Application of drug delivery technologies in lead candidate selection and optimization

Formulation development during early drug discovery and lead optimization, involves several challenges including limited drug supply, the need for rapid turnaround, and limited development time. It is also desirable to develop initial formulations that will be representative of final commercial formulations. Nanoparticles offer a unique platform for the formulation of poorly soluble drugs - such formulations can be injected (intravenous, subcutaneous, intramuscular), as well as administered through other routes, such as oral, ocular and inhalation. Thus, a single formulation can be used to test and eventually develop multiple dosage forms. Furthermore, nanoparticles offer the opportunity for high drug loading, for low potency compounds, and thus support toxicological evaluation of such compounds.     

Detection of intracranial aneurysms: multi-detector row CT angiography compared with DSA

PURPOSE: To prospectively compare the effectiveness of multi-detector row computed tomographic (CT) angiography with that of conventional intraarterial digital subtraction angiography (DSA) used to detect intracranial aneurysms in patients with nontraumatic acute subarachnoid hemorrhage. MATERIALS AND METHODS: Thirty-five consecutive adult patients with acute subarachnoid hemorrhage were recruited into the institutional review board-approved study and gave informed consent. All patients underwent both multi-detector row CT angiography and DSA no more than 12 hours apart. CT angiography was performed with a multi-detector row scanner (four detector rows) by using collimation of 1.25 mm and pitch of 3. Images were interpreted at computer workstations in a blinded fashion. Two radiologists independently reviewed the CT images, and two other radiologists independently reviewed the DSA images. The presence and location of aneurysms were rated on a five-point scale for certainty. Sensitivity and specificity were calculated independently for image interpretation performed by the two CT image readers and the second DSA image reader by using the first DSA reader's interpretation as the reference standard. RESULTS: A total of 26 aneurysms were detected at DSA in 21 patients, and no aneurysms were detected in 14 patients. Sensitivity and specificity for CT angiography were, respectively, 90% and 93% for reader 1 and 81% and 93% for reader 2. The mean diameter of aneurysms detected on CT angiographic images was 4.4 mm, and the smallest aneurysm detected was 2.2 mm in diameter. Aneurysms that were missed at initial interpretation of CT angiographic images were identified at retrospective reading. CONCLUSION: Multi-detector row CT angiography has high sensitivity and specificity for detection of intracranial aneurysms, including small aneurysms, in patients with nontraumatic acute subarachnoid hemorrhage.     

Choroidal neovascular membrane associated with choroidal osteoma (CO) treated with trans-pupillary thermo therapy

Choroidal neovascular membrane, a known complication of choroidal osteoma causing visual loss when located subfoveally, can be successfully treated with transpupillary thermo therapy.     

Animal models of cancer and HIV

PURPOSE OF REVIEW: The purpose of this paper is to review current animal models that may be useful for studying cancer associated with human immunodeficiency virus infection. RECENT FINDINGS: Several animal models, primarily using mice and monkeys, have been developed that recapitulate aspects of the pathology of various malignancies in human acquired immune deficiency syndrome. Studies reviewed here help to elucidate the biology of Kaposi sarcomagenesis and non-Hodgkin lymphomagenesis. Improved understanding through current and future models will better enable clinicians to manage and treat these malignancies. SUMMARY: A number of potential useful models exist that may facilitate improved understanding of the pathogenesis and treatment of cancers associated with human immunodeficiency virus infection.     

Histopathologic analysis of 232 eyes with retinoblastoma conducted in an Indian tertiary-care ophthalmic center

PURPOSE: To study the histopathologic features of 232 enucleated eyes with retinoblastoma. MATERIALS AND METHODS: Two hundred thirty-two enucleated eyes with retinoblastoma in a tertiary-care institute from 1982 to 2001 were reviewed. Data were collected and analyzed about the type of growth and the presence or absence of vitreous or subretinal seeding, rosettes and fleurettes, necrosis, calcification, iris neovascularization, and invasion of the anterior chamber, iris, choroid, optic nerve, and sclera. Choroidal invasion was graded using a new system. Results were analyzed for statistical significance. RESULTS: The endophytic growth pattern was common in 118 (51%) of the eyes. Vitreous seeds were present in 109 (47%) of the tumors, 23 (10%) of the tumors had subretinal seeds, and 14 (6%) of the tumors had both. Poorly differentiated tumors were present in 134 (58%) of the eyes. Iris neovascularization was noted in 71 (31%) of the eyes and choroidal invasion was observed in 78 (34%) of the eyes. Of these 78 eyes, full-thickness (stage 4) choroidal invasion was present in 51 (65%). Optic nerve invasion was observed in 75 (32%) of the eyes, of which prelaminar involvement occurred in 40 (53%) and postlaminar involvement occurred in 22 (29%). CONCLUSION: A higher incidence of choroidal and optic nerve infiltration was noted among Asian Indian children than among children from the West. This could be due to delayed diagnosis or to a difference in the biological behavior of tumors occurring in the Asian Indian population.     

In vitro and in vivo degradation studies of a novel linear copolymer of lactide and ethylphosphate

Poly(lactide-co-ethylphosphate)s, a new class of linear phosphorus-containing copolymers made by chain-extending low-molecular-weight polylactide prepolymers with ethyl dichlorophosphate, were investigated for their in vitro and in vivo degradation mechanism and kinetics. Microspheres made from poly(lactide-co-ethylphosphate) were studied under both accelerated and normal in vitro degradation conditions. Gel permeation chromatography (GPC), 1H- and 31P-NMR, weight loss measurements, and differential scanning calorimetry (DSC) techniques were used to characterize the change of molecular weight (M(w)), chemical composition, and glass transition temperature (T(g)) of the degrading polymers. The results indicated that the copolymers degraded in a two-stage fashion, with cleavage of the phosphate-lactide linkages contributing mostly to the initial more rapid degradation phase and cleavage of the lactide-lactide bonds being responsible for the slower latter stage degradation. The decrease in the copolymer M(w) was accompanied by a continuous mass loss. Results from the accelerated degradation studies confirmed that the copolymers degraded into various monomers of the copolymers, which were non-toxic and biocompatible. A two-stage hydrolysis pathway was thus proposed to explain the degradation behavior of the copolymers. In vivo degradation studies performed in mice demonstrated a good in vitro and in vivo correlation for the degradation rates. In vivo clearance of the polymer was faster and without any lag phase. These copolymers are potentially advantageous for drug delivery and other biomedical applications where rapid clearance of the polymer carrier and repeated dosing capability are essential to the success of the treatment.     

Can p53 staining be used to identify patients with aggressive superficial bladder cancer?

Approximately 10% of patients with superficial bladder cancer (pTa/pT1) recur with life-threatening muscle-invasive disease. Identification of these patients has been a major goal of bladder cancer research. In 1994, it was suggested that p53 immunostaining could identify the cancers that would progress and it was proposed that tumours that stain for p53 should be treated aggressively with radiotherapy or cystectomy. Despite the hundreds of studies published since on the relationship between p53 and progression in superficial bladder cancer, the clinical utility of p53 immunostaining has not been resolved because of limitations concerning the numbers of patients and the length of follow-up. This study set out to overcome these limitations by using tissue from a large multicentre trial that recruited 502 patients with a median follow-up of 10 years. Each of 34 patients that had progressed with >/= pT2 disease or had distant metastases or had died from bladder cancer was compared with one or two matched controls. Sections were stained with a mouse monoclonal antibody to p53, pAb1801. In agreement with many of the earlier studies, p53 immunostaining had prognostic significance. The adjusted hazard ratio for time to progression for the pAb1801-positive versus negative group was 2.5, with 95% confidence intervals of 1.05-5.98 (p = 0.039). The other major risk factor that is associated with progression of superficial bladder cancer is pT1G3 disease. Of the 42 pT1G3 cancers, 14 (33%) progressed. The proportion of cancers with p53 staining that progressed was similar to the proportion of pT1G3 cancers that progressed, but neither the sensitivity nor the specificity of association of p53 staining with progression is sufficient to recommend cystectomy in individual patients.