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PubMed2005

Genomic profiling. Interplay between clinical epidemiology, bioinformatics and biostatistics.

OBJECTIVES: The current literature on the use of microarrays to generate prognostic profiles is still a methodological wasteland. Many valid questions, such as how profiling studies should be evaluated and what conclusions can be drawn, remain unanswered. Or how can flaws in the collection, analysis and interpretation of data be detected? Undiscovered imperfections can lead to a waste of valuable resources as well as be a latent source of false conclusions. METHODS: Three seminal papers on the prognosis of breast cancer using genomic profiling will be discussed. Six principles of good experimental design will be used for methodological guidance: defining relevant endpoints, avoiding systematic bias, generalizability of results, appropriately sized samples to achieve sufficient power, simple design to improve interpretability, and avoiding artificial assumptions. RESULTS: Severe violations of at least one of the six principles of good experimental design can be found in each of the three papers. A strategy is presented to assess whether a study has achieved a high level of methodological quality. This strategy also helps to establish a suitable protocol for future profiling projects. CONCLUSIONS: Determining the design of a study in a protocol is a first step to avoid impending pitfalls. The protocol should deal with the problem of understanding the complex reality behind genomic profiling. There are basic guiding principles which can help handle the complex task of designing prognostic studies to find genomic signatures.

Biometry↗

PubMed2007

The gene expression profile represents the molecular nature of liver metastasis in colorectal cancer.

The major cause of death in colorectal cancer is related to liver metastasis. Although the metastatic process has been well studied, many aspects of the molecular genetic basis of metastasis remain unclear. Elucidation of the molecular nature of liver metastasis is urgent to improve the outcome of colorectal cancer. We analyzed the chronological gene expression profiles of 104 colorectal samples corresponding to oncogenic development including normal mucosa, localized and metastasized primary tumors, and liver metastatic lesions as fundamental samples using a custom cDNA microarray. The gene expression patterns in 104 samples were classified into four groups closely associated with their metastatic status, and the genes of each group appropriately reflected the metastatic process. To investigate the existence of metastatic potential in primary tumors using metastasis-related genes detected by chronological analysis, we performed a hierarchical cluster and supervised classification analysis of 28 independent primary tumors. Hierarchical cluster analysis segregated the tumors according to their final metastatic status, rather than their clinical stages, and the profile of metastasized primary tumors resembled one of a metastatic lesion apart from a primary lesion rather than one of a non-metastasized primary tumor. Using the supervised classification approach, the expression profile of these genes allowed the classification of tumors diagnosed as localized cancer into two classes, the localized and the metastasized class, according to their final metastatic status. The disease-free survival and overall survival were significantly longer in the localized class than the metastasized class. Chronological analysis of the gene expression profile provides a better understanding of the metastatic process. Our results suggest that the metastatic potential is already encoded in the primary tumor and is detectable by a gene expression profile, which allows the prediction of liver metastasis in patients diagnosed with localized tumors and also the design of new strategies for the treatment and diagnosis of colorectal cancer.

Aged↗

PubMed2026

Proteomic Profile in Retinopathy of Prematurity: A Secondary Analysis of the Mega Donna Mega Randomized Clinical Trial.

IMPORTANCE: Identifying early proteomic profiles in infants who develop severe retinopathy of prematurity (ROP) may reveal targets for preventive interventions to reduce retinal vessel loss and the subsequent risk of severe ROP. OBJECTIVE: To assess early longitudinal profiles of blood protein levels in preterm infants with or without severe ROP and the effect of arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation. DESIGN, SETTING, AND PARTICIPANTS: This was an exploratory, post hoc analysis of serum proteome profiles in preterm infants in the double-masked Mega Donna Mega (MDM) randomized clinical trial using targeted Olink Proximity Extension Assay proteomics covering 538 analytes. The setting was 3 university hospitals in Sweden and included extremely preterm infants born before 28 weeks of gestational age (GA), from 2016 to 2019. Data were analyzed from January to March 2025. EXPOSURES: All infants received standard nutrition; additionally, half received enteral lipid supplementation with AA/DHA (100/50 mg/kg per day) from birth to term equivalent age. MAIN OUTCOMES AND MEASURES: Longitudinal protein profiles during the first month of life were examined using mixed models for repeated measures, adjusted for GA, study center, and AA/DHA supplementation, and tested for the interaction between severe ROP (stage ≥3 and/or treated) and postnatal age. RESULTS: A total of 177 extremely preterm infants (mean [SD] GA, 25.6 [1.4] weeks; 100 male [56.5%]) were included, of whom 50 (28.2%) developed severe ROP. Of 538 longitudinal analyzed proteins, 109 protein profiles in the first month of life associated with severe ROP, proteins related to immune response, apoptotic processes, blood coagulation, and lipid metabolism. The most pronounced association with severe ROP was a fast rise in fibroblast growth factor 21 (FGF-21; β = 0.68; 95% CI, 0.39-0.97; Q =.002) and tissue plasminogen activator (tPA; β = 0.21; 95% CI, 0.13-0.29; Q <.001) during the first postnatal days. The increase in serum FGF-21 level in the first week of life was associated with lower GA, lower birth weight, low enteral energy intake, and more days receiving mechanical ventilation. No association was observed between AA/DHA supplementation and the proteome. CONCLUSIONS AND RELEVANCE: In this post hoc exploratory analysis of data from the MDM randomized clinical trial, a fast rise in FGF-21 levels, a metabolic stress-induced hormone, during the first postnatal days was strongly associated with the development of severe ROP in extremely preterm infants. These findings suggest that early interventions improving bioenergetic status may help prevent severe ROP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03201588.

Humans↗

PubMed1997

Discriminant analysis of the Ullrich-Turner syndrome neurocognitive profile.

Ullrich-Turner syndrome (UTS), or monosomy X, is a genetic disorder characterized by short stature, gonadal dysgenesis, and a particular neurocognitive profile of normally developed language abilities (particularly verbal IQ) and impaired visual-spatial and/or visual-perceptual abilities. The most frequently described profile in UTS includes difficulty with tasks involving memory and attention, decreased arithmetic skills, and impaired visual spatial processing. We used discriminant function analysis (DFA) to distinguish between the neurocognitive profiles of girls with UTS vs. controls matched for age, height, IQ, and socioeconomic status. DFA is a statistical method for deriving a linear function that optimally weights parameters to permit sensitive and specific differentiation among groups. We developed a modified discriminant function, based on seven cognitive test scores, that successfully discriminated between the UTS and control subjects with a sensitivity of 0.45 and a specificity of 0.97. To validate its performance, we applied the discriminant function to a small group of 45,X UTS subjects (n = 13) and control female subjects (n = 25), ages 7-16 years, who were not part of the previous analyses. The discriminant function (DF) identified 54% of these 13 UTS subjects as having the "UTS neurocognitive profile" and 92% of the 25 control subjects as not having the profile. We also compared the DF scores of UTS girls with various mosaic karyotypes and found that the group with 46,XX mosaicism had significantly higher scores (i.e., closer to normal controls) than the other two mosaic groups (t = 2.86, P < 0.005). The results of this study should be useful for genetic counseling and planning educational programs for girls with UTS.

Adolescent↗

PubMed1998

Impact of Doppler guidewire size and flow rates on intravascular velocity profiles.

Coronary blood flow velocity measurements by conventional intravascular catheter-based Doppler devices are well known to be affected by catheter size. Moreover, it is of clinical importance that the assessment of maximum vasodilator capacity, i.e., the coronary reserve, might be considerably affected by a shape change of the velocity profile under hyperemia. Therefore, the present in vitro study aimed to assess the impact of a small-size Doppler guidewire on the velocity profiles interrogated in tubes with diameters corresponding to the epicardial coronary arteries at clinically relevant flow rates. A 0.014" guidewire was inserted into four serially connected silicone tubes of known diameter, which were perfused with discarded human whole blood by means of a roller pump. In order to determine the effect of the Doppler guidewire on the velocity profile antegrade and retrograde perfusion were carried out in each vessel segment. Vm, the true mean velocity, was calculated from the time collected flow divided by the corresponding vessel cross-sectional area. Average peak velocity (APV) measurements were obtained by pulling back the Doppler device across each of the four vessel segments with given flow rates ranging from 1.14-5.88 ml/s in antegrade and retrograde direction. The shape factor of the recorded velocity profile (fp) is defined as vm/APV and is generally assumed to be close to 0.5. Antegrade perfusion: APV = 1.63 vm + 5.35 (R2 = 0.98); fp = 0.001 vm + 0.51. Retrograde perfusion: APV = 1.71 vm + 3.33 (R2 = 0.98); fp = 0.001 vm + 0.52. Due to the constant relationship between APV and vm, velocity profiles within vessels of epicardial coronary artery size are not substantially disturbed by the presence of the Doppler guidewire. The slight, but significant increase of experimental fp with increasing flow is at variance with the theoretically expected fp values.

Blood Flow Velocity↗

PubMed1997

A t-statistic for objective interpretation of comparative genomic hybridization (CGH) profiles.

An objective method for interpreting comparative genomic hybridization (CGH) is described and compared with current methods of interpretation. The method is based on a two-sample t-statistic in which composite test:reference and reference:reference CGH profiles are compared at each point along the genome to detect regions of significant differences. Composite profiles are created by combining CGH profiles measured from several metaphase chromosomes for each type of chromosome in the normal human karyotype. Composites for both test:reference and reference:reference CGH analyses are used to generate mean CGH profiles and information about the variance therein. The utility of the method is demonstrated through analysis of aneusomies and partial gain and loss of DNA sequence in a myeloid leukemia specimen. Banding analyses of this specimen indicated inv (3)(q21q26), del (5)(q2?q35), -7, +8 and add (17)(p11.2). The t-statistic analyses of CGH data indicated rev ish enh (8) and rev ish dim (5q31.1q33.1,7q11.23qter). The undetected gain on 17p was small and confined to a single band (17p11.2). Thus, the t-statistic is an objective and effective method for defining significant differences between test and reference CGH profiles.

Humans↗

PubMed2000

Cadaver profile at university of Stellenbosch Medical School, South Africa, 1956-1996.

Data on 1,698 cadavers donated during the period 1956-1996 were obtained from files of the Department of Anatomy and Histology at the University of Stellenbosch Medical School, Tygerberg Hospital, South Africa, to project a profile of the characteristics of those accepted on the program for dissection. A breakdown of the data also provided information on the profile of donors belonging to different population groups. Donors to our program were predominantly male (68%) and predominantly colored, which in South Africa identifies those of mixed heritage (63%). The average age of death was 55 years (range 15-98). Donors belonging to the white population group had the highest female : male ratio. Circulatory disorders accounted for most deaths in the white population group (48%), whereas cancer was the leading cause of death in the colored and black population groups ( approximately 25%). Pulmonary tuberculosis accounted for 13% deaths in the colored population group, 14% of deaths in the black population group, but only 0.5% of deaths in the white population group. Cervical cancer and breast cancer accounted for approximately one-third of cancer deaths in women, with cervical cancer more common in colored and black female donors and breast cancer more common in white female donors. The cadaver profile in general reflects the health status of the different population groups in South Africa. The profiles of the colored and black groups reflect that of disadvantaged population groups (a high prevalence of infectious disease; relatively young populations), whereas the white donor profile is that of a privileged population group (a high prevalence of degenerative disease; aging population).

Adolescent↗

PubMed2000

beta-adrenergic receptors primarily are located on the dendrites of granule cells and interneurons but also are found on astrocytes and a few presynaptic profiles in the rat dentate gyrus.

In the rat dentate gyrus, beta-adrenergic receptor (beta-AR) activation is thought to be important in mediating the effects of norepinephrine (NE). beta-AR-immunoreactivity (beta-AR-I) was localized in this study by light and electron microscopy in the rat dentate gyrus by using two previously characterized antibodies to the beta-AR. By light microscopy, dense beta-AR-I was observed in the somata of granule cells and a few hilar interneurons. Diffuse and slightly granular beta-AR-I was found in all laminae, although it was most noticeable in the molecular layer. Ultrastructurally, the cytoplasm of granule cell and interneuronal perikarya (some of which contained parvalbumin immunoreactivity) contained beta-AR-I. beta-AR-I was associated primarily with the endoplasmic reticula; however, a few patches were observed near the plasmalemma. Quantitative analysis revealed that the greatest proportion of beta-AR-labeled profiles was found in the molecular layer. The majority of beta-AR-labeled profiles were either dendritic or astrocytic. In dendritic profiles, beta-AR-I was prominent near postsynaptic densities in large dendrites, many of which originated from granule cell somata. Moreover, some beta-AR-I was found in dendritic spines, sometimes affiliated with the spine apparati. Astrocytic profiles with beta-AR-I were commonly found next to unlabeled terminals which formed asymmetric (excitatory-type) synapses with dendritic spines. Additionally, beta-AR-I was observed in a few unmyelinated axons and axon terminals, many of which formed synapses with dendritic spines. Dual-labeling studies revealed that axons and axon terminals containing tyrosine hydroxylase (TH), the catecholamine synthesizing enzyme, often were near both neuronal and glial profiles containing beta-AR-I. These studies demonstrate that hippocampal beta-AR-I is localized: 1) principally in postsynaptic sites on granule cells and a few interneurons (some of which were basket cells); and 2) in glial processes. These observations add further support to the contention that beta-AR-activation modulates synaptic function through disparate pathways: directly, at either postsynaptic densities or presynaptic processes, or indirectly, through adjacent glial processes.

Animals↗

PubMed2000

An alternative index for assessing profile similarity in bioequivalence trials.

In a typical bioequivalence trial, summary measures of the plasma concentration versus time profile are used to compare two formulations of a drug product. Commonly used measures include area under the curve (AUC), maximum plasma concentration (C(max)) and time to maximum concentration (T(max)). Equivalence of these summary measures, in general, does not guarantee equivalence of the entire profile. Rescigno and Chinchilli and Elswick propose indices which measure profile similarity, but can be overly sensitive to unimportant differences and are not easily interpreted pharmacologically. We propose an alternative index based on smoothing the relative difference between bioavailability profiles. This provides a method for assessing bioequivalence over the entire profile which has a familiar interpretation and can be tuned to provide a compromise between the insensitivity to pattern differences of summary measures and the oversensitivity of pointwise comparisons.

Area Under Curve↗

PubMed1981

The relationship between surgical outcome and MMPI profiles in chronic pain patients.

Administered the MMPI as part of a comprehensive pain evaluation to 44 patients who were receiving surgery for low back pain. Surgical outcomes then were determined after 6 to 18 months, and the patients were grouped as surgery success (22) or surgery failures (22). MMPI profiles were examined for each group, and while there was a significant difference on the Hs scale, no other mean scores were discriminative. In contrast, when patients were divided into subgroups based upon MMPI profile configurations, a strong relationship existed between subgroup MMPI profile and surgery outcome. Thus, while these data argue against attempting to use group MMPI profiles to predict surgical outcome in patients who are suffering from pain, subgroup profiles do bear a strong relationship with surgery outcome and appear worthy of further investigation.

Adult↗

PubMed1985

Missouri Children's Behavior Checklist profiles with developmentally disabled children: construct validity.

The clinical utility and construct validity of seven new MCBC behavior profiles were evaluated and compared to the original four behavior profiles. The relationship between the seven new behavior profiles and the clinical findings and recommendations that stem from an interdisciplinary evaluation of children referred to a clinic for development disabilities was determined. The seven cluster solution classified equally as well as the four cluster solution, but with increased differentiation into more specific internalizing and externalizing behavior profile subgroups. Construct validity information was provided for several of the new profiles in terms of the association with clinical findings of behavior problems and recommendations for therapy.

Aggression↗

PubMed2000

Biophysical profile for fetal assessment in high risk pregnancies.

BACKGROUND: Biophysical profile usually includes ultrasound monitoring of fetal movements, fetal tone and fetal breathing, ultrasound assessment of amniotic fluid volume and assessment of fetal heart rate by electronic monitoring. OBJECTIVES: The objective of this review was to assess the effects of biophysical profile tests on pregnancy outcome in high risk pregnancies. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth trials register. Date of last search: October 1998. SELECTION CRITERIA: Randomised trials comparing fetal biophysical profile with other forms of fetal assessment in women with high risk pregnancies. DATA COLLECTION AND ANALYSIS: Trial quality was assessed. MAIN RESULTS: Four studies were included. Most trials were not of high quality. No difference was found between biophysical profile and other forms of fetal assessment over a range of fetal and neonatal measures. REVIEWER'S CONCLUSIONS: At present, there is not enough evidence from randomised trials to evaluate the use of biophysical profile as a test of fetal well-being in high risk pregnancies.

Embryonic and Fetal Development↗

PubMed1985

CAMPS: computer-automated metacarpophalangeal profile system.

The metacarpophalangeal profile (MCP) pattern has been proven useful in describing individuals with genetic and nongenetic syndromes. However, the measurement of the 19 bone lengths is a tedious procedure requiring use of hand vernier calipers, detailed normative data to be looked up in extensive tables, hand calculator, and manual graphing techniques. Presently there are no reports of microcomputer-automated systems for the accurate measurement, recording, analysis, and graphing of MCP profiles. We describe a computer-automated metacarpophalangeal profile system (CAMPS) that will assist in the derivation of the MCP profile. This program allows the user to select different program routines that perform the functions necessary for MCP profile construction. The "data acquisition module" (DAM) assists in bone length measurement from contact prints of hand radiographs and stores the 19 measurements on a floppy disk. The "standardization analysis module" (SAM) then compares the 19 measurements to age- and sex-matched normal data and converts the raw data to z-score values. The "Pearson product-moment correlation module" (PPM) generates a correlation coefficient describing the degree of similarity between the two hands measured and graphically illustrates the resulting scatterplot. The "MCP plotting module" (MCPM) provides a graphic plot of the 19 bones in either transverse rows or phalangeal rays on a dot-matrix printer or X-Y plotter.

Bone and Bones↗

PubMed2002

Semiparametric method for estimating paleodemographic profiles from age indicator data.

This paper addresses the problem of estimating an age-at-death distribution or paleodemographic profile from osteological data. It is demonstrated that the classical two-stage procedure whereby one first constructs estimates of age-at-death of individual skeletons and then uses these age estimates to obtain a paleodemographic profile is not a correct approach. This is a consequence of Bayes' theorem. Instead, we demonstrate a valid approach that proceeds from the opposite starting point: given skeletal age-at-death, one first estimates the probability of assigning the skeleton into a specific osteological age-indicator stage. We show that this leads to a statistically valid method for obtaining a paleodemographic profile, and moreover, that valid individual age estimation itself requires a demographic profile and therefore is done subsequent to its construction. Individual age estimation thus becomes the last rather than the first step in the estimation procedure. A central concept of our statistical approach is that of a weight function. A weight function is associated with each osteological age-indicator stage or category, and provides the probability that a specific age indicator stage is observed, given age-at-death of the individual. We recommend that weight functions be estimated nonparametrically from a reference data set. In their entirety, the weight functions characterize the relevant stochastic properties of a chosen age indicator. For actual estimation of the paleodemographic profile, a parametric age distribution in the target sample is assumed. The maximum likelihood method is used to identify the unknown parameters of this distribution. As some components are estimated nonparametrically, one then has a semiparametric model. We show how to obtain valid estimates of individual age-at-death, confidence regions, and goodness-of-fit tests. The methods are illustrated with both real and simulated data.

Adolescent↗

PubMed1995

Pattern profile analysis of hominid and chimpanzee hand bones.

In a study designed to complement morphological research on hominid hand bones, length and width measurements of the thumb, index, and middle rays were obtained from radiographs of modern human hands. These rays are primary in precision-gripping postures and are therefore the ones most relevant for investigating evolutionary changes in fine manipulation. Pattern profile analysis allows individuals or samples to be plotted against a reference sample in standard deviation units, or Z-scores. It provides an indication of how different measurements are from modern human averages, while taking into consideration the degree of variation present within modern human samples. A pattern profile for chimpanzees is clearly distinct from humans but quite similar to that of a bonobo, demonstrating the promise of pattern analysis. Partial pattern profiles of several of the more complete early hominid bones from Hadar, Swartkrans, and Olduvai (O.H. 7) are presented and compared. Hadar bones are long and wide at midshaft relative to articular widths; both body-size effects and functional differences are likely. Thumb distal phalanges from Swartkrans and Olduvai both have relatively small base widths, but they differ in other proportions. Two first metacarpals from Swartkrans show distinct patterns. The profiles of La Ferrassie I and Shanidar IV show the characteristically large Neanderthal distal phalanges. Profiles of Skhul IV and Predmost III are alike in some regions with reference to modern North American white males, though they are less similar overall than are those of the two Neanderthals.

Adult↗

PubMed2006

Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study.

OBJECTIVE: To determine whether prespecified baseline magnetic resonance imaging (MRI) profiles can identify stroke patients who have a robust clinical response after early reperfusion when treated 3 to 6 hours after symptom onset. METHODS: We conducted a prospective, multicenter study of 74 consecutive stroke patients admitted to academic stroke centers in North America and Europe. An MRI scan was obtained immediately before and 3 to 6 hours after treatment with intravenous tissue plasminogen activator 3 to 6 hours after symptom onset. Baseline MRI profiles were used to categorize patients into subgroups, and clinical responses were compared based on whether early reperfusion was achieved. RESULTS: Early reperfusion was associated with significantly increased odds of achieving a favorable clinical response in patients with a perfusion/diffusion mismatch (odds ratio, 5.4; p = 0.039) and an even more favorable response in patients with the Target Mismatch profile (odds ratio, 8.7; p = 0.011). Patients with the No Mismatch profile did not appear to benefit from early reperfusion. Early reperfusion was associated with fatal intracranial hemorrhage in patients with the Malignant profile. INTERPRETATION: For stroke patients treated 3 to 6 hours after onset, baseline MRI findings can identify subgroups that are likely to benefit from reperfusion therapies and can potentially identify subgroups that are unlikely to benefit or may be harmed.

Aged↗

PubMed1993

A distinctive autoantibody profile in black female patients with lupus nephritis.

OBJECTIVE: Lupus nephritis has often been associated with anti-DNA, but, based on the findings in eluate studies, it appears that other antigen-antibody reactions, such as those involving anti-Ro/SS-A, anti-nuclear RNP (anti-nRNP), and/or anti-Sm, may also contribute to the pathogenesis of nephritis. In the present investigation, we identified and further studied a distinctive precipitin profile present in black women with nephritis. METHODS: Longitudinal clinical and serologic studies of a cohort of university-based systemic lupus erythematosus (SLE) patients (n = 120) were carried out over an 8-year period. RESULTS: A subset of 20 black female patients was identified, of whom 8 had lupus nephritis (group I) and 12 did not (group II). Group I was characterized by a distinct precipitin profile consisting of anti-Ro/SS-A, anti-SM, and anti-nRNP, but no anti-La/SS-B. SLE disease duration at presentation was significantly shorter in group I than in group II (mean 1.94 years versus 5.21 years; P = 0.02). The distinctive precipitin profile of anti-Ro/SS-A, anti-Sm, and anti-nRNP occurred exclusively in group I patients (6 of 8, versus 0 of 12 in group II; P < 0.001). In white lupus nephritis patients, this precipitin profile was not seen. CONCLUSION: While the mechanism responsible for the relationship of this distinctive serologic profile to the development of nephritis in black female lupus patients remains to be determined, its presence may be used as a marker for severe and progressive renal disease.

Autoantibodies↗

PubMed1994

Variable gastric emptying and discontinuities in drug absorption profiles: dependence of rates and extent of cimetidine absorption on motility phase and pH.

The influence of various fasting-state gastrointestinal parameters on variability in absorption of cimetidine was studied using simulation and cimetidine administration as a duodenal infusion and as an oral tablet in fistulated mongrel dogs. In the simulation studies, the frequency of double-peak occurrence in plasma profiles was estimated employing average gastric emptying rates as well as interdigestive-migrating-motor-complex (IMMC) phase lengths that were systematically altered. Emptying rates and phase lengths were modeled as periodic step functions. Simulations indicated that double peaks occur when gastric emptying of the drug begins in early phase I or late phase II/III, which represent the periods of very low, medium, and high gastrointestinal motility, respectively. The incidence is increased for longer phase-I duration and higher elimination rate constants. For a compound with a 2 h elimination or disposition half-life, two concentration maxima (double peaks) were found in 12% of the simulated concentration-time profiles. The double peak frequency in simulated curves was considerably higher for t1/2 < 30 min. When cimetidine was administered to dogs as a duodenal infusion in the active and quiescent motility phases, discontinuous profiles were observed, although the variability of the various parameters was reduced when compared. Pharmacokinetic models were set up that were characterized by multi-segmental input (one- to 3-lag-time models were used) for the profiles resulting from oral and duodenal administration. The lag time for the first process characterized the onset of absorption. A significant difference between phases was detected for infusions at pH 8, where the initial lag time was longer in the quiescent phase. The mean input time (MIT) was calculated as the integral input parameter. There was a tendency for the MIT to be higher for pH 6 infusions than for pH 4 and pH 8. Bioavailability analysis indicated that cimetidine was more rapidly and completely absorbed at pH 8 than at pH 6. Bioavailability was also slightly higher at pH 4 than at pH 6. We concluded that gastric emptying increased the variability of the cimetidine concentration-against-time profiles and that it plays a role with respect to double-peak occurrence, although it is only one of several causative factors.

Administration, Oral↗