Lecithin inverse microemulsions for the pulmonary delivery of polar compounds utilizing dimethylether and propane as propellants

Lecithin inverse microemulsions were investigated as a means of pulmonary drug delivery, utilizing dimethylethyleneglycol (DMEG) and hexane as models for dimethyl ether (DME) and propane, respectively. Addition of lecithin to the model propellant mixtures increased the solubility of water in a nonlinear, solvent-dependent manner. The concentration of water necessary to fully hydrate cobalt(II) decreased as the solvent composition was varied from DMEG to hexane. Water proton chemical shift increased in the presence of lecithin, with the largest increases in high hexane content samples. Equilibrium dialysis and component diffusion rate determination (by pulsed-field gradient [PFG]-NMR) indicated the quantity of water associated with the dispersed phase. Collectively, these methods demonstrated that a greater fraction of water was associated with the microemulsion-dispersed phase as the solvent was varied from DMEG to hexane. Iodine solubilization indicated microemulsion formation (operational critical micelle concentration [cmc], 10 moles water per mole lecithin) at approximately 10(-4)-10(-5) molal lecithin. NMR data (trimethylammonium proton chemical shift, water, and lecithin T1) were consistent with microemulsion formation. Water-soluble compounds dissolved in lecithin inverse microemulsions in a lecithin- and water-dependent manner. Experiments with DME/lecithin demonstrated microemulsion characteristics similar to those in the model propellant. DME/lecithin metered-dose inhalers (MDIs) produced a particle size and a fine particle fraction (36% by twin impinger method) suitable for pulmonary drug delivery.     

Outcome in congenital stridor (laryngomalacia)

Twenty-one children who had been diagnosed as having laryngomalacia by direct laryngoscopy in infancy were reviewed 7 to 12 years later. The natural history of the disease is documented. A wide variation in the time of onset and duration of the stridor was found and there was a high incidence of feeding difficulties. A previously reported association with mental retardation or cerebral palsy is not confirmed. 4 out of the 21 children had early speech problems.     

Menkes's syndrome. Report of a patient treated from 21 days of age with parenteral copper

In an infant with Menkes's steely-hair syndrome, early treatment (from 21 days of age) with parenteral copper failed to halt the disease. In addition to urinary tract abnormalities, panlobular emphysema was present a finding not previously noted in the syndrome.     

A dominant positive and negative selectable gene for use in mammalian cells.

We have constructed three different fusion genes containing the herpes simplex virus thymidine kinase (HSV tk) and the bacterial neomycin phosphotransferase (neo) genes. All three fusion genes utilize the HSV tk promoter but differ at the junction of their components. We have determined if the fusion genes are bifunctional by introducing them into mammalian cells and testing for function of the individual components. One of the fusion genes, TNFUS 69, produced a bicistronic message and a fusion protein that has TK and NEO protein functions. This and other fusion genes of a similar nature could serve as dominant positive and negative selectable markers in mammalian cells.     

Factor V deficiency in Philadelphia-positive chronic myelogenous leukemia

Factor V deficiency has been identified in 8 of 8 patients 7--20 yr of age, with Philadelphia-positive (Ph1+) chronic myelogenous leukemia (CML). In these 8 patients, factor V deficiency was not due to hepatic dysfunction, factor V inhibitors, or disseminated intravascular coagulation. In 3 patients, factor V activity rose 10%--12% (0.10--0.12 U/ml) after the infusion of 28--31 ml/kg body weight of fresh frozen plasma (FFP). The rise persisted less than 14 hr. The mean measured postinfusion rise in factor V was 18% of the expected rise calculated from the volume of FFP infused in the patients' plasma volume. In 4 patients, a small transient rise in factor V activity occurred after splenectomy or plateletpheresis. Factor V deficiency was completely corrected after a marked reduction in bone marrow cellularity in 2 patients with Ph1+ CML treated with extensive chemotherapy, total body irradiation, and bone marrow transplantation. Factor V deficiency was retrospectively observed in 6 of 20 patients, ages 20--80 yr, with Ph1+ CML and 3 of 6 patients with other myeloproliferative disorders. The factor V deficiency appears to be associated with the large myeloid- megakaryocytic cell mass characteristic of CML and other myeloproliferative disorders.     

Effect of alpha 1-adrenoceptor blockade on ventricular ectopic beats inacute myocardial infarction

Experimental studies have shown that alpha1-adrenoceptor blockade can reduce ventricular arrhythmia associated with myocardial ischaemia. To examine the efficacy of prazosin in clinical acute infarction 38 patients were randomized, on presentation, to prazosin or placebo. Oral therapy was commenced at 0.5 mg, incremented and continued for seven days, Holter recordings being obtained for the first 48 hours and on day 7. The final dose of prazosin was 2.5 +/- 1.7 (SD) mg and placebo, 3.1 +/- 2.0 mg. During dose titration in the first 24 hours, and on day 7, there was no difference in ventricular ectopic beats. In the second 24 hours, ventricular ectopic beats averaged two per hour in the prazosin group (n = 9) and 60 per hour in placebo (n = 15) (P = 0.05, Mann-Whitney rank testing). The results indicate that alpha1-adrenoceptor blockade may reduce ventricular arrhythmia in clinical acute myocardial infarction. While early and adequate therapy is currently limited by vasodilation, this small study suggests that more extensive clinical trials will be warranted as relatively cardio-selective alpha1-adrenoceptor blocking drugs are developed.     

A longitudinal study of changes in endometrial microvascular density in Norplant implant users.

This study aimed to investigate the effects of the subdermal levonorgestrel contraceptive implant Norplant on endometrial vascular density at different durations of exposure, and the relationship between endometrial histology, vascular density, and bleeding patterns. A prospective controlled trial of Norplant implant users compared endometrial vascular density in biopsies taken before and after Norplant implant insertion. A total of 34 women with regular menstrual cycles requesting long-term contraception were recruited at the Sydney Centre for Reproductive Health Research, Australia. A significant increase in mean endometrial microvascular density was observed from as early as 3 weeks after insertion of Norplant implants. Vascular density was increased from a control secretory phase value of 189.6 (7.0 vessels/mm2 (+/- SEM) to 253.80 +/- 7 vessels/mm2 at 2-13 weeks of Norplant implant exposure (t ratio = 2.08, p = 0.01) and 212.7 +/- 12.9 vessels/mm2 at 14-42 weeks of exposure (t ratio = 2.03, p = 0.02). In those with atrophic endometrium, or in whom myometrium and basalis only were found in biopsies (20 of 66, 30%), mean endometrial vascular density was increased at 273.1 +/- 16.1 vessels/mm2 compared with 210.9 +/- 11.7 vessels/mm2 in other histological groups (F ratio = 9.74, p = 0.0028). Bleeding and spotting in the previous 30 days were less common in those with this histological appearance at a mean of 4.95 days compared with 8.22 days. This is the first study to assess endometrial vascular density in the early months of Norplant implant use. The findings suggest that the endometrial vasculature is profoundly altered in the early months of Norplant implant exposure when bleeding problems are most common.     

Is a family history of coronary heart disease an independent coronary risk factor?

The importance of a positive family history as a primary risk factor for coronary heart disease was examined in a case history study. Of 792 consecutive male patients aged under 60 years who survived a first episode of unstable angina or myocardial infarction, 326 had a negative family history, 298 had a positive history, and in 168 a family history could not be established with certainty. There was no significant difference in the distribution of the three primary coronary risk factors--cigarette smoking, hypertension, and hypercholesterolaemia--between those with and those without a positive family history. The 133 subjects with a positive family history of premature coronary heart disease (occurrence in near relatives under 60 years) were significantly younger than those with a negative family history. It is concluded that there is little evidence to confirm a positive family history as an important independent risk factor for coronary heart disease, although there may be familial aggregation of subjects with a high susceptibility to the effects of the three primary risk factors, cigarette smoking, hypertension, and hyperlipidaemia.