormone response to stimulation with growth hormone-releasing hormone plus arginine during lifespan.

The reliability and reproducibility of provocative stimuli of growth hormone (GH) secretion in the diagnosis of GH deficiency are still controversial both in childhood and in adulthood. The combined administration of GH-releasing hormone (GHRH) and arginine (ARG), which likely acts via inhibition of hypothalamic somatostatin release, is one of the most potent stimuli known so far and has been proposed recently as the best test to explore the maximal somatotrope capacity of somatotrope cells. However, it is well known that, usually, provocative stimuli of GH secretion suffer from poor reproducibility and that of the GHRH + ARG test has still to be verified. We aimed to verify the between- and within-subject variability of the GH response to the GHRH + ARG test in normal subjects during their lifespan as well as in hypopituitaric patients with GH deficiency (GHD). In 10 normal children (C: six male and four female, age 12.3 +/- 0.9 years, body mass index (BMI) = 16.6 +/- 0.7 kg/m2, pubertal stages I-III), 18 normal young adults (Y: ten male and eight female, age 31.1 +/- 1.3 years, BMI = 21.4 +/- 0.4 kg/m2), 12 normal elderly subjects (E: two male and ten female, age 74.4 +/- 1.8 years, BMI= 22.6 +/- 0.6 kg/m2) and 15 panhypopituitaric GH-deficient patients (GHD: nine male and six female, age 40.9 +/- 4.1 years, BMI= 22.7 +/- 1.0 kg/m2), we studied the inter- and intra-individual variability of the GH response to GHRH (1 microg/kg i.v.) + ARG (0.5 g/kg i.v.) in two different sessions at least 3 days apart. The GH responses to GHRH + ARG in C (1st vs 2nd session: 61.6 +/- 8.1 vs 66.5 +/- 9.4 microg/l), Y (70.4 +/- 10.1 vs 76.2 10.7 microg/l) and E (57.9 14.8 vs 52.1 +/- 8.0 microg/l) were similar and reproducible in all groups. The somatotrope responsiveness to GHRH + ARG also showed a limited within-subject variability (r = 0.71, 0.90 and 0.89 and p < 0.02, 0.0005 and 0.0005 for C, Y and E, respectively). Similarly in GHD, the GH response to the GHRH + ARG test showed a good inter- (1st vs 2nd session: 2.3 +/- 0.5 vs 2.2 +/- 0.6 microg/l) and intra-individual reproducibility (r = 0.70, p < 0.005). The GHRH + ARG-induced GH responses in GHD were markedly lower (p < 0.0005) than those in age-matched controls and no overlap was found between GH peak responses in GHD and normal subjects. In normal subjects, the GH response to GHRH + ARG is very marked, independent of age and shows limited inter- and intra-individual variability. The GH response to the GHRH + ARG test is strikingly reduced in panhypopituitaric patients with GHD, in whom the low somatotrope responsiveness is reproducible. Thus, these findings strengthen the hypothesis that GHRH + ARG should be considered the most reliable test to evaluate the maximal secretory capacity of somatotrope cells and to distinguish normal subjects from GHD patients in adulthood.

Adult↗
PubMed2025

Structural diversity and evolutionary constraints of oxidative phosphorylation.

The oxidative phosphorylation (OxPhos) system is central to metabolism. The more than 90 structural subunits are encoded by different chromosome categories (autosomal, X, and mtDNA). The system is envisioned as an invariant structure between cells and individuals. However, a comprehensive analysis of the 1,000 Genomes Project data reveals unexpected genetic intra-individual variability resulting from the heterozygosity of diploid autosomal genes, while diversity at the population level is generated by variability in mtDNA. We characterized the different levels of structural constriction at evolutionary and population levels for all OxPhos protein residues. To support this analysis, we developed ConScore, a conservation-based predictor of variant impact within OxPhos proteins (area under the receiver operating characteristic curve [ROC-AUC] = 0.97; area under the precision-recall curve [PR-AUC] = 0.94). Notably, for the nuclear-encoded subunits, we found mechanisms limiting individual variability as allelic imbalance or homozygosity bias. Integrating structural, functional, and genetic data, we highlight the significance of each OxPhos protein position, expanding insights into its role in speciation and disease.

Oxidative Phosphorylation↗
PubMed2002

Visual event-related potentials to moving stimuli: normative data.

Visual cognitive responses (P300) to moving stimuli were tested in 36 subjects with the aim to find the normal range of P300 parameters. Concomitantly, the circadian intra-individual variability of the P300 was studied in a subgroup of 6 subjects. Visual stimuli consisted of either coherent (frequent stimulus) or non-coherent motion (random stimulus). The oddball paradigm was applied for recording cognitive responses. P300 to rare stimuli had an average latency of 447.3 +/- 46.6 ms and amplitude of 12.9 +/- 6.0 microV. The average reaction time was in the range from 322 to 611 ms and there was no correlation between the reaction time and P300 latency. We did not find any significant circadian changes of the P300 parameters in the 6 subjects tested four times during the same day. Cognitive (event-related) responses (P300) displayed distinctly greater inter-individual variability (S.D. of 50 ms) when compared with pattern-reversal and motion-onset VEPs (S.D. of 6.0 ms and 14 ms, respectively). For this reason, the clinical use of P300 elicited by this kind of visual stimuli seems to be rather restricted and the evaluation of its intra-individual changes is preferable.

Adult↗
PubMed1981

Treadmill exercise tests predischarge and six weeks post-myocardial infarction to detect abnormalities of known prognostic value.

We evaluated 89 patients with predischarge and 6-week post-myocardial infarction treadmill exercise tests to determine the importance of doing repeat tests to identify abnormalities of known prognostic value, and assess the individual variability of treadmill abnormality responses. Nineteen patients (21%) completed only a predischarge exercise test, nine of whom experienced an early cardiac event precluding repeat testing. All nine had a prognostically important treadmill abnormality during the predischarge test. Electrocardiographic ST segment depression was highly reproducible between the early and 6-week tests (k = 0.968). However, angina, inadequate blood pressure response, and ventricular arrhythmias showed limited reproducibility (k = 0.344, 0.50, and 0.166, respectively) and substantial individual variability. Thus, we concluded that: a predischarge treadmill exercise test is important for determining the immediate short-term prognosis of patients after myocardial infarction; and ST segment depression is highly reproducible, whereas other treadmill abnormality responses show substantial variability between the predischarge and 6-week tests.

Adult↗
PubMed2000

DNase use in the daily care of cystic fibrosis: who benefits from it and to what extent? Results of a cohort study of 199 patients in 13 centres. DNase National Study Group.

UNLABELLED: Short-term clinical trials with DNase have shown minor to moderate benefits in cystic fibrosis patients. This study was performed to analyse the effectiveness of DNase use in daily practice and to obtain information on its effects in the long term and at different disease stages. Patients being treated in 13 specialised units were included if they started DNase treatment before June 1996. Baseline data before DNase use and data during the DNase treatment period were recorded. Of the 199 patients included in the study 166 continued on DNase treatment while the data were being collected. The mean age (95% CI) was 14.5 (13.7; 15,2) years; 103 (51.8%) patients were female. The mean maximum change in forced expiratory volume in 1 s (FEV(1)) was observed during the first month of treatment [11.1% (6.1; 16.1)]. By the end of the first and the second year of treatment mean changes in FEV(1) were 3.3% (-1.1; 7. 6) and 5.1% (-0.7; 10.9) respectively; at the end of the same periods 34% of patients had improved their baseline FEV(1) by 10% or more but in around 50% of patients the level fell below the baseline. A large inter-individual variability in changes in pulmonary function after the start of DNase treatment was documented. In addition, the medium-term response to treatment was correlated with early response during the first 3 months. No consistent changes in exacerbation pattern were found during the first year of treatment. CONCLUSIONS: The benefits of DNase use in daily practice are limited but apparently can be maintained in the medium term in some patients. A large inter-individual variability in response to DNase treatment has been documented and the benefits are doubtful in around 50% of patients. This observation points to the need to set up a withdrawal trial in these patients, using as an eligibility criterion the early response observed during the first 3 months of treatment.

Adolescent↗
PubMedDate not supplied

Effect of dose increase or cimetidine co-administration on albendazole bioavailability.

The low bioavailability of albendazole affects the therapeutic response in patients with echinococcosis. Cimetidine co-administration is reported to improve bioavailability. To analyze the assumed dose-dependent bioavailability of albendazole, we administered 5 to 30 mg/kg albendazole to 6 male volunteers in a randomized cross-over study. To assess the effect of cimetidine (10 mg/kg twice daily), the drug was given with albendazole (20 mg/kg). A dose-dependent bioavailability was not observed. This was due to inter-individual variability of the maximal concentration (Cmax 38%-72%) of albendazole sulphoxide (ABZSX), the active metabolite of albendazole. Cmax was 0.21+/-0.14 mg/L after 5 mg/kg and 0.39+/-0.19 mg/L after 30 mg/kg albendazole (P = 0.217). Cimetidine tended to decrease Cmax by 52% (P = 0.109) and significantly inhibited ABZSX breakdown as indicated by the prolongation of ABZSX elimination half-life from 7.4+/-3.3 hr to 19.0+/-11.7 hr (P = 0.028). Remarkably, the inter-individual variability of Cmax was significantly lower during cimetidine co-administration: 14% versus 72%.

Administration, Oral↗
PubMed2024

Exclusive enteral nutrition initiates individual protective microbiome changes to induce remission in pediatric Crohn's disease.

Exclusive enteral nutrition (EEN) is a first-line therapy for pediatric Crohn's disease (CD), but protective mechanisms remain unknown. We established a prospective pediatric cohort to characterize the function of fecal microbiota and metabolite changes of treatment-naive CD patients in response to EEN (German Clinical Trials DRKS00013306). Integrated multi-omics analysis identified network clusters from individually variable microbiome profiles, with Lachnospiraceae and medium-chain fatty acids as protective features. Bioorthogonal non-canonical amino acid tagging selectively identified bacterial species in response to medium-chain fatty acids. Metagenomic analysis identified high strain-level dynamics in response to EEN. Functional changes in diet-exposed fecal microbiota were further validated using gut chemostat cultures and microbiota transfer into germ-free Il10-deficient mice. Dietary model conditions induced individual patient-specific strain signatures to prevent or cause inflammatory bowel disease (IBD)-like inflammation in gnotobiotic mice. Hence, we provide evidence that EEN therapy operates through explicit functional changes of temporally and individually variable microbiome profiles.

Crohn Disease↗