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Clinical Phases (clinical + phase)
Selected Abstracts3224: Chitosan in the treatment of dry eyeACTA OPHTHALMOLOGICA, Issue 2010L SCHMETTERER Purpose To demonstrate the safety and efficacy of a new eye drop formulation containing a novel thiolated biopolymer, namely chitosan-N-acetylcysteine, in a number of pre-clinical tests. It is postulated that interaction between thiol groups of the topically applied chitosan-N-acetylcysteine and cysteine-rich mucin (MUC5AC) increases polymer residence time on the ocular surface and tear film stability. Methods The efficacy of isotonic and buffered chitosan-N-acetylcysteine eye drops was evaluated in two different dry eye mouse models. The dosage dependent ocular residence time and biodistribution were investigated in a rabbit model using microPET technology. Long-term irritation and delayed-type hypersensitivity tests with chitosan-N-acteylcysteine eye drop formulation were conducted in rabbits. Results In both dry eye studies mice treated with chitosan-N-acetylcysteine showed decreased expression of ocular surface mRNA of IL-,, IL-10, IL-12,, and TNF, indicating that the formulation may have protective ocular surface properties. The residence time of chitosan-N-acetylcysteine eye drops on the ocular surface of rabbits was increased (detection up to 22h). Results of a long-term ocular irritation study in rabbits demonstrate that the novel formulation is well tolerated and non-irritant to the eye. Conclusion Based on the promising pre-clinical study results both in terms of efficacy and safety a clinical phase 1 trial is scheduled in the near future. Commercial interest [source] Gene Expression Profiling in Cluster Headache: A Pilot Microarray StudyHEADACHE, Issue 10 2006Christina Sjöstrand MD Background.,Cluster headache (CH) is a primary neurovascular headache disorder characterized by attacks of excruciating pain accompanied by ipsilateral autonomic symptoms. CH pathophysiology is presumed to involve an activation of hypothalamic and trigeminovascular systems, but inflammation and immunological mechanisms have also been hypothesized to be of importance. Objective.,To identify differentially expressed genes during different clinical phases of CH, assuming that changes of pathophysiological importance would also be seen in peripheral venous blood. Methods.,Blood samples were drawn at 3 consecutive occasions from 3 episodic CH patients: during attacks, between attacks and in remission, and at 1 occasion from 3 matched controls. Global gene expression was analyzed with microarray tehnology using the Affymetrix Human Genome U133 2.0 Plus GeneChip® Set, covering more than 54,000 gene transcripts, corresponding to almost 22,000 genes. Quantitative RT-PCR on S100P gene expression was analyzed in 6 patients and 14 controls. Results.,Overall, quite small differences were seen intraindividually and large differences interindividually. However, pairwise comparisons of signal values showed upregulation of several S100 calcium binding proteins; S100A8 (calgranulin A), S100A12 (calgranulin C), and S100P during active phase of the disease compared to remission. Also, annexin A3 (calcium-binding) and ICAM3 showed upregulation. BIRC1 (neuronal apoptosis inhibitory protein), CREB5, HLA-DQA1, and HLA-DQB1 were upregulated in patients compared to controls. The upregulation of S100P during attack versus remission was confirmed by quantitative RT-PCR analysis. Conclusions.,The S100A8 and S100A12 proteins are considered markers of non-infectious inflammatory disease, while the function of S100P is still largely unknown. Furthermore, upregulation of HLA-DQ genes in CH patients may also indicate an inflammatory response. Upregulation of these pro-inflammatory genes during the active phase of CH has not formerly been reported. Data from this pilot microarray study provide a basis for further studies in CH. [source] Current status of amorphous formulation and other special dosage forms as formulations for early clinical phasesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2009Kohsaku Kawakami Abstract Although most chemists in the pharmaceutical industry have a good understanding on favorable physicochemical properties for drug candidates, formulators must still deal with many challenging candidates. On the other hand, formulators are not allowed to spend much time on formulation development for early phases of the clinical studies. Thus, it is basically difficult to apply special dosage form technologies to the candidates for the first-in-human formulations. Despite the availability of numerous reviews on oral special dosage forms, information on their applicability as the early phase formulation has been limited. This article describes quick review on the oral special dosage forms that may be applied to the early clinical formulations, followed by discussion focused on the amorphous formulations, which still has relatively many issues to be proved for the general use. The major problems that inhibit the use of the amorphous formulation are difficulty in the manufacturing and the poor chemical/physical stability. Notably, the poor physical stability can be critical, because of not the poor stability itself but the difficulty in the timely evaluation in the preclinical developmental timeframes. Research directions of the amorphous formulations are suggested to utilize this promising technology without disturbing the preclinical developmental timelines. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2875,2885, 2009 [source] GSK3,: role in therapeutic landscape and development of modulatorsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2010S Phukan Glycogen synthase kinase-3 beta (GSK3,) is a multifunctional serine/threonine kinase which was originally identified as a regulator of glycogen metabolism. It plays a key role in the regulation of numerous signalling pathways including cellular process such as cell cycle, inflammation and cell proliferation. Over the last few years there is a considerable rise in the number of journals and patents publication by different workers worldwide. Many pharmaceutical companies are focusing on GSK3, as a therapeutic target for the treatment of disease conditions. The present review is focused on signalling pathways of different disease conditions where GSK3, is implicated. In this review, we present a comprehensive map of GSK3, signalling pathways in disease physiologies. Structural analysis of GSK3, along with molecular modelling reports from numerous workers are reviewed in context of design and development of GSK3, inhibitors. Patent landscape of the small molecule modulators is profiled. The chemo space for small molecule modulators extracted from public and proprietary Kinase Chembiobase for GSK3, are discussed. Compounds in different clinical phases of discovery are analysed. The review ends with the overall status of this important therapeutic target and challenges in development of its modulators. [source] Advances in the pathophysiology of status epilepticusACTA NEUROLOGICA SCANDINAVICA, Issue 2007J. W. Y. Chen Status epilepticus (SE) describes an enduring epileptic state during which seizures are unremitting and tend to be self-perpetuating. We describe the clinical phases of generalized convulsive SE, impending SE, established SE, and subtle SE. We discuss the physiological and biochemical cascades which characterize self-sustaining SE (SSSE) in animal models. At the transition from single seizures to SSSE, GABAA (gamma-aminobutyric acid) receptors move from the synaptic membrane to the cytoplasm, where they are functionally inactive. This reduces the number of GABAA receptors available for binding GABA or GABAergic drugs, and may in part explain the development of time-dependent pharmacoresistance to benzodiazepines and the tendency of seizures to become self-sustaining. At the same time, ,spare' subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartic acid) receptors move from subsynaptic sites to the synaptic membrane, causing further hyperexcitability and possibly explaining the preserved sensitivity to NMDA blockers late in the course of SE. Maladaptive changes in neuropeptide expression occur on a slower time course, with depletion of the inhibitory peptides dynorphin, galanin, somatostatin and neuropeptide Y, and with an increased expression of the proconvulsant tachykinins, substance P and neurokinin B. Finally, SE-induced neuronal injury and epileptogenesis are briefly discussed. [source] | ||||||||||