Estimated Plasma Concentration Research Articles

Validation of the Friedewald formula for the determination of low-density lipoprotein cholesterol compared with β-quantification in a large population

Lipoprotein data from 9477 subjects, covering a wide range of total plasma cholesterol levels, were used to examine the validity of the Friedewald formula for estimating plasma concentrations of low-density lipoprotein cholesterol (LDL-C) using high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations. Values of LDL-C obtained from the Friedewald formula were compared with values of LDL-C derived from preparative ultracentrifugation used as a reference method. We found that the bias associated with the Friedewald formula was not related to plasma LDL-C levels and was smaller than −4.0% even for plasma LDL-C values <3.0 mmol/l. Moreover, in the subgroup of individuals with plasma TG levels ≤4.5 mmol/l, the Friedewald formula underestimated LDL-C levels with a bias between −3.1% and −1.9% according to TG quartiles. Interestingly, the Friedewald formula showed no significant bias in patients with plasma TG levels between 4.51 and 8.82 mmol/l, suggesting that the calculated LDL-C are reliable and could be clinically useful in patients with plasma TG levels higher than 4.5 mmol/l which is the reference cut-point value used by most clinical laboratories. Finally, multiple regression analyses showed that the very low-density lipoprotein cholesterol (VLDL-C)/TG ratio represented nearly 63% ( P < 0.0001) of the variance of the bias associated with the Friedewald formula. We concluded that the Friedewald formula may be reliable at low LDL-C levels and at TG levels up to 9 mmol/l but may be used with caution when the VLDL-C/TG ratio is high as observed in patients with type III dysbetalipoproteinemia.

Noninvasive brain imaging: Quantifying the time dependence of Remifentanil analgesia in the human brain using functional magnetic resonance imaging

To understand and exploit centrally acting analgesic drugs requires reliable measures of their time-course of action in the human brain. Functional magnetic resonance imaging (FMRI) can measure non-invasively, drug-induced changes in pain-related human brain activity. Here, we have characterized the time of onset of action and the effective half-life of action of a clinically relevant dose of the opioid analgesic agent, remifentanil. Nine male volunteers underwent FMRI (BOLD contrast EPI) at 3T for 30mins (TR=3s, TE=30ms, resolution 4mm, 21x6mm slices). Consistent painful hot stimuli (duration 3s) were applied to the dorsum of the left hand (mean interval=65s). Subjects rated stimuli for pain intensity (5-point scale). Remifentanil was intravenously infused to an estimated plasma concentration of 1.0ng/ml and then cleared as imaging continued. The temporal variation of the amplitude of the BOLD FMRI response to pain, in the insular region contralateral to the stimulus (known to respond to painful stimuli), and the perceived pain intensity were modelled using simple exponential functions. From these we estimated the half-lives of drug onset (equilibration time t1/2ke0) and offset (context sensitive half-life t1/2) of action. Onset time (t1/2ke0) measured from FMRI was 1.83 (-2.17,5.83) min and offset half-life (t1/2) was 3.07 (1.09,5.05) min. Onset time measured from pain intensity scores was 2.80 (-0.12,5.73) min and offset half-life was 2.80 (1.12,4.48) min. 95% confidence intervals are given in parentheses. Onset and offset times of drug action from the insular cortical FMRI signal agreed with the reported analgesia and with previously reported EEG measurements (Minto,C.F. et al. 1997). We demonstrate for the first time, the use of FMRI to measure pharmacokinetic parameters for an analgesic drug from its effect on pain-related activity in a specific brain region, the insular cortex. Acknowledgements: RGW: The Dr Hadwen Trust and The Wellcome Trust. PW: GlaxoSmithKline.

Propofol suppresses the cortical somatosensory evoked potential in rats.

The dose-response curve for the effect of volatile anesthetics on the somatosensory evoked potential (SEP) is well described, but for propofol, the large dose segment of the curve is undefined. We describe the effect of increasing plasma concentrations of propofol on cortical SEPs in 18 rats. After surgical preparation under ketamine anesthesia, a remifentanil infusion was begun at 2.5, 5, or 10 microg x kg(-1) x min(-1). After 20 min, the propofol infusion was initiated at 20 mg x kg(-1) x h(-1) and was increased to 40, 60, and 80 mg x kg(-1) x h(-1) at 20-min intervals. SEP was recorded before remifentanil infusion, before propofol infusion rate changes, and 30 min after discontinuing propofol infusion. In six additional rats, the plasma concentrations of propofol after each 20-min infusion were measured using gas chromatography. Remifentanil did not have a significant effect, but propofol significantly depressed the SEP amplitude and prolonged the latency at infusion rates of 40 mg x kg(-1) x h(-1) and more. Propofol's effect was dose-dependent, but even at 80 mg x kg(-1) x h(-1) with an estimated plasma concentration of 31.6 +/- 3.4 microg/mL (10.8 50% effective concentration), a measurable response was present in 44.5% of rats. These results suggest that even at large doses, propofol and remifentanil provide adequate conditions for SEP monitoring. Rats demonstrate dose-dependent somatosensory evoked potential (SEP) suppression with propofol but not with remifentanil. However, SEP suppression by 50% occurred only at large (1.5 EC(50)) concentrations of propofol, and a measurable SEP was present in 8 of 18 rats, even at 10.8 EC(50).

Measurement of Immunoreactive Angiotensin-(1–7) Heptapeptide in Human Blood

The renal enzyme renin cleaves from the hepatic alpha(2)-globulin angiotensinogen angiotensin-(1-10) decapeptide [Ang-(1-10)], which is further metabolized to smaller peptides that help maintain cardiovascular homeostasis. The Ang-(1-7) heptapeptide has been reported to have several physiological effects, including natriuresis, diuresis, vasodilation, and release of vasopressin and prostaglandins. To investigate Ang-(1-7) in clinical settings, we developed a method to measure immunoreactive (ir-) Ang-(1-7) in 2 mL of human blood and to estimate plasma concentrations by correcting for the hematocrit. A sensitive and specific antiserum against Ang-(1-7) was raised in a rabbit. Human blood was collected in the presence of an inhibitor mixture including a renin inhibitor to prevent peptide generation in vitro. Ang-(1-7) was extracted into ethanol and purified on phenylsilylsilica. The peptide was quantified by radioimmunoassay. Increasing doses of Ang-(1-7) were infused into volunteers, and plasma concentrations of the peptide were measured. The detection limit for plasma ir-Ang-(1-7) was 1 pmol/L. CVs for high and low blood concentrations were 4% and 20%, respectively, and between-assay CVs were 8% and 13%, respectively. Reference values for human plasma concentrations of ir-Ang-(1-7) were 1.0-9.5 pmol/L (median, 4.7 pmol/L) and increased linearly during infusion of increasing doses of Ang-(1-7). Reliable measurement of plasma ir-Ang-(1-7) is achieved with efficient inhibition of enzymes that generate or metabolize Ang-(1-7) after blood sampling, extraction in ethanol, and purification on phenylsilylsilica, and by use of a specific antiserum.

Disodium cromoglycate in children and adolescents with asthma: Correlation between plasma concentrations and protective effects for various inhalation methods

We measured plasma concentrations of disodium cromoglycate for various asthmatic treatments in children and adolescents and estimated plasma concentrations and protective effects. Disodium cromoglycate as a 2mg aerosol (n=13), 4mg aerosol (n=5), or 20mg nebuliser solution (n=13) was inhaled by patients when they had no asthmatic attacks. The plasma concentrations of disodium cromoglycate after 5min of inhalation were 3.04±2.72 ng/mL in the 2mg aerosol group, 2.95±0.86ng/mL in the 4mg aerosol group, and 7.72±4.65ng/mL in the nebuliser solution group. Subjects who used the nebuliser exhibited markedly higher plasma concentrations of disodium cromoglycate. There was a significant correlation between the concentration of disodium cromoglycate at 5min and the protective effect determined by a ratio of the difference in the asthma score between baseline and treatment periods to the baseline asthma score. When the plasma concentration of disodium cromoglycate is low, administration of larger aerosol dose or nebulisation might be necessary.

Cardiovascular effects of equipotent isoflurane and alfentanil/isoflurane minimum alveolar concentration multiple in cats

SUMMARY Objective To determine whether administration of opioids to anesthetized cats induced less cardiovascular depression than that induced by an equivalent amount of anesthetic alone, and to measure endocrine responses to a noxious stimulus. Animals 6 healthy female cats. Procedure Anesthesia was induced with isoflurane and was maintained for 60 minutes at 1.3 isoflurane MAC. Blood gas tensions, pH, and plasma alfentanil and hormone concentrations, blood pressures, and cardiac output were measured. A noxious stimulus was applied for 5 minutes, while blood acquisition and measurements were repeated. Alfentanil was administered IV to achieve estimated plasma concentration of 500 ng/ml, and end-tidal isoflurane concentration was reduced by 35%. After another 60 minutes, blood was obtained and measurements were taken, then a second 5-minute noxious stimulus was applied while blood acquisition and measurements were retaken. Results Alfentanil administration and reduction of isoflurane concentration significantly increased body temperature, heart rate, mean arterial pressure, mean pulmonary arterial pressure, stroke index, cardiac index, hemoglobin, oxygen delivery index, Pvo2 and Pvco2, dopamine, epinephrine (EPI), norepinephrine (NOREPI), and cortisol values, and significantly decreased arterial and venous pH. Application of a noxious stimulus significantly increased heart rate, stroke index, cardiac index, Pao2, oxygen delivery index, arterial and venous pH, and NOREPI values, and decreased bicarbonate, Paco2, Pvco2, and EPI values. Alfentanil administration blunted cardiac index, Paco2, oxygen delivery index, arterial pH, Pao2, and EPI, and NOREPI responses to a noxious stimulus. Conclusions Compared with isoflurane alone, alfentanil administration and reduction of isoflurane MAC improved cardiovascular variables, and blunted respiratory, hormonal, and most hemodynamic responses to a noxious stimulus in cats. Clinical Relevance Use of the balanced opioid anesthesia regimen induced some beneficial effects in healthy cats; effects were similar to, although greater in nature, than effects induced by a noxious stimulus. (Am J Vet Res 1997;58:1267–1273)

Anticonvulsant Efficacy of ADCI (5‐Aminocarbonyl‐10, 11‐dihydro‐5H‐dibenzo[a, d] cyclohepten‐5,10‐imine) After Acute and Chronic Dosing in Mice

ADCI (5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine), a low-affinity uncompetitive N-methyl-D-aspartate (NMDA) antagonist, is a broad-spectrum anticonvulsant with a favorable side-effect profile. In the present study, we sought to determine if tolerance develops to the anticonvulsant activity of ADCI, using the maximal electroshock (MES) test to assess seizure protection. Mice were treated with three daily injections of a 2 x ED50 dose for MES protection (18 mg/kg, intraperitoneally, i.p.) or vehicle for 7 or 14 days. On the day after the chronic treatment protocol, all animals received a challenge dose of ADCI (18 mg/kg) and 15 min later were evaluated in the MES test. In control animals, 83-94% of animals were protected and the ADCI plasma levels immediately after the MES test were 5.5-9.7 micrograms/ml. In treated animals, 29 and 0% of animals were protected at 7 and 14 days, respectively, and the ADCI plasma levels were 77 and 52% of the control values. [3H]Dizocilpine binding to brain NMDA receptors was unaltered by the chronic drug treatment. In subsequent experiments, we determined that 14-day chronically treated animals could be completely protected by increased doses of ADCI (ED50 28.9 mg/kg). In both naive and chronically treated animals receiving a challenge dose of ADCI, plasma drug levels decreased in two phases, the first with a time constant of approximately 55 min and the second with a much slower rate. The estimated plasma concentrations of ADCI reflecting threshold (3-5 micrograms/ml) and 50% protection (5-7.5 micrograms/mg) were similar in naive and chronic animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of arrhythmogenicity of aminophylline in dogs

This study was designed to determine if doses of aminophylline up to 10 mg/kg given i.v. would produce ventricular arrhythmias in seven healthy dogs anaesthetized with fentanyl-droperidol-pentobarbital. Arrhythmias were sought by inspection of ECGs before and after attempts at provoking them with 5 micrograms/kg boluses of epinephrine given i.v., or by programmed electrical stimulation. After cumulative doses of 10 mg aminophylline/kg body weight, producing an estimated plasma concentration of greater than 30 micrograms/ml, no ventricular ectopia other than escape depolarizations were observed. We were unable to document an arrhythmogenic effect of aminophylline when given rapidly by the i.v. route. It is possible that the anaesthetic regimen reduced the arrhythmogenic property of aminophylline, or that arrhythmias might be produced in either obese or ill dogs; but it is unlikely that chronic administration of aminophylline would be more arrhythmogenic.

COMPARISON OF CARDIOPULMONARY RESPONSES TO DETOMIDINE ADMINISTERED AS AN INTRAVENOUS STEADY-STATE INFUSION VS INTRAVENOUS BOLUS IN STANDING HORSES

We compared the cardiopulmonary response to detomidine (DET) administered to two different groups of horses after IV steady-state infusion (n = 7) or IV bolus (n = 6) at similar plasma DET concentrations. Based upon previously reported kinetics, a computer predicted DET plasma concentrations and controlled an infusion pump which maintained steady-state arterial plasma DET for the infusion studies. These pharmacokinetics were used to estimate DET plasma concentrations at measurement times following IV bolus DET in the second group of horses. Cardiopulmonary measurements were made following 15 minutes of steady-state infusion and 30 minutes after IV bolus of DET. DET plasma concentration was estimated to be similar between A), 19 ng DET/ml plasma infusion and 30 minutes following an IV bolus dose of 10 γg DET/kg, (estimated plasma concentration 20.5 ng/ml), and B), 43 ng DET/ml plasma infusion and 30 minutes following an IV bolus of 20 γg DET/kg (estimated plasma concentration 42 ng/ml).

Efficiency of different criteria for selecting pharmacokinetic multiexponential equations

Several statistical and empirical approaches have been proposed to select the multiexponential equation that best describes the time course of the plasma concentration of a drug. Recently, a new criterion (Ip) has been proposed according to which the model that best interprets a set of experimental data points is the one with the smallest area between the approximate confidence limits of estimated plasma concentration. We used large Montecarlo simulations to compare the ability of different selection criteria to select the correct model from data generated with an independent, normally distributed random error. The new criterion (Ip), Akaike's information criterion, the Schwartz test, and the F ratio test were studied. In this situation, the correct model was known and the performances of different selecting methods were assessed by examining their sensitivity to the number of exponential terms, the number of data points, and the size of the exponents in the true model. Mono-, bi-, and triexponential equations were studied. Overall mean percentages of right identification were 98.1 per cent for the new index, 82.8 per cent for Akaike's information criterion, 89.5 per cent for the Schwartz test, and 97.7 per cent for the F ratio test. The Akaike and Schwartz tests were not as efficient as the other tests with few (8-10) data points. The Ip and the F test raise the percentages of right identification of the model when the hybrid elimination rate macroconstants differ by at least a factor of four.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetic studies of the pharmacologic response to captopril in rats. II. Hypotensive effect and plasma angiotensin converting enzyme activity.

The effect of captopril on the mean arterial blood pressure was studied in rats. Two different disease-state rats, namely the sodium-deficient rat (SDR) and the two-kidney-one-clip Goldblatt hypertensive rat (GHR), as well as normotensive rats (NR), were used. After i.v. bolus administration of captopril to each rat, the time course of plasma angiotensin converting enzyme (ACE) activity and mean arterial blood pressure were determined. In a different experiment, the effect of captopril on the plasma ACE activity in vitro was determined. Captopril inhibited the plasma ACE activity in a concentration-dependent manner and the relationship between concentration of captopril and inhibition of plasma ACE activity in vitro was reasonably described by a Langmuir-type equation. Then, plasma concentrations of captopril after i.v. administration were estimated by means of this equation. The estimated plasma concentration of captopril followed a double exponential equation. From the data obtained, a kinetic model including the renin-angiotensin system and pharmacokinetics of captopril was constructed under the following assumptions; (1) the hypotensive effect of captopril is solely attributable to the reduction of angiotensin II level in the body, (2) the production rate of angiotensin II is proportional to the total ACE activity and (3) plasma ACE activity reflects the total ACE activity in the body. Then, the effect of captopril on the mean arterial blood pressure in each type of rat was calculated. The results indicated that the hypotensive effect of captopril in NR was reasonably described by the model. However, the hypotensive effect of captopril in both GHR and SDR could not be well described by the model.(ABSTRACT TRUNCATED AT 250 WORDS)

ROLE OF GROWTH HORMONE ON PLASMA EPIDERMAL GROWTH FACTOR CONCENTRATIONS

Epidermal growth factor (EGF) is known to accelerate proliferation and differentiation of multiple cell types. We previously reported that growth hormone deficient (GHD) children have decreased urinary EGF excretion compared to normal children and the excretion of EGF increases with growth hormone (GH) administration. We developed a heterologous, double antibody radioimmunoassay (RIA) based on mEGF to estimate plasma concentrations of EGF in humans. The detection limit of the assay was 0.10 ng/ml. Using this method, mean concentration of EGF in plasma from adults was 4.8±1.7 ng/ml and the mean concentration in normal children was 8.4±0.3 ng/ml. Plasma and urinary EGF in GHD children before and during treatment (0.08 U GH/kg t.i.w.) are shown in the table below: These data suggest that the plasma concentrations of EGF do not change with GH treatment of GHD children despite increases in urinary excretion. We conclude that the increased urinary excretion of EGF could reflect increased urinary clearance of this factor rather than increased production.

Generation of prostaglandin E2-like radioimmunoreactive material in human plasma during storage at −20 C but not at −80 C

Concentrations of prostaglandin E2 (PGE2) as determined by radioimmunoassay following silicic-acid column chromatography in extracted samples (n=5) of human plasma (Na2EDTA: 18 mg/5 ml blood; indomethacin: 1mg/5 ml blood) were <1.0 pg/ml when the samples were extracted immediately after blood withdrawal. Virtually identical concentrations of PGE2 were determined in samples stored at −80°C for up to 6 months. However, when the same analytical procedures were used after prolonged storage of the plasma samples at −20°C an apparent rise in the estimated plasma concentrations of PGE2 up to 5.1 ± 1.9 pg/ml (3 months) and to 25.2 ± 7.8 pg/ml, (6 months) was observed. Repeated freezing and rethawing of 4 plasma samples within 48 hours after blood withdrawal did not influence concentrations of PGE2 thus excluding acute destruction of residual platelets as the cause of the observed time-dependent rise in radioimmunologically determined ‘PGE2’. Two plasma samples stored at −20°C for 26 months were subjected to HPLC subsequent to silicic acid column chromatography. Radioimmunoassay of PGE2 performed for each eluted fraction resulted in 3 distinct peaks of “PGE2”-like activity, suggesting heterogeneity of cross-reacting compounds generated during prolonged storage at −20°C. In conclusion, to determine concentrations of PGE2 in human plasma by means, of radioimmunoassay the samples should either be extracted immediately after blood withdrawal or be kept at −80°C.

Effects of ranitidine and of cimetidine on pentagastrin-stimulated gastric acid secretion

We compared the effect of oral and intravenous ranitidine, a new H2-receptor antagonist, with that of cimetidine on pentagastrin-stimulated gastric acid secretion in normal subjects. Ranitidine in intravenous doses of 20, 60, and 100 mg and oral doses of 100, 150, and 200 mg inhibited acid secretion. Only the 100 mg iv ranitidine dose was substantially more effective than cimetidine. Comparable dose-related decreases in gastric secretory volume were observed. Acid inhibition correlated strongly (r = 0.90) with plasma ranitidine concentration, with the estimated plasma concentration producing 50% inhibition (IC50) being 95 ng/ml. Maximal acid inhibition achieved was 87.3%. We conclude that ranitidine is a potent inhibitor of gastric acid secretion and should be a valuable addition to the medical treatment of acid-peptic disease.

The relationship between plasma concentration of valproic acid and its anticonvulsant and behavioural effects in the rat

The relationship between the plasma concentration of valproic acid (VPA) and anticonvulsant or neurotoxic effects was studied in the rat. Anticonvulsant activity was assessed against; (1) maximal seizures induced either by electroshock or by intravenous injection of pentylenetetrazol; and (2) kindled amygdaloid epilepsy. Drug-induced neurotoxicity was determined by the rotarod test and by observation of behaviour. In the maximal seizure tests, tonic hindlimb extension was always abolished at plasma valproic acid concentrations of 225 μg ml −1 and above. Tonic forelimb extension was not consistently blocked until the plasma drug concentration exceeded 530 μg ml −1. In fully-kindled rats, plasma valproic acid concentrations of 300 μg ml −1 and above markedly reduced the duration of amygdala afterdischarge activity and the intensity of behavioural seizures produced by amygdala stimulation. Analysis of the data from individual kindled rats revealed that there was a significant correlation between the estimated plasma concentration of valproic acid and the degree of seizure protection. Impairment of rotarod performance and marked ataxia occurred at plasma valproic acid concentrations above 510 μg ml −1 and loss of righting reflex became evident at 970 μg ml −1. From these results, it is concluded that the plasma concentration of valproic acid is closely correlated with the anticonvulsant and neurotoxic effects observed in individual rats after acute administration of sodium valproatc.

Saturable kinetics of intravenous chlorothiazide in the rhesus monkey.

A range of bolus doses of 14C-chlorothiazide and unlabeled drug (6.7-30 mg/kg) were administered to each of three unanesthetized rhesus monkeys with and without concurrent probenecid dosing. Plasma up to 4 h and urine up to 24 h were sampled frequently. Apparent terminal plasma half-lives ranged from 18 to 25 min in the absence of probenecid. No apparent trend was noted for the volume of distribution of the central compartment calculated from estimated plasma concentrations at time zero. For chlorothiazide studies, an average of 92% of the dose was recovered in urine by 24 hr. Plasma and urinary clearances at low doses were 20 to 50% higher than those found with higher doses. These dose-dependent clearances for chlorothiazide were found at doses parallel to the most often prescribed clinical doses in humans on a g chlorothiazide per kg body weight basis. Clearances in the presence of probenecid decreased two- to four-fold over those seen without probenecid. Incremental renal clearances of chlorothiazide in the studies with and without probenecid were also evaluated. Curvilinear segments characteristic of dose-dependent kinetics were demonstrated in graphs of urinary excretion rate versus plasma concentrations. Values of Michaelis-Menten constants Vmax and Km were calculated for renal excretion of chlorothiazide by active transport after intravenous doses in all three monkeys. The contribution of glomerular filtration to chlorothiazide renal clearance was found to be negligible. Values of the constant KI (the concentration of the probenecid competitive inhibitor of chlorothiazide, which double the apparent Km value of chlorothiazide) were calculated using the previously calculated Vmax and Km values.

Estimation of the plasma concentration and course of action of phentolamine based on its inhibitory effect on adrenaline-induced platelet aggregation.

Abstract 1 Orally administered phentolamine retards the first phase of adrenaline-induced platelet aggregation. The extent to which aggregation was inhibited was compared in blood samples from six healthy volunteers treated with phentolamine and samples to which various concentrations of the drug were added in vitro. 2 These experiments permitted conclusions to be drawn concerning the magnitude and time-course of the plasma concentrations reached after the administration of phentolamine. A dose of 40 mg of the standard formulation (SF) produced a maximum effect after 30 min corresponding to that of a phentolamine concentration of approximately 12 × 10-8 M (≈34 ng/ml). After 3 h about one-third of the maximum effect persisted, and after 6 h only a slight degree of activity was still detectable. The slow-release formulation (SR) (100 and 200 mg) had a rapid onset of action (1 h); the maximum effect was observed after 4 h, corresponding to an estimated plasma concentration of phentolamine of 11 and 42 ng/ml respectively, and the duration of action was well in excess of 12 h. 3 The time-course of the increase in heart rate and the increase in myocardial contractility (as determined from the pre-ejection period) was largely consistent with the calculated time-course of the plasma concentrations: A dose of 40 mg SF produced its maximum effect after 30-60 min and had a duration of action of 3 h. The maximum effect of the SR formulation was reached after 4 h, and the duration of action was more than 10 h.

Deoxycorticosterone production and regulation in man.

Secretory rates of deoxycorticosterone(DOC) and urinary excretion of tetrahydro-DOC (THDOC) were determined in normal subjects. Mean THDOC excretion (n = 15) was 24 ± 2.4 μg/24 hr and DOC secretion (n = 26) was 164 ± 22.3 μg/24 hr. The mean metabolic clearance rate by either the single injection or the constant infusion technique was 956 ± 69 1/24 hr in three normal subjects, with higher values noted in a patient with hyperthyroidism and one patient with primary aldosteronism. Plasma disappearance t1/2 (n = 2) averaged 70 min, and estimated plasma concentration (n = 3) was 26.0 ± 5.9 mμg/100 ml. Factors that control DOC production were examined in normal subjects and patients with panhypopituitarism. Urinary THDOC increased five-fold in response to ACTH infusion (n = 6) and decreased 50% when ACTH was suppressed by dexamethasone (n = 7), whereas aldosterone excretion responded to a lesser extent. THDOC also increased promptly after ACTH infusion in one patient with panhypopituitarism, compared to a delaye...