RESEARCH Open Access Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety Akio Ido 1,2* , Akihiro Moriuchi 1,2 , Masatsugu Numata 1,2 , Toshinori Murayama 3 , Satoshi Teramukai 4 , Hiroyuki Marusawa 5 , Naohisa Yamaji 1,2 , Hitoshi Setoyama 1,2 , Il-Deok Kim 1 , Tsutomu Chiba 5 , Shuji Higuchi 6 , Masayuki Yokode 3 , Masanori Fukushima 4 , Akira Shimizu 7 and Hirohito Tsubouchi 1,2 Abstract Background: Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti- apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule. Methods: Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m 2 /day) intravenously for 12 to 14 days. Results: We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF. Conclusions: Intravenous rh-HGF at a dose of 0.6 mg/m 2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose. Background Acuteliverfailure(ALF)isararebutfatalclinicalsyn- drome marked by the abrupt loss of hepatic cellular function, with the subsequent development of coagulo- pathy, jaundice and encephalopathy [1-3]. In Japan, ALF with the histological appearance of hepatitis, caused by viral infection, autoimmune hepatitis and drug allergy-induced liver injury, is classified as fulmi- nant hepatitis (FH) or as the related disease late-onset hepatic failure (LOHF) [4]. FH is identified as hepatitis in which hepatic encephalopathy develops within 8 weeks after the onset of disease symptoms, with pro- thrombin time (PT) less than 40% of the standardized values. Also, FH is further classified into two subtypes: acute (FHA) and subacute type (FHSA) in which the encephalopathy occurs, respectively, within 10 days or after 11 days or more. Patients in whom Human Population Growth Human Population Growth Bởi: OpenStaxCollege Concepts of animal population dynamics can be applied to human population growth Humans are not unique in their ability to alter their environment For example, beaver dams alter the stream environment where they are built Humans, however, have the ability to alter their environment to increase its carrying capacity sometimes to the detriment of other species (e.g., via artificial selection for crops that have a higher yield) Earth’s human population is growing rapidly, to the extent that some worry about the ability of the earth’s environment to sustain this population, as long-term exponential growth carries the potential risks of famine, disease, and large-scale death Although humans have increased the carrying capacity of their environment, the technologies used to achieve this transformation have caused unprecedented changes to Earth’s environment, altering ecosystems to the point where some may be in danger of collapse The depletion of the ozone layer, erosion due to acid rain, and damage from global climate change are caused by human activities The ultimate effect of these changes on our carrying capacity is unknown As some point out, it is likely that the negative effects of increasing carrying capacity will outweigh the positive ones—the carrying capacity of the world for human beings might actually decrease The world’s human population is currently experiencing exponential growth even though human reproduction is far below its biotic potential ([link]) To reach its biotic potential, all females would have to become pregnant every nine months or so during their reproductive years Also, resources would have to be such that the environment would support such growth Neither of these two conditions exists In spite of this fact, human population is still growing exponentially 1/7 Human Population Growth Human population growth since 1000 AD is exponential (dark blue line) Notice that while the population in Asia (yellow line), which has many economically underdeveloped countries, is increasing exponentially, the population in Europe (light blue line), where most of the countries are economically developed, is growing much more slowly A consequence of exponential human population growth is the time that it takes to add a particular number of humans to the Earth is becoming shorter [link] shows that 123 years were necessary to add billion humans in 1930, but it only took 24 years to add two billion people between 1975 and 1999 As already discussed, at some point it would appear that our ability to increase our carrying capacity indefinitely on a finite world is uncertain Without new technological advances, the human growth rate has been predicted to slow in the coming decades However, the population will still be increasing and the threat of overpopulation remains The time between the addition of each billion human beings to Earth decreases over time (credit: modification of work by Ryan T Cragun) Link to Learning 2/7 Human Population Growth Click through this interactive view of how human populations have changed over time Overcoming Density-Dependent Regulation Humans are unique in their ability to alter their environment with the conscious purpose of increasing its carrying capacity This ability is a major factor responsible for human population growth and a way of overcoming density-dependent growth regulation Much of this ability is related to human intelligence, society, and communication Humans can construct shelter to protect them from the elements and have developed agriculture and domesticated animals to increase their food supplies In addition, humans use language to communicate this technology to new generations, allowing them to improve upon previous accomplishments Other factors in human population growth are migration and public health Humans originated in Africa, but have since migrated to nearly all inhabitable land on the Earth Public health, sanitation, and the use of antibiotics and vaccines have decreased the ability of infectious disease to limit human population growth In the past, diseases such as the bubonic plaque of the fourteenth century killed between 30 and 60 percent of Europe’s population and reduced the overall world population by as many as 100 million people Today, the threat of infectious disease, while not gone, is certainly less severe According to the World Health Organization, global death from infectious disease declined from 16.4 million in 1993 to 14.7 million in 1992 To compare to some of the epidemics of the past, the percentage of the world's population killed between 1993 and 2002 decreased from 0.30 percent of the world's population to 0.24 percent Thus, it appears that the influence of infectious disease on human population growth is becoming less significant Age Structure, Population Growth, and Economic Development The age structure of a population is an important factor in population ...RESEARCH Open Access Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety Akio Ido 1,2* , Akihiro Moriuchi 1,2 , Masatsugu Numata 1,2 , Toshinori Murayama 3 , Satoshi Teramukai 4 , Hiroyuki Marusawa 5 , Naohisa Yamaji 1,2 , Hitoshi Setoyama 1,2 , Il-Deok Kim 1 , Tsutomu Chiba 5 , Shuji Higuchi 6 , Masayuki Yokode 3 , Masanori Fukushima 4 , Akira Shimizu 7 and Hirohito Tsubouchi 1,2 Abstract Background: Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti- apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule. Methods: Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m 2 /day) intravenously for 12 to 14 days. Results: We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF. Conclusions: Intravenous rh-HGF at a dose of 0.6 mg/m 2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose. Background Acuteliverfailure(ALF)isararebutfatalclinicalsyn- drome marked by the abrupt loss of hepatic cellular function, with the subsequent development of coagulo- pathy, jaundice and encephalopathy [1-3]. In Japan, ALF with the histological appearance of hepatitis, caused by viral infection, autoimmune hepatitis and drug allergy-induced liver injury, is classified as fulmi- nant hepatitis (FH) or as the related disease late-onset hepatic failure (LOHF) [4]. FH is identified as hepatitis in which hepatic encephalopathy develops within 8 weeks after the onset of disease symptoms, with pro- thrombin time (PT) less than 40% of the standardized values. Also, FH is further classified into two subtypes: acute (FHA) and subacute type (FHSA) in which the encephalopathy occurs, respectively, within 10 days or after 11 days or more. Sokhem Pech and Kengo Sunada Population Growth and Natural-Resources Pressures in the Mekong River Basin The Mekong River Basin possesses the region’s largest potential water source and related resources, which support ongoing economic development and basin com- munity livelihoods. It is currently witnessing a major demographic transition that is creating both opportunities and challenges. An analysis of the complex relationship between demographic changes and impacts on the natural-resource base confirms that resource exploitation is occurring not only to meet growing domestic needs but also for other vested interests. Population, together with other major drivers, such as institutions, markets, and technology, will have a very strong bearing on the way in which the rich resources of the Mekong River Basin are developed and distributed in the present and future. The Mekong River Basin’s rich resources, and the benefits derived from them, are unevenly distributed both in time and geographically. Moreover, since the causes and impacts do not respect political boundaries, the Mekong countries need to jointly develop alternative management strategies to meet projected demands within the sustain- able capacity of the Mekong River Basin natural-resource base. INTRODUCTION The Mekong countries have a complex, but interesting, mosaic of demographic attributes and trends. The population of the Mekong region—whole of Yunnan Province of China, Myan- mar, Laos, Thailand, Cambodia, and Vietnam—is nearly 300 million, and over 70 million people live in the Mekong River Basin (1). The Mekong Basin possesses the region’s largest potential water source and related resources. These resources are fundamental to ongoing economic development in terms of irrigation and agricultural production, fisheries and aquacul- ture, energy and forest products, navigation and other modes of transport, domestic and industrial water supply, and tourism (2). Levels of dependency on the river’s water and related resources are very high, particularly among the rural poor, who rely on subsistence livelihoods and moral economy (3). Rec ent socioeconomic development has begun to slow population growth rates in China, Thailand, and Myanmar, while Cambodia, Laos and Vietnam are expected to experience further positive growth well beyond 2050 (4). It is also true that the population growth rates vary considerably across th e Mekong River Basin, within and between the basin countries (2). For example, Yunnan population density has doubled since the 1950s, reaching the current level of 103 people km À2 , but in the Lancang/Mekong part, the population density is only 62 people km À2 due to the rugged and inhospitable landform (5). On the other hand, Yunnan population growth rate has declined slower than other parts of China (present level of 1.3% y À1 compared to less than 0.7% annually for all of China) (5). Accordingly, the overall Mekong populations are projected to increase well beyond 2050. The population growth and expected demographic changes in these countries create both opportunities and challenges. Population size and its composition have significant impli- cations for pressures on natural resources. Growing populations require more or different food, which typically requires land and water or other forms of production (6). This paper examines population growth and its likely impacts on food demand and land and water resources in the Mekong River Basin in a systematic and integrated manner. As a R132 Introduction Transforming growth factor (TGF)-β is a dimeric protein of 25 kDa molecular weight, originally isolated from platelets [1,2]. There are three distinct mammalian isoforms, TGF-β1, TGF-β2 and TGF-β3, with TGF-β1 being the most abundant isoform. Almost all cell types express TGF-β, but the highest level of expression of TGF-β is in platelets and bone [3]. Mature TGF-β1 consists of two identical peptide chains, each containing 112 amino acids, linked via nine disulfide bonds [4]. TGF-β1 is synthesized as part of a large, latent protein complex, unable to bind to cellular receptors, with mature active TGF-β1 produced by cleavage [5]. TGF-β1 is a mutifunctional cytokine that plays an important role in immunomodulation, inflammation and tissue repair [6]. Many studies have suggested that TGF-β could be a potential therapeutic reagent for the repair of soft tissue and bone, and following ischemic injury. It may also have appli- cations for the treatment of chronic inflammatory fibrotic and autoimmune diseases [7,8]. In contrast, other studies have demonstrated that TGF-β1 can cause inflammation and fibrosis [9,10]. The potential use of TGF-β1 for the treat- ment of human disease thus remains controversial [11]. Rheumatoid arthritis is a systemic, autoimmune disease. It is characterized by a chronic, erosive inflammation of painful and debilitating joints, with progressive degrada- tion of cartilage and bone accompanied by proliferation of the synovium [12]. Rheumatoid arthritis remains incurable and, in many patients, difficult to treat. As a novel Ad.Luc = adenoviral vector expressing luciferase; Ad.TGF = adenoviral vector expressing human transforming growth factor; AIA = antigen-induced arthritis; ELISA = enzyme-linked immunosorbent assay; GAG = glycosaminoglycan; H & E = hematoxylin and eosin; IL = interleukin; TGF = trans- forming growth factor. Arthritis Research & Therapy Vol 5 No 3 Mi et al. Research article Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees Zhibao Mi 1 , Steven C Ghivizzani 1,3 , Eric Lechman 1 , Joseph C Glorioso 1 , Christopher H Evans 2,3 and Paul D Robbins 1 1 Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA 2 Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA 3 Present address: Center for Molecular Orthopaedics, Harvard Medical School, Boston, Massacuhsetts, USA Corresponding author: Paul D Robbins (e-mail: probb@pitt.edu) Received: 18 Mar 2002 Revisions requested: 8 May 2002 Revisions received: 20 Dec 2002 Accepted: 4 Feb 2003 Published: 12 Mar 2003 Arthritis Res Ther 2003, 5:R132-R139 (DOI 10.1186/ar745) © 2003 Mi et al., licensee BioMed Central Ltd (Print ISSN 1478-6354; Online ISSN 1478-6362). This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Abstract To examine the effect of transforming growth factor (TGF)-β1 on the regulation of cartilage synthesis and other articular pathologies, we used adenovirus-mediated intra-articular gene transfer of TGF-β1 to both naïve and arthritic rabbit knee joints. Increasing doses of adenoviral vector expressing TGF-β1 were injected into normal and antigen-induced arthritis rabbit knee joints through the patellar tendon, with the same doses of an adenoviral vector expressing luciferase injected into the contralateral knees as the control. Intra-articular injection of adenoviral vector expressing TGF-β1 into the rabbit knee resulted in dose-dependent TGF-β1 expression in the synovial fluid. Intra-articular TGF-β1 expression in both naïve and arthritic rabbit knee joints resulted in significant pathological changes in the rabbit knee as well as in adjacent muscle tissue. The observed changes CAS E REP O R T Open Access Sustained complete remission of human epidermal growth factor receptor 2-positive metastatic breast cancer in the liver during long-term trastuzumab (Herceptin) maintenance therapy in a woman: a case report John Syrios * , Anna Dokou, Nicolas Tsavaris Abstract Introduction: This case report and short review discusses how long trastuzumab should be continued in metastatic breast cancer, the safety issues in case of pregnancy and the risk of relapse with trastuzumab cessation. Case presentation: We present the case of a 34-year-old Caucasian woman with human epidermal growth factor receptor 2-positive metastatic breast cancer in the liver who achieved prolonged complete remission within six months of receiving trastuzu mab (Herceptin) in combination with vinorelbine and gemcitabine. The patient remains in complete remission seven years later and continues to receive trastuzumab as maintenance therapy. Conclusion: Trastuzumab-based therapies have greatly improved the survival rates of patients with human epidermal growth factor receptor 2- positive metastatic breast cancer. Despite such improvements, the safety of trastuzumab administration during pregnancy is yet to be defined. Introduction The development of trastuzumab (Herceptin), a huma- nized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, has changed the natural history of HER2-positive breast cancer, providing super- ior s urvival benefits in combination or as monotherapy compared with nontrastuzumab-based therapy [1,2]. However, HER2-positive metastatic breast cancer (MBC) is an aggressive disease, and despite these advances, the majority of patients treated with trastuzumab -based regimens progress within one year, with only very few patients experiencing prolonged remission [3]. Thecasereportpresentedheredescribesawoman who u nderwent a mastectomy for invasive ductal carci- noma and subsequently received trastuzumab in combi- nation with chemotherapy as treatment for a single metastatic lesion in the liver. She experienced a complete response, with disappearance of the hepatic lesion , and has been receiving maintenance trastuzumab for seven years. While taking trastuzumab, the patient expressed her intention of starting a family, which raised a number of questions, such as how long maintenance trastuzumab should be administered and whether, in this case, treatment should cease. Case presentation In February 2001, an otherwise healthy 34-year-old Cau- casian woman, with no histor y of hormone therapy, smoking, drinking, or a family history of breast cancer, presented with a lump in the center of her right breast. The axillary and neck lymph nodes were not palpably enlarged. After breast biopsy and computed tomography (CT) of the chest and abdomen, the patient underwent a radical mastectomy. Pathologic examination of the resected spe- cimens diagnosed H ER2-positive (immunohistochemis- try 3+), hormone receptor-negative, grade III, invasive ductal carcinoma of the right breast with two positive * Correspondence: syriosi@yahoo.gr Medical Oncology Unit, Department of Pathophysiology, Laikon General University Hospital, Athens University School of Medicine, Athens 11527, Greece Syrios et al. Journal of Medical Case Reports 2010, 4:401 http://www.jmedicalcasereports.com/content/4/1/401 JOURNAL OF MEDICAL CASE REPORTS © 2010 Syrios et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creati vecommons.org/lice nses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. axillary lymph nodes. The size of the primary tumor was 4.3 × 5.5 × 3 cm. She was treated with sequential adju- vant chemotherapy, four cycles of epirubicin (75 mg/m 2 ) followed by four cycles of docetaxel (70 mg/m 2 ). On completion o f chemotherapy in August 2001, radiation therapy was .. .Human Population Growth Human population growth since 1000 AD is exponential (dark blue line) Notice that while the population in Asia (yellow line), which... that the highest growth is occurring in less economically developed countries in Africa and Asia 4/7 Human Population Growth Long-Term Consequences of Exponential Human Population Growth Many dire... billion human beings to Earth decreases over time (credit: modification of work by Ryan T Cragun) Link to Learning 2/7 Human Population Growth Click through this interactive view of how human populations