Maximum Half-life Research Articles

On the Export of Fatty Acids from the Chloroplast

The model for export of fatty acids from plastids proposes that the acyl-ACP (acyl carrier protein) product of de novo fatty acid synthesis is hydrolyzed in the stroma by acyl-ACP thioesterases and the free fatty acid (FFA) released is then transferred to the outer envelope of the plastid where it is reactivated to acyl-CoA for utilization in cytosolic glycerolipid synthesis. Experiments were performed to assess whether the delivery of nascent FFA from the stroma for long chain acyl-CoA synthesis (LACS) occurs via simple diffusion or a more complex mechanism. The flux through the in vivo FFA pool was estimated using kinetic labeling experiments with spinach and pea leaves. The maximum half-life for FFA in the export pool was < or =1 s. Isolated pea chloroplasts incubated in the light with [14C]acetate gave a linear accumulation of FFA. When CoASH and ATP were present there was also a linear accumulation of acyl-CoA thioesters (plus derived polar lipids), with no measurable lag phase (<30 s), indicating that the FFA pool supplying LACS rapidly reached steady state. The LACS reaction was also measured independently in the dark after in situ generated FFA had accumulated yielding estimates of LACS substrate-velocity relationships. Based on these experiments the LACS reaction with in situ generated FFA as substrate is only about 3% of the LACS activity required in vivo at the very low concentrations of the FFA export pool calculated from the in vivo experiment. Furthermore, bovine serum albumin rapidly removed in situ generated FFA from chloroplasts, but could not compete effectively for "nascent" FFA substrates of LACS. Together the data suggest a locally channeled pool of exported FFA that is closely linked to LACS.

QSAR approach to POPs screening for atmospheric persistence

The environmental behaviour of a persistent organic pollutant (POP) is mainly controlled by its persistence, its tendency to undergo long-range transport (LRT) and its physicochemical properties. Atmospheric half-life is one of the criteria commonly used to study air persistence and LRT potential. For the 12 UNEP POPs and another 48 possible POPs, the mean and maximum half-life estimations for degradation in air are modelled using different molecular structure descriptors (atom and fragment counts, topological and WHIM descriptors), selected by Genetic Algorithm, in QSAR regression models. Both values are modelled to obtain an average estimate and a precautionary value for ranking and screening purposes. The models, validated for their predictivity, could be applied to predict unavailable data. Principal component analysis (PCA) was then used to explore the half-life data in addition to the physicochemical properties that are most relevant to atmospheric mobility; the aim has been to screen and rank POPs with regard to their tendency towards atmospheric persistence and mobility, and to obtain a persistence index in air and an LRT index. These indexes were also modelled by molecular descriptors, thus allowing a preliminary screening of new compounds.

Pharmacokinetics of Valsartan in Hypertensive Patients on Long-Term Haemodialysis

Previous studies have indicated no relationship between renal function (creatinine clearance) and the pharmacokinetics of valsartan in patients with moderately impaired renal function. There are no pharmacokinetic data available for valsartan in patients on long-term haemodialysis. To examine the pharmacokinetics of valsartan 80mg in hypertensive patients on long-term haemodialysis. Secondary objectives were to evaluate the efficacy and tolerability of valsartan in this patient group. Multicentre, nonblind, parallel-group study. 20 hypertensive patients with no renal impairment and 20 hypertensive patients on long-term haemodialysis. All patients were treated with valsartan 80mg once daily for 15 days. After the first dose of valsartan and at the end of the treatment period, plasma concentrations of valsartan were determined over 24 hours. Significant differences in the area under the concentration-time curve from zero to 24 hours (AUC24h) at steady state were found between the patients on haemodialysis and those with normal renal function. In contrast, no differences were found for AUC24h during first-dose pharmacokinetics or for maximum plasma concentration and elimination half-life during first-dose and steady-state pharmacokinetics. Blood pressure decreased significantly in both groups, but the reduction in systolic blood pressure was greater in patients on haemodialysis (18mm Hg) than in the control group (6mm Hg). Valsartan 80mg was well tolerated in patients undergoing haemodialysis. The pharmacokinetic characteristics of valsartan are altered in patients on haemodialysis under steady-state conditions, but not after single-dose administration. The increased bioavailability at steady state was still in the range of the bioavailability for the approved dose of up to 160mg in patients with or without renal impairment. Valsartan 80 mg/day was well tolerated in this patient population.

Modeling Volatilization of MTBE from Standing Surface Waters

The discovery in California of methyl tertiary-butyl ether (MTBE) in surface waters used for recreational boating has raised concerns over the potential impact on drinking water quality. Concentrations of MTBE above the California secondary maximum contaminant level of 5 ppb have been reported. Here we present a model to predict the fate of MTBE in surface waters as a function of wind speed, water temperature, epilimnion depth, and lake surface area. The model was validated with MTBE concentration data from Lake Perris in southern California and Calero Reservoir in northern California. When applied to typical lake conditions in California [i.e., epilimnion depth 15°C], the maximum half-life for MTBE is 4.5 m/s (10 mi/h). The model can be used for management of recreational boating based on a target MTBE concentration in the reservoir.

Stability and in vitro metabolism of dipeptide model prodrugs with affinity for the oligopeptide transporter

One approach to increase drug stability and to facilitate oral absorption of low bioavailability drugs may be to design oligopeptide ester prodrugs which are stable in the gastrointestinal tract, are transported via the oligopeptide transporter, and finally release the parent drug molecule into the blood circulation and/or by its site of action. In these kinds of prodrugs the ester linkage may be broken by pH dependent and/or enzyme catalyzed hydrolysis. The objective of the present study was to investigate the degradation mechanism and rate of the model compounds Glu(OBzl)–Sar, d-Glu(OBzl)–Ala and Asp(OBzl)–Sar in aqueous solution and in relevant biological media and to compare these results with those of our previous study of d-Asp(OBzl)–Ala. Furthermore, the resulting aqueous stability and in vitro metabolism data are related to our previous affinity data to evaluate if Glu–Sar, d-Glu–Ala, and Asp–Sar have potential as pro-moieties in these kinds of prodrugs. The degradation rates follow first-order kinetics, show maximun stability at pH 4–5 with maximum half-lives for Asp(OBzl)–Sar, Glu(OBzl)–Sar, and d-Glu(OBzl)–Ala of 115 h, 30 days and 152 days, respectively. The stability was dependent on buffer concentration, temperature, pH, and ionic strength. In biological media such as 80% human plasma, human gastric juice and intestinal fluid, and 10% rat jejunal homogenate at 37°C, the half-lives were greater than 1 h except for the hydrolysis of Glu(OBzl)–Sar in 10% rat jejunal homogenate, where the half-life was approximately 16 min. All the stabilized dipeptides may have potential as drug carriers targeting hPepT1.

Substituent effects on the kinetics of reductively-initiated fragmentation of nitrobenzyl carbamates designed as triggers for bioreductive prodrugs

4-Nitrobenzyl carbamates are of interest as triggers for bioreductive drugs, particularly in conjunction with the E. coli B nitroreductase, which efficiently reduces them to the corresponding hydroxylamines. These then fragment to release highly toxic amine-based toxins. While many 4-nitrobenzyl carbamate derivatives have been evaluated as bioreductive drugs, there has been no systematic study of substituent effects on the rate of this fragmentation (which should be as fast as possible following reduction). We therefore prepared a series of 2-, 3- and α-substituted 4-[N-methyl-N-(4-nitrobenzyloxycarbonyl)amino]phenylacetamides as model compounds to study these effects. The majority of the carbamates were prepared by in situ formation of the chloroformate of the appropriate 4-nitrobenzyl alcohol and reaction with methyl 4-(methylamino)phenylacetate, followed by ester hydrolysis and 1,1′-carbonyldiimidazole (CDI) mediated coupling with N,N-dimethylaminoethylamine. The hydroxylamines were generated by 60Co γ-ray irradiation of the nitro compounds in aqueous phosphate-buffered-propan-2-ol. The reactions were analysed by reverse-phase HPLC to determine the maximum half-life (Mt1/2) of the hydroxylamines generated, and the extent of release of amine from these after 10 half-lives (t∞). The parent (unsubstituted) hydroxylaminobenzyl carbamate had a Mt1/2 of 16 min under these conditions, while that of the corresponding α-methyl analogue was 9.5 min. Electron-donating substituents on the benzyl ring also accelerated fragmentation, with the data being fitted to the equation log(Mt1/2) = 0.57σ + 1.30, where σ represents σpfor 2-substituents and σm for 3-substituents. The acceleration of fragmentation of the hydroxylamines with increasing substituent electron-donation is consistent with the proposed mechanism, and is presumably due to stabilisation of the developing positive charge on the benzylic carbon. The extent of release of amine (t∞) also increased with increasing substituent electron-donation. These data suggest that the standard 4-nitrobenzyl carbamate trigger for nitroreductase enzyme (NTR) prodrugs can likely be improved on, by increasing the rate of fragmentation by the use of α-methyl and/or electron-donating benzyl substituents.

The degradation kinetics of ethyl-xanthate as a function of pH in aqueous solution

Xanthate degradation kinetics plays an important role in sulfide mineral flotation and in the treatment of flotation tailings. Increasing environmental concern about consequences of flotation tailings makes this information even more important. In this paper, the degradation kinetics of xanthate in homogeneous solution as a function of pH at 5°C, 20°C and 40°C is systematically studied by UV-Visible spectrophotometric measurements. The results indicate that the degradation of ethyl xanthate is rapidly increased with decreasing pH at pH < 7. At pH 7–8, the maximum half-life of the xanthate appears. The degradation was faster at pH 9–10, but at pH > 10 the half-lives of xanthate once again increase. The investigations are also extended to different media other than pure water, such as, 0.1 M NaClO 4, 0.1 M NaNO 3, 0.1 M NaCl as well as in the supernatants of flotation tailings of sulfide minerals. The rate constants of xanthate degradation are calculated and presented together with half-lives and activation energies of xanthate degradation. The degradation products and reaction mechanisms are discussed based on experimental results.

Preparation of Solutions of Dissolved Hydrogen and Oxygen Gases Using an Anaerobic Chamber

The oxygen-tolerant, NAD+-reducing soluble hydrogenase (SH) from Ralstonia eutropha H16 is a promising catalyst for cofactor regeneration in enzyme-catalysed reduction processes. The technical use of the isolated enzyme, however, is limited by its relatively low stability under operational conditions such as agitation, elevated temperature or addition of co-solvents. The maximum half-life at a reaction temperature of 35 °C and pH 8.0 was only 5.3 h. In order to enhance the stability of the enzyme, it was immobilised onto the anionic resin Amberlite™ FPA54. At an immobilisation yield of 93.4% for adsorptive and 100% for covalent attachment, corresponding activities of 48.9 and 39.3%, respectively, were obtained. Covalent binding always yielded superior stabilisation. At elevated temperature and under agitation, stabilisation was further increased by modification of the covalently bound SH with methoxy-poly(ethylene) glycol (mPEG). A comparable effect was not achieved when SH modification was performed before immobilisation. In stationary aqueous solution, half-lives of up to 161 h at 25 °C and 32 h at 35 °C were obtained. In presence of the technically relevant co-solvents DMSO, DMF, 2-propanol and [EMIM][EtSO4] half-lives of 14–29 h can now be achieved.

Environmental fate of rice pesticides in California.

Each of the pesticides reviewed is reported to dissipate from field water after application. Carbofuran is hydrolyzed rapidly under the alkaline conditions usually found in the rice field environment, and its hydrolysis products are also degraded rapidly. The longest half-life reported (18-26 d) was in water that overlaid soil treated with Furadan granular formulation. Generally, carbofuran dissipation ranged from 36 hr to 3 d. Under field application, bensulfuron methyl showed a half-life of 1-3 d, but others have recovered all of the "dissipated" herbicide in the soil compartment. MCPA applied to rice fields is reportedly degraded by the joint action of sunlight and microbial action with a half-life of 3-5 d. Methyl parathion showed a maximum half-life of 9-17 d in a model aquatic ecosystem, but other reports found more rapid dissipation. The half-life of molinate has been observed by numerous researchers to be less than 5 d, with volatility the major route of loss. A half-life as short as 5-7 d has been reported for thiobencarb applied to rice fields, but others report much longer periods; volatility again is expected to be a significant route of loss. Microbial degradation takes place with each of the subject pesticides. Numerous authors have reported enhanced degradation of carbofuran under conditions of repeated application, and this probably holds true for the others. A specialized segment of the microbial population (Pseudomonas spp.) is purported to carry out most of the degradation but is inefficient at degrading the hydrolysis product, carbofuran phenol. Biodegradation of bensulfuron methyl has been observed with actinomycetes, fungi, and bacteria, and takes place primarily by oxidation and hydrolysis. Methyl parathion is biodegraded primarily by nitro reduction to aminomethyl parathion. A fungus, an actinomycete, and a bacterium were shown to biodegrade molinate, primarily by oxidation at the sulfur atom and the azepine ring. Thiobencarb is biodegraded in anaerobic sediments at a slow rate; the dechlorinated thiobencarb was shown to cause dwarfing of rice in some fields. Otherwise, its aerobic biodegradation is rapid and follows the same routes as with molinate. Carbofuran is a systemic insecticide that is rapidly absorbed and translocated to aerial parts of the plant. Carbofuran is metabolized in rice plants to the corresponding phenol, which is irreversibly bound into the plant, as well as to 3-hydroxycarbofuran and other minor components; it is depurated through leaf exudate, from which it volatilizes. Rice plants were observed to take up more bensulfuron methyl through shoots than roots and to metabolize it to the 4-hydroxy analog. The half-life of methyl parathion in Hydrilla verticulla, an aquatic macrophyte, was 1 wk, but little has been reported on methyl parathion in plants. Barnyardgrass was found to absorb greater amounts of molinate than did rice, and it produced larger proportions of basic metabolites, which may form the basis for its selective toxicity. Thiobencarb has been shown to be rapidly absorbed, translocated, and metabolized in rice plants, barnyardgrass, and the broadleaved wild amaranth, smartweed, and lambsquarters. Translocation was more rapid and extensive in barnyardgrass than in rice, and most of the 14C radiolabel was recovered as metabolites. Its terminal metabolite, chlorobenzoic acid, was taken up into lignin-like plant constituents. It is apparent that information on plant uptake and biodegradation is limited--none exists for woody species--but the fact that some species appear resistant to the herbicides suggests that biodegradative ability is general. (ABSTRACT TRUNCATED)

Charcoal and Rifampicin Pharmacokinetics.

We investigated the effect of activated charcoal on rifampicin disposition in six healthy subjects. On three occasions (control, phases II and III, separated by 1 week), each subject received 600 mg of rifampicin with 350 ml of water. On the second and third occasions (phases II and III), each subject received in addition to 600 mg of rifampicin and 7.5 and 15 g of activated charcoal, respectively, in 350 ml of water as charcoal slurry. Plasma rifampicin levels were measured from 1 to 24 h postrifampicin ingestion. Treatment with activated charcoal significantly increased the clearance and decreased the maximum peak concentration, half-lives and area under the curves as compared with control treatment without activated charcoal.

Paracetamol Pharmacokinetics are Independent of Caloric Intake and Physical Activity

Regular physical activity provokes numerous adaptations in the gastrointestinal tract and liver. It has been suggested that these changes may alter the pharmacokinetics of drugs in humans. We addressed this suggestion by measuring paracetamol pharmacokinetics in a group of healthy young males chosen to represent the widest possible range of habitual physical activity and food intake. Daily caloric intake in the 19 men, obtained from 3-day dietary records, ranged from 1680 to 5110 kcal (21 to 66 kcal/kg). Each volunteer ingested paracetamol 1000mg in the fasted, resting state in the morning; antecubital venous blood samples were analysed for the parent compound and its glucuronide and sulfate conjugates by high-performance liquid chromatography for 6 subsequent hours. We found no evidence that paracetamol pharmacokinetics vary with physical activity or with caloric intake: (a) for the parent compound, there was no correlation in maximum blood concentrations, half-life, total clearance, or area under the curve with individual caloric intake, and (b) when volunteers were divided a priori into more active and less active groups, or a posteriori into higher and lower calorie consumers (a 70% difference in daily caloric intake), these groups had identical plasma disappearance curves for paracetamol itself and for both of its metabolites. We conclude that the enormous variation among humans in long term physical activity and food intake fails to alter any aspect of the appearance or disappearance of paracetamol from blood.

Porcine reproductive and respiratory syndrome: temperature and pH stability of Lelystad virus and its survival in tissue specimens from viraemic pigs

We investigated the growth of Lelystad virus (LV) in porcine alveolar macrophages, the thermal and pH stability of the virus in cell culture medium, and its survival in tissue specimens from viraemic pigs. Lelystad virus grew to titres of 10 6 TCID 50/ml, which were found at 40 h after virus inoculation when the macrophage cultures showed a cytopathic effect of approximately 40%. In culture medium at pH 7.5, LV was stable for prolonged periods of storage at −70°C and −20°C. At higher temperatures the half-life of LV was 140 h at 4°C, 20 h at 21°C, 3 h at 37°C and 6 min at 56°C. The half-life of LV, both at 4°C and 37°C, changed considerably when the pH of the medium was varied. At 4°C and pH 6.25 a maximum half-life of 50 h and at 37°C and at pH 6.0 a maximum half-life of 6.5 h was observed. However, increasing or decreasing the pH of the medium rapidly decreased the half-life of LV at both temperatures. Although, LV proved to be more stable at pH 6.00 than at pH 7.5, it did not replicate at pH 6.0. We also tested various tissue specimens from viraemic pigs for the presence of LV. The virus was detected in tonsils, lymph nodes, lungs, serum, and sporadically, albeit at low titres, in muscle tissue. The titre of virus in muscle tissue and organs was only minimally affected by storage for up to 48 h at 4°C.

Single Dose Pharmacokinetics of Temocapril, an ACE Inhibitor with Preferential Biliary Excretion, in Dialysis Patients

The single dose pharmacokinetics of temocapril, a novel prodrug type angiotensin converting enzyme (ACE) inhibitor with preferential biliary excretion, were evaluated in 6 patients maintained on haemodialysis and in 1 patient on continuous ambulatory peritoneal dialysis (CAPD). In a crossover design, each haemodialysis patient received a single oral dose of temocapril 1mg after breakfast on two occasions, on dialysis and nondialysis days, at an interval of 1 week. The CAPD patient received a single oral dose of temocapril 1mg. Plasma concentrations of temocapril and its active metabolite (diacid) and ACE activity were determined after drug administration. Area under the plasma concentration-time curves (AUC) in haemodialysis patients on the non-dialysis day were significantly greater than those in patients with normal renal function who were used as a reference (p < 0.01). Other pharmacokinetic parameters such as maximum plasma drug concentration (Cmax), biological half-life (t½) and time to reach Cmax (tmax) were not significantly different between the 2 groups. 24 hours after administration, the ACE inhibitions in haemodialysis patients were significantly higher than those in patients with normal renal function. There were no other significant differences between the 2 groups. The peak level of diacid (Cmax) in haemodialysis patients on the nondialysis day was significantly greater than that on the dialysis day (p < 0.05). Other pharmacokinetic parameters such as AUC, t½ and tmax were not significantly different between these 2 days. These parameters in the CAPD patient were similar to those in the haemodialysis patients on dialysis day. The results suggest that the elimination route of temocapril is mainly via the biliary route, but is partially a route permeated through a dialyser membrane or peritoneal membrane. It is suggested that temocapril is preferable to ACE inhibitors with renal elimination in the treatment of patients with hypertension undergoing dialysis.

Disposition of the Pharmacologically Active Compound [1-14C-Acetyl]-1-Acetyl-4-Phenyl-1,2,4-Triazolidine-3,5-Dione in CF1 Mice

1-Acetyl-4-phenyl-1,2,4-triazolidine-3,5-dione (APTD) has hypolipidaemic, anti-inflammatory, analgesic, antineoplastic, and aldose reductase inhibitory activities in animals. Disposition studies using pooled plasma and urine samples showed that [1-14C-acetyl]-1-acetyl-4-phenyl-1,2,4-triazolidine-3,5-dione (14C-APTD) had a maximum half-life of 20 hours. Urinary excretion accounted for less than 3% of the radioactivity elimination, while faecal excretion may account for up to 45% of the total elimination. In a 96-hour tissue distribution study, there was no sequestering of 14C-APTD in any of the organs. 14C-APTD demonstrated significant aqueous partitioning, and almost no binding to bovine serum albumin. In L1210 tumour cells, 14C-APTD was bound to DNA and RNA, and there was no binding to intracellular protein. 14C-APTD underwent significant metabolism in mice. One metabolite excreted in urine was identified; two other possible metabolites were proposed.

Microbial dechlorination of hexachlorobenzene in a sedimentation area of the Rhine River

In sedimentation areas of polluted rivers, microbial dechlorination of chlorinated aromatics may be of great environmental significance. This reaction may take place in the deeper, anaerobic sediment layers and involves replacement of a chlorine in the pollutant molecule by hydrogen. In this study, the microbial dechlorination of hexachlorobenzene in a sedimentation area of the Rhine River is evaluated by using Rhine water pollution data, concentrations in historical sediment samples and in recent sediment cores, and the results of anaerobic laboratory incubations with Lake Ketelmeer sediment. The various data support the conclusion that microbial dechlorination of hexachlorobenzene has occurred in the anaerobic sediment. Up to 80% of the hexachlorobenzene deposited in the early 1970s has been dechlorinated. The maximum half-life of hexachlorobenzene in the sediment is found to be 7 years.

Serological Evaluation of the Macrofilaricidal Effects of Diethylcarbamazine Treatment in Bancroftian filariasis

An Mr 200,000 phosphorylcholine-containing antigen (PC-Ag) of predominantly adult worm origin was found in the sera of humans infected with Wuchereria bancrofti. This paper describes results of a longitudinal study of changes in levels of PC-Ag in response to diethylcarbamazine (DEC) therapy as measured by two-site immunoradiometric assay (IRMA) and Western blotting. One hundred thirty-two residents of a bancroftian filariasis-endemic area of Papua New Guinea (PNG) were treated with a 72 mg/kg dose of DEC. A macrofilaricidal effect was seen with this dose of DEC as 34% of the treated subjects had localized side effects and long-term decreases in microfilariae (mf) counts were observed 12 months after treatment. The PC-Ag levels were reduced to 72%, 52%, and 51% of pretreatment values at 21 days and at six and 12 months after treatment. These decreases, observed by IRMA, were specifically associated with loss of the Mr 200,000 PC-Ag detected by immunoadsorption and Western blotting. From drug treatment data, the maximum half-life of PC-Ag in circulation was calculated to be 50 days, assuming a first-order decay process. This maximum half-life indicates that persistent antigenemia observed in the majority of treated subjects could only result from the survival of adult worms. In the absence of methods to directly demonstrate W. bancrofti adult worms, detection of serum PC-Ag levels provides a sensitive indirect measure of the dynamics of adult worm populations. This serological measurement may be useful in optimizing the macrofilaricidal and therapeutic effects of DEC and in assessing the macrofilaricidal action of new antifilarial drugs and immunological interventions.

Influence of surface hydrophilicity of liposomes on their interaction with plasma protein and clearance from the circulation: Studies with poly(ethylene glycol)-coated vesicles

Well-defined liposome systems have previously established the influence of size, surface charge lipid composition and surface ligands, on in vivo fate and behaviour of model compounds entrapped in liposomes. In the present study, preformed liposomes which quantitatively retain aqueous markers were covalenty coupled via dipalmitoylphophatidylethanolamine, to the hydrophilic polymer, monomethoxypoly(ethylene glycol) (MPEG 5000). Such liposomes retain the coating in the presence of plasma, and appear to adsorb plasma components more slowly than liposomes without the polymer, shown using an aqueous two-phase partitioning technique. MPEG-coupled liposomes were cleared from the blood circulation up to 30% more slowly than liposomes without MPEG after intravenous administration to mice, despite the unmodified liposomes being of a composition and size shown previously to favour achievement of maximum half-life. It is suggested that the polymer acts as a surface barrier to plasma factors which otherwise bind to liposomes in the blood and accelerate vesicle removal.

A study of the pharmacokinetics and pharmacodynamics of nifedipine in combination with atenolol

This double-blind randomized, crossover study was undertaken to determine the pharmacokinetic properties of nifedipine retard and atenolol when given separately, as a free or a fixed combination, compared with placebo in 15 healthy male volunteers. There was no difference between the three atenolol formulations in time to maximum blood concentration or elimination half-life. The fixed combination showed significant differences in both maximum observed blood concentrations (+16 per cent) and total area under the curve (+16 per cent) compared to atenolol alone. Urinary recovery of unchanged drug from the fixed combination was also slightly increased but the difference was not statistically significant. Furthermore, statistical evaluation of the plasma pharmacokinetics of nifedipine retard and urinary recovery of nifedipine metabolite showed that all three formulations were indistinguishable. Thus, it is concluded that the fixed combination of nifedipine and atenolol is bioequivalent to the free combination and that the bioavailability of both drugs in the fixed combination is equivalent to that of the single entities.

Effects of low-dose prednisolone on cyclosporine pharmacokinetics in liver transplant recipients: radioimmunoassay with specific and non-specific monoclonal antibodies

The following study of cyclosporine pharmacokinetics was performed to investigate the effects of withdrawal of low-dose maintenance prednisolone (0.3-0.6 mg/kg body weight) from the routine immunosuppressive regimen given to 10 liver transplant recipients with stable liver function tests. After oral administration of cyclosporine (6.4-10.3 mg/kg) whole blood concentrations were measured by radioimmunoassay (RIA) with both a specific monoclonal antibody detecting parent drug and a non-specific antibody additionally detecting a cross-section of metabolites. Withdrawal of prednisolone produced no significant change in the mean time and concentration of maximum blood cyclosporine (3.3 h and 1160 micrograms/l, respectively), the initial and terminal elimination half-life (3.5 h and 18.4 h, respectively) and the area under the blood concentration versus time curve (AUC) measured with either the specific or non-specific monoclonal antibody. Measurements with these two antibodies indicated that the terminal elimination of cyclosporine metabolites was more rapid than for the parent drug (half-life: 14.5 vs 18.4, respectively).

THE APPLICATION OF DECONVOLUTION ANALYSIS TO ELUCIDATE THE PULSATILE NATURE OF GROWTH HORMONE SECRETION USING A VARIABLE HALF‐LIFE OF GROWTH HORMONE

A deconvolution analysis model to calculate pituitary growth hormone (GH) secretion rate from measured serum GH concentration has been developed. This uses an iterative method of 'curve-stripping' based on an estimate of the half-life. The model has been applied to serum GH profiles and demonstrates that GH secretion occurs in discrete bursts with quiescent periods between secretory episodes, an 'on-off' phenomenon. The model can clearly dissect complicated concentration profiles such as the serum GH concentration response to growth hormone releasing hormone. The estimate was derived from calculating the half-life of serum GH in 10 subjects following an intravenous bolus injection of 50 mU of biosynthetic human growth hormone (b-hGH) and following infusions of the exogenous hormone (3 mU/kg/h) for 15, 30, 60 and 180 min. Endogenous GH secretion was suppressed by a continuous infusion of somatostatin (1-14). An asymptotic relationship between the duration of GH infusion and the GH half-life was established. A half-life of 15.3 min was achieved after exposure to GH for 60 min and a maximum half-life of 15.7 min after 180 min exposure.