Constant Plasma Concentration Research Articles

Prediction of plasma concentration of GTS-21 in hairless rats following monolithic transdermal delivery.

The transdermal therapeutic systems (TTS) usually achieve constant plasma concentration for an extended period of time. This is because a sufficient drug stored in the device can keep the constant concentration on the surface of the stratum corneum during the system application. When the drug molecules are not enough to provide the constant surface concentration, the rate of drug penetration decreases with time because of decreased supply of the drug molecules from the delivery device. This paper has proposed an empirical simple approach to predict the plasma concentration for such a TTS. A novel compound, GTS-21, for Alzheimers' disease currently under development was used as a model drug. In vivo and in vitro experiments were carried out in hairless rats. The in vivo plasma concentration-time profile in hairless rats following the application of TTS well agreed with the predicted profile based on the skin pharmacokinetic model together with the model parameters determined from the in vitro experiment.

Mechanism-based pharmacodynamic modeling of the interaction of midazolam, bretazenil, and zolpidem with ethanol.

The pharmacokinetic and pharmacodynamic interactions of ethanol with the full benzodiazepine agonist midazolam, the partial agonist bretazenil and the benzodiazepine BZ1 receptor subtype selective agonist zolpidem have been determined in the rat in vivo, using an integrated pharmacokinetic-pharmacodynamic approach. Ethanol was administered as a constant rate infusion resulting in constant plasma concentrations of 0.5 g/l. The pharmacokinetics and pharmacodynamics of midazolam, bretazenil, and zolpidem were determined following an intravenous infusion of 5.0, 2.5, and 18 mg/kg respectively. The amplitude in the 11.5-30 Hz frequency band of the EEG was used as measure of the pharmacological effect. For each of the benzodiazepines the concentration-EEG effect relationship could be described by the sigmoid Emax pharmacodynamic model. Significant differences in both EC50 and Emax were observed. The values of the EC50 were 76 +/- 11, 12 +/- 3, and 512 +/- 116 ng/ml for midazolam, bretazenil, and zolpidem respectively. The values of the Emax were 113 +/- 9, 44 +/- 3, and 175 +/- 10 microV/s. In the presence of ethanol the values of the EC50 of midazolam and zolpidem were reduced to approximately 50% of the original value. The values for Emax and Hill-factor were unchanged Due to a large interindividual variability no significant change in EC50 was observed for bretazenil. Analysis of the data on basis of a mechanism-based model showed only a decrease in the apparent affinity constant KPD for all three drugs, indicating that changes in EC50 can be explained entirely by a change in the apparent affinity constant KPD without concomitant changes in the efficacy parameter ePD and the stimulus-effect relationship. The findings of this study show that the pharmacodynamic interactions with a low dose of ethanol in vivo are qualitatively and quantitatively similar for benzodiazepine receptor full agonists, partial agonists, and benzodiazepine BZ1 receptor subtype selective agonists. This interaction can be explained entirely by a change in the affinity of the biological system for each benzodiazepine.

Effect of OROS®controlled-release delivery on the pharmacokinetics and pharmacodynamics of oxybutynin chloride

Aims : Dry mouth is a common side-effect seen with immediate-release oxybutynin (IR-Oxy). Ditropan XL [(Oxy-XL), a controlled-release formulation of oxybutynin chloride, is a once-daily oral dosage form that incorporates the OROS technology. Dry mouth as the pharmacodynamic measure was compared between Oxy-XL and IR-Oxy administration. The steady state stereospecific pharmacokinetics were also established for the two formulations and the kinetic-dynamic relationship of oxybutynin was examined. This was a randomized, repeated-dose, double-blind, two-treatment, two-period, crossover study. After a baseline assessment day, volunteers were randomly assigned to one of two treatment sequences and received 4 days of each treatment with a washout period of 7 days between treatments. The treatments were: 1) Oxy-XL 10 mg in the morning and placebo 8 h later, and 2) IR-Oxy 5 mg in the morning and again 8 h later. Volunteers assessed dry mouth severity subjectively using a 100 mm visual analogue scale, VAS (Baseline, treatment days 1 and 4) and objectively by collecting saliva (Baseline and treatment day 4) before dosing and every hour after the morning dose for approximately 16 h. Several blood samples were collected during each treatment, with frequent sampling on day 4 to analyse for plasma R- and S-oxybutynin and R- and S-desethyloxybutynin concentrations. Relatively constant plasma concentrations of oxybutynin and its metabolite were seen over 24 h following Oxy-XL administration with the degree of fluctuation being much lower (P = 0.001; 66% to 81% reduction for the various analytes) than IR-Oxy. Compared with IR-Oxy, Oxy-XL yielded higher (131% and 158% for the R- and S-isomer, respectively) oxybutynin and lower (62% and 78% for the R- and S-isomer, respectively) desethyloxybutynin bioavailability, suggesting reduced first-pass metabolism. Saliva output (area under the effect curve) was significantly higher [P = 0.001; 37% (95% confidence interval: 24, 51%)] with Oxy-XL than with IR-Oxy and, accordingly, dry mouth severity (VAS) integrated over the day was significantly lower with Oxy-XL. The decrease in saliva output and the consequent increase in dry mouth severity correlated with the metabolite R-desethyloxybutynin concentration, and no apparent relationship was observed with the R-oxybutynin concentration. This suggests that the metabolite may contribute to the dry mouth. Therefore, the reduction in metabolite exposure with Oxy-XL may be a possible explanation for the observed decrease in dry mouth severity with OXY-XL compared with IR-Oxy. Oxy-XL maintains relatively constant plasma drug and metabolite concentrations and minimizes first-pass metabolism of oxybutynin. The metabolite appears to contribute to dry mouth associated with oxybutynin, and following Oxy-XL metabolite exposure is reduced compared with IR-Oxy. Consequently less dry mouth was observed with Oxy-XL as compared with IR-Oxy.

Pegylation: a novel process for modifying pharmacokinetics.

The use of liposomal carriers and the modification of therapeutic molecules through the attachment of poly(ethylene glycol) [PEG] moieties ('pegylation') are the most common approaches for enhancing the delivery of parenteral agents. Although 'classical' liposomes (i.e. phospholipid bilayer vehicles) have been effective in decreasing the clearance of encapsulated agents and in passively targeting specific tissues, they are associated with considerable limitations. Pegylation may be an effective method of delivering therapeutic proteins and modifying their pharmacokinetic properties, in turn modifying pharmacodynamics, via a mechanism dependent on altered binding properties of the native protein. Pegylation reduces renal clearance and, for some products, results in a more sustained absorption after subcutaneous administration as well as restricted distribution. These pharmacokinetic changes may result in more constant and sustained plasma concentrations, which can lead to increases in clinical effectiveness when the desired effects are concentration-dependent. Maintaining drug concentrations at or near a target concentration for an extended period of time is often clinically advantageous, and is particularly useful in antiviral therapy, since constant antiviral pressure should prevent replication and may thereby suppress the emergence of resistant variants. Additionally, PEG modification may decrease adverse effects caused by the large variations in peak-to-trough plasma drug concentrations associated with frequent administration and by the immunogenicity of unmodified proteins. Pegylated proteins may have reduced immunogenicity because PEG-induced steric hindrance can prevent immune recognition. Two PEG-modified proteins are currently approved by the US Food and Drug Administration; several others, including cytokines such as interferon-alpha (IFNalpha), growth factors and free radical scavengers, are under development. Careful assessment of various pegylated IFNalpha products suggests that pegylated molecules can be differentiated on the basis of their pharmacokinetic properties and related changes in pharmacodynamics. Because the size, geometry and attachment site of the PEG moiety play a crucial role in determining these properties, therapeutically optimised agents must be designed on a protein-by-protein basis.

Significant improvement of apolipoprotein B-containing lipoprotein metabolism by insulin treatment in patients with non-insulin-dependent diabetes mellitus

Patients with Type II (non-insulin-dependent) diabetes mellitus have multiple abnormalities in apolipoprotein B (apoB)-containing lipoprotein metabolism. These abnormalities are likely to play an important part in the development of premature atherogenesis in these patients. This stable isotope kinetic experiment was designed to study the effect of insulin therapy on apoB metabolism in poorly controlled Type II diabetic patients. Using L-[1-13C] leucine, we studied apoB metabolism in five control subjects without insulin resistance and in six poorly controlled Type II diabetic patients before and 2 months after the introduction of insulin therapy. Insulin treatment induced a decrease of very low density lipoprotein apoB plasma concentration [121 +/- 42 vs 158 +/- 91 mg.l-1, p < 0.05 (control subjects: 48 +/- 20)], related to an increased catabolism of very low density lipoprotein towards intermediate density lipoprotein or low density lipoprotein [0.20 +/- 0.08 vs 0.14 +/- 0.07 pool.h-1, p < 0.05 (control subjects: 0.36 +/- 0.10)]. On the other hand, insulin treatment induced an acceleration of intermediate density lipoprotein apoB turn-over without changing its plasma concentration [77 +/- 37 vs 61 +/- 18 mg.l-1, (control subjects: 17 +/- 3)], by increasing both its production rate [22.6 +/- 9.2 vs 18.2 +/- 9.6 mg.l-1.h-1, p < 0.05 (control subjects: 18.4 +/- 3.2)] and its catabolic rate towards low density lipoprotein [0.34 +/- 0.22 vs 0.22 +/- 0.16 pool.h-1, p < 0.05 (control subjects: 1.02 +/- 0.13)]. Likewise, insulin treatment increased low density lipoprotein apoB production rate [20.2 +/- 7.4 vs 16.9 +/- 7.7 mg.l-1.h-1, p < 0.05 (control subjects: 16.9 +/- 2.3)] and restored a normal low density lipoprotein apoB fractional catabolic rate [0.022 +/- 0.004 vs 0.018 +/- 0.004 pool.h-1, p < 0.05 (control subjects: 0.025 +/- 0.004)], resulting in a constant low density lipoprotein apoB plasma concentration [965 +/- 485 vs 984 +/- 558 mg.l-1 (control subjects: 699 +/- 106)]. Insulin treatment in Type II diabetes induces profound metabolic modifications of lipoprotein, resulting in significant decrease of the intravascular residence time of very low density lipoprotein, intermediate density lipoprotein and low density lipoprotein particles. This is likely to make these particles less harmful.

Clinical positioning of indapamide sustained release 1.5mg in management protocols for hypertension.

Indapamide sustained release (SR) 1.5mg is a new galenic formulation that is characterised by a relatively constant plasma concentration at steady state, with only minor fluctuations during the 24-hour period. A dose-titration study of 3 doses of indapamide SR (1.5, 2 and 2.5mg) given once daily has shown that the 3 dosages are equipotent in lowering blood pressure, and have an effect similar to that of indapamide immediate-release (IR) 2.5mg; all were statistically more effective than placebo. The percentage of hypertensive patients whose serum potassium was less than 3.4 mmol/L was significantly lower after indapamide SR 1.5mg than after indapamide IR 2.5mg. Neither indapamide formulation had any significant effects on lipid profile, glucose, urea and serum creatinine; only uric acid was slightly raised during the 2-month study. In an equivalence study, indapamide SR 1.5mg and IR 2.5mg produced similar blood pressure reductions (within the equivalence limit of +/-5mm Hg), whereas the percentage of patients whose serum potassium fell to less than 3.4 mmol/L was lower in the IR 1.5mg group than in the SR 2.5mg group. Antihypertensive treatment with indapamide SR 1.5mg once daily produced reductions in blood pressure in elderly patients with systolic/diastolic or isolated systolic hypertension that were similar to reductions with amlodipine 5 mg/day. The incidence of adverse effects was very low in all studies with indapamide SR 1.5mg and very similar to that in the placebo group, confirming thereby the improvement in the efficacy: tolerance ratio with the new indapamide compound.

Angina and its treatment.

Angina and its treatment.

Thermally reversible xyloglucan gels as vehicles for oral drug delivery

The potential, as sustained release vehicles, of gels formed in situ following the oral administration of dilute aqueous solutions of a xyloglucan polysaccharide derived from tamarind seed has been assessed by in vitro and in vivo studies. Aqueous solutions of xyloglucan that had been partially degraded by β-galactosidase to eliminate 44% of galactose residues formed rigid gels at concentrations of 1.0 and 1.5% w/w at 37°C. The in vitro release of indomethacin and diltiazem from the enzyme-degraded xyloglucan gels followed root-time kinetics over a period of 5 h at 37°C at pH 6.8. Plasma concentrations of indomethacin and diltiazem, after oral administration to rats of chilled 1% w/w aqueous solutions of the enzyme-degraded xyloglucan containing dissolved drug, and a suspension of indomethacin of the same concentration were compared. Constant indomethacin plasma concentrations were noted from both formulations after 2 h and were maintained over a period of at least 7 h. Bioavailability of indomethacin from xyloglucan gels formed in situ was increased approximately threefold compared with that from the suspension. The results of this study suggest the potential of the enzyme-degraded xyloglucan gels as vehicles for oral delivery of drugs.

Effects of daily sodium intake and ANG II on cortical and medullary renal blood flow in conscious rats.

Implanted optical fibers and laser-Doppler flow measurement techniques were used for the sequential measurement of regional renal blood flow in conscious rats to determine the effects of an increase of daily NaCl intake on the renal cortical blood flow and blood flow to the outer and inner medulla. Cortical blood flow was increased significantly (32%) by the second day when NaCl intake was increased from 1 to 7 meq/day and was increased further (50%) on the second day after a further elevation of NaCl intake to 13 meq/day. Blood flow to the outer and inner medulla was not changed as NaCl intake was elevated. The increase in renal cortical flow was closely associated with significant reductions in circulating concentrations of ANG II from 31 to 16 pg/ml. Rats given a continuous infusion of nonpressor does of ANG II (5.0 ng.kg(-1).min-1) to maintain constant plasma concentrations of ANG II as sodium intake was increased exhibited no increase of cortical flow. We conclude that reductions of plasma ANG II associated with incremental increases of daily sodium intake result in a rise of renal cortical flow. The elevated blood flow to the renal cortex may enhance sodium excretion and contribute to long-term sodium homeostasis.

Development and in Vitro Evaluation of a Buccoadhesive Pindolol Tablet Formulation

Controlled-release buccoadhesive tablets containing pindolol were prepared and evaluated in order to achieve constant plasma concentrations during the treatment of chronic hypertension and to improve the bioavailability of pindolol by the avoidance of hepatic first-pass metabolism. The formulations were tested for weight, hardness, friability, content uniformity, swelling rate, bioadhesive force, and drug release rate values. Carbopol 934 and NaCMC were used as bioadhesive polymers and Methocel K4M, Methocel K15M, and HPC were added as matrix-forming polymers.

Nifedipine gastrointestinal therapeutic system versus atenolol in stable angina pectoris

The gastrointestinal therapeutic system formulation of nifedipine enables a once-daily dosing resulting in predictable, relatively constant plasma concentrations. To evaluate the efficacy and safety of this formulation and to compare this with the β-blocker atenolol, we conducted a double-blind, randomised, multi-centre study in 129 male patients with documented exercise induced angina pectoris. After 4 weeks' treatment, nifedipine (60 mg), improved time to onset of 0.1 mV ST-segment depression from 536 s by 72 ± 117 s, time to onset of pain from 619 s by 56 ± 120 s, and total exercise time from 685 s by 40 ± 88 s. Atenolol 100 mg, had a comparable effect, time to onset of 0.1 mV ST-segment depression improved from 496 s by 53 ± 129 s, time to onset of pain from 572 s by 57 ± 118 s, and total exercise time from 653 s by 33 ± 99 s. Between group analysis revealed no statistically significant differences for these exercise parameters. Atenolol, but not nifedipine, significantly reduced heart rate and systolic blood pressure at rest and during exercise ( P < 0.001 between groups), indicating different modes of action of the drugs. With regard to safety, both drugs were generally well tolerated. There were significantly ( P = 0.01) more vasodilation related side effects with nifedipine. These data demonstrate that gastrointestinal therapeutic system formulation of nifedipine and atenolol as once-daily monotherapy are equally effective and safe, but with different effects on exercise parameters.

Time course characteristics of acute tolerance development to continuously infused alfentanil in rats.

The time course of the development of acute tolerance to alfentanil was characterized in rat experiments using various algorithms of continuous infusion of the drug. To maintain analgesia at a constant level (tail compression test), alfentanil use was steadily increased: Time to 50% increase in alfentanil use was 255 +/- 98 min with analgesia maintained at a level of 50% increase in the pressure threshold, and 203 +/- 116 min with analgesia maintained at a level of 200% increase. With the use of the alfentanil infusion regimen designed to rapidly achieve and maintain the constant alfentanil plasma concentration (120 ng/mL), the rate of development of acute tolerance, measured in terms of time to 50% recovery during continuing infusion, was 81 +/- 26 min with the compression test and 88 +/- 38 min with the hot-plate test, but 374 +/- 46 min with the rotarod test (P < 0.0001). Thus we demonstrated rapid development of acute tolerance to continuously infused alfentanil with different methods of tolerance assessment. The results also indicate that the time course of tolerance development does not depend on the type of noxious stimulation (mechanical versus thermal) if the response is organized predominantly supraspinally, and that acute tolerance to the direct effect of alfentanil on motor functions does not mask the rapid development of tolerance to its analgesic effect.

Pharmacodynamic modeling of the electroencephalographic effects of flumazenil in healthy volunteers sedated with midazolam*

The purpose of this study was to model pharmacodynamically the reversal of midazolam sedation with flumazenil. Ten human volunteers underwent four different sessions. In session 1, individual midazolam pharmacokinetics and electroencephalographic pharmacodynamics were determined. In sessions 2 and 3, a computer-controlled infusion of midazolam with individual volunteer pharmacokinetic data was administered, targeting a plasma concentration corresponding to a light or deep level of sedation (20% or 80% of the maximal midazolam electroencephalographic effect) for a period of 210 minutes. After obtaining a stable electroencephalographic effect and constant midazolam plasma concentrations, a zero-order infusion of flumazenil was started until complete reversal of midazolam electroencephalographic effect was obtained. The flumazenil infusion was then stopped and the volunteer was allowed to resedate because of the constant midazolam drug effect. The electroencephalographic response was measured during a 180-minute period and analyzed by aperiodic analysis and fast-Fourier transforms. In session 4, a midazolam plasma concentration corresponding to a deep level of sedation was targeted for 210 minutes to examine for the possible development of acute tolerance. No flumazenil was given in session 4. For a light sedation level, with a mean midazolam plasma concentration of 160 +/- 64 ng/ml, the mean half-life of the equilibration rate constant of flumazenil reversal is 5.0 +/- 2.5 minutes, and the mean effect site concentration causing 50% of Emax is 13.7 +/- 5.8 ng/ml. For a deep level of sedation, with a mean midazolam plasma concentration of 551 +/- 196 ng/ml, the mean half-life of the equilibration rate constant is 3.9 +/- 1.5 minutes, and the mean effect site concentration causing 50% of Emax is 20.6 +/- 6.8 ng/ml. This study provides an estimate of the magnitude of the blood/central nervous system equilibration delay for flumazenil antagonism of midazolam sedation and further defines the usefulness of the electroencephalogram as a measure of midazolam pharmacodynamic effect.

新規抗アレルギー薬Ｃｅｔｉｒｉｚｉｎｅの単回および反復投与時の薬物動態ならびに安全性の検討

Pharmacokinetic studies and examination of safety on single and multiple oralintake of cetirizine, a new antiallergic drug, were performed in 37 healthy male adult Japanese volunteers (single dose: 15 subjects, multiple dose : 22 subjects, 4 of whomreceived placebo, age: 23-45 years).1) In the single-intake study (cetirizine: 2.5-30mg), the concentration of cetirizineplasma increased in a dose-dependent manner. When 10, 20 and 30mg of the drug wasgiven, the mean Cmax was 214.5, 438.1 and 679.2ng/ml with the mean Tmax of 1.44, 1.50and 2.20hr, respectively. The metabolite (ucb 026) in the plasma was detected in only afew cases and the level was very low, compared with the unchanged form. In the 10, 20and 30mg groups approximately 50% of the given doses was excreted in urine in theunchanged form by 24hr, but the metabolite was not detected in the urine.2) In the multiple-dose study, 20mg(once per day, 20mg×1 group: twice per day, 10mg×2group), 30mg(once per day, 30 mg×1group)or placebo was given for 7 days.On the first day and the 7th day, the mean Cmax was 547.8 and 624.5 ng/ml in the 20mg×1group, 272.7 and 424.2ng/ml in the 10mg×2group, and 852.7 and 832.7 ng/ml in the 30mg×1group, respectively. Simulation usin.g the parameters obtained on the first day ofthe multiple-dose study showed a constant plasma concentration of cetirizine from the2nd day after administration in the 20mg×1 and 30mg×1groups;this concentrationwas almost equivalent to the values obtained in the subsequent days. However, thesimulation did not correspond well with the actual values obtained in the 10mg×2group, this is probably due to the inability to measure the terminal phase. The metabolite inblood was detected on the 2nd day after administration and the level was nearly constanton 6 and 7th day. Urinary excretion of the unchanged form increased almost linearly to48-58% on the first day and 59-70% of the doses given on the 7th day in the three groups, but the metabolite was not detected in urine.3) There were no abnormal findings due to cetirizine in blood, biochemical andurinary examinations, nor physiological signs such as pulse, respiration, blood pressureor ECG in the single or multiple doses study. No subjective symptoms due to the drugwere observed in either study except for one subject who became slightly sleepy duringdays 1-3 after administration of 20mg.

Constant infusion clearance is an inappropriate method for accurate assessment of an impaired glomerular filtration rate

Recently renewed interest has been focused on constant infusion clearance to assess GFR accurately. In this study we compared GFR and ERPF calculated from the constant infusion method (CIM = I x V/P) with that calculated from the standard method (StM = U x V/P), in 100 patients with renal disease who were subdivided in four groups according to their GFR-StM (< 30; 30-60; 60-90; > 90 ml/min). After a priming dose, a constant infusion of 125I-iothalamate (= GFR) and 131I-hippurate (= ERPF) was started at 9 a.m. The infusion rates were individually adjusted to the GFR which was approximated from the serum creatinine concentration. After a 90-min equilibration period, GFR-StM and ERPF-StM were determined for two 2-h periods. These values were compared with GFR-CIM and ERPF-CIM calculated from the plasma concentration of the respective tracers at the end of each 2-h period (= 210 and 330 min). In the patient group with GFR-StM < 30 ml/min, the 125I-iothalamate plasma concentration increased progressively over time. Consequently, average GFR-CIM at 210 min (34.2, SE +/- 2.1 ml/min) was higher than the GFR-CIM at 330 min (31.9, SE +/- 2.0 ml/min; P < 0.001). In addition both values were significantly higher than the corresponding GFR-StM values (18.1 +/- 2.4 and 15.3 +/- 1.6 ml/min respectively). In the two patient groups with GFR-StM > 60 ml/min, the 125I-iothalamate plasma concentration decreased progressively over time.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and dosage regimens of amikacin in intensive care unit patients

The pharmacokinetics of amikacin have been studied in 40 intensive care unit (ICU) patients using a two-compartment model and the Bayesian estimation method implemented in the USC PC-PACK program of Jelliffe et al. The volume of the central compartment was significantly higher in these patients (0.36 1 · kg −1) than in the reference population (0.20 1 · kg −1). A method has been designed to compute dosage regimens in order to maintain a constant steady-state average plasma concentration of 8 mg · 1 −1 for repeated i.v. infusions. The regimen calculated for the ‘average’ ICU patient varies between 11 mg · kg −1 three times per day for the patient with normal renal function and 6 mg · kg −1 every 2 days for the anuric patient. This regimen is intended to begin amikacin therapy in an ICU patient, while the population pharmacokinetic parameters would allow the individualization of the regimen by means of the Bayesian method.

Effects of chlormethiazole on psychological performance under conditions of constant plasma concentrations

Chlormethiazole was administered intravenously to six healthy volunteers (four male, two female, aged 20-33 years) using a loading dose followed by a maintenance infusion lasting ∼ 90 min. Doses were individually calculated from previous pharmacokinetic investigations in these subjects to produce a target steady-state plasma concentration of 1.5 μg ml(-1). Effects of chlormethiazole were determined using a short battery consisting of digit-symbol substitution, body sway and visual analogue scales, which was performed repeatedly before, during and after the active infusion. A more comprehensive battery of performance tests was performed once before and once during the active infusion. The mean plasma concentration of chlormethiazole obtained was 1.33 μg ml(-1). This produced marked sedation, with subjects scoring themselves as much more drowsy on chlormethiazole than on placebo, and global impairment to performance. An analysis of the slopes of scores on the performance tests in the short battery showed no evidence of a diminution of the effects of chlormethiazole over the infusion period. The same was true of the majority of the visual analogue scales, but two scales, rating eye symptoms and nose symptoms, did decline over the period of the infusion. Recovery was rapid, subjects returning to approximately baseline levels of performance within 30 min of discontinuation of the infusion. These results suggest that acute tolerance to the CNS effects of chlormethiazole does not occur over this time scale, but is found for peripheral effects such as eye and nose symptoms.

Comparison of Nifedipine gastrointestinal therapeutic system and Atenolol on antianginal efficacies and exercise hemodynamic responses in stable angina pectoris

A gastrointestinal therapeutic system (GITS) of nifedipine has been developed to provide a once daily dosing, and predictable, relatively constant plasma concentrations. This study compared the antianginal efficacy of nifedipine GITS with a once-a-day β-receptor blocker, atenolol. Seventeen patients with documented coronary artery disease and stable stress-induced angina pectoris were studied during a 2-week, single-blind, placebo baseline phase and a 12-week randomized, double-blind, active drug crossover efficacy phase, using the bicycle exercise test and ambulatory electrocardiographic recordings. Patients exercised significantly longer with nifedipine GITS (883 ± 47 seconds) and atenolol (908 ± 44 seconds) than with placebo (794 ± 41 seconds). Nifedipine GITS reduced systolic blood pressure at all stages of exercise compared with placebo but, because heart rate tended to increase more during nifedipine therapy, there was no difference in rate-pressure products between the placebo and nifedipine GITS periods. In contrast, atenolol reduced heart rate, systolic blood pressure and rate-pressure product during exercise compared with placebo. Whereas left ventricular ejection fractions (by radionuclide angiocardiography) increased with exercise, the maximal increase was smaller with atenolol than with placebo and nifedipine. The net increase in left ventricular ejection fraction at the end of exercise was greater with nifedipine than with placebo or atenolol. Ambulatory electrocardiograms showed only a small number of ischemic events. Neither nifedipine GITS nor atenolol reduced the number of ischemic events or total duration of ST-segment deviations significantly. It is concluded that nifedipine GITS is as effective an antianginal agent as atenolol, but the hemodynamic effects of the 2 agents differ. Left ventricular ejection fraction increases more with nifedipine than with atenolol during bicycle excercise.

Therapeutic efficacy of FK037 at constant plasma concentrations against mouse thigh infection caused by methicillin-resistant Staphylococcus aureus

Therapeutic efficacy of FK037 at constant plasma concentrations against mouse thigh infection caused by methicillin-resistant <I>Staphylococcus aureus</I>

Measurement of capillary permeability from the Gd enhancement curve: A comparison of bolus and constant infusion injection methods

Dynamic imaging of Gd-DTPA uptake has been used by several groups to characterise the permeability of blood-brain barrier and blood-retina barrier lesions, using both bolus and constant infusion rate injections. However, no consensus on which injection protocol is most efficient has been reached. To address this problem, we extend our Simplified Early Enhancement (SEE) theory, applicable to retinal lesions, to cover infusion injections, and demonstrate its application to published data. The two injection methods are compared using computer simulation. We find that, first, an infusion cannot produce a constant plasma concentration in an acceptable time (although a hybrid injection, consisting of a combined bolus and infusion, is able to do this). Second, at any given time after the start of injection, a bolus achieves a higher tissue concentration, and hence enhancement, than does the same dose given as an infusion. Conversely, a bolus achieves any given tissue concentration in a shorter time than the same dose given as an infusion. Consequently, a bolus uses a smaller dose to achieve a given enhancement at a particular time. Third, if renal function is reduced, the error in calculating the permeability from a particular value of enhancement is lower for the bolus than for the infusion. And last, the SEE method is more accurate for a bolus than for an infusion. We conclude that a bolus is always more efficient than an infusion, as well as being easier to administer, and should always be used in preference to an infusion.