Site of ocular hydrolysis of a prodrug, dipivefrin, and a comparison of its ocular metabolism with that of the parent compound, epinephrine. (73/85)

Dipivefrin is a prodrug of epinephrine which is hydrolyzed to epinephrine after absorption into the eye. The major site of this hydrolysis is shown to be the cornea. Some dipivefrin is absorbed unchanged into ocular tissues, but most appears as epinephrine and its metabolites within 15 min after topical application. Metanephrine is the major metabolite of epinephrine found in ocular tissues. It is found as soon as 15 min aftter application of either dipivefrin or epinephrine and appears in all the tissues tested. The data indicate that the peinephrine which is liberated by hydrolysis of topically applied dipivefrin is metabolized similarly to topically applied epinephrine. The monoamine oxidase metabolites of epinephrine appear 1 to 3 hr after treatment and are found mainly in the aqueous humor. After ocular application of either compound there appear to be uptake and storage of the exogenous epinephrine in the iris plus ciliary body. There is also some storage of unmetabolized epinephrine in the cornea.  (+info)

Epinephrine is metabolized by the spinal meninges of monkeys and pigs. (74/85)

BACKGROUND: Epinephrine commonly is added to epidural opioids and local anesthetics, however, little is known about the fate of epidurally administered epinephrine. Studies have identified the epinephrine metabolizing enzyme, catechol-O-methyl transferase (COMT), in the cranial meninges of several species. The purpose of this study was to determine whether the spinal meninges also contain COMT and are capable of metabolizing epinephrine. If so, then the spinal meninges may have an important impact in limiting the bioavailability of epinephrine in both the spinal cord and epidural space. METHODS: Spinal meningeal specimens measuring 4 cm2 were obtained from monkeys (M. nemestrina) and farm-bred pigs and were incubated in bicarbonate-buffered mock cerebrospinal fluid. Epinephrine (200 micrograms base) was added at t = 0, and 200 min later, the mock cerebrospinal fluid was collected for metanephrine analysis. In separate experiments, pig meningeal specimens were separated into dura mater, pia-arachnoid mater, and pia mater, and the experiments were repeated to determine which meninx had the greatest COMT activity. RESULTS: Metanephrine was produced by monkey meninges at the rate of 0.47 ng.min-1.cm-2 and by pig meninges at the rate of 0.23 ng.min-1.cm-2 (P > 0.05). The pia-arachnoid meninx produced metanephrine at a greater rate (4.48 +/- 0.46 ng.min-1.mg-1 tissue) than did the pia mater (1.3 +/- 0.15 ng.min-1.mg-1 tissue) or dura mater alone (1.82 +/- 0.23 ng.min-1.mg-1 tissue). CONCLUSIONS: These data demonstrate the functional presence of COMT in the spinal meninges of pigs and monkeys and suggest that the spinal meninges may limit the spinal bioavailability of epidurally or intrathecally administered epinephrine.  (+info)

Reduction in sympathetic activity after long-term CPAP treatment in sleep apnoea: cardiovascular implications. (75/85)

Twelve patients with severe obstructive sleep apnoea were included in an open, long-term, prospective, follow-up study addressing the effects of nasal continuous positive airway pressure (CPAP) on sympathetic activity, cardiac structure and blood pressure. Plasma norepinephrine (P-NE) (daytime at rest), daytime and night-time urinary excretion of NE (U-NE), vanylmandelic acid and metanephrines, together with 24 h noninvasive blood pressure (BP) recording and Doppler-echocardiography, were assessed before and after a mean of 20.5 (range 14-26) months of CPAP. Average self-reported use of CPAP was 89% (range 65-100%) of time spent in bed. Resting daytime P-NE ranged 0.35-0.83 ng.ml-1, which is elevated compared to healthy controls. Only night-time U-NE, mean daytime BP and average 24 h BP were related to severity of OSA. Night-time metanephrine was related to daytime and night-time diastolic, as well as night-time systolic, BP. Left ventricular mass index (LVMI) at baseline was correlated to daytime systolic BP and P-NE. Long-term CPAP treatment reduced biochemical markers of sympathetic activity. P-NE decreased by approximately 50%, and daytime and night-time vanylmandelic acid and metanephrine by 32-54%. In contrast, there were no overall reductions in BP or LVMI. It is concluded that obstructive sleep apnoea is associated with high sympathetic activity both during sleep and waking periods. Urinary metanephrine excretion seemed to reflect blood pressure, but neither daytime nor night-time catecholamine excretion was directly related to disease severity in patients with severe obstructive sleep apnoea.(ABSTRACT TRUNCATED AT 250 WORDS)  (+info)

Urinary and plasma catecholamines and urinary catecholamine metabolites in pheochromocytoma: diagnostic value in 19 cases. (76/85)

We review our data on the measurement of catecholamines and their metabolites in 19 patients with pheochromocytoma. All the assays were specific high-performance liquid chromatographic procedures with electrochemical detection. The assay of fractionated metanephrines was 100% sensitive. Normal values for both urinary norepinephrine and epinephrine were found in two asymptomatic patients with pheochromocytoma. Normal values for 3-methoxy-4-hydroxymandelic acid (VMA) were found in two patients with pure epinephrine-secreting tumors and in one patient with multiple endocrine neoplasia type II. Plasma catecholamines were usually less increased than their urinary counterparts. We recommend the specific measurement of norepinephrine and epinephrine as the initial test for patients with suggestive symptoms, and specific measurement of normetanephrine and metanephrine for patients in whom an adrenal mass is incidentally found. We argue against the use of total metanephrines, total catecholamines, and VMA because of their lack of diagnostic sensitivity.  (+info)

Urinary metanephrine and normetanephrine determined without extraction by using liquid chromatography and coulometric array detection. (77/85)

We describe a procedure for the direct measurement of metanephrine (MN) and normetanephrine (NMN) in hydrolyzed urine, using HPLC with coulometric array detection. Acid-hydrolyzed samples were diluted and filtered before separation by isocratic reversed-phase ion-pair chromatography. Eight serial coulometric sensors, set at incrementally increasing anodic potentials, were used to screen lower-oxidizing interferences and provide stepwise oxidation of the metanephrines. Voltammetric behavior across three adjacent sensors was used to assess resolution and aid in peak identification. Values obtained in commercial controls were consistently within the specified target range. Variability, expressed as CV, was 5.45-9.22% between runs and 1.60-4.52% within-run for both compounds. The limit of detection was 2.6 micrograms/L for MN and 2.8 micrograms/L for NMN, with a linear response to 15.0 mg/L for both analytes. Results from patients' samples correlated well with those by a method involving dual ion-exchange extraction (r = 0.963, n = 82 for MN; r = 0.9768, n = 83 for NMN). This procedure provided high selectivity and objective peak purity information while greatly simplifying sample preparation.  (+info)

Determination of metanephrines in plasma by liquid chromatography with electrochemical detection. (78/85)

Metanephrines are O-methylated metabolites of catecholamines. We report the use of liquid chromatography with electrochemical detection to determine plasma concentrations of normetanephrine (NMN) and metanephrine (MN). Plasma NMN and MN in 32 normal volunteers and inpatients were compared with concentrations in 23 patients with pheochromocytoma. Metanephrines were adsorbed from plasma onto a cation-exchange column and eluted with ammoniacal methanol. The dried residue was dissolved in mobile phase and injected onto a reversed-phase column. Recoveries of NMN and MN from 1 mL of plasma averaged 50-70%, and results varied linearly with quantity injected over a range of 0.13-55 pmol. The detection limit was 25 fmol for NMN and 50 fmol for MN. Intra-assay CVs were < 5%. In normal volunteers and inpatients, plasma concentrations of NMN ranged between 0.12 and 0.73 nmol/L (mean 0.38 nmol/L), and MN between 0.06 and 0.63 nmol/L (mean 0.19 nmol/L). Plasma NMN concentrations were increased in all 23 patients with pheochromocytoma (range 1-172 nmol/L), whereas MN concentrations (range 0.10-382 nmol/L) were increased in only 9 patients. The assay method is reliable and sensitive and offers an approach to examine the extraneuronal metabolism of catecholamines. The method may also be useful in the diagnosis of pheochromocytoma.  (+info)

Biochemical diagnosis of phaeochromocytoma: two instructive case reports. (79/85)

The biochemical features of two patients with phaeochromocytomas illustrate the inadvisability of depending on a single group of analytes for the diagnosis. The first case presented as a surgical emergency with retroperitoneal haemorrhage. Biochemical diagnosis was difficult since total 24 hour urinary free catecholamine excretion was within normal limits in two out of three samples, and only marginally raised in the third with an atypical preponderance of adrenaline. Plasma catecholamine concentrations were also normal. But urinary excretion of the catecholamine metabolites, metadrenaline and 4-hydroxy-3-methoxy mandelic acid (HMMA), was consistently raised. In contrast, the second patient presenting with headache and labile hypertension showed normal metabolite excretion in the face of grossly increased free noradrenaline excretion and raised plasma noradrenaline concentrations. It is therefore recommend that, as well as urinary free catecholamines, one group of their main metabolites, the 3-methoxy amines (normetadrenaline and metadrenaline) or HMMA, should routinely be measured whenever a phaeochromocytoma is suspected.  (+info)

Radioimmunoassay for free and conjugated urinary metanephrine. (80/85)

We describe a convenient and specific radioimmunoassay for urinary metanephrine, in which we used an antiserum generated in rabbits by injecting with synephrine conjugated to bovine serum albumin as described by Grota and Brown [Endocrinology 98, 615 (1976)]. The antiserum is specific for metanephrine and epinephrine. Epinephrine cross reaction is minimized to 1% by adding 2 ng of epinephrine to each assay tube. Incubation time is 12 h. The sensitivity of the assay is 40 pg. Within-and between-assay coefficients of variation are 7.0 and 9.7%, respectively. We assayed first-voided morning urine and 24-h urine specimens from 15 normal subjects before and after acid hydrolysis, to assess total and free metanephrine concentrations. Mean (+/-SD) total and free urinary metanephrine excretion were 17 +/- 11 and 3.5 +/- 1.0 micrograms/24 h in these subjects; corresponding values for the morning specimens were 13.4 +/- 8.3 and 3.5 +/- 1.5 micrograms/liter, respectively.  (+info)