Sustained Plasma Concentrations Research Articles

Optimizing Coronary Thrombolysis With IV Administration of Recombinant Tissue Plasminogen Activator: Single Bolus vs Double Bolus vs Front-loading

This study was designed to compare the efficacy of coronary thrombolysis obtained with i.v. administration of three dose regimens of recombinant tissue plasminogen activator (rtPA). Although many studies have confirmed the efficacy of thrombolytic therapy in treatment of acute myocardial infarction, few prospective studies have been designed to determine which dose regimen optimizes the rate of coronary thrombolysis. A canine model was used. Coronary thrombosis was induced by injection of radioactive, autologous blood clots through a catheter placed in the left anterior descending coronary artery. Subsequently, 15 dogs were randomized into 3 groups of 5 dogs each. In group 1 dogs, 1.25 mg/kg of rtPA was administered i.v. as a bolus; in the group 2 dogs, 1.25 mg/kg of rtPA was administered over 60 min. The administration was "front loaded" so that 15% was administered as a bolus, 60% over 30 min, and 25% over 30 min; in group 3, 1.25 mg/kg of rtPA was divided into two i.v. boluses and administered 15 min apart. Coronary thrombolysis was assessed with a gamma camera. Despite differences in rate of administration of rtPA, at 15, 30, and 90 min after onset of treatment, extent of clot lysis was similar between groups. These results indicate that despite differences in dose regimens, rates of thrombolysis are similar when i.v. rtPA is relatively rapidly administered. Further, the similar rates of clot lysis over time between groups suggest both an effective upper limit to the dose-thrombolytic rate relationship and relatively high, sustained steady-state plasma concentrations of rtPA.

Pharmacokinetics of Highly Lipophilic Antitumor Agent Palmitoyl Rhizoxin Incorporated in Lipid Emulsions in Rats.

The effects of i.v. formulations on the pharmacokinetics were examined for two antitumor agents with different lipophilicities: rhizoxin and palmitoyl-rhizoxin (RS-1541). Blood disposition and tissue distributions in rats were evaluated using three formulations: polyethylene glycol 400 (PEG)/dimethylacetamide (DMA) solution, colloidal solution, and lipid emulsions composed of dioctanoyl decanoyl glycerol (ODO) and polyoxyethylene-(60)-hydrogenated castor oil (HCO-60). The effects of emulsion particle size on the pharmacokinetics were also investigated. Rhizoxin rapidly disappeared from the plasma and showed high distribution in the tissues, and in vitro rapidly degraded in the plasma independent of the formulations used. In in vitro plasma, rhizoxin was easily released from the emulsion particles. In contrast to rhizoxin, the pharmacokinetics of RS-1541 with greater lipophilicity changed considerably depending on the formulations. The emulsions showed high and sustained plasma concentrations for RS-1541. RS-1541 was stably incorporated in the emulsion droplets and protected from the degradation when it was applied as an emulsion. Tissue distributions of RS-1541 in rats after an injection as lipid emulsion were strongly affected by the emulsion particle size. Small size emulsions (100-110 nm) showed the highest plasma concentrations of RS-1541, though they were unable to suppress distributions of the drug in peripheral tissues. Emulsions larger than 200 nm (approx.) in size, on the contrary, effectively inhibited the drug from entering the bone marrow, small intestine and other non-reticuloendothelial system (non-RES) organs, where many cytotoxic compounds showed undesired toxicities. These results indicate that the lipid emulsions composed of ODO and HCO-60 could be a promising and effective DDS carrier for RS-1541, which is highly lipophilic and stabilized in the emulsions. This was not the case for rhizoxin, however, which was less lipophilic than palmitoyl analogue RS-1541. The work described herein has demonstrated that by properly selecting the particle size, these lipid emulsions can control the behavior of a drug in the body.

Phase I study of suramin given by intermittent infusion without adaptive control in patients with advanced cancer.

Suramin is a promising agent for the treatment of hormone-refractory metastatic prostate cancer. However, questions about the relationship of severe neurotoxicity to sustained peak plasma concentrations greater than 300 micrograms/mL raised concerns that this drug could not be safely administered without adaptive control. To test the adaptive-control hypothesis, we designed a phase I study that relied on clinical end points, using a fixed dosing scheme that did not rely on adaptive control. In a phase I dose-escalation study using fixed dosing without adaptive control, gradually decreasing doses of suramin were administered to 63 patients on days 1 (loading dose), 2, 8, and 9 of a 28-day cycle. Fifty-four patients with hormone-refractory metastatic prostate cancer and nine patients with other solid tumors have been treated. Doses of 400 mg/m2 to 2,080 mg/m2 on the first day have been administered. The mean peak plasma concentration following the loading dose at a dose level of 1,730 mg/m2 was 933 micrograms/mL (26% coefficient of variation), and the mean trough concentration was 139 micrograms/mL (40% CV) on day 1 of cycle 2 [corrected]. At 1,730 mg/m2, five of 13 patients experienced dose-limiting toxicity (DLT), including malaise, neurotoxicity, pericardial effusion, and coagulopathy. At 2,080 mg/m2, three of five patients experienced DLT. Two patients treated at this dose level died while on study. One of these patients died of a subdural hematoma sustained after a fall and had a prolonged prothrombin time at the time of his death. One patient developed classic suramin neurotoxicity, which led to respiratory failure, for which the patient refused intubation. No significant associations were noted between peak or trough concentrations during either cycles 1 or 2 and the occurrence of neurotoxicity. (1) Suramin can be safely administered without adaptive control, (2) suramin on this schedule may exhibit significant activity against hormone-refractory metastatic prostate cancer, and (3) based strictly on toxicity considerations, we recommended that a day-1 dose of 1,440 mg/m2 be used in subsequent clinical trials, with a maximum of three cycles. Further studies to establish the optimal empiric dosing regimen are needed.

Two receptor systems are involved in the plasma clearance of tissue-type plasminogen activator (t-PA) in vivo.

Tissue-type plasminogen activator (t-PA) is a serine protease, catalyzing the initial step in the fibrinolytic process. Intravenously administered t-PA is rapidly cleared from the circulation by the liver. Two distinct clearance mechanisms, which are mediated by the low density lipoprotein receptor-related protein (LRP) on liver parenchymal cells and by the mannose receptor on liver endothelial cells, have been described. Using competitors and inhibitors of the receptors, we investigated the role of LRP and carbohydrate receptors in t-PA clearance in vivo. To inhibit LRP, the 39-kD protein, which is a potent inhibitor of LRP activity, was overexpressed in the liver of mice using an adenoviral gene transfer technique. Expression of the 39-kD protein resulted in a sustained plasma concentration and an increase in the plasma half-life of 125I-t-PA from less than 1 min to 4-5 min. Blockade of the mannose receptor by intravenous administration of ovalbumin also prolonged the plasma half-life of 125I-t-PA to 3-4 min. The same degree of inhibition of t-PA clearance was also observed after administration of an inhibitor of the fucose receptor, fucosyl-BSA. However, under the conditions established for the complete blockade of the mannose receptor, no additional inhibition of t-PA clearance was observed using fucosyl-BSA, suggesting little or no role for the fucose receptor in the clearance of t-PA. Furthermore, a dramatic increase of the plasma half-life of 125I-t-PA (>> 20 min) was observed in mice overexpressing 39-kD protein and administered ovalbumin +/- fucosyl-BSA. Our results clearly demonstrate that two independent receptor systems, LRP and the mannose receptor, are involved in the hepatic clearance of t-PA.

The protective action of chlormethiazole against ischaemia‐induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity

1. The effect of chlormethiazole administration on delayed neuronal death in gerbil hippocampus following transient global ischaemia has been examined. Chlormethiazole was administered either intraperitoneally or by intravenous infusion with either the dose or the time of infusion varied. 2. Chlormethiazole (600 mumol kg-1, i.p.) given 60 min after ischaemia produced substantial (> 60%) neuroprotection when damage was assessed 5, 14 or 21 days later, indicating the drug does not merely delay cell death. 3. Infusion protocols were developed which would result in sustained and defined plasma concentrations. Chlormethiazole (930 mumol kg-1) was then infused intravenously for 30 min, 76.5 min or 110 min in ways resulting in sustained plasma concentrations of 200, 100 and 50 nmol ml-1 respectively. When treatment was initiated 30 min after the ischaemic episode all protocols provided effective neuroprotection. There was a dose-dependent decline in protection when plasma chlormethiazole concentrations of 50, 30 and 10 nmol ml-1 were sustained for 110 min with no protection observed at 10 nmol ml-1. 4. In contrast, when a plasma concentration of 10 nmol ml-1 was sustained by infusion for 24 h, almost total neuroprotection against the ischaemic damage was achieved. This plasma concentration produced no sedative or anticonvulsant activity. 5. These data suggest that neuroprotection depends on both dose and duration of chlormethiazole administration and that excellent neuroprotection is possible in the absence of the sedative and anticonvulsant effects of the drug.

Whole-Body Autoradiographic Disposition and Plasma Pharmacokinetics of 5,10-Dideazatetrahydrofolic Acid in Mice Fed Folic Acid-Deficient or Regular Diets

The effect of folic acid depletion on the tissue distribution and plasma pharmacokinetics of the oncolytic agent 5,10-dideazatetrahy-drofolic acid (DDATHF) was evaluated in mice fed either folic acid-deficient or regular diets. Mice were maintained on diets for 2 weeks prior to receiving a single iv 30 mg/kg dose of [14C]DDATHF (tissue distribution) or DDATHF (plasma pharmacokinetics). Whole-body autoradiographic evaluation and plasma analysis for DDATHF were conducted in mice at 5 min and 6, 24, 48, 96, 120, and 168 h postdose. Radiocarbon associated with [14C]DDATHF was readily distributed to all tissues in both diet groups at the early time points and was rapidly cleared from most tissues at 24 h postdose. At the later time points, substantial amounts of radioactivity remained in liver from mice fed either diet. However, levels of radiocarbon in liver from mice fed the folic acid-deficient diet were approximately 2.5–4.2-fold the radiocarbon levels in liver from mice fed the regular diet. Similarly, plasma pharmacokinetics indicated that mice fed the folic acid-deficient diet had sustained plasma concentrations of DDATHF compared to plasma concentrations in mice fed the regular diet. These data indicated that a deficiency in dietary folic acid in mice caused increased hepatic retention of radioactivity and sustained plasma concentrations of DDATHF which are probably responsible for the observed toxicity of DDATHF in mice.

Value of theophylline treatment in patients handicapped by chronic obstructive lung disease.

It is still not certain whether it is worth using theophylline in addition to inhaled bronchodilators and corticosteroids to treat obstructive airways disease. This trial was designed to test whether the addition of prescribed theophylline in doses sufficient for sustained optimal steady state plasma concentrations would produce any detectable additional advantage in spirometric or functional variables in these handicapped patients. A randomised, double blind, placebo controlled, crossover study of added theophylline treatment was aimed at steady state plasma concentrations of 10 and 17 mg/l, the dose being calculated individually by Bayesian parameter estimation and maintained for six weeks along with the patient's previously prescribed bronchodilators and steroids. Of 20 patients sequentially recruited, 15 provided data that could be analysed. All had chronic obstructive lung disease with a mean forced expiratory volume in the first second (FEV1) up to about 30% of the predicted value and gave no history of being treated with theophylline. The protocol included spirometry, whole body plethysmography, and treadmill exercise. Measurements also included steady state plasma theophylline concentrations and trapped gas volume. Quality of life was assessed by an established questionnaire method covering breathlessness in everyday activities, fatigue, emotional function, and control over the disease. Both target plasma concentrations were achieved. Improvements in peak flow (PEF; mean 20%), trapped gas volumes (38%), two stage vital capacity (15%), distances walked (48%), breathlessness in everyday activities (32%), and fatigue (18%) were found at the higher plasma concentration only. FEV1, forced vital capacity (FVC), emotional function, and control did not change. Theophylline treatment with sustained steady state concentrations about 17 mg/l provides worthwhile objective and subjective further benefits for patients handicapped by chronic obstructive lung disease when it is added to bronchodilators and corticosteroids.

The uptake of fenbendazole by cattle and buffalo following long-term low-level administration in urea-molasses blocks.

Fenbendazole (Panacur bolus, Hoechst India Ltd) was incorporated at a rate of 0.5 g/kg into urea-molasses blocks made by two different processes. The concentration of the drug in blocks and its bioavailability were measured using plasma oxfendazole as marker. The recovery of the drug in blocks made by a warm process was 68% and the plasma oxfendazole concentration remained fairly stable at 0.2 and 0.12 microgram/ml from day 6 of feeding in cattle and buffalo, respectively. The drug seemed to be inactivated in blocks made by a hot process, with reduced bioavailability. A low and sustained plasma concentration of the active metabolite of the drug could be maintained by self-medication using urea-molasses blocks as fenbendazole carrier.

Pharmacokinetics of cyproheptadine and its metabolites in rats.

To investigate the pharmacokinetics of cyproheptadine (CPH) and its metabolites, the plasma concentration and urinary excretion of CPH and its detectable metabolites were determined after intravenous (i.v.) administration of parent or synthesized metabolites to rats. The plasma CPH concentration-time course was subjected to biexponential calculation following the i.v. administration of CPH, producing the temporal and low plasma concentrations of desmethylcyproheptadine (DMCPH) and the sustained plasma concentrations of desmethylcyproheptadine-epoxide (DMCPHepo). DMCPH was also eliminated, according to the biexponential equation, after i.v. administration of performed DMCPH, forming DMCPHepo in plasma. On the other hand, no detectable DMCPHepo was found in plasma after the i.v. administration of cyproheptadine epoxide (CPHepo). All compounds administered had large distribution volumes and were almost entirely excreted as DMCPHepo in urine; this excretion continued for a long time. However, the urinary excretion pattern of DMCPHepo after CPHepo was different from those after CPH and DMCPH. The mean residence times of the epoxidized metabolites estimated from the urinary data were much longer than those from the plasma concentration data, suggesting either a gradual reflux of the metabolites from a tissue depot into systemic circulation under those plasma concentrations close of detection limit, or some interaction which delays excretion into the urine. This study suggests that both metabolic pathways of CPH, through DMCPH and CPHepo, to DMCPHepo are possible, but that the demethylation of CPH largely occurs prior to epoxidation; also that the extensive and persistent distribution of DMCPHepo to tissues may relate to the toxicity of CPH reported in rats.

Multiple-dose pharmacokinetics of lomefloxacin: Rationale for once-a-day dosing

Six dosage regimens of oral lomefloxacin, a new difluorinated quinolone, were given to healthy volunteer subjects for 7 days in a randomized, placebo-controlled trial to evaluate pharmacokinetics and tolerability and to determine the optimum dosage schedule. Single daily doses of lomefloxacin up to 800 mg and multiple doses up to 600 mg twice daily (1,200 mg/day) were well tolerated. At all dose levels and schedules, lomefloxacin was well absorbed and achieved peak plasma concentrations approximately 1 hour after administration. Urine concentrations were approximately 100 times the plasma concentrations. Elimination half-lives of 7–8 hours were found for all dosage regimens. Steady-state was achieved on the second day of dosing. Little accumulation was observed. A 400 mg oral dose provided a mean peak plasma concentration of 3.43 μg/mL, and trough concentrations at steady state that were above the minimum inhibitory concentration for 90% (MIC 90) of most common Enterobacteriaceae. The 400 mg dose produced a urine concentration of >80 μg/mL during the 12- to 24-hour period after the dose, thus exceeding the MIC 90 for clinical isolates such as Pseudomonas aeruginosa, Serratia marcescens, and methicillin-susceptible and -resistant Staphylococcus aureus. There was good agreement between the results of this study and previously reported single-dose data. In summary, lomefloxacin's rapid absorption, long half-life, and high sustained plasma and urine concentrations should permit effective once-daily administration in many clinical situations.

Controlled release metoprolol formulations. A review of their pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and ischaemic heart disease.

Conventional formulations of metoprolol have become well established in cardiovascular medicine and are particularly useful in the management of hypertension and ischaemic heart disease. Recently developed controlled release metoprolol delivery systems (metoprolol CR/ZOK and metoprolol OROS) were designed to overcome the drug delivery problems of matrix-based sustained release forms by releasing the drug at a relatively constant rate over a 24-hour period, and thus producing sustained and consistent metoprolol plasma concentrations and beta 1-blockade while retaining the convenience of once daily administration. Clinically and statistically significant reductions in blood pressure have been observed with metoprolol CR/ZOK and metoprolol OROS 24 hours after administration in mildly or moderately hypertensive patients. Studies in patients with mild to moderate hypertension have demonstrated that a similar or higher percentage of patients achieved a goal response with metoprolol CR/ZOK compared with matrix-based sustained release formulations of metoprolol, or conventional atenolol or bisoprolol, while metoprolol OROS achieved an equal or greater response rate compared with conventional or matrix-based sustained release metoprolol preparations. In patients with stable effort angina pectoris, once daily administration of metoprolol CR/ZOK provided at least equal antianginal efficacy as conventional metoprolol in divided doses, while metoprolol OROS reduced the mean number of anginal attacks by the same margin as atenolol. Controlled release metoprolol formulations have been well tolerated in clinical trials. Metoprolol CR/ZOK was associated with a similar or lesser degree of adverse effects related to the central nervous system compared with atenolol or long acting propranolol. Metoprolol CR/ZOK also demonstrated less pronounced beta 2-mediated bronchoconstrictor effects than atenolol in asthmatics, and less general fatigue and leg fatigue in healthy subjects. Metoprolol OROS produced less pronounced bronchoconstrictor effects than atenolol, matrix-based sustained release metoprolol or long acting propranolol in patients with asthma or obstructive airways disease, and healthy volunteers. These results are presumably due to the beta 1-selectivity of metoprolol in addition to the relatively low plasma concentrations maintained by metoprolol CR/ZOK and metoprolol OROS, and the avoidance of high peak plasma concentrations with these agents. Despite the relative safety of the controlled release forms of metoprolol, the use of all beta-adrenoceptor antagonists should be avoided in patients with a history of bronchospasm. Thus, controlled release metoprolol formulations offer the potential to maximise the confirmed benefits of this agent in the management of hypertension and angina, by maintaining clinically effective plasma concentrations within a narrow therapeutic range over a 24-hour dose interval.

The modifying effects of melatonin, ram exposure and plane of nutrition on the onset of ovarian activity, ovulation rate and the endocrine status of ewes

In four experiments, ewes were kept in natural daylength conditions at 57 °N and given daily at 15:00 h an oral dose of 3 mg of melatonin. Irrespective of feeding level, this method of administering melatonin sustained plasma concentrations of the hormone at night-time values from 1 h after dosing to the onset of natural darkness (7 h or less), but by the following morning concentrations were the same as those for control ewes. For Experiment 1, which started on 6 July and involved 24 Border Leicester × Scottish Blackface ewes, the mean intervals and (ranges) in days to the onset of ovarian activity (plasma progesterone above 1 ng ml −1) were SO (40–61) and 70 (35–96) for melatonin-treated and control ewes kept in isolation from the male. Corresponding values for those exposed once daily to a vasectomized ram were 29 (5–44) and 34 (21–61). In Experiment 2, the intervals from the start of treatment on 6 June were 67(57–75) days for ten Scottish Blackface ewes receiving melatonin compared with 107 (75–141) for nine of ten controls that showed ovarian activity before the experiment ended on 29 October. For a further ten ewes exposed continuously to an cestrous ewe and vasectomized ram, the interval was 72 (36–124) days. Experiment 3 started on 10 June and involved 32 Scottish Blackface ewes which were exposed once daily to a vasectomized ram and received two levels of feeding (5.8 or 11.6 MJ of metabolizable energy daily), either with or without melatonin in a 2 × 2 factorial design. Here, the intervals to behavioural oestrus were 79 (70–91) days and 92 (71–111) days for treated and control ewes, respectively, given the low feeding level and 74 (57–86) days and 83 (70–102) days for those given the high feeding level. Melatonin increased the ovulation rate and litter size, with the increases being greater for the low-than high-plane ewes. In Experiment 4, the mean interval from the start of meiatonin treatment on 7 July to the onset of ovarian activity for low-plane Scottish Blackface ewes was 61 ± 12.5 days versus 78 ± 11.4 days for controls ( n = 10 per group). The ovulation rate at first behavioural oestrus was not affected by melatonin, but at the subsequent three oestrous cycles was always higher for those receiving melatonin. Melatonin decreased circulating prolactin concentrations and obliterated their circadian rhythm (Experiment 1). Luteinizing hormone concentrations in plasma samples taken at frequent intervals for up to 24 h at 1, 3, 6 and 9 weeks after the start of melatonin treatment (Experiments 1 and 3), favoured the hypothesis that it initiates ovarian activity in ewes via a sudden increase in the activity of the hypothalamic gonadotrophin-releasing hormone pulse generator just prior to oestrus, rather than by a gradual and progressive increase throughout the treatment period.

Atracurium Decay and the Formation of Laudanosine in Humans

Several groups of investigators have reported that the plasma concentrations of laudanosine, a metabolite of atracurium, are high immediately after administration of atracurium and thereafter decline. Such a time profile of a metabolite in plasma is very unusual. The authors describe a model of atracurium decay and laudanosine disposition that satisfactorily explains these data. The model reveals the following: 1) each atracurium molecule is degraded into two of laudanosine; 2) the generation of laudanosine occurs through two processes--a rapid one, involving approximately 31% of the atracurium dose and proceeding with a half-life of 0.25 min, and a slower one, involving the residual 69% and proceeding with a half-life of 51 min; 3) atracurium degradation by Hofmann elimination proceeds in the central and the noncentral compartments; 4) laudanosine formed from atracurium gains access to its central compartment and disappears from plasma in a biexponential pattern; 5) in cirrhotic patients, only 18% of the atracurium dose is degraded rapidly and laudanosine is disposed of more slowly. The authors propose that the rapid degradation of atracurium in plasma proceeds through a nucleophilic substitution reaction, with plasma nucleophiles substituting for the laudanosine moiety in atracurium. Because both laudanosine moieties in atracurium are required to establish and sustain plasma concentrations of laudanosine, excretion of atracurium or its degradation through pathways not generating laudanosine must be small.

Catecholamines, Cocaine Toxicity, and Their Antidotes in the Rat

Acute lethal cocaine intoxication in the rat induces significant increases of plasma dopamine, norepinephrine, and epinephrine concentrations associated with cardiac functional and morphologic changes. Nitrendipine (a calcium channel antagonist) administered 5 min following cocaine administration lowers catecholamine concentration and restores cardiovascular function to normal, while preventing lethality, and so does enalaprilat (an enzyme-converting inhibitor) administration with diazepam. Cocaine cardiac toxicity in the rat appears to be associated with a significant stimulation of the sympathoadrenal and a sustained elevated plasma concentration of epinephrine. The renin angiotensin system also appears to be activated.

Pharmacologic and pharmacokinetic profile of SK&F S-106203, a potent, orally active peptidoleukotriene receptor antagonist, in guinea-pig

In this report the pharmacologic and pharmacokinetic profile of the leukotriene receptor antagonist 3(S)-1(2-carboxyethyl)thio]-3-12-(8-phenyloctyl)phenyl] propanoic acid (SK&F S-106203) in guinea-pigs is described. In isolated guinea-pig tracheae SK&F S-106203 was a potent, competitive antagonist of leukotriene (LT) D 4-induced contractions (pA 2 = 7.6). SK&F S-106203 was also a potent antagonist of LTE 4-induced contractions (pK B = 7.3), but had little effect on those elicited by LTC 4 (pK B = 5.5). SK&F S-106203 (10 μM) had no effect on contractions produced by histamine, carbachol, KCI, U-44069, PGF 2α or PGD 2. In addition, SK&F S-106203 (10 μM) did not inhibit cyclic nucleotide phosphodiesterase (PDE) activity of several PDE isozymes. In guinea-pig lung membrane preparations, SK&F S-106203 was a potent antagonist of 3H-LTD 4 binding with a K i = 19.4 ± 2.1 nM (n = 5). The pharmacokinetic profile of SK&F S-106203 was determined in unanesthetized guinea-pigs. Following an i.v. (bolus) dose (25 mg/kg), SK&F S-106203 disappeared from plasma in a biphasic fashion with half-lives of 0.1 h (50% of the area under the plasma concentration-time curve, AUC) and 11 h. The AUC obtained for SK&F S-106203 following i.v. administration was 87.3 ± 7.5 μg-h/ml. Following an oral dose of SK&F S-106203 (100 mg/kg), the maximal plasma concentration (C max) and the time C max was achieved (T max were 21.62 ± 2.26 kg/ml and 4 ± 1 h, respectively; the AUC was 279.9 ± 41.8 μg-h/ml. Studies examining the effects of i.v. infusion of SK&F S-106203 revealed that marked inhibition of LTD 4-induced bronchospasm was produced with steady-state plasma levels of SK&F S-106203 < 1 μg/ml (< 2 μM). Oral (p.o.) pretreatment with 100 μmol/kg SK&F S-106203 for up to 24 h essentially abolished LTD 4-induced bronchospasm; this correlated with sustained plasma concentrations of > 2 μg/ml. The results indicate that in guinea-pig airways, SK&F S-106203 is a potent and selective LT receptor antagonist that is active via aerosol, oral and i.v. routes of administration. When given orally, SK&F S-106203 is highly bioavailable and has a very long duration of action which correlates with the pharmacokinetic profile of the compound. SK&F S-106203 may be useful therapy in asthma and other disorders in which the Us are thought to play a prominent pathophysiological role.

Pharmacokinetics of fenbendazole in dogs

Fenbendazole was administered to dogs at a dose rate of 20 mg/kg body weight on a single occasion in gelatin capsules, on 5 consecutive days in feed, and on a single occasion as an alginate suspension. It was also administered at a dose rate of 100 mg/kg body weight on a single occasion in feed. Following single administration of 20 mg/kg fenbendazole mean maximum concentrations (Cmax) of the parent drug and its known active sulphoxide metabolite were 0.42 +/- 0.05 and 0.31 +/- 0.05 microgram/ml, respectively. Mean times until maximum concentrations were achieved (tmax) were 12.67 +/- 4.18 and 15.33 +/- 2.81 h, respectively, and areas under the plasma concentration-time curves (AUC) were 5.83 +/- 0.65 and 4.60 +/- 0.57 microgram.h/ml, respectively. Administration in feed increased the apparent bioavailability and administration for 5 consecutive days provided sustained plasma concentrations, generally greater than 0.2 microgram/ml. Administration as an alginate did not increase bioavailability or extend the persistence in plasma. It did increase the tmax to 16.80 +/- 2.93 and 20.00 +/- 2.53 h for fenbendazole and its sulphoxide metabolite, respectively. Increasing the dose from 20 mg/kg to 100 mg/kg did not substantially increase the Cmax or AUC.

Pharmacokinetics and hemodynamic and diuretic/natriuretic effects of felodipine administered as an extended-release tablet

In this study the pharmacokinetics, and the hemodynamic and diuretic/natriuretic effects of three different doses of felodipine ER-10, 20, and 40 mg--were evaluated in healthy subjects. There was a linear correlation between the dose of felodipine, Cmax, and AUC24, showing that the absorption was linearly related to the dose. The diastolic blood pressure was reduced by 15-20% after the two highest doses. The maximal blood-pressure lowering effect was seen 4 hours after drug intake, and a small reduction in diastolic blood pressure was still present after 24 hours. This was, however, not statistically significant but was related to a sustained effective plasma concentration of the drug (6 nmol/l). Systolic blood pressure was not affected. The two highest doses of felodipine ER produced a significant increase in heart rate 2 and 6 hours after the dose, compared with placebo. There was also a significant decrease in forearm vascular resistance after the 20- and 40-mg doses. Both diuresis and natriuresis were significantly increased by about 100% each during the first 4 hours after the 20-mg dose. Following the 40-mg dose, diuresis and natriuresis were lower than after 20 mg and were not significantly different from placebo.

Pharmacokinetics of CGP 6140 (amocarzine) after oral administration of single 100‐1600 mg doses to patients with onchocerciasis.

The concentrations of CGP 6140 [4-nitro-4'-(N-methyl-piperazinylthiocarbonylamido)-diphenylamine] and of its N-oxide metabolite, CGP 13,231, were measured in plasma and urine after single oral dose of 100-1600 mg of CGP 6140 to 41 fasted Ghanaian patients with Onchocerca volvulus infections. The absorption of CGP 6140 was rapid and its terminal elimination half-life was about 3 h. The plasma concentrations of CGP 6140 were essentially proportional to the dose. A greater variability in plasma concentrations was apparent after the 800 and 1600 mg doses indicating a poor bioavailability of the drug administered in fasting conditions to several patients. In plasma, the concentrations of CGP 13,231 were similar to those of CGP 6140. The amount of CGP 13,231 excreted in urine was 25-40% of the dose of CGP 6140 whereas only 1.5% was excreted as unchanged drug. If a single dose of drug is used for the treatment, the plasma concentration would be maintained for 3-4 h at a high level. At 8 h, the concentration falls to about 10% of the Cmax. If sustained plasma concentrations of the drug are needed for efficacy, twice daily administration would maintain the minimum concentration at about 10% of the Cmax.

Augmented and sustained plasma concentrations after intramuscular injections of molecular variants and deglycosylated forms of tissue-type plasminogen activators.

We have previously explored induction of coronary thrombolysis with tissue-type plasminogen activator (t-PA) administered intramuscularly. Absorption-enhancing agents that rendered the approach feasible were identified, but large amounts of activator were required and initial elevations of concentrations in plasma could not be sustained. The present study was designed to determine whether more therapeutically favorable plasma concentrations could be induced by genetically engineering or chemically modifying t-PA to prolong its half-life based on the hypothesis that the ratio of absorption to clearance would be increased. Each of four genetically engineered variants (one variant with growth factor and kringle 1 domains deleted and kringle 2 duplicated, a second variant with a cysteine for Arg substitution in the growth factor domain, a third variant with an additional urokinase kringle inserted, and a fourth variant with the growth factor domain deleted) and enzymatically deglycosylated t-PA exhibited prolonged half-life after bolus intravenous injection in rabbits. Each elicited substantially higher and more sustained elevations in plasma after intramuscular injection in rabbits or dogs with absorption-enhancing agents as compared with wild-type t-PA that were not accompanied by a systemic lytic state. Thus, use of molecular variants of t-PA with prolonged half-lives in the circulation permits induction of augmented and sustained elevations of plasma concentrations after intramuscular injection with absorption-enhancing agents as compared with wild-type t-PA, rendering potentially therapeutic blood levels more attainable with relatively modest amounts of material.

Plasma concentration profiles and antihypertensive effect of conventional and extended‐release felodipine tablets.

1. The rate and extent of felodipine absorption from an oral solution, conventional and extended-release tablets were investigated in two groups of healthy volunteers (n = 18 + 15). 2. The antihypertensive effect of felodipine conventional tablets twice daily (n = 71) and extended-release tablets once daily (n = 76) were compared in a parallel-group study in hypertensive patients. 3. As from a solution, felodipine was completely absorbed from the two solid dosage forms. The rate of absorption increased in the order extended-release tablets, conventional tablets, solution. 4. The extended-release tablet gave more sustained plasma concentrations than the conventional tablet. 5. The extended-release tablet given once daily gave similar blood pressure control to the conventional tablet given twice daily.