Perceptions of vaccine safety in a global context.

UNLABELLED: Given the serious consequences of low vaccine coverage, concerns and misconceptions need to be taken seriously and responded to appropriately to sustain accomplishments of immunization programmes. For parental decisions related to childhood vaccinations, it seems reasonable to assume that the cultural context of the immunization programme is of importance. This article is a short review of some recent studies of parental decision-making on vaccination in developed countries Kazaktstan, Uzbekistan and Northern Nigeria. Furthermore, an attempt is made to relate the findings in these studies to theoretical models of parental decision-making. CONCLUSION: For the implementation of immunization programmes, it is important to develop an in-depth understanding of mechanisms underlying decisions to accept or reject the vaccination of a child. Theoretical models may aid in the understanding of these mechanisms.

Pharmacokinetics and antidiuretic effect of a new vasopressin analogue (F992) in overhydrated male volunteers.

OBJECTIVE: The aim of the present study was to study the pharmacokinetics, the antidiuretic effects and the safety of [D-Phe2, Thi3, alpha-Me-Abu4, Hyp7, D-Arg8]dC1-vasopressin, a new antidiuretic peptide (F992, Ferring, Sweden), administered as intravenous infusion to orally overhydrated male volunteers. METHODS: Eight healthy male volunteers participated in this open study consisting of two parts: a dose titration study and a safety study. In the dose titration study ascending doses of F992 were administered to volunteers in pairs in order to find a dose that within 1 h after the infusion, in both subjects, caused a reduction of the urine flow rate to below 5 ml x min(-1) (target dose). Subsequently, this target dose was administered to all volunteers. In the safety study the target dose was doubled and given to all volunteers. On each study occasion, in both study parts, the subjects were orally overhydrated with water. F992 was administered as i.v. infusion approximately 1.5 h after the start of the hydration procedure. Throughout the study days, blood was sampled for determination of plasma concentrations of F992 and for safety evaluation. Urine was collected at intervals in order to estimate flow rate and osmolality. RESULTS: The target dose was found to be 4.0 microg as this dose fulfilled the criteria regarding antidiuretic effect, consequently 8.0 microg was administered to all subjects in the safety study. After infusion of 4.0 and 8.0 microg, the median half-lives of elimination were 4.72 (range 3.99-6.53) h and 3.85 (range 3.04-11.08) h, respectively. The plasma clearance and the volume of distribution at steady state were estimated to be 0.88 (SD 0.24) ml x min(-1) x kg(-1) and 326 (SD 68) ml x kg(-1)] after infusion of 4 microg. After the highest dose (8 microg), the corresponding estimates were 0.86 (SD 0.32) ml x min(-1) x kg(-1) and 299 (SD 81) ml x kg(-1), respectively. Significantly (P = 0.033) different maximum mean urine osmolalities were produced after infusion of 4.0 and 8.0 microg of F992 (534 (SD 318) vs 732 (SD 189) mOsmol x kg(-1)). The median times to reach these values showed some tendency to be longer for the highest dose, however statistical significance was not reached. No serious adverse events were observed during the study. CONCLUSION: We found it safe to administer F992 as infusion to overhydrated male volunteers. The results suggest that F992 has a longer half-life and a lower potency than the widely used peptide desmopressin.

Changes in gastrointestinal motility influence the absorption of desmopressin.

OBJECTIVE: The antidiuretic effect of desmopressin is widely utilized in the treatment of neurogenic diabetes insipidus and nocturnal enuresis in children. The objective of the present study was to assess how changes in gastrointestinal motility, induced by erythromycin and loperamide, influence the pharmacokinetics of orally administered desmopressin. METHODS: This study was conducted using an open randomized, three-period, three-treatment design in 18 healthy subjects. On each study day a single oral dose of 400 microg desmopressin was administered in the morning. The desmopressin dose was either given alone (reference) or after pretreatment with either loperamide tablets (4 mg at -24, -12 h and -1 h) or erythromycin capsules (250 mg q.i.d, with the first dose in the morning 3 days before the study day and the last dose at -1 h). On each study day, blood was sampled up to 8 h after dosing for assessment of desmopressin concentration. RESULTS: Compared with administration of 400 microg of desmopressin alone, pretreatment with loperamide produced significantly (P < 0.05) altered pharmacokinetics of desmopressin as the endpoints; area under the curve up to infinity (AUC), area up to the last determinable plasma concentration (AUCt) and maximum plasma concentration (Cmax) increased 3.1-fold (95% CI 2.3-4.2), 3.2 (2.3-4.4) and 2.3 (1.6 3.2), respectively. Although the estimates were lower, pretreatment with erythromycin did not result in any significant changes in these endpoints. There were no significant changes observed between the three treatments regarding the terminal elimination half-life (t1/2). However, significant (P < 0.05) changes in the time to reach Cmax (tmax) values (median and range) were observed as, compared with administration of desmopressin alone (1.3 h and 0.5-4.0), it was longer after pretreatment with loperamide (2.0 h and 0.5-3.0) and shorter following pre-treatment with erythromycin (0.9 h and 0.5-1.3). CONCLUSION: Presumably due to slower gastrointestinal motility, pretreatment with loperamide significantly increases the gastrointestinal absorption of desmopressin. Except for a shortening of tmax pretreatment with erythromycin did not significantly influence absorption of the drug.

Indirect-response modeling of desmopressin at different levels of hydration.

The objective of the present study was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of desmopressin in healthy male subjects at different levels of overhydration. Also, we examined if an indirect-response model could be related to renal physiology and the pharmacological action of desmopressin. Eight healthy male subjects participated in this open, randomized crossover study with three periods. Each subject was orally water loaded (0 to 20 ml.kg-1 body weight) on 3 study days in order to achieve three different levels of hydration. After the initial water load, urine was voided every 15 min and the volumes were measured. To ensure continuous overhydration the subjects replaced their fluid loss with drinking-water. When a steady-state diuresis was achieved after approximately 2 hr, 0.396 microgram of desmopressin was administered intravenously as a bolus injection. Blood was sampled and urine was collected at intervals throughout the study day (10 hr). An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fit to the urine osmolarity data. There were no statistically significant effects of different levels of hydration, as expressed by urine flow rate at baseline, on the estimates of the PK and PD model parameters. The calculated terminal half-lives of elimination (t1/2 beta) ranged between 2.76 and 8.37 hr with an overall mean of 4.36 hr. The overall means of plasma clearance and the volumes of distribution of the central compartment (Vc) and at steady state (Vss) were estimated to be 1.34 (SD 0.35) ml.min-1.kg-1, 151 (SD28) ml.kg-1, and 386 (SD 63) ml.kg-1, respectively. High urine flow rate, indicating overhydration, produced a diluted urine and thus a low osmolarity at baseline (R0). The effect of the urine flow rate on the urine osmolarity at baseline was highly significant (p < 0.0001). The mean values for IC50 and the sigmodicity factor (gamma) were 3.7 (SD 1.2) pg ml-1 and 13.0 (SD 3.5), respectively. In most cases when there was a high urine flow rate at baseline, the model and the estimated PD parameters could be related to the pharmacological action of desmopressin and renal physiology. Thus, the indirect-response model used in this study offers a mechanistic approach of modeling the effect of desmopressin in overhydrated subjects.

Pharmacokinetics and antidiuretic effect of intravenous administration of desmopressin in orally overhydrated male volunteers.

In order to study the antidiuretic activity of desmopressin in healthy human subjects, a study design has previously been used with subjects orally hydrated. The objective of the present study was to investigate the pharmacokinetics and the antidiuretic activity of desmopressin administered as an intravenous infusion to eight orally hydrated male volunteers. After initial ingestion of water corresponding to 15 ml.kg-1 body weight, the overhydration was maintained by replacing the urinary fluid loss by drinking-water. Desmopressin (4 micrograms) was administered intravenously over 10 min. 1.5 hr after the start of the hydration procedure. Blood was sampled and urine was collected at intervals throughout the study day (9.5 hr). The terminal half-life of elimination (t1/2,) of desmopressin was calculated to be 2.97 +/- 0.24 (S.E.M.) hr while the clearance was 1.77 +/- 0.10 ml.min.-1.kg-1 and the volume of distribution at steady state was 373 +/- 30 ml.kg-1. The infusion caused a marked and long-lasting reduction of the urine flow rate. Four hr after the start of the infusion the mean urine osmolality was 909 +/- 46 mOsm.kg-1.

Ligand binding and functional effects of systematic double D-amino acid residue substituted neuropeptide Y analogs on Y1 and Y2 receptor types.

In order to identify the signal epitopes of the neuropeptide Y (NPY) molecule, the conformation of the NPY molecule was pertubated by a systematic double D-amino acid replacement of neighbouring residues. These NPY-analogs were examined for receptor affinity and on biological activity. The rat cerebral cortex and hippocampus were used for binding characteristics on Y1 and Y2 binding sites, respectively, while the isolated guinea pig caval vein and rat vas deferens were used in functional characterization of Y1 and Y2 receptors, respectively. The NPY analogs were examined as ligands at [3H]NPY binding sites in homogenates of the rat brain. Pairwise D-substitutions of either of the first 6 amino acid residues in the N-terminal part of the molecule resulted in a 20-100-fold loss of affinity for Y1 binding sites compared with the native peptide. In comparison, the same analogs displayed affinities, which were about 8-40 times lower than NPY itself at Y2 binding sites. Especially [D-Ser3,D-Lys4]NPY had a low affinity to Y1 and Y2 binding sites. For many of the pairwise D-amino acid substituted NPY analogs, there were similar affinities for Y1 and Y2 binding sites in the cerebral cortex and hippocampus, respectively. D-Amino acid residue substitutions in positions 7 and 8 did essentially not affect the affinity to either type of binding site, while such replacements in positions 19 and 20 resulted in a drastic loss of affinity to both types of NPY binding site. In contrast, [D-Tyr21,D-Ser22]NPY was only slightly less potent than NPY itself on either type of binding site. Pairwise D-amino acid substitutions in the C-terminal (positions 27 to 36) decreased the affinity to Y1 and Y2 binding sites by 2 to 3 orders of magnitude. In the guinea pig vena cava the D-amino acid substituted NPY analogs evoked a concentration-dependent contraction with an rank order of potency similar to that of the respective analog at Y1 binding sites in the cerebral cortex. Similarly, in the rat vas deferens the D-amino acid substituted NPY analogs evoked a concentration-dependent inhibition of the electrically-stimulated twitches with a rank order of potency similar to that of the respective analog at Y2 binding sites in the hippocampus. However, D-amino acid replacements in positions 25 and 26 resulted in an analog which was virtually inactive in the vas deferens, but almost equipotent with NPY in the vena cava. In conclusion, the present study has shown that N-terminal double D-amino acid substitutions in the NPY molecule reduced the binding affinity to and activation more of the Y1 receptor, than of the Y2 receptor, while both receptors were quite sensitive to double D-amino acid changes in positions 19 and 20 and in the C-terminal end of the NPY molecule.