Inability of recombinant human thyrotropin to predict the evolution from subclinical hypothyroidism to overt disease. A pilot study.

BACKGROUND: The use of recombinant human TSH (rhTSH) is indicated to evaluate thyroid carcinoma patients. In recent years, some authors have reported that rhTSH could serve as a dynamic test of thyroid reserve. The aim of the present study was to determine whether or not rhTSH can predict the evolution from subclinical hypothyroidism (SH) to overt hypothyroidism. MATERIALS AND METHODS: Twenty-one women who met the diagnostic criteria of SH were enrolled. All patients received a single dose of rhTSH (0.1 mg). Basal blood samples for TSH, free T4 (fT4), thyroglobulin (Tg), and anti-thyoperoxidase and anti-Tg antibodies were obtained before and 1 day after rhTSH administration. All patients were followed for 2 yr, and blood samples were obtained every 6 months. RESULTS: Twenty-four hours after rhTSH administration, the TSH level increased to >20 mU/l in 14 patients; the serum peak TSH levels remained <10 mU/l in only 5 patients. On follow-up, 7 women (33%) required L-T4 replacement therapy for overt hypothyroidism or a persistent TSH level >10 mlU/l. None of the parameters analyzed differed significantly between patients who developed overt hypothyroidism from those who had persistent SH. CONCLUSIONS: The response of thyroid function tests to a single low dose of rhTSH is not useful in identifying those patients with SH who will develop overt hypothyroidism over a 2-yr period.

Effects of competition and its outcome on serum testosterone, cortisol and prolactin.

In various species, competitive encounters influence hormonal responses in a different way depending on their outcome, victory or defeat. This study aimed to investigate the effects of sports competition and its outcome on hormonal response, comparing it with those displayed in situations involving non-effort and non-competitive effort. To this end, serum testosterone (T), cortisol (C) and prolactin (PRL) were measured in 26 judoists who participated in three sessions (control, judo fight and ergometry). The relationship between hormonal changes and psychological variables before and after the fight were also analysed. Our results showed a hormonal response to competition, which was especially characterized by an anticipatory rise of T and C. Depending on outcome, significant higher C levels were found in winners in comparison to losers through all the competition but not in T or PRL, both groups expending a similar physical effort. Furthermore, similar hormonal responses to the fight and to a non-competitive effort with the same caloric cost were found, other than with PRL. Winners showed a higher appraisal of their performance and satisfaction with the outcome, and perceived themselves as having more ability to win than losers, although there were no significant differences in motivation to win. Finally, the relationships found between T changes in competition and motivation to win, as well as between C response and self-efficacy suggest that in humans hormonal response to competition is not a direct consequence of winning and losing but rather is mediated by complex psychological processes.

Recombinant factor VIIa in continuous infusion during central line insertion in a child with factor VIII high-titre inhibitor.

Recombinant factor VIIa (rFVIIa) is a recently added new tool for the treatment of haemophilia patients with inhibitors. A major drawback in the use of rFVIIa is its short half-life, which necessitates frequent bolus injections. Thus the use of rFVIIa in continuous infusion appears to be a good alternative. We describe the use of rFVIIa, administered by continuous infusion with a minipump during the insertion of a central venous catheter in a child with a high-titre factor VIII inhibitor. rFVIIa was administered as an intravenous bolus (90 micrograms kg-1 [4.5 kIU kg-1]), 1 h prior to central line insertion, after which the continuous infusion was immediately started for 5 days. The infusion rate was based on the clearance obtained from a previous pharmacokinetic study. Effective haemostasis and normal healing of surgical incisions were achieved after central line insertion. No local thrombophlebitis nor evidence of generalized activation of the coagulation cascade was observed. Single-dose pharmacokinetic parameter values were clearance (Cl) 34.6 mL h-1 kg-1, volume of distribution (Vd) 40.6 mL kg-1 and mean residence time (MRT) 1.17 h. The recovery was 2.27% U-1 kg-1. rFVIIa showed a monophasic decay. Cl during continuous infusion was 23.4 +/- 6.9 mL h-1 kg-1. The administration of rFVIIa by continuous infusion is effective, safe and more convenient when compared to other clotting factors. Moreover, continuous infusion provides significant economic savings (77% decrease in rFVIIa requirements).

Comparative study of four different pharmacokinetic computer programs: case study of a factor VIII preparation.

OBJECTIVE: To compare the pharmacokinetic parameters after a single dose of a monoclonally purified factor VIII concentrate in four different computer programs for pharmacokinetic analysis. SETTING: Haemophilia unit of a tertiary care university hospital. METHODS: Ten patients with severe haemophilia A were administered a single dose of 30-50 IU kg-1 body weight. Blood samples were drawn at different times during the first 48 h after infusion of factor VIII. Plasma factor VIII activity was measured by standard one-stage clotting assay and experimental data were analysed using four computer programs: JANA, PKCALC, F8SD and PCNONLIN. The pharmacokinetic models of analysis employed in the study were both compartmental and non-compartmental. The parameters compared were half-lives (t1/2) and mean residence time (MRT), volumes of distribution (V) and clearance (CL). Values obtained for each pharmacokinetic parameter in each program for the same model were tested for differences with a multiple analysis of variance (MANOVA). Linear correlation with the equivalent parameters for each program was also performed. RESULTS: Pharmacokinetic parameters differed depending on the computer program used to analyse the same data set. There were differences of statistical significance in t1/2 and V for one-compartment and two-compartment models derived by some of the programs, but none with the non-compartmental one. CL, considered model independent, showed differences between the programs evaluated. Correlations for each parameter generated were in general good (P < 0.05). CONCLUSION: Pharmacokinetic parameters differed depending on the computer program used to analyse the same data set. The same patient data used in different computer programs will result in significantly different parameter estimations, although the non-compartmental approach is less affected by variation, and this should be taken into consideration for comparative purposes, for the development of new preparations and for the implications in patient care and therapy monitoring.

Stability of amphotericin B in an extemporaneously prepared i.v. fat emulsion.

The stability of amphotericin B in an extemporaneously prepared i.v. fat emulsion was studied. Admixtures of amphotericin B 0.5, 1, and 2 mg/mL were prepared by adding 10, 20, and 40 mL of amphotericin B 5 mg/mL to 90, 80, and 60 mL, respectively, of 20% fat emulsion. The admixtures were stored in glass vacuum containers at 20-25 degrees C and exposed to fluorescent light, 20-25 degrees C and protected from light, or 4-8 degrees C and protected from light. A sample was withdrawn from each container at 0, 4, 12, and 24 hours and at 2, 4, 7, and 15 days for analysis of amphotericin B concentration by high-performance liquid chromatography and for visual evaluations; these samples were immediately frozen until analyzed. A sample was withdrawn from one container of amphotericin B 1 and 2 mg/mL for each storage condition at 0, 7, and 15 days for immediate determination of particle-size distribution with a fluorescinated-antibody cell sorter. Amphotericin B 0.5 mg/mL in 20% fat emulsion was stable for one week under all the storage conditions. Amphotericin B in the 1- and 2-mg/mL admixtures was stable for up to four days at 20-25 degrees C exposed to fluorescent light, and for up to one week at 20-25 degrees C protected from light and at 4-8 degrees C protected from light. There was no visible evidence of incompatibility. There were no substantial changes in particle-size distribution for the 1-mg/mL admixtures; appreciable changes were detected for the 2-mg/mL admixtures. Amphotericin B 1 and 2 mg/mL was stable in 20% fat emulsion for four days at 20-25 degrees C exposed to fluorescent light and for seven days at 20-25 degrees C protected from light or at 4-8 degrees C; amphotericin B 0.5 mg/mL was stable in 20% fat emulsion for seven days under the three storage conditions.

Pharmacokinetics of conventional formulation versus fat emulsion formulation of amphotericin B in a group of patients with neutropenia.

The pharmacokinetics of amphotericin B administered in a conventional 5% dextrose (glucose) (5% D) solution and in a 20% fat emulsion formulation (Intralipid; 20% IL) were compared in 16 patients (mean age, 42 years [range, 18 to 70 years]) who had been hospitalized for hematological malignancies and with proven or suspected fungal infections. All of the patients received 50 mg (approximately 1 mg/kg of body weight per day) of amphotericin B daily in random order, either as a 50-ml lipid emulsion (20% IL) (group I) or in 500 ml of 5% D (group II). Five serum samples were taken during the 24 h after drug administration, and the levels of amphotericin B were measured by high-pressure liquid chromatography. Serum amphotericin B concentrations declined rapidly during the first 6 h, and subsequent measurements revealed a slow terminal elimination phase in both groups. The maximum serum amphotericin B concentration was significantly lower when the drug was administered in 20% IL (1.46 +/- 0.61 versus 2.83 +/- 1.17 micrograms/ml; P = 0.02). The area under the concentration-time curve from 0 to 24 h was also much lower in group I (17.22 +/- 11.15 versus 28.98 +/- 15.46 micrograms.h/ml). The half-life of the distribution phase was approximately three times longer in group I (2.92 +/- 2.34 h versus 0.64 +/- 0.24 h; P = 0.011). Conversely, the half-lives of the elimination phase were approximately equal in the two groups (11.44 +/- 5.18 versus 15.23 +/- 5.25 h). The mean residence times were also similar in both groups (19.41 +/- 11.13 versus 19.65 +/- 7.86 h). The clearance and the steady-state volume of distribution of amphotericin B in group I were about twice as great as those in group II (62.97 +/- 35.51 versus 33.01 +/- 14.33 ml/kg/h and 1,043.92 +/- 512.10 versus 562.32 +/- 152.05 ml/kg [P = 0.034], respectively). Finally, the volume of distribution in the central compartment was greater in group I than in group II (618.17 +/- 231.80 versus 328.19 +/- 151.71 ml/kg; P = 0.013), but there were no differences in the volume of distribution in the peripheral compartment (425.75 +/- 352.87 versus 234.14 +/- 75.92 ml/kg). These results suggest that amphotericin B has a different pharmacokinetic profile when it is administered in 20% IL than when it is administered in the standard 5% D form and that the main difference is due to a clear-cut difference in the steady-state volume of distribution, especially that in the central compartment.

Administration of lipid-emulsion versus conventional amphotericin B in patients with neutropenia.

OBJECTIVE: To evaluate the usefulness of a 20% lipid emulsion as a delivery system for amphotericin B (1 mg/mL) administered over 1 hour to patients with neutropenia with hematologic malignancies compared with amphotericin B (0.1 mg/mL) administered in dextrose 5% solution over the same time. DESIGN: A prospective, comparative, randomized, labeled study. SETTING: Hematology unit, pharmacy service, university general hospital. PARTICIPANTS: Twenty patients with neutropenia with hematologic malignancies and proven or suspected fungal infections, 10 in the fat emulsion group (group 1) and 10 in the dextrose 5% group (group 2). MAIN OUTCOME MEASURES: Clinical tolerance (i.e., fever, shaking chills, nausea, blood pressure, pulse rate) and biologic tolerance (i.e., urea, creatinine, sodium, potassium). RESULTS: Clinical tolerance was comparable in both groups although amphotericin B in fat emulsion was better tolerated. Medication for symptoms related to the administration of amphotericin B was given in 6 cases in group 1 and in 8 cases in group 2. There was a statistically significant difference in the urea concentrations between the 2 groups (p = 0.023); there was an observed increase between the initial and the final serum urea (56.8 mg/d in group 1, 79.8 mg/dL in group 2). Statistically significant differences in creatinine serum concentrations (84.9 mumol/L in group 1, 123.8 mumol/L in group 2) (p = 0.047) were found. No differences were found in the antifungal efficacy of the treatment. However, as amphotericin B was started in the majority of cases (75%) as empiric treatment for fever unresponsive to antibiotic therapy, it is difficult to compare the efficacy of both preparations. CONCLUSIONS: The clinical tolerance of lipid-emulsion infusions is similar to that of conventionally administered amphotericin B therapy. Renal toxicity appears to be decreased when the drug is administered in a fat emulsion. This type of preparation permits the reduction of the volume and the time of administration for amphotericin B therapy.

An association between clotting factor concentrates use and mortality in human immunodeficiency virus-infected hemophilic patients.

There is much evidence that clotting factor concentrates (CFC), especially the so-called intermediate-purity preparations, exert an immunomodulating effect in vitro. The impact of this effect on the outcome of human immunodeficiency virus (HIV) infection in hemophiliacs is still controversial. In this retrospective cohort study, the effects of treatment with CFC on mortality and progression to acquired immunodeficiency syndrome (AIDS) were estimated while controlling for individual risk factors. Logistic regression and survival analysis, including the Cox proportional-hazards regression model, were performed with data from a 11-year follow-up of 225 hemophilic patients seropositive for HIV type 1 (HIV-1) of two hemophilia centers. Mortality and progression to AIDS rates were strongly associated with lower administration of CFC. After adjusting for age, a statistically significant and robust association was observed. The use of CFC was negatively associated with progression to AIDS (P = .0252) and mortality (P = .0033). The adjusted relative hazards of mortality and progression to AIDS rate between the most treated patients (> 700 IU/kg/yr) versus the least treated (< or = 700 IU/kg/yr) were 0.53 (confidence limits, 0.33 to 0.86) and 0.57 (0.39 to 0.84), respectively. Although the effects of other unmeasured risk factors cannot be excluded with certainty, these results suggest that there is a negative association between treatment with CFC and progression to AIDS and mortality.

Seroprevalence of parvovirus B19, cytomegalovirus, hepatitis A virus and hepatitis E virus antibodies in haemophiliacs treated exclusively with clotting-factor concentrates considered safe against human immunodeficiency and hepatitis C viruses.

Clotting-factor concentrates (CFC) are a potential source of transmission of blood-borne viruses. Newer physical and chemical methods (pasteurization, wet-heating, solvent/detergent treating) developed to inactivate viruses are effective against HIV, HBV and HCV. However, it is not clear if these methods protect against other pathogenic viruses such as parvovirus B19, cytomegalovirus (CMV), hepatitis A virus (HAV) and hepatitis E virus (HEV). To evaluate the safety of current CFC we have studied seroprevalence of parovirus B19, CMV, HAV and HEV antibodies in 22 HIV and HCV negative haemophiliacs who were treated exclusively with clotting-factor concentrates considered safe with respect to HIV and HCV transmission, 22 healthy individuals served as controls. Neither HAV nor HEV antibodies were detected in haemophiliacs or controls. Two controls and two haemophiliacs were seropositive for CMV. Five controls (32% prevalence) and 15 haemophiliacs (77%) were positive to parovirus B19. No statistical differences can be established for seropositivity with CMV, HAV and HEV between haemophilic patients and controls. In the case of parvovirus B19 the differences are statistically significant (P= 0.0128). The relative risk of parvovirus B19 is 2.4 in the case of haemophiliacs. CFC considered safe against HIV and HCV are not safe against parvovirus B19, although they seem to be safe against CMV, HAV and HEV.

Stability of somatostatin in total parenteral nutrition.

The stability of somatostatin, added to a total parenteral nutrition formula, in glass containers and in plastic ethylene vinyl acetate containers was investigated. The somatostatin concentration decreased immediately from 3 micrograms/ml to 0.3-0.6 micrograms/ml after addition to the emulsion. In spite of this rapid decrease, somatostatin concentrations remained stable with values of 0.4-0.7 micrograms/ml during the follow-up period (24 h). These findings could be explained assuming adsorption to the surface of the container.