Chronopharmacokinetics of beta-receptor blocking drugs of different lipophilicity (propranolol,metoprolol, sotalol,atenolol) in plasma and tissues after single and multiple dosing in the rat

Summary Comparative pharmacokinetic studies with the -receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 moles/kg) or multiple (6x6 moles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C₀-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance,V _d) with the exception inV _d of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L. It is concluded that L-D-differences in drug half-lives after single dose application are mainly due to circadian variations in drug elimination with a higher hepatic (propranolol, metoprolol) or renal (sotalol, atenolol) elimination in the activity period of rats during D. Additional studies with propranolol on heart rate of conscious rats revealed that a maximum in -receptor blockade was achieved at 10 moles/kg in L but not in D. Thus, it is assumed that abolition of circadian-phase-dependency in half-lives after 6x6 moles/kg of the drugs may be due to the longer lasting and more pronounced -receptor blockade after multiple drug dosing over a period of several hours in D. Thereby, liver-flow-dependent elimination of propranolol and metoprolol and renal elimination of sotalol and atenolol is reduced to base-line levels found in L.Parts of this work were presented at the 22nd Spring Meeting (Lemmer 1981) and at the Joint Meeting (Lemmer et al. 1983a) of the German Pharmacological Society     

Differential effect of nerve fiber structure on block by local anesthetic

The incidence of conduction block by lidocaine 0.3 mmol/l (8.1 mg/dl) in several successive lengths of individual afferent axons of rabbit was compared. The conduction velocity of the axons was either "slow," "intermediate" (1.3-4 m/s), or "fast." The "intermediate" group showed a higher incidence of proximal acceleration of conduction (P less than 0.001) and a greater incidence of block (P less than 0.001) than the "slow" and "fast" fiber groups. The results were interpreted as indicating that the fibers of the "intermediate" group had an unmyelinated peripheral and a myelinated proximal length, with a junctional heminodal region that was the seat of the high sensitivity to block. The potential clinical significance of the observation is discussed in terms of the known distribution of heminodes in the peripheral nervous system.     

Convulsive Therapy: Fifty Years of Progress

The origins of convulsive therapy, its early developments, present practice, central elements of the treatment, and neurohumoral and neuroendocrine theories of its antidepressant action are reviewed on the 50th anniversary of its introduction.     

Serial Dexamethasone Suppression Tests and Clinical Outcome in ECT

Serial dexamethasone suppression tests (DST), obtained during a course of electroconvulsive therapy in 43 severely depressed patients, did not exhibit relationships between the initial DST, final DST, or the change in DST with clinical outcome measures at the time of discharge. In 37 patients reviewed six months after discharge, no relationship with the continuation of improvement, rehospitalization, or suicide was found. We are unable to confirm a clinical application for the DST in the management of patients during a course of convulsive therapy.     

Trends and Outcomes in Simultaneous Liver and Kidney Transplantation in Australia and New Zealand

AimRates of simultaneous liver and kidney transplantation (SLKT) have increased, but indications for SLKT remain poorly defined. Additional data are needed to determine which patients benefit from SLKT to best direct use of scarce donor kidneys.MethodsData were extracted from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) database for all SLKT performed until the end of 2017. Patients were divided by pretransplant dialysis status into no dialysis before SLKT (preemptive kidney transplant) and any dialysis before SLKT (nonpreemptive). Baseline characteristics and outcomes were compared.ResultsBetween 1989 and 2017, inclusive, 84 SLKT procedures were performed in Australia, of which 24% were preemptive. Preemptive and nonpreemptive SLKT recipients did not significantly differ in age (P = .267), sex (P = .526), or ethnicity (P = .870). Over a median follow-up time of 4.5 years, preemptively transplanted patients had a statistically equivalent risk of kidney graft failure (hazard ratio (HR) 1.83, 95% confidence interval [CI]: 0.36-12.86, P = .474) and all-cause mortality (HR 1.69, 95% CI: 0.51-5.6, P = .226) compared to nonpreemptive patients. Overall, 1- and 5-year survival rates for all SLKTs were 92% (95% CI: 86-96) and 60% (95% CI: 45-75), respectively.ConclusionKidney graft and overall patient survival were similar between patients with preemptive kidney transplant and those who were dialysis dependent.     

Chaperone-mediated protein folding

The folding of most newly synthesized proteins in the cell requires the interaction of a variety of protein cofactors known as molecular chaperones. These molecules recognize and bind to nascent polypeptide chains and partially folded intermediates of proteins, preventing their aggregation and misfolding. There are several families of chaperones; those most involved in protein folding are the 40-kDa heat shock protein (HSP40; DnaJ), 60-kDa heat shock protein (HSP60; GroEL), and 70-kDa heat shock protein (HSP70; DnaK) families. The availability of high-resolution structures has facilitated a more detailed understanding of the complex chaperone machinery and mechanisms, including the ATP-dependent reaction cycles of the GroEL and HSP70 chaperones. For both of these chaperones, the binding of ATP triggers a critical conformational change leading to release of the bound substrate protein. Whereas the main role of the HSP70/HSP40 chaperone system is to minimize aggregation of newly synthesized proteins, the HSP60 chaperones also facilitate the actual folding process by providing a secluded environment for individual folding molecules and may also promote the unfolding and refolding of misfolded intermediates.     

Human V5/MT+: comparison of functional and cytoarchitectonic data

To date, the delineation of the human visual “motion area” still relies on functional paradigms originally devised to identify monkey area MT. Using fMRI, we have identified putative human area V5/MT+ in normals by modelling the BOLD responses to alternating radially moving and stationary dot patterns. Functional activations were compared with cytoarchitectonic probability maps of its putative correlate area hOc5, which was calculated based upon data from histological sections of ten human post-mortem brains. Bilateral visual cortex activations were seen in the single subject dynamic versus stationary contrasts and in the group random-effects analysis. Comparison of group data with area hOc5 revealed that 19.0%/39.5% of the right/left functional activation was assigned to the right/left hOc5. Conversely, 83.2%/53.5% of the right/left hOc5 was functionally activated. Comparison of functional probability maps (fPM) with area hOc5 showed that 28.6%/18.1% of the fPM was assigned to hOc5. In turn, 84.9%/41.5% of the area hOc5 was covered by the respective fPM. Thus, random-effects data and fPMs yielded similar results. The present study shows for the first time the correspondence between the functionally defined human V5/MT+ and the post-mortem cytoarchitectonic area hOc5.