Biochemical characterization and autoradiographic localization of central substance P receptors using [I]physalaemin

The binding of [¹²⁵I]physalaemin to rat brain slices was investigated. Radiolabeled physalaemin bound with high affinity (K_d = 0.3 nM) to a single class of sites (B_max = 22 fmol/mg protein). Kinetic studies indicated that binding was time-dependent and all specific binding was reversible. Pharmacology studies indicated that specific [¹²⁵I]physalaemin binding was inhibited by structurally related peptides such as substance P and eledoisin. Biochemical studies indicated that specific binding of radiolabeled physalaemin was greatly reduced if the brain slices were pretreated with heat, trypsin or N-ethyl maleimide. Autoradiographic studies indicated that the [¹²⁵I]physalaemin binding sites were discretely distributed throughout the brain. Highest grain densities were present in the olfactory bulb, dentate gyrus, amygdala, superficial layers of the superior colliculus, subiculum, dorsal parabrachial nucleus, locus coeruleus, nucleus tractus solitarii and dorsal horn of the spinal cord. Moderate grain densities were present in the nucleus accumbens, olfactory tubercle, pyriform cortex, striatum, hippocampus, inferior colliculus and central gray of the midbrain. Low grain densities were present in most thalamic nuclei, the substantia nigra and cerebellum. The corpus callosum and controls treated with 1 μM unlabeled physalaemin had negligible levels of binding. The unique pharmacological and regional distribution data obtained suggest that [¹²⁵I]physalaemin may serve as a valuable probe to study central substance P receptors.     

Effect of benzodiazepines on the metabolism of buprenorphine in human liver microsomes

Objective To determine whether enzyme inhibition explains the clinical adverse interaction of benzodiazepines and buprenorphine.Methods Buprenorphine was incubated in the presence of benzodiazepines (or metabolites) with human liver microsomes (HLMs). A number of benzodiazepines were screened at therapeutic concentrations after 0-min and 15-min preincubation times. For tentative metabolically activated inhibitors, the kinetics of inhibition was studied in a secondary incubation system. Buprenorphine and norbuprenorphine were quantified by means of liquid chromatography–mass spectrometry.Results Buprenorphine elimination and norbuprenorphine formation were at most reduced by 26% (i.e., weak or negligible inhibition). Evidence of metabolically activated inhibition suggested the need for further studies on the inhibitory kinetics. Midazolam caused time- and concentration-dependent inhibition of norbuprenorphine formation with pseudo-first-order kinetics, and K _I and k _inact values of 10.5 M and 0.045 min^–1, respectively. Mixed-type inhibition of buprenorphine elimination (K_i=30–35 M) and a noncompetitive inhibition of norbuprenorphine formation were also observed. For clonazepam (up to 10 M), 3-hydroxy-7-acetamidoclonazepam (up to 10 M), and -hydroxy-triazolam (up to 1.0 M), no time- or concentration-dependent inhibition of buprenorphine metabolism was found.Conclusion A single benzodiazepine, midazolam, is a moderate mechanism-based inactivator of buprenorphine N-dealkylation. It is anticipated that repeated exposures to midazolam might alter the in vivo metabolism of buprenorphine.     

Response of a recurrent choroid plexus tumor to combination chemotherapy

Summary Choroid Plexus tumors are rare. Surgery and biopsy is diagnostic, and radiotherapy has been used as the treatment of choice for choroid plexus carcinoma (CPC) and recurrent choroid plexus papilloma (CPP). We report the first case of CPP responding to combination chemotherapy consisting of cisplatin, bleomycin and vinblastine (CBV). This chemotherapy regimen should be considered for future trials in patients with choroid plexus tumors and recurrence after surgery and/ or radiotherapy. Address for offprints: Bernard L. Maria, M.D., Division of Pediatric Neurology, Department of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland.     

Effect of ultrasonic nebulization on arterial oxygen saturation in chronic obstructive pulmonary disease.

Twenty patients with mild to severe chronic obstructive pulmonary disease received ultrasonic nebulization to assess the danger of short-term changes in blood gas levels during this therapy. The status of arterial oxygenation was monitored during 20 minutes of therapy and for 20 minutes following therapy. In nine patients with periodic studies of arterial blood, the mean change in arterial oxygen pressure from base line was a decrease of 0.8 mm Hg at ten minutes into therapy, 2.8 mm Hg at the conclusion of therapy, and 2.9 mm Hg 20 minutes after therapy. In all 20 patients, ear oximetric studies showed only a small mean change at ten minutes into therapy, at the end of therapy, and at 20 minutes after therapy. Changes in the status of arterial oxygenation during and after therapy with ultrasonic nebulization in a group of patients with chronic obstructive pulmonary disease are generally small and of no statistical and limited clinical significance; however, alarming falls in arterial oxygenation can occur and cannot be predicted by base-line testing of pulmonary function or studies of arterial blood. It would be prudent to monitor patients with chronic obstructive pulmonary disease during therapy with ultrasonic nebulization or to withhold therapy altogether.     

A cardiac output computer for the rapid analysis of indicator dilution curves

The determination of cardiac output and central blood volume is of considerable importance, not only in cardiac research but i the diagnosis and treatment of heart disease. At present, the most clinically adaptable method of determining these parameters is the indicator-dilution technique. However, analysis of indicator-dilution curves is laborious, requiring 20–40 min. of a skilled operator's time. A simple instrument has been devised which permits the determination of cardiac output and central blood volume in less than one min. The computer described in this paper makes use of an electronically-generated curve which is displayed on a CRT and optically superimposed on the actual indicator-dilution curve. Three manual controls, used to match the curves, yield the desired parameters. The computer may be used to analyse curves within the following ranges: Curve amplitude (2A)—2.5–10 cm; Period (T)—2.5–10 sec; Time constant (CT)—(0.25–1)×T sec; Injection (I)—5–12.5 mgm; Calibration (M)—5–1.2 cm/mgm-liter; Cardiac output—0–48 liters/min Mean transit time—25 sec full scale.