Cyclodextrin formulation of dorzolamide and its distribution in the eye after topical administration.

Due to limited aqueous solubility of dorzolamide at physiologic pH, the pH of Trusopt eye drops (cont. 2% dorzolamide) has to be kept at about 5.65, and to increase the topical bioavailability of the drug from Trusopt the contact time of the drug with the eye surface is increased by increasing the viscosity of the eye drops to 100 cps. This low pH and high viscosity can lead to local irritation. In this study, dorzolamide hydrochloride was formulated as 2% and 4% low viscosity solutions (viscosity 3 to 5 cps) containing randomly methylated beta-cyclodextrin at pH 7.45. These formulations were evaluated in rabbits. The animals were sacrificed at various time points after topical administration of the drug and the dorzolamide concentration determined in the different parts of the eye. Trusopt was used as a reference standard. The topical availability of dorzolamide from the cyclodextrin-containing eye drops appeared to be comparable to that from Trusopt and the drug reached retina and optic nerve to give measurable concentrations for at least 8 h after administration of the eye drops.     

Olfactory Absorption of Insulin to the Brain

A vast number of potent neuropharmaceuticals, many of which are peptides, are excluded from entry into the brain because of the highly selective blood-brain barrier. The fact that a number of drugs have been shown to be transported directly to the central nervous system following application to the olfactory region of the nose is therefore of major interest. In the present study, the feasibility of delivering peptides to the brain via the olfactory route was assessed using insulin as a model peptide. Systemic hyperinsulinemia induced by subcutaneous injection did not significantly reduce the amount of ¹²⁵I-insulin transported from the nose to the brain in vivo, which suggests that the impact of systemic absorption on drug transport is minimal. A linear relationship was seen between insulin accumulation in the brain and the dose applied, without any relevant saturation. Contrary to what was expected, both systemic and olfactory absorption of insulin was enhanced when the pH of the medium was near the isoelectric point. The amount absorbed to the brain was found to be linearly related to the net charge of the molecule (r = -0.61; n = 20). It was concluded that insulin gains access to the central nervous system from the olfactory region of the nose by a nonspecific pathway. The olfactory route may therefore become an important means to deliver peptides to the brain.     

Intraaortic balloon tamponade during hemorrhagic shock in sheep

Two groups (n = 10 in each) of adult sheep were exposed to hemorrhagic shock resulting in mean arterial pressure (MAP) below 25 mmHg for 10 min. Following that, group A received crystalloids (8% of body wt) during one hr together with supraceliac intraaortic balloon tamponade during the first 30 min, while group B (controls) received crystalloids only. The central circulation was rapidly restored in group A, as indicated by increased MAP and increased systemic vascular resistance (SVR). After deflation of the balloon MAP dropped to the same value as in the control group, while cardiac index increased gradually with volume replacement and was significantly higher at the end of the resuscitation period (60 min) than in the control group (P less than 0.05). Despite a more rapid restoration of central hemodynamics in group A, lactic acidosis was more severe, acute renal failure and neurological complications more frequent, and mortality higher than in the control group. It was concluded that continuous supraceliac aortic occlusion for 30 min had deleterious effects on organs dependent on aortic blood flow distal to the aortic tamponade and may contribute to the development of multiple organ failure after resuscitation from hemorrhagic shock. Further studies are needed to evaluate the effects of intermittent intraaortic balloon tamponade in hemorrhagic shock.     

The volume-deficient orbit: clinical characteristics, surgical management, and results after extraperiorbital implantation of Silastic block.

The surgical techniques and results after extraperiorbital implantation of Silastic on the orbital floor of 70 patients are reviewed. In 11 patients the implant was through a subciliary approach and in 59 through an inferolateral cantholysis. The inferolateral cantholysis, a simplification of the McCord and Moses approach to the orbital floor, is particularly suited to this application. The implanted Silastic was retained in 66 patients, with an average follow up of 3.5 years (range less than 1 to 9.5 years), though six required surgery to debulk the anterior end of the implant. Further surgery was required in 27 patients, this generally being to correct the position of either the upper or the lower lid. Volume enhancement was effective in most cases, there being a significant reduction in the degree of recession of the prosthesis and the depth of the unsightly sunken sulci of the upper and lower lids. The mobility of the orbital contents, the prosthesis, and the upper lid was not improved.     

Access to primary health care in urban Iceland

The accessibility by telephone of primary health care was studied in Reykjavik and its surrounding municipalities. Comparison was also made between community run health centres and private practices. About 60% of the total population of Iceland live within the study area. The study used medical secretaries as patient substitutes. During the prescribed telephone time, all "patients" were able to make telephone contact with their practice facilities, and 80% reached their doctor within 10 min. The waiting time for non-acute appointments was never more than three days. The study did not detect any difference in accessibility between community run health centres and privately owned GP practices.     

Differential effects of interleukin 12 and interleukin 10 on superantigen-induced expression of cutaneous lymphocyte-associated antigen (CLA) and alphaEbeta7 integrin (CD103) by CD8+ T cells

At both cutaneous and mucosal sites, interleukin (IL)-10, IL-12 and transforming growth factor (TGF)-beta are important regulators of chronic inflammatory disease, where cutaneous lymphocyte-associated antigen (CLA) and alphaE integrin (CD103) may be expressed. Stimulation with streptococcal pyrogenic exotoxin C (SpeC) increased the expression of CD103 by CD8+ but not CD4+ T cells. While adding IL-12 augmented the expression of CLA, superantigen-induced expression of CD103 was markedly suppressed by IL-12, which could be reversed by TGF-beta. Antibodies against TGF-beta inhibited, and a combination of anti-TGF-beta and IL-12 completely abrogated the induced CD103 expression. IL-10 strongly decreased the frequency of CLA+ and although not increasing the frequency of CD103+CD8+ T cells, the amount of CD103 expressed per cell was markedly increased. Thus, the expression of CLA and CD103 may be antagonistically regulated by IL-10 and IL-12 and the balance between these cytokines could influence the T cell migration of inflammatory cells into epithelial tissues.     

Pneumococcal serotype 19F conjugate vaccine induces cross-protective immunity to serotype 19A in a murine pneumococcal pneumonia model

Immunization with a pneumococcal conjugate vaccine (PNC) containing serotype 19F induces cross-reactive antibodies to 19A in mice and human infants. Active immunization with PNC and passive immunization with serum samples from infants vaccinated with PNC containing serotype 19F, but not serotype 19A, protected against lung infection caused by both serotypes in a murine model.     

Genetic basis for individual variations in pain perception and the development of a chronic pain condition

Pain sensitivity varies substantially among humans. A significantpart of the human population develops chronic pain conditionsthat are characterized by heightened pain sensitivity. We identifiedthree genetic variants (haplotypes) of the gene encoding catecholamine-O-methyltransferase(COMT) that we designated as low pain sensitivity (LPS), averagepain sensitivity (APS) and high pain sensitivity (HPS). We showthat these haplotypes encompass 96% of the human population,and five combinations of these haplotypes are strongly associated(P=0.0004) with variation in the sensitivity to experimentalpain. The presence of even a single LPS haplotype diminishes,by as much as 2.3 times, the risk of developing myogenous temporomandibularjoint disorder (TMD), a common musculoskeletal pain condition.The LPS haplotype produces much higher levels of COMT enzymaticactivity when compared with the APS or HPS haplotypes. Inhibitionof COMT in the rat results in a profound increase in pain sensitivity.Thus, COMT activity substantially influences pain sensitivity,and the three major haplotypes determine COMT activity in humansthat inversely correlates with pain sensitivity and the riskof developing TMD.     

APOE ε4 and late-life cognition: mediation by structural brain imaging markers

European Journal of Epidemiology - The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer’s disease....