Salmeterol. An appraisal of its quality-of-life benefits and potential pharmacoeconomic positioning in asthma

Salmeterol is a selective beta 2-receptor agonist with a long duration of action that permits twice daily administration. It is effective in the prophylaxis of asthma symptoms, including nocturnal and exercise-induced asthma, and it has shown clinical benefits in both adults and children. Because of its slow onset of action, salmeterol is not intended for relief of acute symptoms. The addition of salmeterol 50 micrograms twice daily to existing asthma therapy has a positive effect on patient quality of life in the short term (up to 3 months), as assessed by the Living With Asthma Questionnaire and Asthma Quality of Life Questionnaire. This improvement in well-being appears to be greater than that associated with salbutamol (albuterol). Furthermore, in patients with asthma symptoms despite inhaled corticosteroid therapy, a reduced dose of corticosteroid plus salmeterol produced a greater improvement in quality of life as assessed by a daily symptom diary (but not by the Living With Asthma Questionnaire), and was more clinically effective than a higher dose of corticosteroid alone. Evaluation of the effects of salmeterol on quality of life compared with other standard therapies, and extension of these results into the long term are required to consolidate these conclusions. Salmeterol 50 micrograms twice daily was associated with an estimated incremental cost of 736 pounds per symptom-free patient in the final week of 7.5 months' therapy, 648 pounds per patient with improved morning (am) peak expiratory flow rate (PEFR) and 1013 pounds per patient with improved evening (pm) PEFR compared with salbutamol (400 micrograms twice daily) in a cost-effectiveness analysis. However, these results should be tested by sensitivity analyses and compared with the incremental costs of other asthma interventions more applicable to recommended clinical practice. The cost effectiveness of salmeterol relative to other asthma therapies, and the effect of salmeterol on patient quality of life in the long term require further investigation. However, when added to existing asthma therapy, salmeterol improves patient quality of life in the short term (up to 3 months). It may also have some beneficial effects on patient well-being when used to provide a steroid-sparing effect.     

Intranasal budesonide once daily in seasonal allergic rhinitis

A double-blind, parallel-group, multi-centre study was carried out in 248 patients with symptomatic seasonal allergic rhinitis to assess the effectiveness and tolerability of intranasal aqueous budesonide given as a single daily dose each morning of 400 micrograms compared with the conventional dosage regimen of 200 micrograms twice daily. After a 1-week run-in period during which only oral terfenadine was allowed for intolerable symptom relief, symptomatic patients were allocated at random to receive budesonide in one or other dosage regimen for 3 weeks. The results of assessments made by the physician at clinic visits and by patients recording daily data on diary record cards showed that specific nasal symptom incidence and severity were significantly (p less than 0.001) reduced in both treatment groups. The proportions of patients symptom-free at 3 weeks were 40% in the 400 micrograms once daily and 45% in the 200 micrograms twice daily group; in addition, mean nasal symptom scores from the daily diary cards were significantly (p less than 0.001) reduced in both groups, with a reduction in total symptom scores of 53% and 60%, respectively. The differences between the groups were not statistically significant. Total symptom scores were significantly (p less than 0.01) reduced in both dosage groups at all levels of pollen exposure. Patients rated treatment overall as being highly effective, mean scores being very similar in both groups, and tolerability was similar and good whether budesonide was given as a 400 micrograms once daily dose or as 200 micrograms twice daily. Assuming equal symptom control, 74% of patients stated they would prefer once daily to twice daily treatment.     

Effects of 15(R)-15-methyl prostaglandin E2 (arbaprostil) on gastric secretion and various gastric lesions induced in rats

We studied the effects of 15(R)-15-methyl prostaglandin E2 (arbaprostil) on gastric secretion and various acute and chronic gastric lesions produced in rats. Arbaprostil significantly inhibited gastric secretion in 4 hr-pylorus-ligated preparations when given intraduodenally in a dose of 30 or 100 micrograms/kg. The agent, however, significantly stimulated gastric secretion of rats with either a ligated or intact pylorus when given orally in doses of 3-100 micrograms/kg. Orally administered arbaprostil dose-dependently prevented the development of HCI-ethanol-, histamine-, water-immersion stress-, or indomethacin-induced gastric erosions. Intraduodenally administered arbaprostil also dose-dependently prevented the development of aspirin-induced gastric erosions in pylorus-ligated rats. Arbaprostil, given orally in doses of 1-100 micrograms/kg twice daily for 2 weeks, had little or no effect on the healing of acetic acid-induced gastric ulcers. However, oral administration of the agent in a dose of 3 or 10 micrograms/kg twice daily for 4 weeks significantly accelerated the healing of acetic acid-induced gastric ulcers. The increase in doses up to 100 micrograms/kg twice daily for 4 weeks had no effect on ulcer healing. These results indicate that arbaprostil, at either antisecretory or even acid stimulating doses, is effective in preventing the development of acute gastric erosions and in accelerating the healing of chronic gastric ulcers.     

Pharmacokinetics of pirazolac, a new anti-inflammatory drug, in human volunteers. III. Steady state plasma levels

Seven male, young subjects received twice daily 300 mg of pirazolac (PAA) for one week and twice daily 600 mg PAA for a further week as tablet. Plasma levels of PAA were monitored every day just before dosing and up to 72 hours after the last dose using a specific HPLC-method. During the first week of treatment trough steady state levels of Cssmin = 24 +/- 8 micrograms/ml were reached at day 4. After changing of dose regimen to twice daily 600 mg a new steady was established four days later with Cssmin = 62 +/- 15 micrograms/ml. PAA in the plasma was highly (99.2 +/- 0.8%) bound to plasma proteins. Time course of the decay of PAA levels in the plasma after the last dose was similar to that after a single administration.     

Lack of an effect of nefazodone on the pharmacokinetics and pharmacodynamics of theophylline during concurrent administration in patients with chronic obstructive pulmonary disease.

The effect of nefazodone on the pharmacokinetics and pharmacodynamics of theophylline was evaluated in a multiple-dose, randomized placebo-controlled, double-blind two-period crossover study in 13 patients who were undergoing theophylline therapy for chronic obstructive pulmonary disease. Two treatments were administered, each for 7 days: theophylline + 200 mg nefazodone twice daily (every 12h) and theophylline+matching nefazodone placebo capsule twice daily (every 12h). Mean peak and trough plasma concentrations of theophylline ranged from 13.1 to 14.5 micrograms ml-1 and 11.6 to 14.2 micrograms ml-1, respectively, at steady-state when theophylline was administered with or without concurrent dosing of nefazodone. Similarly, the mean area under the curve for theophylline ranged from 93.5 to 103 micrograms ml-1 h. When nefazodone and theophylline were co-administered, theophylline pharmacokinetic parameters did not significantly differ from those obtained when theophylline was administered with placebo. Forced expiratory volume in one second (FEV1) measurements taken when nefazodone or placebo were administered with theophylline did not differ from those obtained at baseline. The plasma concentration-time profiles for nefazodone and its metabolites were similar to those in other studies where nefazodone was administered alone. Since nefazodone did not affect the pharmacokinetics or the pharmacodynamics of theophylline, no change in theophylline dose should be needed as a consequence of nefazodone co-administration.     

An assessment of the systemic activity of single doses of inhaled fluticasone propionate in healthy volunteers.

1. The systemic effects of inhaled fluticasone propionate (FP), administered via Diskhaler, on the hypothalamo-pituitary-adrenal (HPA) axis were assessed primarily by measuring plasma cortisol at frequent intervals for 20 h after drug administration. 2. FP showed a dose-related suppression of plasma cortisol measured as area under the plasma cortisol vs time curve (AUC 0-20). The cortisol suppression (expressed as % fall from placebo) was 8, 19, and 28% for single doses of 250 micrograms FP, 500 micrograms FP and 1000 micrograms FP, respectively. A single dose of budesonide, 800 micrograms (via Turbuhaler), resulted in a 16% cortisol suppression. The cortisol suppression for all three single doses of FP, and for the single dose of budesonide, was statistically significantly different from placebo. 3. Repeated dosing of FP (1000 micrograms twice daily for 3.5 days) resulted in a more marked plasma cortisol suppression; a fall of 65% from placebo (AUC FP 1000 mg twice daily vs AUC placebo, P < 0.001). 4. In a well-controlled study in healthy volunteers, inhaled FP, in therapeutic doses, was shown to exhibit systemic effects which appear to be more pronounced after repeated dosing.     

Twenty-four-hour intragastric acidity and clinical trial of bedtime enprostil 70 μg compared with ranitidine 300 mg in duodenal ulcer

The effects of bedtime 70 micrograms and twice daily 35 micrograms doses of enprostil on 24-hour intragastric acidity were investigated in nine duodenal ulcer patients in remission. Median nocturnal acidity decreased significantly by 30% with 35 micrograms twice daily, and by 48% with 70 micrograms at bedtime. In a clinical trial using bedtime dosing, 102 duodenal ulcer patients randomly received either ranitidine 300 mg or enprostil 70 micrograms. More ulcers healed after 4 and 8 weeks treatment with ranitidine than with enprostil (76% ranitidine vs 52% enprostil, at 4 weeks p = 0.0065 and 94% vs 68%, respectively at 8 weeks, P = 0.0007). However, 6 months after cessation of treatment there was no material difference in overall outcome. Despite combining mucosal protection with acid inhibition enprostil treatment conferred no advantage over simple acid inhibition.     

Reduction by lifarizine of the neuronal damage induced by cerebral ischaemia in rodents.

1. The objective of this study was to evaluate the broad neurocytoprotective potential of the novel sodium-calcium ion channel modulator, lifarizine (RS-87476), in two rodent 72 h survival models of forebrain ischaemia. 2. Under fluothane anaesthesia, rats were subjected to 10 min four vessel occlusion and gerbils to either (i) 5 or (ii) 10 min bilateral carotid artery occlusion. 3. Rats were dosed parenterally solely post-ischaemia (reperfusion) in a series of five studies covering a range of intra-arterial/intraperitoneal (i.a./i.p.) combination doses from 2/10, 5/20, 20/100, 50/200 and 100/500 micrograms kg-1, where the initial loading dose was injected i.a. at 5 min. An i.p. dose was given at 15 min and repeated twice daily. In a sixth study, treatment at 50/200 micrograms kg-1 was deferred for 1 h. 4. Gerbils were treated (i) 15 min pre-ischaemia with either (a) 250, (b) 500 micrograms kg-1 i.p., or (c) 5 mg kg-1 by gavage (p.o.) for 3 days then at 1 h pre-ischaemia. Animals treated as (ii) received 500 micrograms kg-1 i.p. 15 min pre-ischaemia. The above doses were repeated twice daily for 3 days post-ischaemia for the respective groups. 5. In rats, the protective effect of lifarizine was regionally and cumulatively assessed in six brain regions (anterior and posterior neocortex, hippocampal CA1 subfield, thalamus, striatum, cerebellar Purkinje cells-brain stem) at each dose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Salmeterol xinafoate. A review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease.

Salmeterol xinafoate, like salbutamol (albuterol), is a saligenin derivative, and a selective beta 2-adrenoceptor agonist. It produces bronchodilation for at least 12 hours following inhalation of a single 50 micrograms dose. Salmeterol is intended for regular twice-daily treatment of reversible airways obstruction and not for immediate symptomatic relief, and when used in this manner, 50 micrograms twice daily is more effective than salbutamol 200 micrograms or terbutaline 500 micrograms administered 4 times daily, or individually titrated oral doses of theophylline in improving objective and subjective criteria of efficacy in patients with mild to moderate asthma. Salmeterol 100 micrograms inhaled twice daily may provide better control than the lower dose in patients with severe asthma. The long duration of effect of salmeterol makes it particularly suitable for treating patients with nocturnal asthma in whom it improves sleep quality. The place of salmeterol, like that of other beta 2-adrenoceptor agonists used regularly in the treatment of asthma, is being debated. Patients in need of regular beta 2-agonist therapy should also be regarded as candidates for inhaled corticosteroids to counteract underlying inflammation. Thus, salmeterol may be particularly useful in patients requiring regular treatment with beta 2-agonists for nocturnal asthma and results of trials in progress involving large numbers of patients are awaited with interest.     

Cefetamet pivoxil in community-acquired pneumonia: an overview.

A total of 305 patients with community-acquired pneumonia have participated in comparative or non-comparative studies involving cefetamet pivoxil. Of these, 211 (55 adults and 156 children) were involved in a series of open, prospective, comparator-controlled, multi-centre studies. Adults were randomized to receive either cefetamet pivoxil 1000 mg twice daily or amoxycillin 750 mg 3-times daily for 10 days. Children received either cefetamet pivoxil 10 mg/kg twice daily, cefetamet pivoxil 20 mg/kg twice daily or cefaclor 10 mg/kg 3-times daily for 7 to 8 days. The remaining 94 patients were treated openly with cefetamet pivoxil, with most patients receiving cefetamet pivoxil 500 mg twice daily for an average of 10 days; an elderly sub-group of these patients aged 70 to 103 years received therapy for an average of 11 days. The main causative organisms isolated were Streptococcus pneumoniae and Haemophilus influenzae. In adult patients, a successful clinical outcome was achieved in 100% of assessable patients receiving cefetamet pivoxil 1000 mg twice daily, and about 90% in those receiving 500 mg twice daily. The success rate in children was 98% for both dose levels of cefetamet pivoxil and 90% for those receiving cefaclor. In elderly patients, the percentage was 78% for the 500 mg twice daily patients. Thus, the standard dose of cefetamet pivoxil (500 mg twice daily in adults, 10 mg/kg twice daily in children) was well tolerated and proved to be at least as effective as the comparator drugs which were given 3-times a day.     

Metformin efficacy and tolerance in obese non-insulin dependent diabetics: a comparison of two dosage schedules

A comparative open study of metformin unit doses of 500 mg and 850 mg was carried out in 64 obese, non-insulin dependent diabetics on 1.5 to 3 g metformin daily. Glycaemic response, blood lactate, plasma metformin concentrations and tolerance for metformin were assessed. On changing from a 500 mg unit dose to an equivalent total dose of metformin using the 850 mg preparation, there were no significant changes in the random blood glucose, glycated haemoglobin, or blood lactate concentrations. Metformin plasma concentrations remained unchanged except for patients transferred from 1.5 to 2.0 g daily to 850 mg twice daily; in these patients plasma concentrations increased from 1.83 +/- 0.87 to 2.50 +/- 0.89 micrograms/l (p less than 0.01). Seven patients (3 asymptomatic and 4 with background symptoms) became intolerant of the 850 mg regimen and required to return to the 500 mg dose regimen. After exclusion of patients intolerant of the 850 mg dose regimen (11%), the remaining patients noted no significant change in symptoms and 28% of all patients transferred to the 850 mg dose unit indicated an overall preference for this regimen.     

Phase I clinical studies of 7432-S, a new oral cephalosporin: safety and pharmacokinetics

Phase I clinical studies of 7432-S, a new oral cephalosporin, including a randomized placebo-controlled trial were conducted with 40 healthy volunteers. In single-dose studies, 7432-S was orally administered at doses of 25, 50, 100, and 200 mg. The mean plasma levels peaked at 2.1 to 3.0 hours and reached 1.9, 3.6, 5.6, and 11.6 micrograms/ml, respectively. Linear correlation was observed between plasma AUC values and doses given. The half-lives of the plasma levels were 0.88 to 2.26 hours with a mean of 1.53 +/- 0.33 hours. The mean urinary recoveries were 67.5 to 75.2% of the dose within 24 hours. 7432-S was partially metabolized to 7432-S-trans which was excreted in urine at 7.2 to 9.2% of the doses. Study of the meal effect showed that AUC values and peak levels were not altered although the time to the peak levels was slightly prolonged. In multiple-dose studies, 100 mg of 7432-S twice daily for 2 weeks and 200 mg twice daily for 1 week were administered and there was no abnormal accumulation of 7432-S in plasma throughout the study. No significant differences were observed in plasma levels and urinary recoveries between single- and multiple-dose regimens. Clinical symptoms, physical tests, laboratory parameters, and fecal levels of vitamins K1 and K2 were in normal ranges. 7432-S was concluded to be safe and well tolerated.     

Accumulation of caffeine in healthy volunteers treated with furafylline.

The pharmacokinetics and tolerance of repeated oral doses of furafylline were investigated in normal volunteers. In accord with predictions from single dose studies, steady state was achieved on the first day following the administration of 90 mg and maintained by subsequent daily doses of 30 mg. When corrected for body weight there were no significant differences in minimum and maximum plateau levels of furafylline between males (1.2-2.0 micrograms ml-1; mean body weight 67.2 kg) and females (1.6-2.6 micrograms ml-1; mean body weight 54.9 kg). The half-life of elimination was less when the plasma concentration was lower than 600 ng ml-1 than during the stationary phase of treatment. Despite constant plasma levels the repeated administration of furafylline appeared to be associated with the onset of adverse xanthine-like side effects, a finding which was subsequently traced to the presence of, and possible synergism with, accumulating serum levels of caffeine in those volunteers drinking caffeine containing beverages. Subsequent studies showed that a single dose (90 mg) of furafylline results in a rapid accumulation of caffeine given orally (100 mg twice daily) and that this is accompanied by an elimination half-life of some 50 h and an abrupt decrease in metabolite levels. The furafylline-induced accumulation of caffeine was not influenced by the smoking habits of the subjects, implying that the metabolite pathway blocked by furafylline is the demethylation of caffeine in position 3, an implication confirmed by the reduced formation of paraxanthine. This demonstration of an unacceptable level of adverse side effects resulting from a potent inhibiting effect of furafylline on the metabolism of a normal dietary constituent has obvious implications in the interpretation of drug-induced toxicity.     

Contrasting effects of fluconazole and ketoconazole on phenytoin and testosterone disposition in man.

Nine healthy male subjects received oral fluconazole 400 mg daily, ketoconazole 200 mg twice daily or no treatment for 6 days according to a randomized, cross-over design. A single 250 mg oral dose of phenytoin suspension was administered on day 5 and serum phenytoin concentrations were measured over the following 48 h. Serum testosterone concentrations were measured for 10 h after each dose of phenytoin. Ketoconazole had no significant effect on phenytoin concentrations while the mean AUC(0,48) for phenytoin was significantly higher with fluconazole (195.2 +/- 47.8 micrograms ml-1 h) than control (146.3 +/- 49.6 micrograms ml-1 h). At 48 h, the serum phenytoin concentration averaged 1.72 micrograms ml-1 under control conditions and 3.99 micrograms ml-1 with fluconazole (132% increase). AUC(0,10) for testosterone was 42% lower than control after ketoconazole administration (P less than 0.05) but increased by 33% from 55.6 +/- 9.4 ng ml-1 h (control) to 73.8 +/- 12.6 ng ml-1 h with fluconazole. AUC(0,10) values for the testosterone precursors androstenedione and 17 alpha-hydroxyprogesterone were significantly higher in the fluconazole treatment phase as were concentrations of luteinizing hormone. The mechanism and clinical significance of the increase in testosterone concentration caused by fluconazole remains to be determined.     

Clonidine kinetics in man--evidence for dose dependency and changed pharmacokinetics during chronic therapy.

1 Clonidine kinetics were studied in 21 patients with essential hypertension. All received two bolus i.v. injections in the mean dose range of (0.78--3.36 micrograms kg-1) and one single oral dose (mean dose 1.7--2.3 micrograms kg-1) on separate occasions. The kinetics were also studied in some of these patients after multiple therapeutic oral dose (mean dose 1.1 or 1.9 micrograms kg-1) twice daily during a dosage interval after 6--12 months monotherapy with clonidine. The multiple oral dosage was based on the therapeutic response. 2 With increasing i.v. doses the rate constants (alpha, beta) decreased and the plasma clearance was reduced by 74% (9.94--2.61 ml min-1 kg-1) indicating dose-dependent kinetics. The volume of distribution (Vd beta) did not change with dose in contrast to the volume of the plasma compartment (Vc) which was increased at the highest doses. 3 The single oral dose kinetics agreed with the i.v. kinetics at comparable dose. The bioavailability was 90%. 4 During multiple oral dosing the elimination rate constants decreased compared to the single dose. The plasma clearance increased (7.18 ml min-1 kg-1) compared to the corresponding single dose (4.17 ml min-1 kg-1). The latter change was probably caused by the decrease in bioavailability to about 65%. 5 The pharmacodynamic properties of the drug could explain the changes in pharmacokinetics with increased dose and during multiple doses.     

Pharmacokinetic and clinical studies of cefuzonam in the field of obstetrics and gynecology

Pharmacokinetic and clinical studies on cefuzonam (CZON) were performed to evaluate its usefulness in the field of obstetrics and gynecology. A summary of the results is as follows: 1. Concentrations of CZON in female genital organ tissues showed a little variance among organs. Mean concentrations were 3.34-7.83 micrograms/g at 40 minutes, 0.523-1.08 micrograms/g at 2 hours 15 minutes and 0.286 micrograms/g (in the myometrium) at 3 hours 10 minutes after the end of drip infusion. 2. Mean concentrations of CZON in the pelvic dead space exudate were 31.0 micrograms/ml immediately after the end of drip infusion (1 hour after the start of infusion), and 37.2 micrograms/ml 1 hour after the end of infusion, then they gradually decreased to 25.6 micrograms/ml after 3 hours and 21.4 micrograms/ml after 5 hours. Mean serum concentrations of CZON in concurrently collected samples from the peripheral vein were 30.0 micrograms/ml immediately after the end of drip infusion, 14.4 micrograms/ml after 1 hour, 4.00 micrograms/ml after 3 hours and 1.84 micrograms/ml after 5 hours. The T 1/2 beta was 1.03 hours. 3. Clinical trial in 7 patients, with CZON administered at a dose level of 1 g at a time, twice daily, showed "excellent" and "good" efficacy in all the patients. No side effects were noted. From the results of the above studies, CZON seems to be highly useful for infections in the field of obstetrics and gynecology.     

Central and peripheral effects of oxytocin administration in prairie voles (Microtus ochrogaster)

The present study examined the hypothesis that oxytocin (OT) may influence female sexual behavior in prairie voles (Microtus ochrogaster). The effectiveness of OT to induce sexual behavior was tested in ovariectomized females that were injected daily with estradiol benzoate (EB, 0.02 micrograms, twice), a dose insufficient for estrus induction. On the third day females received intracerebroventricular (ICV) injections of OT (1, 300, or 1000 ng) or saline vehicle. In the presence of minimal estrogen stimulation, OT did not induce sexual receptivity, or influence autogrooming or other social interactions. The behavioral effects of OT were examined in another group of ovariectomized females that received daily oil or EB injections (10 micrograms, twice) followed on the third day by either ICV (1, 300, or 1000 ng) or intraperitoneal (IP) (1, 3, or 10 micrograms) injections of OT. Among EB-treated females, only those in confirmed estrus, prior to ICV or IP injection, were included in these studies. There was a dose-related decrease in the percentage of females that remained in behavioral estrus after ICV OT. In those females that continued to show sexual behavior, lordosis frequencies and durations were unaffected by ICV OT. Nonsexual behavior did not differ between mated females and those exhibiting OT-inhibited sexual behavior. In females that were EB-treated, autogrooming and side-by-side behavior increased after ICV OT, while there was a decline in aggression. Female sexual and nonsexual behaviors were not significantly affected by IP OT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic studies on cefsulodin in perinatal period

Pharmacokinetic studies on cefsulodin (CFS) were carried out in perinatal mothers and infants. The results obtained are summarized as follows. 1. CFS was promptly absorbed upon intravenous drip infusion in pregnant women, producing dose-related peak serum levels. Placental transference to the fetus occurred quickly and at high levels. Upon intravenous drip infusion of 1-2 g of CFS, drug concentration of the cord blood and amniotic fluid exceeded MICs of clinically isolated strains of Pseudomonas aeruginosa. These levels in cord blood ranged 3.3-16.9 micrograms/ml upon 1 g intravenous drip infusion and 0.8-21.6 micrograms/ml upon 2 g intravenous drip infusion, and in amniotic fluid they were 1.3-15.6 micrograms/ml upon 1 g administration and 5.5-17.9 micrograms/ml upon 2 g administration. The drug was transferred into newborn infant through placenta, showing no tendency to accumulate. According to the above results, it appears possible to successfully prevent or treat perinatal infections through administration of the dose of 1-2 g twice daily. 2. Moreover, newborn infants delivered from mothers receiving CFS administration showed no laboratory test abnormalities. 3. The penetration of CFS into mother's milk occurred at low levels, and the transference from milk to newborn infants appeared to occur at even low levels. The above results have demonstrated that CFS is a clinically useful antibiotic for prophylaxis and treatment of perinatal Pseudomonas infections.     

Clinical pharmacology and toxicity of low daily administration of oral etoposide in advanced lung cancer patients.

In this study, pharmacokinetics, clinical effects, and toxicity of daily oral etoposide were studied in 12 patients with advanced lung cancers. Administration schedule was 25 mg/body everyday of a 4-week cycle or 50 mg (25 mg twice)/body for 14 consecutive days of a 4-week cycle. The pharmacokinetic parameters of both groups in serum were as follows: 1) mean peak plasma concentration of 0.91 +/- 0.18 micrograms/mL (25 mg) and 1.24 +/- 0.12 micrograms/mL (25 mg twice); 2) elimination half-lives of 6.48 +/- 1.09 hours (25 mg) and 3.64 +/- 0.27 hours (25 mg twice); and 3) the area under the plasma concentration curve of 7.09 +/- 1.26 micrograms.hr/mL (25 mg) and 8.67 +/- 0.77 micrograms.hr/mL (25 mg twice). There was a significant difference between those two schedules in terms of the plasma concentration and the duration at a low concentration (greater than 1 micrograms/mL) of etoposide. Low daily administration of oral etoposide is shown to be well tolerated and easy on the patient. More studies are needed to study whether prolonged schedules of lower doses of etoposide could result in improved prognosis.     

Prazosin once or twice daily?

In 20 patients with long-standing essential hypertension, a comparison was made in a randomized cross-over study of the effect of once and twice daily prazosin administration on blood pressure levels. Concurrent medication (beta-blocker and/or saluretic once daily) remained constant throughout the study. Blood pressure measurements were carried out by a nurse using a Hawksley random zero sphygmomanometer, both in the clinic and at home, and using a Roche Kontron Arteriosonde SR-2 at home. Observations made in the morning and in the evening showed no significant difference in blood pressure between the once and twice daily treatments. Eight patients complained of dizziness and faintness half an hour after taking the once daily dose. However, they felt quite well on the twice daily regimen. The mean daily dose in these 8 patients was prazosin 8.4 mg, range 6-12 mg. No indication was found that the subjective adverse side effects were correlated with the serum prazosin level. The complaints noted may possibly be overcome by taking the once daily dose late in the evening, just before retiring. Better still, the development of a slow-release formulation for daily dosages of 6 mg and over is suggested.