Pharmacokinetics and brain penetration study of chlorogenic acid in rats

1. The present study is designed to investigate the brain distribution and plasma pharmacokinetics profiles of chlorogenic acid (CGA) after intranasal administration in Charles–Foster rats to evaluate whether the CGA molecules are transported directly via the nose-to-brain path.

2. The CGA is administered intravenously (IV) and intranasally (IN) at the dose of 10?mg/kg. Further, its concentration in the plasma, cerebrospinal fluid (CSF) and the whole brain is analyzed by HPLC-UV method.

3. The study observes that CGA is rapidly absorbed in plasma with t_max of 1?min similar to IV route after IN administration. The peak plasma concentration and AUC_0–24 are higher by 3.5 and 4.0 times respectively in IV administration, compared to IN delivery that represents the significant less systemic exposure of CGA in IN route.

4. However, the concentration of CGA in the brain is 4, 6.5, 5.3, 5.2 and 4.5 times higher at 30, 60, 120, 240 and 360?min, respectively in IN administration compared to IV administration. The exposure of CGA in the brain after IN administration (AUC_{brain, IN}) was significantly greater (4 times) as compared to the exposure of CGA in the brain (AUC_{brain, IV}) after IV administration reflecting significant brain uptake of CGA through nasal route. Therefore, IN delivery of CGA can be a promising approach for the treatment of stroke and neurodegenerative disorders.     

Concurrent ferromagnetic hyperthermia and 125I brachytherapy in a rabbit choroidal melanoma model.

Ferromagnetic (FM) thermoseeds and radioactive (125I) seeds were combined in an episcleral plaque to give concurrent hyperthermia and irradiation for enhanced tumour destruction. A Greene melanoma cell line was utilized to study the interaction between these treatment modalities. We attached five FM thermoseeds (with an operating temperature of 48 degrees C) in parallel with alternating rows of 125I seeds onto the inner surface of each 14 mm Silastic plaque. Plaques were centred over a 3-6 mm (diameter) intraocular melanoma in each rabbit. Some rabbits were then placed within a heating coil, and their eye tumours were warmed rapidly to therapeutic temperatures (43.6 degrees C across the tumour base) while the temperature of normal conjunctiva across the globe did not exceed 38.5 degrees C. Analysis of 49 treated eye melanomas showed 50% local tumour control at 41.7 Gy for 125I alone, whereas only 9.5 Gy were needed to give the same local control rate after 125I with concurrent FM hyperthermia. Thus, a thermal enhancement ratio of 4.4 was obtained. Hyperthermia alone gave a 20% tumour response rate, but responses were only temporary. We conclude that FM thermoseeds can be used to deliver biologically effective hyperthermia concurrently with radiation, thereby reducing the dose of radiation needed for tumour control.     

Quality assurance of a helical tomotherapy machine

Helical tomotherapy has been developed at the University of Wisconsin, and 'Hi-Art II' clinical machines are now commercially manufactured. At the core of each machine lies a ring-gantry-mounted short linear accelerator which generates x-rays that are collimated into a fan beam of intensity-modulated radiation by a binary multileaf, the modulation being variable with gantry angle. Patients are treated lying on a couch which is translated continuously through the bore of the machine as the gantry rotates. Highly conformal dose-distributions can be delivered using this technique, which is the therapy equivalent of spiral computed tomography. The approach requires synchrony of gantry rotation, couch translation, accelerator pulsing and the opening and closing of the leaves of the binary multileaf collimator used to modulate the radiation beam. In the course of clinically implementing helical tomotherapy, we have developed a quality assurance (QA) system for our machine. The system is analogous to that recommended for conventional clinical linear accelerator QA by AAPM Task Group 40 but contains some novel components, reflecting differences between the Hi-Art devices and conventional clinical accelerators. Here the design and dosimetric characteristics of Hi-Art machines are summarized and the QA system is set out along with experimental details of its implementation. Connections between this machine-based QA work, pre-treatment patient-specific delivery QA and fraction-by-fraction dose verification are discussed.     

Airway hyper-reactivity mediated by B-1 cell immunoglobulin M antibody generating complement C5a at 1 day post-immunization in a murine hapten model of non-atopic asthma

Contact skin immunization of mice with reactive hapten antigen and subsequent airway challenge with the same hapten induces immediate airflow obstruction and subsequent airway hyper‐reactivity (AHR) to methacholine challenge, which is dependent on B cells but not on T cells. This responsiveness to airway challenge with antigen is elicited as early as 1 day postimmunization and can be adoptively transferred to naïve recipients via 1‐day immune cells. Responses are absent in 1‐day immune B‐cell‐deficient JH^?/? mice and B‐1 B‐cell‐deficient xid male mice, as well as in recipients of 1‐day immune cells depleted of cells with the B‐1 cell phenotype (CD19⁺ B220⁺ CD5⁺). As B‐1 cells produce immunoglobulin M (IgM), we sought and found significantly increased numbers of anti‐hapten IgM‐producing cells in the spleen and lymph nodes of 1‐day immune wild‐type mice, but not in xid mice. Then, we passively immunized naive mice with anti‐hapten IgM monoclonal antibody and, following airway hapten challenge of the recipients, we showed both immediate airflow obstruction and AHR. In addition, AHR was absent in complement C5 and C5a receptor‐deficient mice. In summary, this study of the very early elicited phase of a hapten asthma model suggests, for the first time, a role of B‐1 cells in producing IgM to activate complement to rapidly mediate asthma airway reactivity only 1 day after immunization.     

Relationship of wheat streak mosaic and barley stripe mosaic viruses to vector and nonvector eriophyid mites

Summary Large amounts of wheat streak mosaic virus (WSMV) accumulate in the midgut of its mite vectorEriophyes tulipae reared on virus infected plants. Masses of flexuous rod shaped virus particles persisted in the midgut, without degradation, for at least 5 of the 6–9 day adult life of mites. WSMV particles also were found distributed in the body cavity and in salivary glands of mites suggesting that the virus is circulative inE. tulipae. Abacarus hystrix, a nonvector of WSMV, when reared on virus infected plants, occasionally contained a small number of virus particles in its gut only. Extracts of such mites were not infective. Barley stripe mosaic (BSMV)—a rod-shaped virus, was not transmitted byE. tulipae, although a large concentration of virus particles was found in the midgut of mites reared on virus infected plants. Extracts of such mites were infective and the virus particles were retained for several days in the gut of such mites held on virus-free plants. BSMV particles were also found in the body cavity of mites. Possible reasons forE. tulipae being a nonvector of BSMV are discussed.With 9 FiguresContribution No. 1094 Chemistry and Biology Research Institute.     

Sensitivity and specificity of CT scan in revealing skull fracture in medico-legal head injury victims

Background

Emergency departments rely on CT scans to manage trauma victims, especially for head injuries. Although the detection of an undisplaced fracture on a CT scan of the head without significant intracranial findings may be insignificant for a clinician, such cases are of paramount importance for medico-legal purposes because they help ascertain the nature, manner, and cause of the head injury.

Aims

The study was conducted with the objective of knowing the sensitivity and specificity of ante-mortem CT scan findings indicating the presence or absence of skull fractures.

Methods

Findings were confirmed during post-mortem examination of the subjects who had died during management but who had not had any surgical intervention. A comparative study of ante-mortem CT scan and autopsy findings with respect to fracture in traumatic head injuries was undertaken on 60 deceased individuals brought in for medico-legal post-mortem examination over a period of two years.

Results

Considering the autopsy findings as the gold standard, we have concluded that 14.6 per cent of the fractures were missed on CT scan findings compared to fractures found during autopsy. The sensitivity of CT scan for skull fractures was found to be 85.4 per cent and specificity was 100 per cent. Kappa was 0.787, which shows good agreement with p<0.001, which was highly significant.

Conclusion

In developing countries, images are interpreted in the axial plane only on a CT scan of the head, which may be due to a lack of financial and human resources. For better delineation of fractures, the use of techniques like multi-detector CT with sagittal and coronal reformations should be considered in the routine interpretation of a CT scan of the head.     

A novel approach to formulation factor of aceclofenac eye drops efficiency evaluation based on physicochemical characteristics of in vitro and in vivo permeation

The purpose of the present study was to evaluate aceclofenac eye drop through excised goat cornea. Raising pH of the formulation from 6.0 to 8.0, effect of different preservatives or effect of viscosity enhancer decreases apparent permeability coefficient. Topical ophthalmic NSAID are used to treat ocular surface and anterior segment inflammation as well as post operative management of pain and inflammation. Aceclofenac’s unique chemical structure makes it both a potent anti inflammatory drug and lipophilic molecule that penetrates ocular tissue, ensuring relief of pain in cataract and refractive surgery and corneal abrasion. The octanol/water partition coefficient of aceclofenac drug is 1.86 ± 0.75. Permeation characteristics of the drug were evaluated by putting 1 ml formulation on freshly excised goat cornea fixed between donor and receptor compartments of an all-glass modified Franz diffusion cell and measuring the drug permeated in the receptor by spectrophotometry at 275 nm, after 120 min. The results suggest that aceclofenac ophthalmic solution (pH 7) containing BAC provides increased in vitro ocular availability through goat corneas. The combination of methyl paraben and propyl paraben MP–PP preservative in aceclofenac ophthalmic eye drop 0.1% formulated in phosphate buffer increases transcorneal permeation. The developed formulations were evaluated for their pharmacodynamics in albino rabbits, by measuring in-vivo study and were compared to a marketed voltrane ophthalmic solution.