Effect-time Curve Research Articles

Orally Administered Progesterone Enhances Sensitivity to Triazolam in Postmenopausal Women

An endogenously formed metabolite of progesterone, 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha-OH-5 alpha-DHP) modulates the gamma-aminobutyric acid receptor complex and plays a physiologic role in brain excitability regulation. On the basis of in vitro observations of 3 alpha-OH-5 alpha-DHP-enhanced [3H]flunitrazepam binding, we investigated the potential clinical effect of coadministering oral progesterone and triazolam. Sixteen postmenopausal women were randomly assigned to receive either intravenous triazolam plus oral progesterone 300 mg (TRZPROG) or intravenous triazolam plus oral placebo (TRZ). Triazolam was infused until 0.5 mg was given or until a predetermined maximal response was attained. Pharmacodynamic evaluation included DSST, continuous performance test, hand-eye coordination, short-term memory, and sedation. Effect ratios were calculated as the ratio of area under the effect-time curve to area under the curve (AUC). Variants of the sigmoid Emax model were fit to the data from the three psychomotor performance tests. A triazolam dose of less than 0.5 mg was administered to seven of eight subjects in the TRZPROG and five of eight subjects in the TRZ group, resulting in lower triazolam AUC values for the TRZPROG than for the TRZ group (p = 0.0275). There was clear evidence for a pharmacodynamic interaction. Mean effect ratios for all tests were greater in the TRZPROG group than in the TRZ group (DSST, p = 0.0097; continuous performance test, p = 0.0338; hand-eye coordination, p = 0.0041). The TRZPROG group had lower EC50 values than the TRZ group (DSST, p = 0.0435; continuous performance test, p = 0.0381; hand-eye coordination, p = 0.0154).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intravenous temazepam. II. A study of the long-term reproducibility of pharmacokinetics, pharmacodynamics, and concentration-effect parameters.

To evaluate the long-term reproducibility of pharmacokinetic, pharmacodynamic, and concentration-effect parameters after intravenous administration of temazepam. Nine healthy volunteers were studied. Temazepam, 0.4 mg/kg, was infused intravenously for 30 minutes on two occasions 6 months apart. Venous plasma concentrations of temazepam were measured by HPLC in samples obtained between 0 and 24 hours. Pharmacodynamic effects were evaluated up to 8 hours for saccadic peak velocity and electroencephalogram (EEG) beta amplitudes. Subjects' state and trait anxiety were assessed by use of the Spielberger anxiety inventory. Significant correlations between occasions were found for area under the plasma concentration-time curve (AUC) values (r = 0.91; p < 0.01) but not for maximum concentration and half-life. Significant correlations were also found for area under the effect-time curve (AUEC) values of peak velocity (r = 0.88; p < 0.01) but not for peak velocity (r = 0.48; p > 0.05). Significant differences between the slopes of concentration effect plots on different occasions were observed in two subjects for EEG beta and in three subjects for peak velocity, with one subject showing a similar change for both parameters. Trait anxiety scores were higher on the first occasion (33 +/- 7) than on the second occasion (29 +/- 7; p < 0.01). A negative correlation was found between trait anxiety scores and the slopes of concentration-effect plots for peak velocity (r = -0.63; p < 0.01). For AUC and AUEC values the results indicate a reasonable long-term reproducibility of differences between subjects in the pharmacokinetics and pharmacodynamics of temazepam. However, there were limitations to the predictive value of derived concentration-effect parameters.

Pharmacodynamic Aspects of Systemic Drug Delivery

AbstractSome of the most common cases of drug delivery (i.v. bolus, first-order absorption and zero-order absorption) are evaluated with respect to the relationship between extent and/or rate of drug absorption and pharmacodynamic outcome. Each case is evaluated after a single dose and at steady state after multiple dosing in a one-compartment body model. The pharmacodynamic model used is the Emax-model with and without an effect compartment. The area under the effect-time curve (AUCe) is used as a cumulative measure for overall drug activity. After first-order absorption, AUCe can vary as a function of absorption rate between a minimum, the AUCE of the equivalent i.v. bolus, Emax/ke*ln[1+D/(E50*Vd)], and a maximum, Emax*D/(E50*CL). After multiple dosing, the degree of fluctuation of the pharmacodynamic effect will depend on the dose and will always be less than the degree of pharmacokinetic fluctuation. A dosing rate (DR50=CL*E50/fu) is proposed that allows calculation of the dose necessary to produce an...

The kinetics of effect of neuromuscular blocking drugs.

In attempts to derive pharmacokinetic constants from effect data three methods were explored, using non-depolarizing neuromuscular blocking drugs as the paradigm for obtaining effect data. The first method, based on the simple assumption that following two doses, the drug concentrations at times of equal effect during recovery, were equal. Provided that recovery took place in the log-linear drug elimination phase, the elimination rate constant (beta) could be calculated. This method proved rather inaccurate, a second method, again dependent on recovery in the log-linear phase yielded a constant which was the product of beta and the exponent of the Hill equation (s). This method yielded results within 20% of values calculated from plasma drug assays, and it was demonstrated that the time-effect curve could be described from knowledge of this constant. The third method, using non-linear curve fitting technique, derived values for the rate constants of plasma redistribution (alpha) and elimination (beta) as well as for the rate constant of elimination from an effect compartment (keo). If the values were derived from the effect of two doses of a drug, the intensity and duration of effect of a third dose could be predicted with reasonable accuracy. The dose dependent constants of the usual compartmental equations for the plasma concentration of a drug (A and B) could be derived in terms of the EC50. The method can be applied to any drug whose effect can be measured and whose maximal effect can be defined. We believe that the method may be useful in rapidly and inexpensively estimating population kinetic parameters, and in screening drugs.

Amlodipine versus atenolol in essential hypertension

The efficacy and safety of amlodipine (2.5–10 mg) once daily was compared with atenolol (50–100 mg) once daily in patients with mild-to-moderate essential hypertension in a randomized, doubleblind, parallel, placebo-controlled study. A total of 125 patients were randomly allocated at the end of a 4-week run-in placebo period to 8 weeks of double-blind treatment with amlodipine (n = 41), atenolol (n = 43), or placebo (n = 41). The placebo group had small mean changes in supine and standing blood pressure compared with baseline. The mean blood pressure changes from baseline 24 hours postdose in the amlodipine group (mean daily dose 8.8 mg) were −12.8/−10.1 mm Hg for supine blood pressure and −11.5/−9.8 mm Hg for standing blood pressure (p < 0.001 compared with placebo), and for the atenolol group (mean daily dose 83.7 mg) the changes were −11.3/−11.7 mm Hg for supine blood pressure and −13.3/−12.3 mm Hg for standing blood pressure (p < 0.001 compared with placebo). There were no statistically significant blood pressure differences between active treatments. The responder rates for amlodipine, atenolol, and placebo were 61.1, 64.9, and 11.1%, respectively. The blood pressure values taken over the 24-hour period at final visit revealed that amlodipine and atenolol maintained the supine blood pressure ≤ 140/90 mm Hg throughout the period of observation; the corresponding time-effect curve for the placebo group was clearly in the hypertensive range. Heart rate was significantly lowered by atenolol only. Both amlodipine and atenolol were well tolerated. Only 1 patient was withdrawn due to adverse effects (development of peripheral edema, arthralgia and fatigue) related to amlodipine. This study demonstrates that once-daily therapy with amlodipine or atenolol was well tolerated in patients with mild-to-moderate essential hypertension and provided control of blood pressure throughout the 24-hour dosing interval.

抗生物質の効果比較のための新しい方法

New time-effect curve (TEC) of antibiotics to compare antibacterial activity is proposed. It consists of a comparison of MIC with drug concentration in blood. A drug concentration at a certain time is obtained from time-concentration curve (TCC), and the expecting effect of antibacterial activity is obtained from MIC-cumulative percent of strain inhibited curves.Antibiotics such as CCL or CPDX-PR show different TECs against each bacteria. Different TECs were obtained using only MIC when comparing with IPM/CS, CPZ and CFS. In the case of DKB, the speed of dropping injections was examined. Against E. coli, different shape of TEC was obtained for each dropping speed, but against P. aeruginosa and Staphylococcus, almost the same TECs were obtained. The dropping speed might not be so important in the latters.

Interaction of intrathecal morphine with bupivacaine and lidocaine in the rat.

The interaction in the rat between intrathecal morphine and local anesthetics (bupivacaine and lidocaine) on nociception (52.5 degrees C hot plate and paw pressure), motor function, and autonomic function (blood pressure [BP] and heart rate [HR]) was examined over a range of doses for both morphine and the local anesthetics. High doses of intrathecal bupivacaine (75 micrograms) or lidocaine (500 micrograms) produced motor block and hypotension (150 micrograms bupivacaine) lasting approximately 15 and 7 min, respectively, whereas low doses of intrathecal bupivacaine (25 micrograms) and lidocaine (100 micrograms) produced only a transient motor weakness lasting 2 min or less. Alone, neither agent altered the hot plate or paw pressure response at doses, or at times, where the agents had no effect upon motor function. In contrast, at the low dose of either local anesthetic, after the resolution of the transient motor weakness, these doses resulted in a significant leftward shift in the dose-response curves for intrathecal morphine on both the hot plate and paw pressure, as measured by the maximum observed peak effect and by the area under the time-effect curve. Thus, for example, the morphine ED50 (95% confidence intervals) for morphine/saline was 1.7 micrograms (0.7-1.9) on the hot plate and 1.1 micrograms (0.8-1.4) on the paw pressure versus for morphine/bupivacaine (25 micrograms): hot plate 0.25 micrograms (0.21-0.42) and paw pressure 0.28 micrograms (0.2-0.4). Intrathecal morphine was not observed to have any effect on the dose-dependent effects of intrathecal bupivacaine on motor or autonomic blockade. Comparable results were also observed with lidocaine (bupivacaine was found to have no significant effect on spinal cord morphine clearance). We conclude that low doses of intrathecal lidocaine and bupivacaine, which alone have no antinociceptive effect, at times when motor function was clearly unimpaired, are able to significantly augment the antinociceptive activity of intrathecal morphine on the hot plate and paw pressure tests. This prominent and selective potentiation appears to occur via a non-pharmacokinetic mechanism and probably reflects upon the interaction of low concentrations of local anesthetics with systems in the spinal dorsal horn that process acute high threshold afferent input.

Pharmacodynamics of methylprednisolone phosphate after single intravenous administration to healthy volunteers.

The pharmacokinetics and pharmacodynamics of methylprednisolone were investigated after intravenous administration of methylprednisolone phosphate to healthy subjects at seven different doses (16 to 1000 mg). Forty different pharmacodynamic parameters were followed for 1 week. The pharmacodynamic data were analyzed as a function of time as well as cumulative effects in form of the areas under the effect-time curves. Statistically significant dose-dependent effects of methylprednisolone were observed for 15 pharmacodynamic parameters. Highly significant (P less than or equal to 0.0001) effects were increases in glucose levels, number of white blood cells, and segmented granulocytes as well as a decrease in the number of lymphocytes. For these pharmacodynamic effects an integrated pharmacokinetic/pharmacodynamic model was derived that translates the methylprednisolone plasma concentration-time profiles into effect-time profiles. This model allows prediction of pharmacodynamic effects for any single dose in the range studied at any time point.

Circadian changes in stimulus threshold and in the effect of a local anaesthetic drug in human teeth: studies with an electronic pulptester.

An electronic pulptester with constant testing current was used to study the stimulus threshold in human teeth of 28 healthy volunteers and the duration of local anaesthesia by articaine plus epinephrine in 55 patients with caries who underwent a filling therapy. In 21 out of the 28 volunteers, significant daily variations in stimulus threshold were detected by cosinor analysis. Acrophases, however, were scattered over the 24-hr scale. In patients, the local anaesthetic effect was studied at four different times of day (0800, 1100, 1400 and 1700 hr). The electronic device allowed one to accurately determine the time to peak effect (Tmax), duration of effect (Emax, time to return to baseline threshold (Tret) and the area under the time-effect curve (AUC) as a measure of the total local anaesthetic effect. Significant diurnal variations in AUC and Emax were found in 36 patients with the 0.8 ml dose, with peak and trough values at 1400 and 1700 hr, respectively. No differences in effect were found with the low dose of 0.4 ml applied to 19 patients either at 1400 or 1700 hr giving evidence for a circadian phase-dependency in the dose-response relationship of a local anaesthetic drug. The results clearly demonstrate that this electronic device is suitable for exact evaluation of circadian changes in local anaesthetic effects. Under drug-free control conditions, however, the low stimulus frequency of 5 Hz of this device obviously does not allow to discriminate between stimuli modified by pain perception and/or alertness.

Differential tolerance development to buprenorphine-, Diprenorphine-, and heroin-induced disruption of food-maintained responding in Macaque monkeys

Single daily subcutaneous injections of buprenorphine (1.0 mg/kg), diprenorphine (1.0 mg/kg), or heroin (1.0 mg/kg) were given over 25 consecutive days to examine the degree and the rate of tolerance development to drug-induced suppression of food maintained responding. One gram food pellets were available on a second order schedule (FR 4 VR 16:S) during the 1-hr sessions three times a day. All drug and saline control injections were given at 10:00 a.m., 1 hr before a food session. During the first three days of treatment all three drugs produced marked suppression of food-maintained performance. Recovery from buprenorphine-and diprenorphine-induced suppression of food-maintained responding occurred within four and eight days, respectively. By the 25th day of buprenorphine and diprenorphine treatment, operant responding for food increased significantly above control levels ( p<0.01). In contrast, the significant heroin-induced disruption of food-maintained responding ( p<0.01) persisted throughout the 25-day treatment period. Saline substitution for all three drugs resulted in a gradual return to control levels of food pellets earned. Linear regression analysis of the linear portion of the time-effect curve revealed significant differences in both the rate and the degree of tolerance development of these three drugs. These differences in tolerance development may reflect pharmacokinetic differences between the relatively short-acting heroin and the longer-acting diprenorphine and buprenorphine.

Propranolol pharmacokinetics and pharmacodynamics after single doses and at steady-state.

The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0-24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.

Interactions between Δ9-tetrahydrocannabinol and cannabidiol as evaluated by drug discrimination procedures in rats and pigeons

Animals (rats and pigeons) were trained to discriminate between the presence and absence of Δ 9-THC; the training doses were respectively: 0.56 mg/kg (pigeons) and 3.0 mg/kg (rats). Once the drug discrimination was mastered the pigeons were tested repeatedly after a single intramuscular (i.m.) injection of Δ 9-THC (0.56 mg/kg) at the following intervals 0.5, 1.5, 4.5 and 9 hr after the injection. These results were compared with data from a separate procedure, i.e. where the various intervals after injection were examined only once per injection and both procedures yielded essentially the same outcome. Thus, less than 50% appropriate responding to THC was observed at 0.5 and 9 hr after injection whereas greater than 90% responding to THC occurred at 1.5 and 4.5 hr. The two procedures have previously been compared in rats (Järbe Swedberg and Mechoulam 1981). The repeated tests procedure was then used to evaluate combinations of Δ 9-THC and cannabidiol in both species. Cannabidiol prolonged the cue effects of 1 mg/kg of Δ 9-THC (intraperitoneal route of administration) in rats but did not change the time-effect curve for Δ 9-THC in pigeons (dose range examined: 0.10–0.56 mg/kg); the challenge doses of cannabidiol were, respectively: 30.0 mg/kg (i.p.) and 17.5 mg/kg (i.m.). The rate of responding did not differ in tests with combinations of Δ 9-THC and cannabidiol as compared to Δ 9-THC given alone in pigeons. Subcutaneously administered 3-PPP a dopamine pre-synaptic blocker, did not induce responding appropriate for Δ 9-THC in rats.

Effects of naloxone and naltrexone on morphine-elicited changes in hamster locomotor activity

Four experiments investigated the effects of naloxone (0.4 mg/kg) and naltrexone (1.0 mg/kg) on morphine(15 mg/kg)-elicited sedation and hyperactivity in the hamster. Experiments 1 and 2 demonstrated that naloxone blocks morphine sedation and hyperactivity, respectively. Experiments 3 and 4 demonstrated that naltrexone blocks morphine sedation and hyperactivity, respectively. Moreover, in Experiments 2 and 4, morphine-elicited hyperactivity was replaced by sedation following administration of the antagonists. In Experiment 1, morphine-elicited sedation was replaced by hyperactivity following administration of naloxone. These results are consistent with the hypothesis that morphine’s biphasic time-effect curve is the behavioral resultant of two underlying processes.

Tolerance and sensitization to the biphasic effects of low doses of morphine in the hamster

Two experiments investigated the dose and time related effects of morphine sulfate on wheel running behavior in golden Syrian hamsters. In Experiment 1, within-subject comparisons were made of the acute effects of 5, 20, and 40 mg/kg doses of morphine sulfate on running wheel activity. Compared with saline, morphine produced a dose related decrease in activity followed by a dose related recovery. At the lowest dose, the time effect curve was biphasic, with sustained hyperactivity following the recovery. In Experiment 2, the effects of low doses of morphine sulfate (0.5, 1.0, 2.5, 5.0 mg/kg) on running wheel activity were monitored for three days. Biphasic time effect patterns were evident at each dose: An initial period of hypoactivity was followed by recovery and subsequent hyperactivity. Moreover, repeated administration produced both tolerance and sensitization to morphine's effects on activity. Implications for mechanisms underlying the biphasic response pattern are discussed.

Respiratory Depression of Intravenous Hydroxyzine in Man

The effects of intravenous hydroxyzine and hydroxyzine with naloxone on respiration were determined in man. Drug effect was expressed as the shift in the 20-L intercept of the respiratory response curve measured by a rebreathing technique. The time-effect curve of hydroxyzine was found to be the same for hydroxyzine alone and in combination with naloxone, but significantly different from placebo or naloxone alone. The duration of respiratory depression in man resulting from hydroxyzine, 100 mg IV, is greater than 3 hours. Our data did not support the hypothesis that the respiratory depressant and recently discovered antinociceptive effects of hydroxyzine result from endorphin release or are mediated by opiate receptors.

The Effect of Single Dose Ergotamine Tartrate on Peripheral Arteries in Migraine Patients: Methodological Aspects and Time Effect Curve

Ergotamine tartrate (0.5 mg/70 kg) was given intravenously to 17 migraine patients. Arm, finger, ankle and big toe systolic blood pressures were measured with strain gauge technique for up to 4 hours and again after 22 hours. Systolic arm blood pressure increased transiently (duration less than 3 hours). Peripheral systolic blood pressures decreased in all patients (for toes a few to 55 mmHg) and at 22 hours well sustained decreases were still found. Further 10 migraine patients received 2-4 mg ergotamine tartrate as suppositories and peripheral systolic blood pressures were measured for 3 days. A decrease in peripheral systolic blood pressure was found after 24 hours but had disappeared after 48 hours. Contrary to common belief the present study investigating the effect of ergotamine directly on arteries has shown a long duration of its vasoconstrictory effect. Thus the effect of a single dose of ergotamine on the arteries should be followed for days.

RELAXANT ACTION IN MAN OF DIPYRANDIUM CHLORIDE (M B 9105A) (A steroid bis-quaternary ammonium salt)

SUMMARY In a number of animal species dipyrandium chloride (M B 9105A) was known to be a curare-like relaxant with an effect-time curve similar to that of suxamethonium (Biggs, Davis and Wien, 1964). The drug was tested in eight conscious human volunteers by stimulating the median nerve at the wrist and recording the contraction of the short muscles of the thumb. The drug was found to be 3.5 to 4.5 times as potent as gallamine but recovery from it was very variable—sometimes it was faster than from gallamine, sometimes it was slower, and never as rapid as from suxamethonium. It is suggested that, in anaesthetized patients, recovery from dipyrandium chloride might be more consistent, and perhaps faster on the average than from gallamine, but clinical observations in six patients who received the drug were inadequate to confirm or contradict this hypothesis.