Pharmacological and analytical aspects of alkannin/shikonin and their derivatives: An update from 2008 to 2022

Alkannin/shikonin (A/S) and their derivatives are naturally occurring naphthoquinones majorly found in Boraginaceae family plants. They are integral constituents of traditional Chinese medicine Zicao (roots of Lithospermum erythrorhizon). In last two decades significant increase in pharmacological investigations on alkannin/shikonin and their derivatives has been reported that resulted in discovery of their novel mechanisms in various diseases and disorders. This review throws light on recently conducted pharmacological investigations on alkannin/shikonin and their derivatives and their outputs. Various analytical aspects are also discussed and brief summary of patent applications on inventions containing alkannin/shikonin and its derivatives is also provided.     

地黄相关药物专利研发竞争态势及启示

目的 通过探索地黄相关专利保护的技术布局、主题分布等方面的规律与特征，为地黄药物研发和生产机构的管理运营及知识产权保护提供参考与建议。方法 以国内外专利为数据源，利用智慧芽专利分析平台和EXCEL软件对近20年来地黄相关药物的专利年度申请态势、技术布局、主要申请机构及其运营情况进行统计与分析。结果 地黄相关专利从2010开始快速增长，但授权发明少；在地黄的种植栽培方面，专利的申请量较少，有待加大该领域专利布局力度。在地黄的加工炮制和药物新用途方面，原始创新有着较大空间。结论 建议地黄研发机构应围绕核心产品对其专利进行全面布局，分析专利价值并进行分类管理和运营，关注该领域专利申请动态预警和防范侵权和被侵权，同时应注重“知识产权”先行，开拓国际市场。     

HIV cure: global overview of bNAbs’ patents and related scientific publications

Introduction: This article provides a global overview of patent deposits for broadly neutralizing antibodies (bNAbs), which have emerged as a key strategy for HIV cure and future HIV vaccines. Scientific and technological barriers to the discovery of an effective HIV vaccine in the last 40 years have raised concerns on the potential for relevant advances in this area. Nevertheless, recent breakthrough studies have identified novel immune pathways for new innovative HIV vaccine and HIV cure strategies.

Areas covered: In our patent study, we have identified in a global scale, in the last decade, a sharp increase in the number of bNAbs’ patent deposits related to HIV prevention and treatment strategies, reaching 90 bNAbs in 2017, protected by 184 different patent deposits. Refining our patent search to the different stages of bNAbs’ development has also allowed us to identify 12 of them already at clinical stage of research (VRC01, 10E8, 3BNC117, 10-1074, 2G12, 2F5, KD-247, 4E10, PG9, PGDM1400, PGT121, and VRC07). We describe these recent breakthroughs and discuss the prospects and limitations of these novel strategies.

Expert opinion: Our results indicate the intellectual property outcomes of a scientific revolution in this field, expressing innovative modifications in antibodies to increase their potency and half-life, which have resulted in extremely potent antibodies that could provide novel preventive and therapeutic HIV strategies.     

国家中药复方专利治疗男性不育症的用药规律分析

目的通过对治疗男性不育症中药复方专利的挖掘,研究其配伍用药规律,为临床遣药组方及新药开发提供依据。方法检索2010至2021年国家专利数据库中治疗男性不育症的中药复方专利,运用中医传承计算平台V3.0,对中药的药性、药味、归经、功效及中药频次进行统计,通过关联规则和复杂系统熵聚类法等方法分析中药复方的配伍规律。结果共纳入治疗男性不育症中药复方123首,涉及中药220味,使用频次前6位分别是菟丝子、枸杞子、淫羊藿、熟地黄、当归、肉苁蓉。涉及药物药性以温为主,其次为平、寒;药味以甘居多,其次为苦、辛;归经以肾、肝经为主;功效以补虚类为主,其次为活血化瘀类;"菟丝子-枸杞子"药对组合出现频次最高;置信度居首位的关联组合为"菟丝子,山药→枸杞子";聚类分析得到男性不育症中药复方专利5个核心类方。结论诸医家治疗男性不育症重视标本兼治,以补肾益精治其本,活血化瘀、清热利湿、健脾益气治其标,注重肝肾同治,脾肾并调,常用五子衍宗丸、左归丸、右归丸、四物汤等经典方加减治疗男性不育症。     

Caffeic acid derivatives,analogs and applications: a patent review (2009 – 2013)

Introduction: Caffeic acid (CA) is broadly distributed in several species of the plant kingdom and is widely consumed in human diet. CA and derivatives have been extensively studied in the past years, which unveiled a broad spectrum of biological activities and potential therapeutic applications. As a result, there has been an upsurge in the development of new chemical entities based on the CA scaffold.

Areas covered: The scope of this review is to revisit the therapeutic potential of CA and derivatives. It provides an overview of patented processes and applications thereof between 2009 and 2013.

Expert opinion: The phenylpropanoid framework is currently considered a valid structure for drug discovery programs. Actually, CA has been widely used as a template for the development of new chemical entities with potential therapeutic interest in human diseases associated with oxidative stress. Additionally, the applicability of CA derivatives expands to the realms of cosmetic industry due to its stabilizing properties. The synthesis of esters, amides and hybrids with currently marketed drugs is a trending strategy for the development of derivatives with therapeutic application. It is our opinion that the innovative artwork currently being developed involving this chemical scaffold will yield new and effective therapeutic agents in a foreseeable future.     

Tissue engineering: a historical review as seen through the US Patent Office

Issued US patents are utilised to describe the history of tissue engineering by implantation of dissociated cells in polymeric matrices. The history begins with patents issuing on applications filed in the late 1970s by Drs Yannas and Bell, who later founded Organogenesis. Next, the pivotal role of the technology developed by Drs Joseph Vacanti and Robert Langer is discussed, then the stromal cell matrices of Dr Gail Naughton, who founded Advance Tissue Sciences. The formation of businesses and product development is briefly correlated with the patents. Additional developments as described in the patents relate to methods for making polymeric matrices, methods for modifying polymers to interact with and modify the cellular interactions with the matrices, including cell attachment, differentiation and proliferation, and more recent advances specific to developments with stem cells and genetically engineered cells.     

Farnesoid X receptor modulators (2011 – 2014): a patent review

Introduction: Farnesoid-X-receptor (FXR) is the receptor for primary bile acids expressed in enterohepatic tissues where it regulates bile acid uptake, metabolism and disposal. For its role as a bile acid sensor, FXR has been thought to be an important target in the treatment of cholestatic disorders, a family of diseases in which endogenous bile acids accumulate in the body. Cholestasis might occur as a consequence of inborn metabolic errors and three major disorders, intra-hepatic cholestasis in pregnancy, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis account for the vast majority of clinical cholestasis occurring in adulthood. In addition, FXR agonists are gaining attention as potential regulators of lipid and glucose metabolism and therefore as new therapeutical approaches to the treatment of fatty liver disease, type 2 diabetes and obesity.

Areas covered: New chemical entities as FXR modulators and their in vitro and in vivo efficacy are reviewed with particular focus on patents and peer-reviewed publications in the period 2011 – 2014.

Expert opinion: FXR agonists have shown robust therapeutic potential and results from clinical trials have supported their use in the treatment of liver disorders including PBC and fatty liver disease despite side effects.     

Drug resistance,patent resistance: Indian pharmaceuticals and the impact of a new patent regime

Abstract

This article highlights potential public health effects of India's Patents Act of 2005, which was implemented to conform to the requirements of the World Trade Organisation's Trade-Related Aspects of Intellectual Property Agreement (TRIPS), a new legal regime that will likely have a significant impact on access to HIV/AIDS medications in much of the world. This new patent law may play a role in keeping new antiretroviral (ARV) medications, including improved first-line medications and second-line drugs that are being developed for first-line drug resistant HIV, financially out of reach for many people living with HIV/AIDS in poor countries. India's drug industry, which had thrived under earlier patent laws that protected processes but not products in the case of medications, had brought down the price of ARV drugs in South Asia and Africa by more than 90%. While most existing drugs are grandfathered under the new patent laws, newer ARV medications may be barred from manufacture by Indian companies. This article analyses the effects of the coming together of this new legal regime, the global political economy and emerging resistance to HIV/AIDS medications, and evaluates efforts to mitigate the negative public health effects of the new patent laws.