Hemodynamic and metabolic alterations during experimental sepsis in young and adult rats.

Cecal ligation and puncture (CLP) has been extensively used as a model of sepsis in adult rats. It is not known if the response to sepsis is similar in young and adult rats. This investigation was done to compare hemodynamic and metabolic alterations in young (four to six weeks of age, 60 to 90 grams) and adult (12 to 14 weeks of age, 270 to 340 grams) rats after CLP. In one series of experiments, survival rate was determined for 96 hours, and in other experiments, mean arterial blood pressure (MAP), heart rate (HR), white blood cell count, hematocrit, platelets, plasma glucose, lactate, amino acids, blood urea nitrogen (BUN), blood and peritoneal cultures and resting energy expenditure (REE) were determined eight and 16 hours after CLP. Levels of glycogen in liver and muscle were determined 16 hours after CLP. Mortality rate was similar in young and adult rats. MAP was stable throughout the course of sepsis, with no significant differences between the two groups of rats. HR was higher in young rats at all times studied. The adult rats became hyperglycemic after CLP while the young were hypoglycemic eight hours after CLP but normalized at 16 hours. Plasma lactate and BUN were similar in the two groups of rats, and no alterations were seen during sepsis. Both young and adult rats became hypoaminoacidemic after CLP. The phenylalanine to tyrosine ratio increased in a similar manner during sepsis in both experimental groups. REE was higher in young than in adult rats, but no significant changes were observed during the course of sepsis in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Intranasal LH-RH treatment of cryptorchidism. A clinical trial and 5 years follow-up.

The effect of intranasal LH-RH on cryptorchidism was investigated in 45 prepubertal boys with 68 undescended testes. A daily dose of 1.2 mg LH-RH was given for 4 weeks. A total of 16 testes (24%) descended. Follow-up examination 5 years later showed that relapse had occurred in two cases. Fifty-two testes did not descend during the LH-RH treatment. However, seven of these testes descended spontaneously during puberty. So far surgical treatment has been carried out in 39 of the remaining 45 testes. Anatomical anomalies (ectopic position of the testis, open processus vaginalis, abnormal epididymis) explained the failure of LH-RH to cause descent in the majority of the surgically treated cases.

Late return of function after intrathoracic torsion of the spleen in congenital diaphragmatic hernia.

A case of late presentation of a left posterolateral diaphragmatic hernia in a four-year-old boy is reported. Shortly after incidental diagnosis of the diaphragmatic hernia, he was admitted with acute abdominal symptoms and laparotomy was performed. The stomach, small intestine, part of the colon, and the spleen were intrathoracic. There was a 720 degree torsion of the splenic pedicle. After reduction, the spleen was placed in the abdomen. At scintiscans 12 days and 14 weeks after operation, no certain splenic function was demonstrated, but at follow-up up 21/2 years later the splenic scan was normal.

Pharmacokinetics and bioavailability of cimetidine in humans.

Cimetidine given orally without food after an overnight fast produces a blood concentration curve with a pronounced second peak that does not appear after parenteral administration or when the drug is taken with food. The following interpretation of this kinetic phenomenon is proposed: 1. The drug cumulates in a tissue or organ that is well perfused in the first-pass transfer. 2. The hepatic parenchymal tissue and the bile phase are the most likely storage areas. 3. The high capacity of the cumulation may be due to the formation of conjugates or other modifications of the drug with a pronounced affinity for the hepatic-biliary system. 4. The rate of cumulation is much higher in the first-pass transfer than from the systemic circulation, possibly due to the difference in the drug concentrations and the conjugation rate. 5. The cumulation appears to occur by a competitive process. 6. Absorbed elements of food seem to compete in this process. 7. The second peak apparently is the result of a rapid release of drug and bioreversible drug compounds from the hepatic-biliary system with subsequent reabsorption. 8. This release may occur spontaneously but appears to be triggered by food intake. A pharmacokinetic model constructed according to this interpretation showed good agreement with data from oral, intravenous, and intramuscular administration. The special problems associated with the evaluation of bioavailability in the presence of reabsorption are discussed.

Model-independent method of analyzing input in linear pharmacokinetic systems having polyexponential impulse response I: Theoretical analysis.

A rigorous treatment of linear compartmental systems is presented, which allows the input rate of drugs into the systemic circulation to be evaluated without assuming a specific kinetic model. The method allows the input to be evaluated in the presence or absence of any combination of intravenous bolus input and infusion input. Only data for the blood drug concentration are required; there are no requirements for specific sampling times. Applications of the equations are given in several examples. The input rate is evaluated with data obtained from a disposition experiment involving an intravenous bolus or zero-order infusion input and an experiment involving the input to be evaluated. The two experiments can be merged so that the input can be evaluated without a washout period between the two drug administrations. The equations also enable model-independent calculations of the optimal drug input control that produces any desirable drug concentration profile. The approach is a useful deconvolution method for any linear pharmacokinetic system where the impulse response can be approximated by a polyexponential expression.

Model-independent method of analyzing input in linear pharmacokinetic systems having polyexponential impulse response II: Numerical evaluation.

The investigated method is based on an exact mathematical solution to the deconvolution problem of linear pharmacokinetic systems with a polyexponential impulse response. The accuracy of the method is determined only by how well the curves fitted to the intravenous and absorption data represent the true drug level. Consequently, the method enables objective evaluation of the input. It permits the user to assess whether discrepancies in a calculated input are due to an improper data representation, as judged from the fitted curves, to the inherent nature of the data, or to a violation of the pharmacokinetic assumptions. The method is compared to another method using simulated data containing various degrees of random noise. The accuracy of the two methods was not significantly different and was of the same magnitude as the noise level of the data. The theoretical properties of the two methods and their expected performance in various pharmacokinetic situations are discussed. The method is applied to pentobarbital data from oral and intravenous administrations.

Novel deconvolution method for linear pharmacokinetic systems with polyexponential impulse response.

A novel least-squares deconvolution method for estimating the rate and the extent of drug input into the systemic circulation is presented. The method is based on a polyexponential approximation of the impulse response and a polynomial approximation of the input rate. The method, which is readily implemented on a computer using any multiple linear regression program with a zero-intercept option, is compared to two other deconvolution methods using simulated data with various degrees of random noise added. It appears to have several significant advantages. The method is applied to plasma pentobarbital level data from oral and intravenous administration. The assumptions and limitations of deconvolution methods for analyzing drug input into the blood are discussed.

Novel approach to bioavailability testing: statistical method for comparing drug input calculated by a least-squares deconvolution technique.

A novel approach to bioavailability testing is presented. The approach is model independent because it does not assume a specific pharmacokinetic model and does not use absorption, distribution, or elimination rate constants or a volume term. The method, which requires intravenous administration, is compared to classical bioavailability evaluation methods. Evaluation of drug input is based on the same assumptions required for using the area under the curve. No extrapolation beyond the last data point is required. Two statistics are derived that enable a comparison of the rate and the cumulative amount of input of two inputs for various times. A differential confidence profile is calculated that allows a more detailed and intrinsic bioavailability comparison than previous methods. The approach is demonstrated on simulated data containing random noise and shows satisfactory performance.

Pharmacokinetics of doxycycline reabsorption.

Two cyclic linear compartment models are proposed to investigate the reabsorption mechanism of doxycycline. In one model, reabsorption is considered to be continuous; in the other model, it is discontinuous. The continuous model, when fitted, leads to one real and two complex conjugate eigenvalues, corresponding to a regression equation consisting of a regular exponential term and an exponentially damped trigonometric expression. In spite of the apparent oscillatory nature of this regression equation, the fitted curves show no secondary peaks or humps apparent in the data. Simulation studies indicate that it may not be possible to get response profiles showing secondary peaks or humps that are experimentally detectable with linear compartment systems with cyclic pathways and continuous transfer. The model with discontinuous cyclic transfer was more flexible in describing the discrepancies in the data and appeared to be preferable to the continuous cyclic transfer model judged by the Akaike information criterion.

Congenital ascites due to mesenteric vessel constriction caused by malrotation of the intestines.

A newborn premature girl with congenital, non-chylous ascites is presented. The ascites recurred although laparocentesis was performed three times. The ascites was probably due to a superior mesenteric vein constriction caused by a malrotation of the intestines. After division of the Ladd-bands no ascites recurred. Non-chylous, congenital ascites may have a surgically treatable cause.

Versatile kinetic-approach to analysis of dissolution data.

A new kinetically based dissolution equation is presented that considers dissolution of polydisperse systems and disintegrating solid dosage forms. The equation is applicable under sink as well as nonsink conditions and enables the specific dissolution rate parameter, the dispersion parameter, the disintegration lag time, and a newly introduced parameter, the dissolution availability, to be evaluated simultaneously and directly from percent of label claim dissolved versus time data. The equation showed excellent fit to dissolution data for aminophylline tablets. The kinetic significance of the estimated parameters of the equation is discussed. The method of analysis is compared to an approach employing an empirical equation based on a modified Weibull distribution function.

General treatment of competitive binding of small molecules to macromolecules as applied to dynamic dialysis: theoretical analysis.

A mathematical analysis of the dynamic dialysis process is presented, demonstrating how the process can be applied generally to study competitive and noncompetitive binding between small molecules and macromolecules. A law of mass action model for competitive binding with independent sites and classes with equivalent sites (CIE) is considered as a specific case without loss of generality. The escape profiles of two compounds are calculated to illustrate the effect of an increasing degree of binding competition. Noisy data are generated using the CIE model to test the presented method of estimating competitive binding parameters. The parameters estimated by the nonlinear regression technique came close to the true values, considering the degree of noise added to the exact dialysis data. A transformation approach is presented, enabling initial estimates of the binding parameters in the CIE model to be determined by multiple linear regression, thereby eliminating the main problem in the nonlinear estimation. The presented method of analysis is extended to strongly bound compounds, which also bind significantly to the dialysis membrane.

General treatment of linear pharmacokinetics.

A general treatment of linear pharmacokinetics that enables equations to be obtained simply for all linear compartmental models, with input in one or more compartments, is presented. Two approaches are described: one based on a full Laplace transformation and one that avoids transformation of the input functions and the use of convolution integrals. The latter approach is of particular interest when dealing with complex input functions not having a simple Laplace transform. The concept of acceptor and donor subsystems is introduced. It is demonstrated that disposition in certain models may be simplified and analyzed in terms of disposition in subsystems of simpler composition. The treatment presented is illustrated with several examples.