Animal pharmacokinetics and interspecies scaling of Ro 25-6833 and related (lactamylvinyl)cephalosporins

To evaluate the potential of distortion product otoacoustic emissions (DPOAEs) in differential diagnosis of hearing loss, these were routinely measured in 232 ears of severe or profound sensorineural hearing loss. Normally recordable DPOAEs were found in 16 ears (8 patients) and the results were confirmed through retests after intervals; positive responses of transiently evoked otoacoustic emissions (TEOAEs) were additionally tested. The findings suggest that nerve deafness and hair cell deafness may be partly distinguishable.     

Interspecies scaling of cimetidine-theophylline pharmacokinetic interaction: interspecies scaling in pharmacokinetic interactions

The aim of the present study was the use of an interspecies scaling approach to predict drug interactions during preclinical drug disposition studies. Theophylline and cimetidine were selected because of their documented interaction. The literature was searched for pharmacokinetic data of intravenously administered theophylline alone and in the presence of cimetidine in humans, dogs and rats. Further, we determined the theophylline-cimetidine drug interaction in rabbits. Application of allometric equations to the pharmacokinetic parameters and the conversion of chronological time into pharmacokinetic time allowed us to obtain the complex Dedrick plot for theophylline when administered alone or in combination with cimetidine. A superimposable kinetic profile was obtained for the plasma levels of theophylline in all species studied, both with and without cimetidine. From the terminal phase of the curves it is possible to calculate the elimination half-life: 2.69 apolisychrons for theophylline when it is administered alone and 3.86 apolisychrons when it is administered in combination with cimetidine. This 43% increase in t1/2 is similar to the increase in the elimination half-life of theophylline in humans when it is administered after pretreatment with cimetidine. These results show that an interspecies scaling approach may be useful to predict the effect of interactions in humans from the results obtained in preclinical research with new drugs.     

Tissue dosimetry, pharmacokinetic modeling, and interspecies scaling factors

Interspecies scaling factors (ISFs) are numbers used to adjust the potency factor (for example, the q1* for carcinogens or reference doses for compounds eliciting other toxic endpoints) determined in experimental animals to account for expected differences in potency between test animals and people. ISFs have been developed for both cancer and non-cancer risk assessments in response to a common issue: toxicologists often determine adverse effects of chemicals in test animals and then they, or more commonly risk assessors and risk managers, have to draw inferences about what these observations mean for the human population. This perspective briefly reviews the development of ISFs and their applications in health risk assessments over the past 20 years, examining the impact of pharmacokinetic principles in altering current perceptions of the ISFs applied in these health risk assessments, and assessing future directions in applying both pharmacokinetic and pharmacodynamic principles for developing ISFs.     

Interspecies allometric scaling in pharmacokinetics of drugs

Cytomegalovirus infections and their sequelae are the most serious complications in patients after allogenic bone marrow transplantations. Therefore in recent years quite rightly attention is paid to new diagnostic methods which make earlier and more sensitive detection of incipient CMV infection possible. The method of the two-stage polymerase chain reaction (PCR) was used for early detection of CMV infection and its possible further monitoring in 38 recipients of allogenic bone marrow. A positive result was recorded in 15 (39%) patients whereby in 10 (13%) repeated positivity was involved. In three in this group of patients (8%) CMV disease developed, always preceded by PCR positivity. Sensitivity, specificity, positive and negative predictive CMV PCR values were 100, 66, 20 and 100%. Concomitant comparison with serological examination (antibody titre class IgM/seroconversion) revealed the small contribution of serology (corresponding values are 67, 54, 11 and 95%) in patients after bone marrow transplantations. The presented results provide evidence of the contribution of PCR in the diagnosis of CMV in those patients where due to their high sensitivity and excellent predictive value it is possible to avoid the toxicity of unnecessary antiviral treatment.     

Applications and limitations of air dispersion modeling in environmental epidemiology

In epidemiological investigations, when the estimation of integrated exposures over long time intervals covering years or decades is required, the quantitative assignment of exposure levels by simplistic models may prove to be inadequate for most applications. This difficulty may be partially addressed by modifying the mathematical models used for the prediction of dispersions of emissions from pollution sources. A theoretical model based on the atmospheric dispersion of contaminants is proposed. While the development of the theoretical model is straightforward, the data requirements in the application of the model may impose some limitations. The methods developed to resolve or alleviate these limitations suggest that many currently used environmental exposure assignment techniques may be too crude to be of value; even the more sophisticated method proposed can only be used with some reservations. Although several difficulties associated with environmental exposure estimation remain unresolved, the careful and rigorous analysis of the available data and the application of the method suggested here can reduce the exposure misclassification errors to acceptable levels. The quantitative estimations of the limitations are based on estimation procedures and aerometric data used in a hilly terrain, and thus should represent testing of the method under an extreme condition.     

Application of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry extrapolation of acidic vapors in the upper airways

This study provides a scientific basis for interspecies extrapolation of nasal olfactory irritants from rodents to humans. By using a series of short-term in vivo studies, in vitro studies with nasal explants, and computer modeling, regional nasal tissue dose estimates were made and comparisons of tissue doses between species were conducted. To make these comparisons, this study assumes that human and rodent olfactory epithelium have similar susceptibility to the cytotoxic effects of organic acids based on similar histological structure and common mode of action considerations. Interspecies differences in susceptibility to the toxic effects of acidic vapors are therefore assumed to be driven primarily by differences in nasal tissue concentrations that result from regional differences in nasal air flow patterns relative to the species-specific distribution of olfactory epithelium in the nasal cavity. The acute, subchronic, and in vitro studies have demonstrated that the nasal olfactory epithelium is the most sensitive tissue to the effects of inhalation exposure to organic acids and that the sustentacular cells are the most sensitive cell type of this epithelium. A hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of organic acids in the rodent and human nasal cavity. The CFD-PBPK model simulations indicate that the olfactory epithelium of the human nasal cavity is exposed to two- to threefold lower tissue concentrations of a representative inhaled organic acid vapor, acrylic acid, than the olfactory epithelium of the rodent nasal cavity when the exposure conditions are the same. The magnitude of this difference varies somewhat with the specific exposure scenario that is simulated. The increased olfactory tissue dose in rats relative to humans may be attributed to the large rodent olfactory surface area (greater than 50% of the nasal cavity) and its highly susceptible location (particularly, a projection of olfactory epithelium extending anteriorly in the dorsal meatus region). In contrast, human olfactory epithelium occupies a much smaller surface area (less than 5% of the nasal cavity), and it is in a much less accessible dorsal posterior location. In addition, CFD simulations indicate that human olfactory epithelium is poorly ventilated relative to rodent olfactory epithelium. These studies suggest that the human olfactory epithelium is protected from irritating acidic vapors significantly better than rat olfactory epithelium due to substantive differences in nasal anatomy and nasal air flow. Furthermore, the general structure of the hybrid CFD-PBPK model used for this study appears to be useful for target tissue dosimetry and interspecies dose comparisons for a wide range of inhaled vapors.     

Disposition of the selective alpha1A-adrenoceptor antagonist tamsulosin in humans: comparison with data from interspecies scaling

Tamsulosin-HCl is an alpha1A-adrenoceptor antagonist that is mainly eliminated by metabolism in animals and humans and is highly bound to alpha1-acid glycoprotein in blood plasma. The disposition of the compound (0.4 mg as modified-release granules in a capsule) was determined in male volunteers, using intravenous (iv) infusion of tamsulosin-HCl (0.125 mg over 4 h) as reference treatment for the assessment of absolute oral bioavailability. Disposition parameters of iv tamsulosin in humans was compared with data predicted from animal data by interspecies scaling techniques. Levels after iv dosing in humans showed a biexponential decline, with mean half-lives (+/-SD) of 1.2 +/- 0.6 and 6.8 +/- 3.5 h, respectively. The mean systemic clearance (+/-SD) was low (viz., 48 +/- 24 mL/min). The mean volume of distribution (+/-SD) was rather small (21 +/- 6 L), and was estimated at 16 +/- 4 L in the steady state. The mean absolute oral bioavailability (+/-SD) was approximated at 100 +/- 19%. Systemic clearance in humans was poorly predictable from a logarithmic clearance versus body weight relation of rat, rabbit, and dog data. The prediction improved dramatically (accuracy 213%) when scaling was done with systemic clearance values of unbound drug, and it improved further (accuracy 59%) with the product of unbound clearance and maximum life-span potential. Also, the prediction of volume of distribution improved dramatically (accuracy 81%) after correction for differences in extent of protein binding between species. The terminal disposition half-life of 7.0 h, as predicted after integrating maximum life-span potential and protein binding in scaling of clearance, was very close to the value of 6.8 h established experimentally in humans. The present results with tamsulosin underline the importance of correction for extent of protein binding in allometric scaling of clearance and distribution volume.     

Mixed effect modeling of sumatriptan pharmacokinetics during drug development. I: Interspecies allometric scaling

A sample of 22 subjects was studied from a population of adults who had suffered from bacterial meningitis in childhood. Audiovestibular, oculomotor and neuropsychological investigations were performed and quality of life was assessed. An age-matched control group of 20 subjects was recruited. In the meningitis group, nine subjects had abnormal pure tone audiograms. One was previously undiagnosed and a progression was found in four. There was an overrepresentation of subclinical vestibular pathology (6 out of 9 (67%)) in this group. Audiovestibular test results showed a peripheral pattern and oculomotor tests were normal. The quality of life scores of those with hearing loss were significantly higher than those in the control group. Neuropsychological tests of brain dysfunction were abnormal in six out of 22 (27%) who had recovered from meningitis. The prevalence of such dysfunctions was not related to audiovestibular disorder. The quality of life scores of those with brain dysfunctions were similar to those of the control group. The findings of reduced auditory memory and tone level perception in four out of 22 (18%), suggest that lesions of central auditory pathways may follow from bacterial meningitis. The results support the idea that inner ear damage is the major cause of hearing loss after bacterial meningitis. Despite the absence of brainstem involvement, central nervous system lesions with disturbed auditory processing and language functions can be of significance. The high frequency of discrete brain dysfunctions indicate that a thorough neuropsychological investigation is required after bacterial meningitis.     

In vitro maintenance of Leishmania amastigotes directly from lesions: advantages and limitations

Leishmania amazonensis (MHOM/BR/77/LTB0016) amastigotes were obtained from mouse cutaneous lesions and maintained in vitro for 48 hr at pH 4.6, 33 C. These organisms were reproducing, capable of transformation to promastigotes, and did not display the promastigote-specific antigen, GP46. In contrast, 97% of the organisms maintained for 24 hr at 31 C, pH 7.3, were positive for GP46. Thus, short-term cultivation of this L. amazonensis strain under appropriate conditions can provide a high yield of amastigotes for various in vivo and in vitro studies. However, the possible interference of host immunoglobin on the surface of these amastigotes needs to be considered because fluorescent-labeled anti-mouse immunoglobulin was detected on 16% of lesion-derived amastigotes even after 114 hr of cultivation.     

Efficacy of artemisinin and mefloquine combinations against Plasmodium falciparum. In vitro simulation of in vivo pharmacokinetics

The activity of artemisinin in combination with mefloquine was tested in vitro against a chloroquine-sensitive (F32) strain of Plasmodium falciparum. A method of repetitive dosing and extending the culture observation period to 28-30 days was used to mimic the in vivo pharmacokinetic situation. Plasmodium falciparum was exposed to artemisinin from 10(-8) to 10(-5) M, mefloquine from 3 x 10(-9) to 10(-5) M and their combinations. The exposure time for artemisinin was 3 hours twice daily and for mefloquine 24 hours. The drug-dosing duration was 3 days. Neither artemisinin nor mefloquine alone provided radical clearance of P. falciparum, even when maximum concentrations (10(-5) M) were applied. The antiparasitic activity of artemisinin and mefloquine were significantly higher when dosed alone. Effective concentrations for different degrees of inhibition (EC 50, 90 and 99) of both artemisinin and mefloquine respectively were significantly lower when used in combination. At concentrations normally reached in vivo, this effect was clearly synergistic (P = 0.016) Our in vitro model of intermittent dosing of artemisinin and mefloquine combinations for 3 days provides significant evidence of positive interaction between the two compounds. Lower combination concentrations around the MIC-values for the individual compounds showed synergistic effect, and high concentrations showed additive effect. This indicates that such drug combinations may provide radical clearance at concentrations lower than those required for single-drug treatment.     

Melphalan estimation by quantitative thin-layer chromatography. Observations on melphalan hydrolysis in vitro and pharmacokinetics in rabbits

A simple and specific quantitative high-performance thin-layer chromatographic (HPTLC) assay for melphalan in plasma is described. This assay was linear over the investigated range of 50--3,000 ng/ml, with a minimum level of detection of 20 ng/ml. Comparison with a high-pressure liquid chromatographic (HPLC) technique yielded similar estimates for melphalan concentrations in human plasma samples. The HPTLC method, unlike the HPLC technique, does not resolve monohydroxymelphalan satisfactorily. The HPTLC method was used to determine the activation energy for in vitro melphalan hydrolysis: this was 14.5 kcal/mole. The pharmacokinetics of melphalan in rabbits were also investigated. The mean t1/2 in four animals was 32.6 +/- 10.3 (S.D.) min and following IV administration to two animals the apparent volumes of distribution were 2.20 and 1.73 l/kg.     

Cognitive motion extrapolation and cognitive clocking in prediction motion task

An interruption paradigm was used to measure judgments that rely on cognitive extrapolation of approach and lateral motion. In some conditions the pattern of errors was consistent with that obtained with time-to-contact (TTC) judgments measured with a prediction motion (PM) task. Also, the slope of the relationship between estimated and actual TTC in judgments of approaching objects decreased when visual information about the environment between the observer and the display was minimized. Moreover, the accuracy of relative duration judgments of visual (but not auditory) stimuli decreased when a PM task was performed concurrently. Results are consistent with the notion that PM tasks involve cognitive motion extrapolation rather than solely a clocking process that counts down TTC.     

Cross-specialty linkage and extrapolation of resource-based relative value scales

We used the fluorescent labelled dopamine D1-receptor antagonist Bodipy-SCH 23390 for the cellular localization of D1-ligand binding sites in the retinae of different vertebrates (teleosts, Xenopus, turtle, rat and rabbit). Competition experiments with unfixed cryosections of fish retina were performed to characterize the binding conditions of Bodipy-labelled SCH 23390. Tissue bound [3H]SCH 23390 was displaceable with increased amounts of bodipy-SCH 23390. The pharmacological specificity of the D1 fluorescent antagonist was determined by competition experiments with an excess of unlabelled SCH 23390. This treatment significantly reduced the level of fluorescence of the retina confirming the specificity of the binding. We observed a homogeneously distributed fluorescence signal in both plexiform layers in unfixed cryosections of fish, frog, turtle, rat and rabbit. Similar staining intensities of both plexiform layers were found in frog, turtle, rat and rabbit retina. In teleosts, the label of the outer plexiform layer was markedly more intense. Non-specific label was associated with photoreceptor outer and inner segments. The specific labelling of both plexiform layers indicates a mismatch of dopamine releasing and D1-binding sites, and suggests a possible extrasynaptic localization of the D1-receptor. The physiological significance of the observed distribution of D1-ligand binding sites is discussed with respect to the role of dopamine in controlling adaptational processes in the retina.     

Loudness scaling in rats and chinchillas.

In 2 experiments, 10 male chinchillas and 24 male Sprague-Dawley-derived rats were trained on operant discriminations in which the discriminative stimuli were 2 different sound pressure levels of a 4-kHz tone. Two or more of these 2-intensity discriminations were used at each of 3 levels of discriminability: high, medium, and low. For any given level, each of the stimulus pairs used differed in decibel separation but were similar in loudness-unit differences calculated from a power function. Different groups of Ss trained on stimuli separated by equal numbers of loudness units produced equivalent performances at each of the 3 levels of discriminability. It is concluded that loudness growth for both of these species, as for humans, is well described by a power function (S. S. Stevens's 1961 law). For the chinchilla the exponent is .25, and for the rat it is .35. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Loudness scaling and masking in rats.

Two groups of Sprague-Dawley-derived rats (N?=?16) were trained on operant discriminations in which the discriminanda were 2 sound pressure levels of a 4-kHz tone. The discriminanda were chosen so that the loudness difference between stimuli was equivalent for each group when calculated from a power function with an exponent of .35. Half of each group learned the discrimination in quiet, and the other half learned it in a background of white noise. Within the quiet and the noise conditions, the asymptotic discriminability of stimuli separated by equal loudness differences was equivalent, and discriminability was lower in noise. This is consistent with both the human literature on masked loudness and a model of psychophysical scaling (R. Pierrel-Sorrentino and T. G. Raslear; see record 1981-20539-001) in which animals judge perceived differences between stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)