Pharmacokinetics of the antiarrhythmic disopyramide in healthy humans

The pharmacokinetics of the antiarrhythmic disopyramide, 4-diisopropylamino-2-phenyl-2-(2-pyridyl)butyramide phosphate, and its monodealkylated metabolite were investigated in seven volunteers after intravenous (1 and 2 mg/kg) and oral (3 and 6 mg/kg) administration. Unchanged drug (52%) and the monodealkylated metabolite (25%) were renally excreted on intravenous administration. The pharmacokinetics of disopyramide were first order and dose independent only when referenced to the drug not bound to plasma proteins since this binding was dose dependent. The apparent half-lives of the and phases on intravenous administration were 2 min and 4.5 hr, respectively. The apparent volumes of distribution of the central and peripheral compartments, referenced to unbound disopyramide in the plasma, were 9 and 80 liters, respectively. The half-life of absorption of oral aqueous disopyramide phosphate was 30 min with a lag time of 16 min and an apparent first-pass metabolism of 16% of the absorbed dose, consistent with the hepatic efficiency of 14%. The renal and metabolic clearances were 125 and 111 ml/min, respectively. Graphical and computer analysis of the plasma and urine data showed dose-independent first-order pharmacokinetics of plasma unbound drug in a two-compartment-body model to give two metabolites and a first-pass transformation of a fraction of the oral dose. The absorption efficiency of unchanged drug was 83%.Supported in part by Grant No. NIH-RR-82 from the National Institutes of Health, Bethesda, Maryland, and by an unrestricted grant from Searle Laboratories, Skokie, Illinois.     

Archaebacterial DNA-dependent RNA polymerases testify to the evolution of the eukaryotic nuclear genome.

Genes for DNA-dependent RNA polymerase components B, A, and C from the archaebacterium Sulfolobus acidocaldarius and for components B", B', A, and C from the archaebacterium Halobacterium halobium were cloned and sequenced. They are organized in gene clusters in the order above, which corresponds to the order of the homologous rpoB and rpoC genes in the corresponding operon of the Escherichia coli genome. Derived amino acid sequences of archaebacterial components A and C were aligned with each other and with the sequences of corresponding (largest) subunits from the archaebacterium Methanobacterium thermoautotrophicum, with sequences of various eukaryotic nuclear RNA polymerases I, II, and III, and with the sequence of the beta' component from E. coli polymerase. The archaebacterial genes for component A are homologous to about the first two-thirds of genes for the eukaryotic component A and the eubacterial component beta', and the archaebacterial genes for component C are homologous to the last third of the genes for the eukaryotic component A and the eubacterial component beta'. Unrooted phylogenetic dendrograms derived from both distance matrix and parsimony analyses show the archaebacteria are a coherent group closely related to the eukaryotic nuclear RNA polymerase II and/or III lineages. The eukaryotic polymerase I lineage appears to arise separately from a bifurcation with the eubacterial beta' component lineage.     

Pharmacokinetics of the immunomodulatory 1,2-O-isopropylidene-3-O-3′-(N′,N′-dimethyl-amino-n-propyl)-D-glucofuranose hydrochloride in normal human volunteers

1,2-O-Isopropylidene-3-O-3(N,N-dimethyl-amino-n-propyl)-D-glucofuranose hydrochloride, I, is a substituted sugar with claimed immunomodulatory action. Pharmacokinetic studies in 10 volunteers (bolus i.v., 100 mg) showed respective half-lives for each exponential in the sum of two exponentials that characterized plasma level decay with time of 4.6 ± 0.4 (SEM) min, t_1/2(₁), and 244±20 min, t_1/2(₂)), The total and renal clearances were 277±20 and 2S4±18 (SEM) ml/min, indicative of tubular secretion. Urinary recovery was 93 ± 2%. The estimated volumes of distribution of the central compartment and overall equilibrated tissues were 14.7±1.9 and 96±8 liters, respectively. Sequential daily oral administration of large amounts in capsules (1.2, 2.1, 2.9, 4.1, and 5.0 g) permitted an estimate of 63±4 (SEM)% bioavailability from urinary recovery of drug, with estimated terminal half-lives of 454 ± 25 min from minimal data. Orally administered 2.03 g showed a rapid absorption (t_1/2=10 min) after a lag time of 23 min, and a terminal plasma half-life of 344 min. Plasma protein binding of I was negligible. The erythrocyte/plasma water partition coefficient was close to unity.     

Simplified methods for the evaluation of the parameters of the time course of plasma concentration in the one-compartment body model with first-order invasion and first-order drug elimination including methods for ascertaining when such rate constants are equal

The many limitations in determining the pharmacokinetic parameters of firstorder invasion of, and elimination from, the onecompartment body model by the method of residuals or by feathering Ct data can be minimized by applying the simplified methods outlined herein. Comparisons of the apparent volumes of distribution, V, calculated on the premises that the Bateman Function represents k_a>k_e or its converse, k_e>k_a,i.e., flip-flop, can permit a proper choice of the correct version. Estimation of k_e can be obtained by regression of (A₀/V)/C(oncentration) on AUC₁/ Cwhere A₀/Vis estimable from knowledge of C_max and t_max since .The ratio of the magnitude of the rate constant of invasion to that of elimination, m=k_a/k_e,is related to k_et_max by the expression k_et_max=ln m/ (m–1)for all possible values of m.A table for the determination of m from values of k_et_max is given. When bioavailability, =A₀/Dose,is known or complete, k_e and Vcan be determined from the respective ordinate and abscissa of the intersection of and Cl(clearance)/k_e,both plotted against arbitrary k_e values. The two functions may not intersect at low values of mdue to errored C-t values but the k_e value when the two curves are closest (k_min)may approximate k_e.The intersections of and k_eAUCT (AUC_trap)plotted against variable k_e values (Method A) provide estimates of k_e from their abscissa values and A/Vfrom their ordinate values when is unknown. Method B appears to give more reliable estimates of k_e at the k_min of the difference plotted against k_e.Since k_min of this plot is 1/t_max when m=1,the identity of the mas unity underlying the C-t data is indicated when either k_mint_max is approximately unity or k_min ispractically synonymous with 1/t_max.This was clearly shown when 12 constructed m=1,C-t cases with 10% random error were evaluated by Method B. Better estimates were effected by all procedures when the raw C-t data were smoothed.We regretfully announce that Dr. Edward Garrett passed away on October 25, 1993, after an extended illness.     

Anterior cruciate ligament tears: MR imaging compared with arthroscopy and clinical tests

Seventy-nine magnetic resonance (MR) studies of the knee were reviewed in an evaluation of the ability of MR imaging to demonstrate arthroscopically proved anterior cruciate ligament (ACL) tears. MR findings were also compared with the findings of two commonly applied clinical tests of ACL instability: the Lachman test and the anterior drawer test. The sensitivity of MR imaging was 94% (17 of 18), compared with 78% (14 of 18) for the anterior drawer test and 89% (16 of 18) for the Lachman test. The specificity was 100% for all three. Three MR criteria were applied: irregularity or a wavy contour of the anterior margin of the ligament, high-signal-intensity change within the substance of the ligament on T2-weighted images, and discontinuity of that substance. The sagittal T2-weighted image was especially helpful, producing an "arthrographic" effect, in which the anterior margin of the ACL is outlined by high-signal-intensity joint fluid. By demonstrating ACL and other extrameniscal lesions, MR imaging may help clarify the mechanisms of knee injury.     

Atypical distribution of Pneumocystis carinii infiltrates during radiation therapy

Bilateral peripheral pulmonary infiltrates caused by Pneumocystis carinii developed in a patient undergoing mediastinal irradiation after chemotherapy for Hodgkin disease. The paramediastinal part of the lung included within the treatment port remained clear during the 2 1/2 weeks of radiation therapy. The distribution of the pneumocystis infiltrates was altered by the radiation, producing a pattern that is the "radiographic negative" of typical post-radiation therapy paramediastinal fibrosis.     

Computed axial tomography of the heart

CT scanning provides useful cardiac imaging but has not become a routine clinical tool for heart disease due to long exposure times (2–5 seconds) and the limitation of single slice acquisition. A revolutionary high speed (Cine) CT electron beam scanner was designed at UCSF, with multilevel millisecond scanning speed at rates of 17 scans per second. Table tilt and swivel permits direct imaging in various planes including the half axis view. Images can be analysed as closed loop movies, and quantitation of wall thickening, wall mass and ejection fractions are being validated. High resolution imaging without the need for gated acquisition is a significant advantage over nuclear medicine and magnetic resonance imaging, and physiology can be studied with exercise of other interventions. Fast CT can measure vessel blood flow and has great potential for estimating myocardial perfusion using indicator dilution theory and small peripheral intravenous injection of contrast medium. Cine CT could become the noninvasive modality of choice in cardiovascular diagnosis the scanner has universal application for all organ systems.     

Understanding the role of COVID-19–related workplace stress and institutional betrayal on mental health in nurses: Some heroes wear scrubs

This study examined the association of three specific COVID-19–related workplace stressors (percentage of nursing work with COVID-positive [COVID+] patients, number of COVID-19–related patient deaths witnessed, and living separately from family for safety) and their associations with posttraumatic stress symptoms (PTSS) and symptoms of major depressive disorder (MDD) and generalized anxiety disorder (GAD) among 391 nurses (93.6% White, 93.4% utilize she/her pronouns). Cross-sectional data were collected via an online survey. Institutional betrayal (i.e., the perception that an institution failed to protect a member who depends on and trusts it) was examined as a moderator of these associations. Although institutional betrayal was not a significant moderator in the three individual models, it held small-to-medium–sized positive main effects with PTSS and symptoms of GAD and MDD in both the individual and combined models. In the individual models, the percentage of nursing work with COVID+ patients was significantly positively associated with all three mental health conditions, f² = .019–.195, whereas it only showed a significant effect with PTSS in the combined model, f² = .138. Living separately from family was significantly positively associated with PTSS and MDD symptoms in both the individual, f² = .037 and .015, respectively, and combined models, f² = .025 and .013, respectively. Number of patient deaths held a significant positive association with PTSS alone, f² = .022, in the individual model only. The findings are discussed in light of ways in which health care settings can better support and prioritize mental health among nursing staff.