Systemic effects of two nasally administered glucocorticosteroids

Two topical corticosteroids, budesonide (BUD) and beclomethasone dipropionate (BDP), both administered as suspensions in water, were investigated in healthy volunteers regarding influence on cortisol in plasma and urine (U-cortisol) after nasal application. In the first study, single doses of 200, 400, and 800 μg of BDP and BUD were given at 10:00 pm. In the second study, 100, 200, and 400 μg were given mornings and evenings for 4 days. In the single-dose study, none of the drugs or doses showed any significant influence on cortisol in plasma. However, U-cortisol decreased significantly after BUD 400 and 800 μg. In the multidose study, U-cortisol values were significantly reduced after all doses of BUD and the highest dose of BDP. The compounds tested showed different ability to cause measurable systemic effects after nasal application. The clinical implication is that the prescriber, when choosing a compound, should take the application site into consideration and should also be encouraged to find the lowest effective dose.     

Endocrinology: Gonadotrophins and prolactin rise after bilateral oophorectomy for benign conditions

The aim of this study was to analyse the changes in folliclestimulating hormone (FSH), luteinizing hormone (LH) and prolactinconcentrations in the 3 months following oophorectomy in pre-menopausalwomen operated on for benign gynaecological conditions. Includedin this analysis were 21 women (mean age 47 years, range 46–52)who underwent bilateral oophorectomy plus hysterectomy for fibroidsor ovarian cysts. Plasma concentrations of FSH, LH and prolactinwere measured before and on days 2, 4, 6, 14 and 30 after surgery;in 10 cases measurements were made on day 60, and in five caseson day 90 after surgery. Hormone concentrations were measuredin duplicate daily samples, and immunoenzymatic assay kits wereused for all the immunoassays. The FSH and LH concentrationsincreased constantly after surgery. Mean prolactin concentrationsalso increased from 12.1 ng/ml before surgery to 31.5 ng/mlon day 14 after bilateral oophorectomy, but decreased thereafterto 18.2 ng/ml on day 30, 10.9 ng/ml on day 60 and 6 ng/ml onday 90. In conclusion, transient (2–3 weeks) increasedprolactin concentrations are observed after surgical castration.     

Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses,linearity and plasma protein binding

The pharmacokinetics of reboxetine, a new antidepressant agent, were found to be close to linear in a crossover study comparing administration of single 2, 3, 4 and 5 mg capsule doses in 15 healthy male volunteers, and in the same study the capsules were bioequivalent to the proposed therapeutic tablet formulation (4mg). Kinetic analysis was based on HPLC assay of reboxetine in plasma and urine collected up to 72 h after each administration. Plasma levels indicated a rapid absorption (t_max?2h) and an elimination half-life of about 13 h. Clearance and volume of distribution were modest (ratios to bioavailability: CL/F?29 mL min^?1; V_z/F?32L); urinary excretion was ～9% of dose, corresponding to a renal clearance of only 3 mL min^?1 (a value consistent with the rate of glomerular filtration of unbound drug). In vitro, binding to plasma proteins, estimated from radioactivity levels following dialysis of ¹⁴C-labelled reboxetine, appeared to be dominated by α₁-acid glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL^?1 (2.8–3.1% unbound with human plasma from three additional volunteers; 1.8–2.0% for 2gL^?1 orosomucoid α₁-acid glycoprotein, and 46.4–47.4% for 40 gL^?1 albumin), whilst the mean C_max in the current study was much lower (164 ng mL^?1 after a 5 mg dose).     

Pharmacokinetics of orally administered hexobarbital in plasma and saliva of healthy subjects

Hexobarbital (HB) concentrations were determined in plasma and saliva of 8 healthy subjects, following oral administration of 500 mg HB-Na. Mean plasma half-lives were 3.2 +/- 0.1 h, and salivary half-lives 3.3 +/- 0.2 h. Mean plasma clearance was 22.9 +/- 2.3 1 h-1. There was a linear relationship between HB concentrations in saliva and plasma (r = 0.92). Mean salivary levels were 34 per cent of plasma levels. Salivary pH was constant throughout the experiment, 7.06 +/- 0.09. There was an inconsistent tendency of the saliva over plasma ratios to increase as a function of time. The percentage of protein binding calculated from saliva over plasma ratios was in reasonable agreement with in vitro data of equilibrium dialysis, 64.1 +/- 2.6 per cent and 65.9 +/- 0.8 per cent, respectively. The experiment was repeated in 4 subjects, and considerable intraindividual differences were shown to exist in saliva over plasma ratio, half-lives, and protein binding. It was concluded that HB elimination half-lives can relatively accurately be determined from salivary concentrations. Oral plasma clearance can only be estimated if the individual saliva over plasma ratios are known; this would require the taking of at least one blood sample during the experiment. When employing HB as a model substrate for drug metabolizing enzyme activity in vivo, the determination of its pharmacokinetic parameters, particularly oral plasma clearance as a reflection of cytochrome P-450 activity, cannot be achieved by taking saliva samples only.     

Plasma protein binding of furosemide in the elderly

Summary The protein binding of furosemide was investigated in plasma from 22 old and 11 young subjects by equilibrium dialysis. The unbound fraction of furosemide was 3.16% in plasma from the elderly and 1.71% in plasma from the young. A significant correlation was found between the unbound fraction of furosemide and the plasma concentration of albumin. The average number of binding sites was 3.8 (elderly) and 2.7 (young) 10^–6 mol/g albumin. The average association constant (K) was 4.3 (elderly) and 4.2 (young) 10⁵ M^–1. By increasing the concentration of furosemide up to 200 µg/ml buffer the unbound fraction of the drug rose to 5.2% (elderly) and 3.5% (young).     

Nucleolus-associated J chains in myeloma cells: clinical significance

Bone marrow aspirates from 20 patients with multiple myeloma (MM), 4 with smoldering multiple myeloma (S-MM), 1 with idiopathic Bence Jones proteinuria (I-BJP), and 6 with primary macroglobulinemia (PMG) were examined for nucleolus-associated J chain. The incidence of nucleolar J chain-positive (J+) cells among nucleolated cells producing M-component was measured. This incidence (94.0-100%) in terminal MM was significantly higher than that (0-58.0%) in non-terminal MM. Judging from a low incidence in the remission phase, chemotherapy might cause a selective elimination of less differentiated myeloma cells with J+ nucleoli and might have some effect on J chain synthesis. The incidence of nucleolar J+ cells was very low in S-MM. The IgM cells in PMG, where J chain is present in a disulfide-linked form, had no or few J+ nucleoli. No correlation between the incidence of nucleolar J+ cells among nucleolated plasma cells and the percentage of nucleolated cells or that of J+ cells was found. Large J+ nucleoli seemed to be another morphological feature indicating anaplastic myeloma cells. A high incidence of nucleolar J+ cells may be one of the indicators for progressive disease.     

Prolactin responses to haloperidol in drug-free and treated schizophrenic patients

Summary The prolactin response to 5 mg haloperidol i.m. was studied in 12 schizophrenic patients in a drug-free state and after a month treatment with haloperidol, as a possible index of dopamine receptor sensitivity and occupancy. Blood samples were taken at times 0, 60, 90 and 120 minutes. The increase in PRL observed in the drug-free state disappeared after drug treatment. The PRL plasma levels after treatment with 60 mg haloperidol per os were higher than the maximal PRL responses after 5 mg i.m. The increases in baseline PRL caused by the treatment correlated positively to the reduction in the BPRS score. The test was also performed in a group of 11 patients chronically treated with haloperidol during a daily dose of 60 mg, and 15 days after reduction of the dose to 30 mg. PRL increases after 5 mg haloperidol i.m. were observed only after reduction of the dose. It is suggested that the prolactin response to haloperidol is an index of the occupancy of receptors that are involved in the PRL releasing mechanisms, and could be used to verify their blockade by the neuroleptics, especially in patients that do not respond positively to drug treatment.     

Plasma volume estimation using indocyanine green with biexponential regression analysis of the decay curves

We studied seven analytical methods of estimating the plasma volume from the decay curves of indocyanine green. Fifteen volunteers received 1.0 mgkg⁻¹ of the dye by intravenous injection and the plasma concentration was measured continuously using spectrophotometry. Plasma volumes were calculated using three single-regression methods (1-a, 1-b, 1-c) and four biexponential regression methods (2-a, 2-b, 2-c, 2-d). The means (SD) of 1-a, 1-b and 1-c were 39 (5.0), 44 (5.7) and 54 (11.5) mlkg⁻¹, respectively, and these were significantly different from each other (p < 0.05). The values for methods 2-b, 2-c and 2-d were similar to each other: 39 (4.6), 40 (4.1) and 40 (4.0) mlkg⁻¹, respectively. These required more than 3 min circulation or mixing time. When the time allowed for mixing was less than 3 min (method 2-a) the plasma volume was underestimated. We conclude that plasma volume estimation using indocyanine green and spectrophotometry is most accurate when the mixing time is adequate (3–5 min) and the decay curves are analysed using biexponential regression.