Safety and immunogenicity of adjuvanted and unadjuvanted subunit influenza vaccines administered intranasally to healthy adults.

Antigen-specific mucosal immunity is thought to be important for protection against influenza virus infection. Currently licensed parenteral influenza vaccines stimulate the production of serum antibodies, but are poor inducers of mucosal immunity. The adjuvant MF59 has been shown to enhance the humoral immune response to parenteral influenza vaccine in humans and the mucosal immune response to intranasally-administered influenza vaccine in mice. We conducted an open-label safety study followed by an observer-blind, randomized trial comparing the immune response to intranasally-administered subunit influenza vaccine adjuvanted with MF59, unadjuvanted subunit influenza vaccine, and placebo. Adverse reactions did not occur significantly more frequently in vaccinees than placebo recipients. Of 31 subjects receiving 2 doses of MF59-adjuvanted influenza vaccine, 19 (61%), 8 (26%), and 11 (35%) developed a mucosal IgA response to influenza A/H1N1, A/H3N2, and B, respectively. The percentage of subjects with a serum antibody response was slightly lower. The immune responses to adjuvanted vaccine were not significantly different from those to unadjuvanted vaccine. Both vaccines gave more frequent responses than seen in placebo recipients, indicating the potential of intranasal inactivated vaccines to stimulate local IgA responses.

Gait, estimated net cost of transport and heat production at different speeds in three-day-event horses.

Heart rate and gait characteristics (stride length and frequency) were studied in 6 horses subjected to a standardised incremental exercise test, involving moving at the trot and increasing speeds up to a fast gallop and subsequently during the steeplechase phase of a 3-day-event. The studies were performed in hot conditions. Appropriate scaling, based on hindleg length (hh), stride length (L), stride frequency (f) and speed (Sp) for nondimensional stride length (lambda = (L/hh), nondimensional stride frequency (phi = f(hh/g)1/2) and nondimensional velocity (û = Sp/(ghh)1/2), where g is the gravitational acceleration, demonstrated that there were no major differences in characteristics over the full range studied lambda = 2.3 û0.68. However, there were subtle differences in some horses that could endow a benefit in locomotory efficiency when compared to others exercising at the same absolute speed. There were clear changes in the relationship between nondimensional stride length and frequency with increasing speed, from trot to canter (at û approximately 1.4) and to full gallop (at û approximately 2.3); when trotting, lambda was less than 2.2 and the transition from canter to gallop took place at lambda approximately 3.2. The cost of transport/kg/m, estimated from the heart rates measured continuously during each study, decreased with increasing speed and bodyweight. In some animals, there appeared to be a weak minimum around the canter-gallop transition speed. When interpreted as oxygen cost, using published values for the oxygen consumption-heart rate relationship, the cost fell from an average of 0.201 ml/kg/m at the trot to 0.161 mlO2/kg/m when galloping during the incremental exercise tests. During the steeplechase, the cost was approximately 7.5% higher than at the same speed in the exercise tests; this was probably due to jumping effort. Estimated power consumption increased linearly with speed. In the steeplechase, power consumption was also 7.5% higher than during the exercise tests at the same absolute speed; this was equivalent to an average rate of heat production of 346 kcal/min (24 kW) or 59.5 kcal/min/m2 of the measured body surface area.

Methylprednisolone-hemisuccinate and its metabolites in serum, urine and bile from two patients with acute graft rejection.

Methylprednisolone-hemisuccinate (MPHS), methylprednisolone (MP), 20-alpha-hydroxy- (20 alpha HMP) and 20-beta-hydroxymethyl-prednisolone (20 beta HMP) concentrations were measured in serum, urine and bile from two liver transplant recipients who had received 1 g MPHS by a 1 h intravenous infusion for treatment of an acute rejection episode. These patients excreted similar total amounts of the dose in urine as patients with rheumatoid arthritis (historical controls) who had normal liver function. The transplant patients showed a ratio in urine of 'total metabolites'/MPHS that was one third that of patients with rheumatoid arthritis. Less than 0.2% of the administered MPHS appeared in bile as MPHS, MP, 20 alpha HMP and 20 beta HMP during the 24 h following infusion. Liver transplantation did not affect the overall elimination of drug in urine. However, the impaired liver function following transplantation resulted in reduced conversion of MPHS to its active form (MP).

Methylprednisolone hemisuccinate and metabolites in urine from patients receiving high-dose corticosteroid therapy.

A reversed-phase high-performance liquid chromatographic (RP-HPLC) method for the measurement of methylprednisolone hemisuccinate (MPHS) and its metabolites methylprednisolone (MP), 20-alpha- (20a-HMP), and 20-beta-hydroxymethylprednisolone (20b-HMP) in urine is described. The metabolites were extracted from urine samples using Extrelut columns and eluted with ethylacetate. The mobile phase for RP-HPLC comprised methanol:citrate buffer:tetrahydrofuran (30:65:5, vol/vol/vol) with UV detection at 251 nm. Fractions were collected, pooled and the metabolites present were identified by gas chromatography-mass spectrometry and normal-phase HPLC (NP-HPLC). By RP-HPLC 30 +/- 7.3% (mean +/- 1 SD) of the dose was detected in the 0-24 h urine sample following a 1 g MPHS infusion to patients with rheumatoid arthritis; MPHS contributed 9.9 +/- 5.0%, MP 12.1 +/- 2.9%, 20a-HMP 7.8 +/- 2.2%, and 20b-HMP 1.0 +/- 0.3%, respectively. A further 1.0 +/- 0.9% of the administered dose was detected in urine collected 24-48 h postinfusion.

High-dose methylprednisolone sodium succinate (pulse therapy) in the treatment of renal disease: plasma and urine concentrations.

Methylprednisolone hemisuccinate (MPS) and methylprednisolone (MP) concentrations in plasma and urine were monitored in renal transplant and glomerulonephritis patients who were given i.v. infusions of 0.5 g or 1 g of MPS. A marked individual variation of peak plasma levels of both MPS and MP was observed after the same dose and MPS disappeared from plasma more rapidly than MP. Their clearances from the circulation, however, did not appear to be significantly influenced by the peak plasma levels of the drug, creatinine clearance, administration of previous pulses of MPS or the urinary excretion of unconjugated MPS and MP. Even in patients with profoundly reduced renal function, no accumulation of the drug was apparent when repeated doses of MPS were administered at 48-h intervals.

The symptomatology of the climacteric in relation to hormonal and cytological factors.

Climacteric symptomatology was investigated in a group of non-selected women aged between 54 and 56 years of age, Vasomotor complaints and dyspareunia, in particular, were noted and related to plasma hormone levels and vaginal cytology. Only 33% of those women who were within 5 years of the menopause had symptoms of a magnitude that might require hormone replacement therapy. Neither the vasomotor complaints nor dyspareunia correlated with the hormone levels or cytology findings to such an extent as to be helpful in planning treatment. Apparently only a minority of women in their middle 50s demonstrate a symptomatic need for hormone replacement therapy and laboratory investigations are of little use in their identification.

Alteration of plasma prednisolone levels by indomethacin and naproxen.

Eleven patients with stable rheumatoid disease (RD) who were receiving regular corticosteroid therapy (CS) were investigated to discover the effect on plasma prednisolone levels of additional therapy with the non-steroidal anti-inflammatory (NSAI) drugs, indomethacin and naproxen. There was a highly significant (P less than 0.001) increase in free prednisolone levels after concurrent therapy with either indomethacin or naproxen for 2 weeks. Total prednisolone levels were unchanged. These results could provide an explanation for clinical reports that these two NSAI drugs possess a steroid-sparing effect.

A double-blind placebo-controlled trial of methylprednisolone pulse therapy in active rheumatoid disease.

To confirm the findings of uncontrolled trials that methylprednisolone pulse therapy (MPPT) is a safe treatment for active rheumatoid disease, a double-blind trial was conducted in which 20 patients with active rheumatoid disease were randomly allocated to receive an infusion of either 1 g methylprednisolone or placebo. Methylprednisolone produced significant improvement in all clinical variables measured, a benefit which was sustained for at least 6 weeks. The placebo produced only transient improvement in some of the clinical variables measured. when the 10 placebo groups patients were later given an infusion of 1 g methylprednisolone, they too showed significant clinical benefit. The methylprednisolone also gave rise to improvements in some haematological and biochemical variables.

High dose intravenous methylprednisolone "pulse" therapy in patients with rheumatoid disease. Plasma methylprednisolone levels and adrenal function.

Twenty seven patients with acute rheumatoid disease who had not previously received systemic corticosteroid therapy were given a pulse(s) of high dose methylprednisolone sodium succinate (MPS) intravenously. Of the 27 patients 22 received 1 g MPS once and 5 were given the drug on three consecutive days. Plasma "MP" (total MPS plus hydrolysed methylprednisolone) and cortisol levels were measured at various intervals post infusion. Clinical assessments were made before and at 2 week intervals after each infusion for 12 weeks. Patients showed objective improvement for up to 12 weeks post infusion. Maximum "MP" levels ranging between 16 and 72 mumol/l were obtained after single infusions. In a majority of the patients "MP" concentrations in plasma were reduced to values between 0.12-3.4 mumol/l in 24 h, 0.06 to 0.13 mumol/l in 48 h. Plasma cortisol levels were incompletely suppressed for a few days in all patients, but the drug was removed from plasma and normal adrenal function restored within a fortnight after steroid infusion at the latest.

Effects of renal function on plasma digoxin levels in elderly ambulant patients in domiciliary practice.

An investigation into the relations between the daily dose of digoxin, drug regimen, serum digoxin concentration, and creatinine and digoxin clearance was carried out in a group of elderly ambulant patients in domiciliary practice. Moderate to severe impairment of renal function was found both in patients taking digoxin and in elderly control subjects. Plasma digoxin levels were not related to blood urea concentrations or creatinine clearance. Digoxin clearance was less than creatinine clearance. Now that plasma digoxin levels can be measured relatively easily their estimation should become part of clinical practice.

Serum globulins and infection in mongolism.

Comparisons are made between a large group of mongols cared for in institutions and their carefully matched controls in respect of (a) serum levels of immuno-gamma-globulin (gammaA, gammaG, and gammaM) and (b) the incidence of pyrexial illnesses over a retrospective five-year period. Male mongols are found to have higher levels of gammaA-globulin than their male controls and a higher incidence of pyrexial illnesses. Otherwise no significant differences were found. The findings are discussed in the light of previous studies.