Bioavailability Studies of Acetaminophen and Nitrofurantoin

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97190/1/j.1552-4604.1974.tb02312.x.pd

Hepatic Abnormalities Associated with Aluminum Loading in Piglets

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141476/1/jpen0293.pd

Linear pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficients and exponents of polyexponential equations which have been fitted to the data

It is shown that if the numerical values of the coefficients and exponents of the polyexponential equation describing the whole blood (plasma or serum) concentration after administration of a drug by bolus intravenous injection, or during or after termination of a constantrate intravenous infusion, are known, then many needed pharmacokinetic parameters may be obtained directly. Parameters readily calculated by simple arithmetic are as follows: plasma or serum clearance, Cl p ; volume of plasma compartment, V p ; volume of distribution at steady state, V dss ; V{darea} or V β , extrapolated volume of distribution, V dexr ; half-life of elimination, t 1/2 ; amount metabolized and/or excreted to time t, (A e ); amount in the body at time t, A b ; amount in the plasma (reference) compartment at time t, A p ; and amount in other compartments at time t, A o . Simulations have shown that the equations yield the correct answers for an n-compartment mammillary model with central compartment elimination only, when rate constants, dose, and a value of V p have been assigned. Since whole blood (plasma or serum) concentrationtime data always lead to ambiguities as to which specific model is involved, the equations are most appropriate.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45069/1/10928_2005_Article_BF01062831.pd

Pharmacokinetics of ethanol after oral administration in the fasting state

A nonlinear relationship between the total area under the blood ethanol concentration-time curve and the orally administered dose (mg/kg) of ethanol was observed in fasting subjects. A preliminary model, based on physiological considerations, was elaborated and shown, for the first time, to describe the entire time course of blood alcohol concentrations after four different doses of alcohol. The model could be refined by further experimentation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45071/1/10928_2005_Article_BF01065396.pd

Novel method of estimating volume of distribution of a drug obeying Michaelis-Menten elimination kinetics

The novel method of estimating the volume of distribution involves (a) administering an appropriate bolus intravenous dose of the drug, (b) starting a constant-rate intravenous infusion of the drug at the same time, (c) maintaining the infusion for a given number of hours, (a) measuring the drug concentration over the entire time course, (e) computer-fitting the post-infusion data to obtain estimates of V m and K m , (f) estimating the total area under the concentration-time curve from zero time to infinity, and (g) iteratively solving a cubic equation to obtain the estimate of the volume of distribution. The method was applied to ethanol in the cat and yielded an average value of 635ml/kg (63.5% of body weight) with a coefficient of variation of 23.0%. This is equivalent to total body water in the cat.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45074/1/10928_2005_Article_BF01312262.pd

C-Terminal Extension of the Yeast Mitochondrial DNA Polymerase Determines the Balance between Synthesis and Degradation

Saccharomyces cerevisiae mitochondrial DNA polymerase (Mip1) contains a C-terminal extension (CTE) of 279 amino acid residues. The CTE is required for mitochondrial DNA maintenance in yeast but is absent in higher eukaryotes. Here we use recombinant Mip1 C-terminal deletion mutants to investigate functional importance of the CTE. We show that partial removal of the CTE in Mip1Δ216 results in strong preference for exonucleolytic degradation rather than DNA polymerization. This disbalance in exonuclease and polymerase activities is prominent at suboptimal dNTP concentrations and in the absence of correctly pairing nucleotide. Mip1Δ216 also displays reduced ability to synthesize DNA through double-stranded regions. Full removal of the CTE in Mip1Δ279 results in complete loss of Mip1 polymerase activity, however the mutant retains its exonuclease activity. These results allow us to propose that CTE functions as a part of Mip1 polymerase domain that stabilizes the substrate primer end at the polymerase active site, and is therefore required for efficient mitochondrial DNA replication in vivo

Obesity surgery makes patients healthier and more functional - real world results from the United Kingdom National Bariatric Surgery Registry

Background The National Bariatric Surgery Registry (NBSR) is the largest bespoke database in the field in the United Kingdom. Objectives Our aim was to analyze the NBSR to determine whether the effects of obesity surgery on associated co-morbidities observed in small randomized controlled clinical trials could be replicated in a "real life" setting within U.K. healthcare. Setting United Kingdom. Methods All NBSR entries for operations between 2000 and 2015 with associated demographic and co-morbidity data were analyzed retrospectively. Results A total of 50,782 entries were analyzed. The patients were predominantly female (78%) and white European with a mean age of 45 ± 11 years and a mean body mass index of 48 ± 8 kg/m2. Over 5 years of follow-up, statistically significant reductions in the prevalence of type 2 diabetes, hypertension, dyslipidemia, sleep apnea, asthma, functional impairment, arthritis, and gastroesophageal reflux disease were observed. The "remission" of these co-morbidities was evident 1 year postoperatively and reached a plateau 2 to 5 years after surgery. Obesity surgery was particularly effective on functional impairment and diabetes, almost doubling the proportion of patients able to climb 3 flights of stairs and halving the proportion of patients with diabetes related hyperglycemia compared with preoperatively. Surgery was safe with a morbidity of 3.1% and in-hospital mortality of .07% and a reduced median inpatient stay of 2 days, despite an increasingly sick patient population. Conclusions Obesity surgery in the U.K. results not only in weight loss, but also in substantial improvements in obesity-related co-morbidities. Appropriate support and funding will help improve the quality of the NBSR data set even further, thus enabling its use to inform healthcare policy

Renal obstructive dysplasia: Ultrasound diagnosis and therapeutic implications

57 cases of renal obstructive dysplasia (defined as the abnormal development of nephronic and ductal structures due to in utero obstruction of the urinary tract) were evaluated in terms of sonographic findings, renal and other associated anomalies, and current status of the child. More than one-third of the cases had bilateral disease and although not uniformly fatal bilateral involvement was associated with significant morbidity and mortality. In 12 of the 33 cases with unilateral dysplasia there was an association with contralateral renal problems including ureteropelvic junction obstruction, vesicoureteral reflux and aplasia. Almost one-half of the cases had congenital anomalies, these included VACTERL association, congenital heart disease, cranial abnormalities and gastrointestinal malformations. Fifteen stillborns and 12 of the patients with bilateral involvement and four with unilateral involvement have died. Four patients are on dialysis (two with bilateral involvement and two with unilateral renal obstructive dysplasia). Only one-quarter are otherwise normal. More serious problems are reported in this mixed age population of patients with obstructive renal dysplasia than has been identified in previous studies. Management decisions of the fetus and child must be based on this new age-expanded population.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46696/1/247_2005_Article_BF02018623.pd

Genetic Rearrangements Can Modify Chromatin Features at Epialleles

Analogous to genetically distinct alleles, epialleles represent heritable states of different gene expression from sequence-identical genes. Alleles and epialleles both contribute to phenotypic heterogeneity. While alleles originate from mutation and recombination, the source of epialleles is less well understood. We analyze active and inactive epialleles that were found at a transgenic insert with a selectable marker gene in Arabidopsis. Both converse expression states are stably transmitted to progeny. The silent epiallele was previously shown to change its state upon loss-of-function of trans-acting regulators and drug treatments. We analyzed the composition of the epialleles, their chromatin features, their nuclear localization, transcripts, and homologous small RNA. After mutagenesis by T-DNA transformation of plants carrying the silent epiallele, we found new active alleles. These switches were associated with different, larger or smaller, and non-overlapping deletions or rearrangements in the 3′ regions of the epiallele. These cis-mutations caused different degrees of gene expression stability depending on the nature of the sequence alteration, the consequences for transcription and transcripts, and the resulting chromatin organization upstream. This illustrates a tight dependence of epigenetic regulation on local structures and indicates that sequence alterations can cause epigenetic changes at some distance in regions not directly affected by the mutation. Similar effects may also be involved in gene expression and chromatin changes in the vicinity of transposon insertions or excisions, recombination events, or DNA repair processes and could contribute to the origin of new epialleles

Pharmacokinetic parameters estimated from intravenous data by uniform methods and some of their uses

This article summarizes phamacokinetic parameters of 20 different drugs. The parameters were estimated by uniform methods for an n- compartment open mammillary model in which elimination was assumed to occur only from the central compartment. For various reasons, some of the reported parameters differ appreciably from those reported in the original articles. Some uses of the parameters are discussed .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45070/1/10928_2005_Article_BF01066219.pd