Prevalences of CT-detected calcification in the basal ganglia in idiophathic hypoparathyroidism and pseudohypoparathyroidism

Summary Sixteen patients with idiopathic hypoparathyroidism (IHP) and eight patients with pseudohypoparathyroidism (PHP) were examined by CT scan of the brain. Calcification in the basal ganglia was observed in 11 patients with IHP (69%) and in all eight patients with PHP. Of the 19 patients with basal ganglia calcification, nine had calcification in the cerebral cortex (47%), and four had calcification in the cerebellum (21%). Observation of basal ganglia calcification on CT gave rise to suspicion of IHP or PHP in three patients (12%). The remaining patients were examined at varying time after diagnosis. Since arrest in growth of calcification after institution of treatment has never been proven, the reported prevalences of calcification may not be valid to the situation at the time of diagnosis.     

Spinal cord injury at birth: a hidden causative factor

A case of perinatally acquired spinal cord injury (SCI) is presented. The foetus was vigorous until birth, the breech presented and delivery was performed by a non-traumatic Caesarean section. The infant displayed symptoms of severe SCI but diagnosis was delayed due to severe co-morbidity. Diagnostic considerations are briefly reviewed. Ventilatory support was withdrawn at the age of 20 days when the infant had still not exhibited any respiratory effort or spontaneous movements. Autopsy revealed a serious congenital malalignment of the upper cervical vertebrae and at the histological examination extensive reactive changes were observed in the same area. To our knowledge such findings have not been published previously. CONCLUSION: In cases of serious perinatally acquired SCI, claim of malpractice is often apparent. In this case a hidden congenital malformation of the cervical vertebrae was revealed, highlighting the need of careful postmortem examinations in such cases.     

Drug-polyionic block copolymer interactions for micelle formation: physicochemical characterisation.

While covalent attachment of small drug molecules to AB copolymers for the formation of polymeric micelles for drug delivery has been investigated, few studies have focused on non-covalent interactions. The aim of this study was therefore to explore the potential of non-covalent interactions between an AB copolymer, Poly(aspartic acid)-poly(ethylene glycol) (Pasp-PEG), with anionic pendant groups and diminazene aceturate, a small molecular weight cationic drug. Micelles were prepared by mixing solutions of Pasp-PEG and diminazene in 25 mM Tris-HCl buffer. At all Pasp-PEG concentrations studied, the micelles appeared to be water soluble with a unimodal size distribution and ranged in size from approximately 22 to 60 nm. The polyionic micelles also displayed similar and small absolute zeta potential values at various drug:monomer molar ratios which confirmed stabilisation by the PEG corona. The scattering intensity was maximal and remained unchanged, while particle size increased slightly at pH range from 3.4 to 7.2. At this pH range both the polymer and drug would be ionised and ionic interactions possible to drive micellar formation. An increase in size and scattering intensity with addition of NaCl to the micelles was attributed to dehydration of the PEG corona which may have led to aggregation of the micelles. The absence of micellar dissociation upon addition of salt was attributed to the dominance of hydrogen bonding between Pasp and diminazene aceturate, as assessed by isothermal titration microcalorimetry. Morphological evaluation of these constructs showed them to be discrete and fairly uniform in size and shape. This study was therefore successful in confirming the potential of non-covalent interactions using an AB copolymer to form polyionic micelles for drug delivery.     

Protective levels of diphtheria-neutralizing antibody induced in healthy volunteers by unilateral priming-boosting intranasal immunization associated with restricted ipsilateral mucosal secretory immunoglobulin a

Subunit intranasal vaccines offer the prospect of inducing combined systemic-mucosal immunity against mucosally transmitted infections such as human immunodeficiency virus. However, although human studies have demonstrated the induction of active immunity, secretory immunoglobulin A (sIgA) responses are variable, and no study has demonstrated protection by accepted vaccine-licensing criteria as measured by direct toxin-neutralizing activity. Using the genetically inactivated mutant diphtheria toxoid CRM(197) in a bioadhesive polycationic polysaccharide chitosan delivery system, we found that a single nasal immunization was well tolerated and boosted antitoxin neutralizing activity in healthy volunteers, which could be further boosted by a second immunization. The neutralizing activity far exceeded accepted protective levels and was equivalent to that induced by standard intramuscular vaccine and significantly greater than intranasal immunization with CRM(197) in the absence of chitosan. A striking but unexpected observation was that although unilateral intranasal immunization induced circulating antitoxin antibody-secreting cells, a nasal antitoxin sIgA response was seen only after the second immunization and only in the vaccinated nostril. If these data are reproduced in larger studies, an intranasal diphtheria vaccine based on CRM(197)-chitosan could be rapidly licensed for human use. However, a restricted sIgA response suggests that care must be taken in the priming-boosting strategy and clinical sampling techniques when evaluating such vaccines for the induction of local mucosal immunity.     

Perennial rhinitis treated with a new steroid: fluocortin butylester (FCB)

The effect of fluocortin butylester (FCB) in the topical treatment of perennial rhinitis was investigated in a double-blind study using a cross-over technique. The daily dose was 4 mg. Of the 30 patients who completed the trial, 26 had either allergy or nasal eosinophilia. 20 of the 30 patients preferred FCB to placebo. Moreover, there was a positive, but not statistically significant, therapeutic effect according to the patient score cards (0.1 less than p less than 0.2). In other words, the results are positive, but not definite. It is concluded that possibly the dose ought to be increased to obtain a more reliable effect.     

A randomized comparison of intranasal and injectable octreotide administration in patients with acromegaly.

Fifteen acromegalic patients received four single doses of octreotide in random order (500 micrograms, 1000 micrograms, and 2000 micrograms applied intranasally and 100 micrograms given sc). Serum octreotide and GH data were subjected to pharmacokinetic analyses, and local nasal effects were evaluated by acoustic rhinometry. Average areas (+/- SEM) under the serum octreotide curves were: 2000 micrograms: 4597 +/- 536; 1000 micrograms: 1923 +/- 439; 500 micrograms: 957 +/- 168; and 100 micrograms sc: 896 +/- 81 micrograms.L-1.min (n = 13). The calculated relative availability was 27% +/- 0.03; 22% +/- 0.05; 22% +/- 0.03, respectively, for the three nasal doses. The rate of absorption after intranasally administered octreotide was greater than after sc application: t1/2 ka: 7.1 +/- 1.6; 7.9 +/- 1.6; 11.3 +/- 1.9, respectively, vs. 24.1 +/- 2.5 min, whereas the rates of disappearance were similar. GH suppression started immediately after application and reached minimum levels 1-2 h later. The average intervals during which serum GH was below 50% of preadministration values were: 2000 micrograms: 544 +/- 47; 1000 micrograms: 423 +/- 56; 500 micrograms: 289 +/- 52 vs. 351 +/- 34 min after sc injection of 100 micrograms. With 2000 micrograms intranasally all but one of the 15 patients attained constant suppression of serum GH below 5 micrograms/L for 273 to 680 min. Pharmacokinetic analysis demonstrated that 100 micrograms sc and 1000 micrograms intranasally induced the same GH suppressive effect and that 2000 micrograms intranasally approximately doubled the duration of action. Acoustic rhinometry was performed after nasal application of the largest dose of 2000 micrograms and after carrier (n = 9). A highly significant tumescence of the nasal mucosa was maximal after 10 min and gradually receded over the next 2 h. However, this was felt by the patients to be acceptable. The effect was caused by octreotide per se and was probably due to vasodilation.     

Modification of the Copolymers Poloxamer 407 and Poloxamine 908 can Affect the Physical and Biological Properties of Surface Modified Nanospheres

Purpose. To investigate the effects of the modification of the copolymers poloxamer 407 and poloxamine 908 on the physical and biological properties surface modified polystyrene nanospheres. Methods. A method to modify poloxamer 407 and poloxamine 908, introducing a terminal amine group to each PEO chain has been developed. The aminated copolymers can be subsequently radiolabelled with lodinated (I¹²⁵) Bolton-Hunter reagent. The aminated copolymers were used to surface modify polystyrene nanospheres. The physical and biological properties of the coated nanospheres were studied using particle size, zeta potential, in vitro non-parenchymal cell uptake and in vivo biodistribution experiments. Results. The presence of protonated amine groups in the modified copolymers significantly affected the physical and biological properties of the resulting nanospheres, although the effects were copolymer specific. The protonated surface amine groups in both copolymers reduced the negative zeta potential of the nanospheres. Acetylation of the copolymer's free amine groups resulted in the production of nanospheres with comparable physical properties to control unmodified copolymer coated nanospheres. In vivo, the protonated amine groups in the copolymers increased the removal of the nanospheres by the liver and spleen, although these effects were more pronounced with the modified poloxamer 407 coated nanospheres. Acetylation of the amine groups improved the blood circulation time of the nanospheres providing modified poloxamine 908 coated nanospheres with comparable biological properties to control poloxamine 908 coated nanospheres. Similarly, modified poloxamer 407 coated nanospheres had only slightly reduced circulation times in comparison to control nanospheres. Conclusions. The experiments have demonstrated the importance of copolymer structure on the biological properties of surface modified nanospheres. Modified copolymers, which possess comparable properties to their unmodified forms, could be used in nanosphere systems where antibody fragments can be attached to the copolymers, thereby producing nanospheres which target to specific body sites.     

Chitosan as a novel nasal delivery system for vaccines

A variety of different types of nasal vaccine systems has been described to include cholera toxin, microspheres, nanoparticles, liposomes, attenuated virus and cells and outer membrane proteins (proteosomes). The present review describes our work on the use of the cationic polysaccharide, chitosan as a delivery system for nasally administered vaccines. Several animal studies have been carried out on influenza, pertussis and diphtheria vaccines with good results. After nasal administration of the chitosan-antigen nasal vaccines it was generally found that the nasal formulation induced significant serum IgG responses similar to and secretory IgA levels superior to what was induced by a parenteral administration of the vaccine. Animals vaccinated via the nasal route with the various chitosan-antigen vaccines were also found to be protected against the appropriate challenge. So far the nasal chitosan vaccine delivery system has been tested for vaccination against influenza in human subjects. The results of the study showed that the nasal chitosan influenza vaccine was both effective and protective according to the CPMP requirements. The mechanism of action of the chitosan nasal vaccine delivery system is also discussed.