A critical reevaluation of the "therapeutic range" of aminoglycosides.

Routine pharmacokinetic drug monitoring has become an inherent component of aminoglycoside therapy over the last 10-15 years. The intent of this monitoring is to improve the outcome of treatment and to decrease the incidence of toxicity through the attainment and maintenance of serum aminoglycoside concentrations within a normal therapeutic range. The primary objective of this review was to critically analyze the scientific support for the following premises: (1) there is a causal relation between peak serum aminoglycoside concentrations in serum and the outcome of treatment; (2) there is a causal relation between trough serum aminoglycoside concentrations in serum and the outcome of treatment; (3) outcome is improved by monitoring and maintenance of serum aminoglycoside concentrations in the normal therapeutic range; (4) there is a causal relation between serum aminoglycoside concentrations and toxicity; and (5) monitoring and maintenance of serum aminoglycoside concentrations within a normal therapeutic range decrease the risk of toxicity. After a critical review of the literature, it was concluded that the evidence was insufficient to support the presently accepted normal therapeutic range. Recommendations for the monitoring of aminoglycoside therapy were drawn up.     

Enhanced exercise noradrenaline concentrations during propranolol treatment: a limiting factor in cardiac beta-adrenoceptor blockade

Treatment with beta-adrenoceptor blocking drugs may result in augmented plasma concentrations of noradrenaline during exercise. The effect of propranolol on exercise heart rate and its relationship to plasma concentrations of propranolol and noradrenaline were examined in 10 hospitalized volunteers following treatment with propranolol, in doses of 80 mg and 320 mg daily. Responses to submaximal treadmill exercise during propranolol treatment and following discontinuation of the higher dose were compared to pre-drug and post drug placebo values. Exercise noradrenaline was increased by 67% over baseline values by treatment with the 320 mg daily dose of propranolol; this increment was present at 4 h and returned to baseline by 16 h after drug administration. Augmentation of exercise noradrenaline was correlated with plasma propranolol concentrations; the threshold concentration for this effect was 10-fold higher than the threshold for reduction in exercise heart rate. The effect of propranolol on heart rate was blunted in relation to the augmentation of exercise noradrenaline (P less than 0.001). These relationships suggest that, in patients taking high doses of propranolol, drug induced augmentation of plasma levels of noradrenaline during exercise may have physiologic importance. Enhanced effects on adrenergic receptors could have clinical relevance in certain groups of patients.     

Purine Bases Oxidation and Repair Following Permethrin Insecticide Treatment in Rat Heart Cells

Pollutants including insecticides have been recently reported to be a risk factor involved in various diseases. Permethrin, a member of the family of synthetic pyrethroids, is widely used as insecticide in agriculture and other domestic applications. To investigate possible cardiotoxicity, we had examined different concentrations of permethrin on the freshly isolated rat heart cells using the alkaline comet assay. A significant difference in % tail DNA between all concentrations of permethrin (5, 10, 20 μM) and vehicle (control) without enzymes and with Fpg-treated cells were measured. The results indicated that permethrin induced oxidative damage to purine bases in the heart cells. Pyrimidines oxidation was evaluated using Endonuclease III (Endo III), but the results did not reveal any significant changes. After permethrin exposure, cells were studied to evaluate their DNA repair capacity. A complete DNA repair at 10 and 20 μM was measured after 30 and 60 min of repair intervals. Significant change in plasma membrane fluidity at different depths of bilayer was measured following permethrin treatment. Membrane fluidity in the hydrophilic–hydrophobic region was reduced, while the hydrophobic inner resulted more fluid following permethrin treatment of heart cells. This work points to standardize conditions applicable to ex vivo cells following in vivo treatment in order to study the cardiotoxicity of insecticide.     

Comparative effects of adefovir and selected nucleoside inhibitors of hepatitis B virus DNA polymerase on mitochondrial DNA in liver and skeletal muscle cells

summary . Adefovir is a potent nucleotide analog inhibitor of hepatitis B virus (HBV) DNA polymerase. Its oral prodrug adefovir dipivoxil has been approved for the treatment of chronic HBV infection. In this study, adefovir was characterized for its in vitro effects on mitochondrial DNA (mtDNA) synthesis and compared with the nucleoside analogues lamivudine (3TC), fialuridine (FIAU), and zalcitabine (ddC). No substantial changes in mtDNA content were detected in human hepatoblastoma HepG2 cells and normal human skeletal muscle cells following a 9-day treatment with 0.3–30  μ m adefovir, concentrations up to 500-fold higher than the peak serum levels in patients treated with adefovir dipivoxil. Similarly, mtDNA was unchanged in both cell types following treatment with 3TC. In contrast, 30–55% and > 90% reductions in mtDNA were observed following incubation with 30  μ m FIAU and ddC, respectively. The effects of FIAU on mtDNA became more pronounced following prolonged 18-day treatment of skeletal muscle cells while the effects of other drugs remained unchanged.     

Osteopenia, excess adiposity and hyperleptinaemia during 2 years of treatment for childhood acute lymphoblastic leukaemia without cranial irradiation

OBJECTIVE: Osteopenia and excess adiposity occur following treatment of childhood acute lymphoblastic leukaemia (ALL) and the use of cranial irradiation is thought to be a significant contributory factor. Hyperleptinaemia has also been demonstrated following cessation of treatment for childhood ALL. Therefore a prospective study was undertaken to evaluate serial changes in percentage bone mineral content (BMC), adiposity and serum leptin concentrations during 2 years of treatment of children with ALL with chemotherapy but without cranial irradiation. DESIGN AND PATIENT: Only patients treated using the MRC ALL 97/ALL 97 (modified 99) protocols for childhood ALL were eligible for entry into the study. A total of 14 patients (seven male, with a median age of 7.5 years (range 3.4-16.7 years) were recruited. Serial dual energy X-ray absorptiometry (DEXA) scanning was undertaken at diagnosis and during two years of treatment. Serum leptin concentrations were determined at the same time as the scans. RESULTS: Reductions in %BMC were observed at the hip and lumbar spine by 12 months (P < 0.01) and remained low after 24 months of treatment. Subanalysis of %BMC measurements at the hip demonstrated a greater reduction in %BMC at the trochanteric region compared to the femoral neck. The percentage corrected fat mass increased from 6 months whereas the body mass index (BMI) standard deviation score (SDS) was increased after 24 months of treatment (P < 0.05). Serum leptin concentrations increased following 24 months of therapy (P < 0.05). CONCLUSIONS: Children treated for ALL with contemporary regimens have a predisposition to osteopenia, excess adiposity and hyperleptinaemia during treatment without cranial irradiation administration. We speculate that in addition to glucocorticoid administration, leptin resistance may account in part for these observations.     

Circulating PTH and PTHrP levels before and after treatment of tumor induced hypercalcemia with Pamidronate Disodium (APD).

The effect of lowering ionized calcium on circulating parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) was assessed in twenty patients with hypercalcemia of malignancy following treatment with Pamidronate Disodium. Ionized calcium levels fell rapidly in all treated patients. PTH concentrations were initially suppressed below normal in 18 patients, but rose from 0.48 +/- 0.42 pmol/L to 3.63 +/- 3.13 pmol/L (p less than 0.01) after treatment, reaching higher than normal values in some patients even in the presence of persistent hypercalcemia. PTHrP concentrations did not change significantly after treatment. These findings are consistent with an increased sensitivity of parathyroid tissue to changes in ionized calcium following prolonged exposure to hypercalcemia. Regulation of tumor secretion of PTHrP by calcium was not apparent within the range of calcium concentrations in this study.     

Blood folate concentrations and in vivo sulfadoxine-pyrimethamine failure in Malawian children with uncomplicated Plasmodium falciparum malaria

Folate antagonizes the antimalarial action of sulfadoxine-pyrimethamine (SP) in vitro, but its role in vivo is not well understood. We measured blood folate concentrations and SP therapeutic outcomes in Malawian children. Children with late treatment failure and those with adequate clinical and parasitologic responses had similar demographic characteristics, prevalence of parasite mutations conferring resistance to SP, and blood concentrations of anti-malarial drugs following treatment. However, a higher folate concentration was associated with late treatment failure. Patients from a low malaria transmission site had higher blood folate concentrations than those in a higher transmission site (mean +/- SEM = 39 +/- 9.3 ng/mL versus 29 +/- 10 ng/mL; P < 0.0001), and there was a higher rate of late treatment failure in the low transmission area (54.4% versus 40.2%; P = 0.010). This study also provides the first evidence of the independent role of physiologic folate concentrations in in vivo SP therapeutic efficacy, and the critical role of pyrimethamine concentrations in the therapeutic efficacy of SP when one controls physiologic folate levels and the frequency of critical dihydrofolate reductase/dihydropteroate synthase mutations.     

Biphasic effect of estradiol on luteinzing hormone response to gonadotropin-releasing hormone in castrated men

This study was designed to investigate the possibility that in men estradiol (E₂) has a stimulatory effect on the gonadotropin response to GnRH. Nine castrated adult men, who presented extremely low testosterone (T) concentrations, received 5 mg/day estradiol benzoate (E₂B) i.m. every 24 hr for several days, starting 5 days after orchidectomy. During E₂B treatment the pituitary responsiveness to GnRH (100 μg given as an iv bolus) was tested after 24, 48, 72, 96, 120, and 144 hrs of E₂B administration. The pituitary responsiveness to GnRH was also tested in untreated men from day 5 to day 10 following bilateral orchidectomy. In the E₂B-treated subjects the increased serum estradiol concentrations induced an initial decrease and a subsequent increase of the LH response to GnRH. The responses were decreased after 24 hr of treatment; thereafter, the LH responses were progressively increased and were markedly augmented after 120 hr of E₂B treatment. On the contrary, during treatment the FSH response to GnRH was preferentially blunted. In the untreated castrated men the LH and FSH responses to GnRH increased progressively from day 5 to day 10 after orchidectomy, but decreased responses were never observed during this period of observation. The maximum LH concentrations, which occurred at 30–60 min following GnRH in untreated castrated men, did not occur until 120–150 min in the E₂B treated men.     

Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes

This study was initiated to see if plasma asymmetric dimethylarginine (ADMA) concentrations decreased in hyperglycemic patients with type 2 diabetes following metformin treatment, either as monotherapy or following its addition to sulfonylurea-treated patients. Fasting plasma glucose, dimethylarginine, and L-arginine concentrations were measured before and 3 months after the administration of a maximally effective dose of metformin to 31 patients with type 2 diabetes in poor glycemic control (fasting plasma concentrations > 9.7 mmol/L), while being treated with either diet (n = 16) or a maximal amount of a sulfonylurea compound (n = 15). Fasting plasma glucose concentration (mean +/- SEM) decreased to a similar degree (P <.01) in patients treated with either metformin alone (12.4 +/- 0.5 to 9.5 +/- 0.5 mmol/L) or when it was added to a sulfonylurea compound (14.1 +/- 0.5 to 10.6 +/- 0.9 mmol/L). The improvement in glycemic control was associated with similar decreases (P <.01) in ADMA concentrations in metformin (1.65 +/- 0.21 to 1.18 +/- 0.13 micromol/L) and sulfonylurea + metformin-treated patients (1.75 +/- 0.13 to 1.19 +/- 0.08 micromol/L). Plasma L-arginine concentrations were similar in the 2 groups at baseline and did not change in response to metformin. Thus, metformin treatment was associated with a favorable increase in the plasma L-arginine/ADMA ratio. These results provide the first evidence that plasma ADMA concentrations decrease in association with improved glycemic control in patients with type 2 diabetes and demonstrate that the magnitude of the change in metformin-treated patients was similar, irrespective of whether it was used as monotherapy or in combination with sulfonylurea treatment.     

Clinical aspects and molecular genetics of the persistent Müllerian duct syndrome

OBJECTIVE The 5α-reductase inhibitor, finasteride, provides a logical medical treatment for benign prostatic hyperplasia (BPH). However, the effects of chronic finasteride treatment on prostatic androgen levels, 5α-reductase activity and tissue prostatic specific antigen (PSA) have not been studied. We have examined prostate tissue androgen concentrations and 5α-reductase activity of the gland in men with BPH treated with the drug for 3 months. DESIGN AND PATIENTS Twenty-eight patients with clinically diagnosed BPH, awaiting transurethral resection of the prostate, were entered in a double-blind placebo controlled study. Nineteen patients were randomly allocated to treatment with finasteride (5 mg daily) and 9 received placebo for 3 months. MEASUREMENTS Prostate specimens were collected immediately following surgery and analysed for testosterone, dihydrotestosterone (DHT), androstenedione, 5α-reductase activity and PSA. Blood specimens obtained before the start and immediately following treatment were also tested for steroid hormone concentrations and PSA levels. RESULTS There was no significant difference in the median levels of intraprostatic testosterone (P = 0.77), DHT(P= 0.46) and androstenedione (P = 0.09) between the finasteride and placebo groups. However, the 5α-reductase activity of the placebo group (237.9 pmol DHT/g tissue/30 min) was approximately 10 times that of the finasteride group (21.5 pmol DHT/g tissue/30 min; P = 0.0008). Although we were unable to detect any differences in the PSA concentrations of the prostate glands, there was a significant difference (P = 0.0002) in the median percentage change of serum PSA concentrations for the two patient groups. Serum DHT levels were also depleted (P = 0.038) whilst serum testosterone was increased (P = 0.054) in the finasteride patients when compared to the placebo group. Furthermore our study demonstrated no correlation between the in vitro 5α-reductase activity of the gland and tissue DHT concentrations. CONCLUSIONS Whilst finasteride treatment induced a reduction in serum dihydrotestosterone and prostatic specific antigen levels with a concomittant increase in blood testosterone concentrations, the impact of the drug on tissue androgen concentrations varied considerably from one patient to another. The differential effect of the drug on tissue androgen concentrations suggests that in the human prostate there are possibly more than one isoform of 5α-reductase responsible for the accumulation of DHT in the gland.     

Recycling processes of cellular ascorbate generate oxidative stress in pancreatic tissues in in vitro system

Ascorbate is a reducing agent, which is also known to oxidize cellular compoentns. Our proposed mechanism of the oxidative action is as follows: Ascorbate is concentrated in the pancreas and is leaked in adverse conditions, and oxidized to dehydroascorbate. The dehydroascorbate is carried into cells by a glucose transporter (GLUT) and reduced back to ascorbate. The reduction processes take electrons from other cellular components. Ascorbate or dehydroascorbate treatment elevated thiobarbituric acid-reactive substance (TBARS) concentrations in pancreas. The elevation in TBARS concentrations were blocked by cytochalasin B, a GLUT inhibitor. To confirm further the prooxidative action, changes in glutathione content were quantified. Glutathione concentrations were lower in ascorbate- or dehydroascorbate-treated groups. The ascorbate-induced decrease in glutathione was blocked by cytochalasin B. To prevent oxidation of ascorbate to dehydroascorbate, glutathione was added to the medium. The ascorbate plus glutathione and dehydroascorbate plus glutathione groups showed lower TBARS concentrations than those of the ascorbate and dehydroascorbate groups, respectively. There were changes in the morphology of Langerhans islets following ascorbate treatment, which disappeared following treatment with ascorbate plus cyto-chalasin B. The observations indicate that ascorbate generates oxidative stress and affects the structure of islets.     

Isometamidium concentrations in the sera of cattle maintained under a chemoprophylactic regime in a tsetse-infested area of Zimbabwe

An experiment was carried out to determine the concentrations of the trypanocidal drug isometamidium chloride in the sera of cattle maintained under a chemoprophylactic regimen at Rekomitjie, Zimbabwe, an area of high tsetse challenge in the Zambezi valley. In February 1993, 24 cattle at this site were treated intramuscularly with isometamidium chloride at a dose of 1.0 mg/kg body weight. Thereafter all animals were monitored regularly for 6 months for the presence of trypanosomes and sera were collected to determine the concentrations of isometamidium using an ELISA. Isometamidium treated cattle appeared to be protected against trypanosome infections for at least 18 weeks following treatment. Thereafter, three trypanosome infections were detected, between 20 and 22 weeks following treatment. In contrast, in 18 untreated control cattle at the same site, 9 trypanosome infections were detected over the first 18 weeks of the experiment. Quantification of the isometamidium concentration in sera from the drug treated cattle indicated that the apparent half‐life of iso‐metamidium in these animals was 23 days. This was similar to the half‐life observed previously in cattle treated under laboratory conditions. The isometamidium ELISA was shown to be capable of quantifying drug levels in 20 out of 23 cattle for at least 70 days after treatment. There was no evidence of drug resistant trypanosomes at this site.     

Inhibition of folliculogenesis in the monkey following early follicular phase administration of an LRH agonist

This study was undertaken to determine if early follicular phase administration of a synthetic luteinizing hormone releasing hormone (LRH) agonist would produce luteal phase defects in the monkey. [D-His(im-Bzl)6,Pro9]LRH N-ethylamide was administered to groups of rhesus monkeys on days 1-3 of the menstrual cycle. Two responses were observed: a) anovulatory menstrual cycles of less than 14 days duration, and b) ovulatory menstrual cycles characterized by unusually long follicular phases. All 4 monkeys with shortened menstrual cycles had prominent increases in serum gonadotrophin and oestradiol concentrations during treatment with the LRH agonist; early menses in these animals was attributed to uterine bleeding upon oestrogen withdrawal. Serum FSH concentrations declined, serum LH concentrations were unaltered, and only 2 of 8 monkeys had elevations in serum oestradiol during ovulatory menstrual cycles. The mean interval from cessation of treatment with the LRH agonist to the next preovulatory gonadotrophin surge was 21.5 +/- 3.2 days in ovulatory menstrual cycles. Corpus luteum function was normal following treatment with the LRH agonist in ovulatory cycles. The results indicate that both the long and short menstrual cycles observed following early follicular phase administration of the LRH agonist to monkeys can be attributed to a profound inhibition in follicle recruitment. [D-His(im-Bzl)6,Pro9]LRH N-ethylamide did not alter corpus luteum function in the monkeys.     

The use of low dose Orgaran in heparin-induced thrombocytopenia associated with in vitro platelet aggregation at higher Orgaran concentrations

We report a case of heparin-induced thrombocytopenia with in vitro antibody cross-reactivity by platelet aggregometry to both low molecular weight heparin and the heparinoid Org 10172 (Orgaran). The in vitro reactivity with Orgaran was only present at the upper limit of concentrations that would normally be used therapeutically. Low dose Orgaran therapy was initiated, allowing successful renal replacement therapy without invoking further thrombocytopenia or thrombosis. Interestingly, in vitro platelet aggregometry following treatment did not reveal increasing sensitivity to Orgaran. This case indicates that negative in vitro platelet aggregometry at defined lower concentrations of Orgaran may predict in vivo safety at the same levels despite positive platelet aggregometry reactions at higher concentrations of Orgaran.     

Biphasic changes in anterior pituitary Met-enkephalin concentration following reserpine treatment

Met-enkephalin concentrations in the anterior pituitary gland were shown to decline dramatically within the first 24 h after reserpine treatment, with effects apparent as early as 6 h. This was followed by subsequent repletion and late augmentation of Met-enkephalin levels 3 weeks following reserpine. Treatment with the alpha-1-adrenergic agonist methoxamine had no effect, whereas the alpha-1-antagonist prazosin lowered Met-enkephalin concentrations. Treatment with the dopamine agonists bromocriptine or apomorphine had no effect, but haloperidol treatment increased anterior pituitary Met-enkephalin which was reversed by concomitant bromocriptine administration. We postulate that the changes in anterior pituitary Met-enkephalin following reserpine were related to alterations in the monoamine neurotransmitters. Adrenergic and dopaminergic mechanisms may have opposing roles in the maintenance of Met-enkephalin concentrations in the anterior pituitary gland.     

A COMPARISON OF THE EFFECTS OF CLOMIPHENE AND TAMOXIFEN TREATMENT ON THE CONCENTRATIONS OF OESTRADIOL AND PROGESTERONE IN THE PERIPHERAL PLASMA OF INFERTILE WOMEN

The effects of clomiphene and tamoxifen treatment on the concentrations of oestradiol and progesterone in plasma were compared in the same infertile women. Nine patients, three with anovulation and six with suspected luteal phase deficiency, were given clomiphene during 2 months and tamoxifen during 2 months. Placebo treatment was given in the month before the first drug and during a month between drug treatments. The concentrations of oestradiol and progesterone were determined by radioimmunoassay in three samples collected each month between days 6 and 8, 11 and 13, and 18 and 20. The mean concentration of oestradiol at the time of the expected pre-ovulatory rise was 0.82 nmol/l with placebo treatment, 1.20 nmol/l following tamoxifen treatment and 5.00 nmol/l after clomiphene treatment (normal menstrual cycle maximum, 2.0 nmol/l). The mean concentration of progesterone in the luteal phases reached maxima of 41 nmol/l, 47 nmol/l and >72 nmol/l, respectively (normal menstrual cycle maximum, 60 nmol/l). When the frequency distributions of hormone concentrations were examined for each treatment, clomiphene and tamoxifen were both found to alter the distribution from that of placebo treatment (Chi-square analysis), giving a larger proportion of high concentrations. In the six patients with suspected luteal phase deficiency clomiphene treatment was followed by biochemical evidence of ovarian hyperstimulation. There was no evidence of this when any of these patients were treated with tamoxifen, nor in anovulatory patients treated with clomiphene.     

Inhibitory effect of cyclosporin A on erythroid and stromal colonies

Cyclosporin A is used to prevent graft-versus-host disease (GvHD) following bone marrow transplantation (BMT) and it has been implicated in reducing the time to engraftment for leukaemia and aplastic anaemia patients. To evaluate the effect of cyclosporin A on engraftment, the proliferative capacity of bone marrow progenitors (CFU-E, CFU-F and CFU-C) was assessed both in vitro and following treatment with cyclosporin A over a 9-week period using an animal model. Cyclosporin had a differential effect on the haemopoietic progenitors, with the myeloid series unaffected at therapeutic concentrations. Both erythroid and stromal progenitors were significantly inhibited at similar concentrations. The mechanism by which cyclosporin A enhances engraftment remains unclear; however, it is not mediated by enhancing any of the haemopoietic progenitors.     

Inhibition of hypothalamic GnRH secretion in the ewe by antigonadotropic decapeptide during the estrous cycle and nonbreeding season

Previous experiments from our laboratory and others have shown that the peptide antigonadotropic decapeptide (AGD) has marked inhibitory effects on luteinizing hormone (LH) secretion in rats and ewes. The first objective of this study was to determine whether AGD inhibits LH secretion by regulating hypothalamic release of gonadotropin hormone (GnRH). AGD (200 μg in 200 μL of 0.3% bovine serum albumin [BSA] saline) or vehicle was infused into the lateral ventricle of ovariectomized (OVX) ewes with hypophyseal-portal cannulae, and GnRH secretion was monitored. The frequency of GnRH and LH pulses in AGD-treated ewes was significantly decreased (p<0.05) but did not change in the control ewes. The second objective of this investigation was to evaluate changes in hypothalamic sensitivity to AGD in the ewe during the estrous cycle and nonbreeding season. During the estrous cycle, the effects of AGD on LH secretion were assessed following ovariectomy, during the metestrous, diestrous, and proestrous phases of the estrous cycle. The response to AGD during the estrous cycle was compared to its effect during the anestrous season. LH, cortisol, and prolactin (PRL) concentrations were assayed in peripheral blood samples obtained at 10-min intervals over a 6-h period prior to injection of either vehicle (200 μL of 0.3% BSA in 0.9% saline) or AGD (200 μg in 200 μL of vehicle), and for an additional 10 h following treatment. LH pulse frequency decreased after treatment with AGD (p<0.05) at all times in OVX and intact ewes compared to vehicle-treated controls. During the anestrous season, AGD treatment was more effective in inhibiting LH pulse frequency than during the breeding season (p<0.05). Furthermore, there was a significant increase (p<0.05) in mean cortisol concentrations after AGD infusion in all AGD-treated groups compared to controls independent of season or reproductive status. PRL concentrations were also increased (p<0.05) following treatment with AGD. These results suggest that inhibition of pulsatile LH release induced by AGD is modulated by alterations in frequency of hypothalamic discharges of GnRH. Furthermore, changes in the inhibitory actions of AGD may contribute to the seasonal regulation of hypothalamic GnRH secretion in the ewe.     

Lack of Effect of Sucralfate on Prednisone Bioavailability

The relative bioavailability of single oral doses of prednisone with and without sucralfate administration was determined in 12 healthy male volunteers. Each subject participated in a randomized three-way cross-over study consisting of the following three phases: treatment A, prednisone given alone; treatment B, 2 days pretreatment with sucralfate with a concomitant dose of sucralfate administered with prednisone; and treatment C, 2 days pretreatment with sucralfate with a sucralfate dose administered 2 h after the oral prednisone dose. Plasma prednisolone concentrations (active moiety of prednisone) were determined by a specific and sensitive high-performance liquid chromatographic assay and unbound prednisolone concentrations were determined by equilibrium dialysis. Bioavailability was assessed by comparing the areas under the plasma prednisolone concentration-time curves as well as peak concentrations, time to peak concentration, elimination rate constant, and half-life. No significant differences were noted in any of the treatment phases for any of the parameters except for the time of peak concentration which was slightly delayed from 1.0 +/- 0.6 to 1.7 +/- 0.9 h when sucralfate was concomitantly administered with the prednisone. Thus, the data from this study indicate that sucralfate does not have a clinically significant effect on the bioavailability of orally administered prednisone. The use of these two drugs in combination does not result in an interaction requiring dosage regimen alteration.     

Time course of total cysteine,glutathione and homocysteine in plasma of patients with chronic hepatitis C treated with interferon-α with and without supplementation with N-acetylcysteine

Background/Aims: Glutathione depletion might be one reason for the low rate of response of patients with chronic hepatitis C to treatment with interferon. The aim of the present study was to document the thiol status of patients with chronic hepatitis C and the effects of N-acetylcysteine, a precursor for glutathione synthesis, on the concentrations of total cysteine, glutathione and homocysteine during treatment of chronic hepatitis C with interferon.Methods: Total cysteine, glutathione and homocysteine in plasma were measured by high performance liquid chromatography, following reduction of disulfides and derivatization of thiols with monobromobimane in a group of 36 patients with chronic hepatitis C, who participated in a multicenter, double-blind, randomized, placebo-controlled clinical trial studying the effect of supplementation with N-acetylcysteine (600 mg three times daily) on the response to treatment with interferon-α (3 MU three times per week) for 6 months.Results: The concentrations of total cysteine (367.0±43.9 vs 360.4±33.5 nmol/ml, mean±95% confidence interval), glutathione (12.5+1.6 vs 14.1+1.3 nmol/ml) and homocysteine (21.2±4.5 vs 19.6±5.2 nmol/ml) were similar in patients with chronic hepatitic C and healthy control subjects. Supplementation with N-acetylcysteine resulted in measurable concentrations of N-acetylcysteine in plasma, but did not significantly increase the concentrations of cysteine, glutathione or homocysteine. There was no difference between the two treatment groups with regard to transaminases and clearance of HCV RNA.Conclusions: Circulating concentrations of total cysteine, glutathione and homocysteine are normal in patients with chronic hepatitis C. Supplementation with N-acetylcysteine did not increase the circulating concentrations of total cysteine, glutathione and homocysteine.