TRIPS,the Doha Declaration and increasing access to medicines: policy options for Ghana

There are acute disparities in pharmaceutical access between developing and industrialized countries. Developing countries make up approximately 80% of the world's population but only represent approximately 20% of global pharmaceutical consumption. Among the many barriers to drug access are the potential consequences of the Trade Related Aspects of Intellectual Property Rights (TRIPS) Agreement. Many developing countries have recently modified their patent laws to conform to the TRIPS standards, given the 2005 deadline for developing countries. Safeguards to protect public health have been incorporated into the TRIPS Agreement; however, in practice governments may be reluctant to exercise such rights given concern about the international trade and political ramifications. The Doha Declaration and the recent Decision on the Implementation of Paragraph 6 of the Doha Declaration on the TRIPS Agreement and Public Health may provide more freedom for developing countries in using these safeguards. This paper focuses on Ghana, a developing country that recently changed its patent laws to conform to TRIPS standards. We examine Ghana's patent law changes in the context of the Doha Declaration and assess their meaning for access to drugs of its population. We discuss new and existing barriers, as well as possible solutions, to provide policy-makers with lessons learned from the Ghanaian experience.     

Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly

Holoprosencephaly (HPE) is the most common brain anomaly in humans, involving abnormal formation and septation of the developing central nervous system. Among the heterogeneous causes of HPE, mutations in the Sonic Hedgehog (SHH) gene have been shown to result in an autosomal dominant form of the disorder. Here we describe a total of five different mutations in the processing domain encoded by exon 3 of SHH in familial and sporadic HPE. This is the first instance in humans where SHH mutations in the domain responsible for autocatalytic cleavage and cholesterol modification of the N-terminal signaling domain of the protein have been observed.      

组织工程技术仿生构建颅颌骨组织的研究

目的:探索构建组织工程化仿生骨种植体的方法流程,并制备成骨细胞-可吸收载体种植体样品,同时尝试建立组织工程化非承载骨种植体的评价方法。方法:实验于2001-05/2005-12分别在天津市口腔医院组织工程实验室和天津大学材料学院高分子材料研究所完成。①通过相分离技术制备壳聚糖/明胶三维网络多孔支架,在支架材料表面原位沉积纳米级的羟基磷灰石晶体,构筑纳米羟基磷灰石/壳聚糖/明胶仿生骨组织工程支架材料,并进行表征和性能检测。②用酶消化法和条件培养法分离、诱导培养中国小型猪成骨细胞作为组织工程种子细胞。③用静态复合共培养法体外构建2种骨组织工程种植体样品:成骨细胞-纳米羟基磷灰石/壳聚糖/明胶仿生骨种植体,成骨细胞-纳米羟基磷灰石/胶原种植体。④采用扫描电镜、透射电镜、FDA荧光、LDH、MTT等定期观测仿生骨样品中细胞形态、细胞增殖速率、碱性磷酸酶活性、矿化结节形成等指标,以比较样品的细胞增殖活性和成骨活性。结果:①成功构筑了具有良好的生物相容性和力学相容性的纳米羟基磷灰石/壳聚糖/明胶,这种材料具有适于细胞黏附与生长的(90±1)%的孔隙率,孔径为100￣300μm的微孔结构,且原位沉积的纳米羟基磷灰石晶体的粒径为50nm左右,接近与天然骨的组成。②自中国小型猪腿骨成功分离培养了成骨细胞,并在诱导培养条件下,表现出很强的增殖活力和成骨活性,适合作为实验用骨组织工程的种子细胞。③成功构建了两种成骨细胞-可吸收载体种植体样品:经检验仿生构建的小型猪成骨细胞-纳米羟基磷灰石/壳聚糖/明胶种植体具有细胞亲和性和体外成骨活性。结论:①在体外成功仿生构建了结构与活性接近天然骨的骨组织工程种植体--纳米羟基磷灰石/壳聚糖/明胶种植体。②初步建立了仿生组织工程化非承载骨种植体的评价方法,为其进一步用于体内修复颅颌骨组织损伤的深化研究提供了实验数据和科学依据。     

Syngeneic bone marrow transplantation reduces the hearing loss associated with murine mucopolysaccharidosis type VII

MPS VII mice are deficient in beta-glucuronidase and share many clinical, biochemical, and pathologic characteristics with human mucopolysaccharidosis type VII (MPS VII). We have shown that syngeneic bone marrow transplantation (BMT) prolongs survival and reduces lysosomal storage in many organs of the MPS VII mouse. In this report, we quantify the hearing loss and determine the impact of syngeneic BMT on the development of deafness and the associated pathology in the MPS VII mouse. Eleven weeks after syngeneic BMT performed at birth, treated MPS VII mice had normal auditory-evoked brainstem responses (ABR), whereas untreated MPS VII mice had ABR thresholds 43 dB higher than normal. Treated MPS VII mice had beta-glucuronidase-positive cells in the temporal bone and in the subepithelial connective tissue of the external auditory canal. There was less thickening of the tympanic membrane and middle ear mucosa and decreased distortion of the ossicles and the cochlear bone. Although transplanted MPS VII mice had increased ABR thresholds by 33 weeks of age, four of the six had thresholds 12 to 32 dB lower than untreated mutants. These data indicate that syngeneic BMT in newborn MPS VII mice prevents early hearing loss and, in some animals, results in long-term improved auditory function.     

Immunohistochemical study on gastroenteric nervous system in trisomy 16 mice:an animal model of Down syndrome

AIM:To study the development of gastroenteric nervous system in trisomy 16 mouse embryos.The gastroenteric nervous system in trisomy 16 mice and their normal littermates, serving as controls from embryonic days 13 to 18 (ED13-18) was identified by using primary antibody against protein gene product (PGP) 9.5.METHODS:Trisomy 16 mouse breeding and trisomy 16 mouse embryos were identified from their normal littermates by chromosome examination; PGP 9.5 immunohistochemical stainning.RESULTS:In normal littermates embryos, the precursor cells from the neural crest migrated into stomach and intestine at ED 13 and ED 14 respectively.Numerous nervous processes connected to each other and formed early nervous networks at ED 14 stomach and ED 15 intestine. Original ganglia in the muscular nervous plexus of the stomach appeared at ED15 with very simple arrangement. At ED 16 the early developed myenteric nervous plexuses were regularly found in the stomach and intestine respectively. In both stomach and intestine, the development of submucosal nervous plexuses were finished at ED17. However, the myenteric nervous plexus and the internal and external submucosal nervous plexuses were differentiated only in the stomach at ED 18.In comparison with the normal littermates, stomach and intestine nervous system developed much slower in trisomy 16 mice. Their immature neurons did not appear in the stomach and intestine until ED 14 and ED 15. Between ED 14 and ED 16, the gastroenteric nervous system was composed of only some scattered neurons with different distribution density and size. The development and differentiation of the gastroenteric nervous system were delayed and the myenteric nervous plexus did not appear until ED 18. There was no submucosal nervous plexus in all stomach and intestine specimens. A semiquantitative analysis and rank sum test of the data showed that the trisomy 16 mouse embryos were markedly retarded in the gastroenteric nervous development compared with their normal littermates.CONCLUSION:Trisomy 16 mice, as an animal model for Down syndrome, has abnormality not only in several systems and organs but also in gastroenteric innervation. This report describes for the first time that the development of the gastroenteric nervous system was not only delayed but also pathological.     

α-Adrenergic regulation of human renal function

Summary— Pharmacological and molecular cloning techniques have identified six human subtypes of α-adrenoceptors which are designated α_1A, α_1B, α_1D, α_2A, α_2B and α_2C. At the protein level human kidney expresses predominantly α_2A-adrenoceptors while other α₂-adrenoceptor subtypes or α₁-adrenoceptors have not been detected consistently in radioligand binding studies. However, the presynaptic receptors, which inhibit noradrenaline release in the human kidney, appear to belong to the α_2C-subtype. Intrarenal infusion of the nonselective α₁-adrenoceptor antagonist, phentolamine, and of the selective α₂-adrenoceptor antagonist, yohimbine, but not of the selective α₁-adrenoceptor antagonist, doxazosin, increase renal blood flow and renin release in hypertensive patients undergoing diagnostic renal angiography. Thus, α₂- but not α₁-adrenoceptors appear to mediate a tonic renal vasoconstriction and inhibition of renin release. Effects of systemically given α-adrenoceptor agonists and antagonists are difficult to interpret on a mechanistic level since direct effects in the kidney and indirect effects due to baroreflex activation and peripheral presynaptic and central sympatholytic actions may at least partially offset each other. Moreover, some of these drugs may additionally act independent of α-adrenoceptors, for example, via imidazoline recognition sits. The net result in a given subject may depend on the endogenous sympatho-adrenal tone. Thus, for each target population of interest, effects have to be described empirically for each drug.     

Tc-99m antifibrin Fab' fragments for imaging venous thrombi: evaluation in a canine model

An antifibrin antibody (T2G1s) Fab' fragment labeled with technetium-99m was tested for its ability to produce images of fresh thrombi in dogs. In gamma camera images, all thrombi were evident by 2-4 hours after injection. Mean thrombus-to-blood and thrombus-to-muscle ratios averaged 4.0 and 69 at four hours after injection and increased to 24 and 270, respectively, by 24 hours after injection. When compared with I-125 fibrinogen injected into the same dogs, Tc-99m-antifibrin Fab' had lower absolute uptake in thrombus but higher thrombus-to-blood ratios due to a faster rate of disappearance from the blood. The primary route of excretion was through the kidneys. Tc-99m-antifibrin Fab' was highly stable in vivo, with an average of 82% of the circulating radioactivity able to bind to fibrin at 4 hours after injection. When compared with an In-111-labeled Fab fragment of antifibrin antibody 59D8, thrombus-to-blood and thrombus-to-muscle ratios were slightly higher for the Tc-99m-labeled antibody, and the blood disappearance rate was slightly faster. The absolute uptake in thrombus, however, was not significantly different, and the thrombus was visualized at about the same time after injection. These studies suggest that Tc-99m T2G1s Fab' is a potential agent for detecting thrombi in a clinical setting.