LETTER TO THE EDITOR: Regarding Bettauer 2010 (39:9–23)
D. Rick Lee DVM 1, Stuart M. Zola PhD 2, John L. VandeBerg PhD 3, Thomas J. Rowell DVM 4, Christian Abee DVM 5
Journal of Medical Primatology
Early View (Articles online in advance of print)
Article first published online: 18 AUG 2010
DOI: 10.1111/j.1600-0684.2010.00437.x
Author Information
1 Washington National Primate Research Center, Seattle, WA, USA
2 Yerkes National Primate Research Center, Atlanta, GA, USA
3 Southwest National Primate Research Center, San Antonio, TX, USA
4 New Iberia Research Center, New Iberia, LA, USA
5 Center for Comparative Medicine and Research, Bastrop, TX, USA
Publication History
Article first published online: 18 AUG 2010
The Journal of Medical Primatology recently published a paper entitled ‘Chimpanzees in hepatitis C virus research: 1998–2007’ by R.H. Bettauer (2010, 39:9–23). This paper concluded that there is no ‘sufficient data, or scientific consensus,... [for] the biological relevance of’ the use of chimpanzees as a model for hepatitis C virus (HCV) research. In addition, this article claimed that because chimpanzee studies ‘have not produced a reliable... vaccine’, the chimpanzee model should be abandoned. We, the National Chimpanzee Resource Consortium, have major concerns regarding the validity of this article, and we consider it to be inappropriate for publication in a scientific journal.
It appears that this study was initiated and supported by The Humane Society of the United States (HSUS), an organization that openly advocates an ‘end to the use of animals in biomedical research’ [1]. As stated by the author, the purpose of this article ‘was to ascertain the extent of chimpanzee use... and any related health and welfare issues.’ It is our view that this article does not objectively evaluate the effectiveness of the chimpanzee model in hepatitis C research. The article appears to contain numerous unsubstantiated conclusions that support the HSUS agenda of banning the use of chimpanzees in biomedical research.
It is our position that the chimpanzee is the only scientifically validated model for in vivo studies of hepatitis C infection [2], and it is essential for the evaluation of antiviral and vaccine efficacy, as well as safety. Research with chimpanzees over many years was critical to the development of the hepatitis B vaccine (licensed in 1982) and the hepatitis A vaccine (licensed in 1992). We consider the argument that the chimpanzee model for hepatitis C research should be abandoned because a hepatitis C vaccine has not yet been developed is as absurd as the same argument regarding hepatitis A and B would have been in 1980. It took 47 years to develop the polio vaccine. Hepatitis C virus was discovered in 1989, only 21 years ago, and great progress has been made in developing an understanding of HCV biology and virus–host interactions from research with chimpanzees, as we move toward developing an effective vaccine.
The author argues that because HCV infections were not found in wild chimpanzees, ‘humans and chimpanzees may respond to HCV exposure differently.’ However, HCV is transmitted almost exclusively by transfusion (prior to testing the blood supply) and intravenous injection with contaminated needles. Not finding HCV in wild chimpanzees has nothing to do with response to exposure, as the animals are never exposed. Very few animal models mimic the human disease exactly.
The author states that ‘small study sizes [in HCV research] lack statistical power and therefore affect our ability to draw broader conclusions.’ Many citations refute that conclusion. For example, in one study two chimpanzees were infected with HIV and infused 60 minutes later with a monoclonal antibody that blocks the HIV receptor on CD34 cells [3]. The chimpanzees did not become infected, although the single control animal did become infected. The monoclonal antibody has since been humanized and is expected to enter clinical trials this year. The results speak for themselves. Therefore, no statistical analyses were needed.
The author states that ‘studies that involve human patients...included large numbers of subjects, which avoids the problem of small sample sizes found in chimpanzees studies.’ The implied conclusion seems to be that we should use humans instead of chimpanzees. However, the kinds of experiments that can be conducted with chimpanzees cannot be conducted with human subjects (e.g., the HIV experiment mentioned earlier).
The author states that ‘there is currently not sufficient data or scientific consensus to establish the biological relevance of the chimpanzee model for HCV.’ As evidence that is contrary to the author’s statement, we refer the readers to the recent publication in Science of results from chimpanzees that establish great promise for a microRNA-silencing drug (SPC3649) for treating hepatitis C patients [4].
The author makes several references to the ‘lack of information on anesthesia and analgesia’ in the articles she surveyed. The implication appears to be that studies upon chimpanzees are carried out without regard to anesthesia and/or analgesia. Initiation of any research study with chimpanzees requires that the study be approved by an Institutional Animal Care and Use Committee and that the study conform to guidelines set forth by the Animal Welfare Act (as amended) and the Guide for the Care and Use of Laboratory Animals [5, 6]. These regulations require the use of anesthesia and analgesia, and the implication that HCV studies were conducted with chimpanzees were without anesthesia and analgesia is in our view unwarranted.
We are concerned that the Journal of Medical Primatology, a reputable scientific journal whose mission is to disseminate knowledge regarding primates as models to study, prevent, and/or treat human diseases, has published this article as we contend that it lacks objectivity critical to research work and is influenced by the animal rights lobby.
Respectfully submitted by the National Chimpanzee Resource Consortium
References
1 The Humane Society of the United States. [Internet]. Recent hepatitis C study challenges chimpanzee use. Press Release December 15, 2009. Available at: http://www.humanesociety.org/news/press_releases/2009/12/hepatitis_c_research_using_chimps_121509.html
Accessed date: 02/05/10.
2 Amako Y, Tsukiyama-Kohara K, Katsume A, Hirata Y, Sekiguchi S, Tobita Y, Hayashi Y, Hishima T, Funata N, Yonekawa H, Kohara M: Pathogenesis of hepatitis C virus infection in Tupaia belangeri. J Virol 2010; 84:303–311.
3 Wang CY, Sawyer LS, Murthy KK, Fang X, Walfield AM, Ye J, Wang JJ, Chen PD, Li ML, Salas MT, Shen M, Gauduin MC, Boyle RW, Koup RA, Montefiori DC, Mascola JR, Koff WC, Hanson CV: Postexposure immunoprophylaxis of primary isolates by an antibody to HIV receptor complex. Proc Natl Acad Sci USA 1999; 96:10367–10372.
4 Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, Kauppinen S, Ørum H: Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 2010; 327:198–201.
5 Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals. Washington (DC): National Academies Press, 1996.
6 United States Department of Agriculture: Animal Welfare Act as Amended. 7 USC §2131–2156, 2007.
Source
August 21, 2010
Low alpha-fetoprotein HCC
Brian I. Carr M.D. F.R.C.P., Ph.D. 1,*, Petr Pancoska Ph.D. 2, Robert A. Branch M.D. 2
Article first published online: 25 FEB 2010
DOI: 10.1111/j.1440-1746.2010.06303.x
Journal of Gastroenterology and Hepatology
Accepted Article (Accepted, unedited articles published online for future issues)
Author Information
1 Liver Tumor Program of Kimmel Cancer Center, Thomas Jefferson University, Philadelphia,
2 Center for Clinical Pharmacology, University of Pittsburgh.
* Correspondence: Brian I. Carr M.D., F.R.C.P., Ph.D. Liver Tumor Program, Kimmel Cancer Center, Thomas Jefferson University, Bluemle building, room 519, 233 S.10th Street, Philadelphia, PA 19107 Tel: 215 503 8842 Fax: 215 503 8755 E-mail: brian.carr@jefferson.edu
Keywords: low AFP;HCC;survival;GGTP;tumor size
Abstract
BACKGROUND: A large proportion of HCC patients do not secrete elevated levels of the tumor marker alpha-fetoprotein. There is little published guide to prognostic features of this patient subset. METHODS: We interrogated a large HCC database in which all patients had been followed till death, to examine which features might be prognostically useful. RESULTS: We found 413 biopsy-proven unresectable HCC patients with low serum AFP values. Serum GGTP levels were one of the most significant factors for survival. This dichotomization into low and high GGTP levels separated the patients into distinctive survival ranges. Patients with GGTP levels <110 U/100 ml and small tumors had longest survival >795 days. Patients with GGTP ≥110 U/ml and large tumors with presence of PVT had the shortest survival range of 300-560 days. CONCLUSIONS: Serum levels of the onco-fetal protein GGTP represent a useful prognostic parameter in HCC patients with low AFP levels.
Source
Article first published online: 25 FEB 2010
DOI: 10.1111/j.1440-1746.2010.06303.x
Journal of Gastroenterology and Hepatology
Accepted Article (Accepted, unedited articles published online for future issues)
Author Information
1 Liver Tumor Program of Kimmel Cancer Center, Thomas Jefferson University, Philadelphia,
2 Center for Clinical Pharmacology, University of Pittsburgh.
* Correspondence: Brian I. Carr M.D., F.R.C.P., Ph.D. Liver Tumor Program, Kimmel Cancer Center, Thomas Jefferson University, Bluemle building, room 519, 233 S.10th Street, Philadelphia, PA 19107 Tel: 215 503 8842 Fax: 215 503 8755 E-mail: brian.carr@jefferson.edu
Keywords: low AFP;HCC;survival;GGTP;tumor size
Abstract
BACKGROUND: A large proportion of HCC patients do not secrete elevated levels of the tumor marker alpha-fetoprotein. There is little published guide to prognostic features of this patient subset. METHODS: We interrogated a large HCC database in which all patients had been followed till death, to examine which features might be prognostically useful. RESULTS: We found 413 biopsy-proven unresectable HCC patients with low serum AFP values. Serum GGTP levels were one of the most significant factors for survival. This dichotomization into low and high GGTP levels separated the patients into distinctive survival ranges. Patients with GGTP levels <110 U/100 ml and small tumors had longest survival >795 days. Patients with GGTP ≥110 U/ml and large tumors with presence of PVT had the shortest survival range of 300-560 days. CONCLUSIONS: Serum levels of the onco-fetal protein GGTP represent a useful prognostic parameter in HCC patients with low AFP levels.
Source
Central nervous system dysfunction in primary biliary cirrhosis and its relationship to symptoms
Claire McDonald 1,2, Julia Newton 1, H. Ming Lai 3, Stuart N. Baker 2, David E. Jones 1
Received 15 December 2009; received in revised form 24 May 2010; accepted 26 May 2010. published online 18 August 2010.
Uncorrected Proof
Background & Aims
Primary biliary cirrhosis (PBC) is associated with fatigue, memory impairment, and sleep disturbances. These symptoms suggest the possibility of underlying central nervous system (CNS) dysfunction. During exercise, fatigue develops due to muscular processes (peripheral fatigue) and decreased neurological activation of the muscle (central fatigue). In this study we objectively quantify central and peripheral fatigue in PBC and investigate the integrity of cortical inhibitory and excitatory circuits. Finally we determine the relationship of these indices to the symptoms of PBC.
Methods
16 early-stage PBC patients, 8 post-liver transplant PBC patients, and 12 age-matched controls were studied at the Specialist PBC clinic and neuroscience research unit. In these patients, twitch interpolation was used to measure peripheral and central fatigue. Paired-pulse trans-cranial magnetic stimulation was used to assess intra-cortical inhibition (ICI) and facilitation (ICF).
Results
PBC patients had a significantly lower central activation before fatiguing exercise (mean 86.6.8% (±12.75) vs. 95.2% (±7.4); p<0.05) and a greater response variability than controls. The decline in central activation during exercise and peripheral fatigue were normal. ICI was significantly reduced in PBC patients and daytime somnolence was greater in patients where net inhibition exceeded facilitation. Transplanted and non-transplanted patients had similar central activation, ICI, and ICF.
Conclusions
PBC patients have impaired central activation and abnormal ICI, suggesting CNS abnormalities beyond voluntary control. Transplanted and non-transplanted patients show similar abnormalities raising interesting questions about the mechanisms underpinning these changes and the permanence of neurological dysfunction in PBC. ICI and ICF and the balance between them are related to daytime somnolence (an important symptom in PBC).
Keywords: Muscle, Trans-cranial magnetic stimulation, Twitch interpolation, Cortical inhibition, Liver cirrhosis, Biliary
Abbreviations: TMS, trans-cranial magnetic stimulation, ICI, intra-cortical inhibition, ICF, intra-cortical facilitation, ESS, Epworth Sleepiness Scale, PBC, primary biliary cirrhosis, MVC, maximal voluntary contraction
1 Institute of Cellular Medicine, Newcastle University, UK
2 Institute of Neuroscience, Newcastle University, UK
3 Department of Clinical Neurophysiology, Royal Victoria Infirmary, Newcastle-Upon-Tyne, UK
Corresponding author. Address: Institute of Cellular Medicine, Newcastle University, 4th Floor William Leech Building, The Medical School, Newcastle University, Newcastle, NE2 4HH. Tel.: +44 191 222 5784; fax: +44 191 222 0723.
PII: S0168-8278(10)00699-9
doi:10.1016/j.jhep.2010.05.036
© 2010 Published by Elsevier Inc
Source
Received 15 December 2009; received in revised form 24 May 2010; accepted 26 May 2010. published online 18 August 2010.
Uncorrected Proof
Background & Aims
Primary biliary cirrhosis (PBC) is associated with fatigue, memory impairment, and sleep disturbances. These symptoms suggest the possibility of underlying central nervous system (CNS) dysfunction. During exercise, fatigue develops due to muscular processes (peripheral fatigue) and decreased neurological activation of the muscle (central fatigue). In this study we objectively quantify central and peripheral fatigue in PBC and investigate the integrity of cortical inhibitory and excitatory circuits. Finally we determine the relationship of these indices to the symptoms of PBC.
Methods
16 early-stage PBC patients, 8 post-liver transplant PBC patients, and 12 age-matched controls were studied at the Specialist PBC clinic and neuroscience research unit. In these patients, twitch interpolation was used to measure peripheral and central fatigue. Paired-pulse trans-cranial magnetic stimulation was used to assess intra-cortical inhibition (ICI) and facilitation (ICF).
Results
PBC patients had a significantly lower central activation before fatiguing exercise (mean 86.6.8% (±12.75) vs. 95.2% (±7.4); p<0.05) and a greater response variability than controls. The decline in central activation during exercise and peripheral fatigue were normal. ICI was significantly reduced in PBC patients and daytime somnolence was greater in patients where net inhibition exceeded facilitation. Transplanted and non-transplanted patients had similar central activation, ICI, and ICF.
Conclusions
PBC patients have impaired central activation and abnormal ICI, suggesting CNS abnormalities beyond voluntary control. Transplanted and non-transplanted patients show similar abnormalities raising interesting questions about the mechanisms underpinning these changes and the permanence of neurological dysfunction in PBC. ICI and ICF and the balance between them are related to daytime somnolence (an important symptom in PBC).
Keywords: Muscle, Trans-cranial magnetic stimulation, Twitch interpolation, Cortical inhibition, Liver cirrhosis, Biliary
Abbreviations: TMS, trans-cranial magnetic stimulation, ICI, intra-cortical inhibition, ICF, intra-cortical facilitation, ESS, Epworth Sleepiness Scale, PBC, primary biliary cirrhosis, MVC, maximal voluntary contraction
1 Institute of Cellular Medicine, Newcastle University, UK
2 Institute of Neuroscience, Newcastle University, UK
3 Department of Clinical Neurophysiology, Royal Victoria Infirmary, Newcastle-Upon-Tyne, UK
Corresponding author. Address: Institute of Cellular Medicine, Newcastle University, 4th Floor William Leech Building, The Medical School, Newcastle University, Newcastle, NE2 4HH. Tel.: +44 191 222 5784; fax: +44 191 222 0723.
PII: S0168-8278(10)00699-9
doi:10.1016/j.jhep.2010.05.036
© 2010 Published by Elsevier Inc
Source
Hepatitis C virus entry and glucocorticosteroids
Samira Fafi-Kremer 1,2,3, François Habersetzer 1,2,4, Thomas F. Baumert 1,2,4
Received 5 July 2010; accepted 8 July 2010. published online 18 August 2010.
Uncorrected Proof
COMMENT ON:
Ciesek S, Steinmann E, Iken M, Ott M, Helfritz FA, Wappler I et al. Glucocorticosteroids increase cell entry by hepatitis C virus. Gastroenterology 2010;138:1875–84.
Background & Aims
Corticosteroids are used as immunosuppressants in patients with autoimmune disorders and transplant recipients. However, these drugs worsen hepatitis C virus (HCV) recurrence after liver transplantation, suggesting that they may directly exacerbate HCV infection.
Methods
The influence of immunosuppressive drugs on HCV replication, assembly, and entry was assessed in Huh-7.5 cells and primary human hepatocytes using cell culture- and patient-derived HCV. Replication was quantified by immunofluorescence, luciferase assays, quantitative reverse-transcriptase polymerase chain reaction, or core enzyme-linked immunosorbent assays. Expression of HCV entry factors was evaluated by cell sorting and immunoblot analyses.
Results
Glucocorticosteroids slightly reduced HCV RNA replication but increased efficiency of HCV entry by up to 10-fold. This was independent of HCV genotype but specific to HCV because vesicular stomatitis virus glycoprotein-dependent infection was not affected by these drugs. The increase in HCV entry was accompanied by up-regulation of messenger RNA and protein levels of occludin and the scavenger receptor class B type I – 2 host cell proteins required for HCV infection; increase of entry by glucocorticosteroids was ablated by RU-486, an inhibitor of glucocorticosteroid signaling. Glucocorticosteroids increased propagation of cell culture-derived HCV approximately 5- to 10-fold in partially differentiated human hepatoma cells and increased infection of primary human hepatocytes by cell culture- and patient-derived HCV.
Conclusions
Glucocorticosteroids specifically increase HCV entry by up-regulating the cell entry factors occludin and scavenger receptor class B type I. Our data suggest that the potential effects of high-dose glucocorticosteroids on HCV infection in vivo may be due to increased HCV dissemination [Reprinted with permission of the publisher].
Abbreviations: CLDN1, claudin-1, HCV, hepatitis C virus, HCVcc, cell culture-derived HCV, HCVpp, HCV pseudoparticles, LDLR, low-density lipoprotein receptor, OCLN, occludin, SR-BI, scavenger receptor class B type I
1 Inserm, U748, Strasbourg, France
2 Université de Strasbourg, Strasbourg, France
3 Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
4 Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Corresponding author. Address: Inserm U748, Université de Strasbourg, 3 rue Koeberlé, F-67000 Strasbourg, France. Tel.: +33 3 68 85 37 03; fax: +33 3 68 85 37 24.
PII: S0168-8278(10)00701-4
doi:10.1016/j.jhep.2010.07.007
© 2010 Published by Elsevier Inc.
Source
Received 5 July 2010; accepted 8 July 2010. published online 18 August 2010.
Uncorrected Proof
COMMENT ON:
Ciesek S, Steinmann E, Iken M, Ott M, Helfritz FA, Wappler I et al. Glucocorticosteroids increase cell entry by hepatitis C virus. Gastroenterology 2010;138:1875–84.
Background & Aims
Corticosteroids are used as immunosuppressants in patients with autoimmune disorders and transplant recipients. However, these drugs worsen hepatitis C virus (HCV) recurrence after liver transplantation, suggesting that they may directly exacerbate HCV infection.
Methods
The influence of immunosuppressive drugs on HCV replication, assembly, and entry was assessed in Huh-7.5 cells and primary human hepatocytes using cell culture- and patient-derived HCV. Replication was quantified by immunofluorescence, luciferase assays, quantitative reverse-transcriptase polymerase chain reaction, or core enzyme-linked immunosorbent assays. Expression of HCV entry factors was evaluated by cell sorting and immunoblot analyses.
Results
Glucocorticosteroids slightly reduced HCV RNA replication but increased efficiency of HCV entry by up to 10-fold. This was independent of HCV genotype but specific to HCV because vesicular stomatitis virus glycoprotein-dependent infection was not affected by these drugs. The increase in HCV entry was accompanied by up-regulation of messenger RNA and protein levels of occludin and the scavenger receptor class B type I – 2 host cell proteins required for HCV infection; increase of entry by glucocorticosteroids was ablated by RU-486, an inhibitor of glucocorticosteroid signaling. Glucocorticosteroids increased propagation of cell culture-derived HCV approximately 5- to 10-fold in partially differentiated human hepatoma cells and increased infection of primary human hepatocytes by cell culture- and patient-derived HCV.
Conclusions
Glucocorticosteroids specifically increase HCV entry by up-regulating the cell entry factors occludin and scavenger receptor class B type I. Our data suggest that the potential effects of high-dose glucocorticosteroids on HCV infection in vivo may be due to increased HCV dissemination [Reprinted with permission of the publisher].
Abbreviations: CLDN1, claudin-1, HCV, hepatitis C virus, HCVcc, cell culture-derived HCV, HCVpp, HCV pseudoparticles, LDLR, low-density lipoprotein receptor, OCLN, occludin, SR-BI, scavenger receptor class B type I
1 Inserm, U748, Strasbourg, France
2 Université de Strasbourg, Strasbourg, France
3 Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
4 Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Corresponding author. Address: Inserm U748, Université de Strasbourg, 3 rue Koeberlé, F-67000 Strasbourg, France. Tel.: +33 3 68 85 37 03; fax: +33 3 68 85 37 24.
PII: S0168-8278(10)00701-4
doi:10.1016/j.jhep.2010.07.007
© 2010 Published by Elsevier Inc.
Source
The Odd, Yet Dangerous Connection Between Grapefruit Juice and Prescription Drugs
Posted by David Mittleman
August 20, 2010 10:17 AM
If you enjoy a glass of grapefruit juice with your breakfast, you should check to make sure that it doesn't interact with your prescription medications. Unfortunately, many Americans learn this lesson the hard way. Take, for example, Lucas King, a 59-year-old retiree who suffers from heart disease and is on prescription heart medication to treat his condition.
King's heart disease is attributable to many factors: he is obese, inactive, and has a family history of the health condition. In addition, his LDL or "bad" cholesterol level was too high: 225 mg/dL. However, even after following his doctor's advice to get more exercise and change his unhealthy diet, his numbers just wouldn't budge. So, to help King, his doctor prescribed the drug Lipitor, along with continued diet and exercise. Over time, King's doctor raised the dosage to the maximum, which helped him to lose over 36 pounds and bring his LDL cholesterol down to 104.
Feeling much healthier, King decided to travel to his winter home in Florida. Naturally, he took advantage of the grapefruit tree growing in his yard and drank at least 2 glasses of juice each day from the fruit. But just two months after receiving the good news about his health, King was rushed to a Florida emergency room with muscle pain, fever, and fatigue. Subsequently, King was diagnosed with rhabdomyolysis, a severe muscle reaction that can cause death.
While King's diagnosis might seem bizarre and unusual, it is actually more common for individuals who take prescription cholesterol-lowering medications than you might think. Prescription statins can already cause rhabdomyolysis, which is indicated on the warning label and the fact sheet that patients receive with the medication. What most patients don't realize, however, is that grapefruit juice slows the activity of the liver enzyme responsible for metabolizing the drugs. In fact, the Florida Department of Citrus acknowledges that grapefruit juice interacts with some cholesterol-lowering drugs. Thankfully, not all prescription statins interact with the fruit juice, so if you enjoy a glass or two with your morning meal, there are other statins that you could take instead. King did just that: he switched to Pravachol and is doing much better. Read below for a list of prescription drugs that interact with grapefruit juice, including some for other health problems:
Anxiety: Xanax, Buspar, Versed, Halcion
Depression: Luvox, Zoloft
Allergies: Allegra
Abnormal heart rhythm: Cordarone, quinidine
Heart disease/stroke/blood clots: Coumadin
Epilepsy: Tegretol
Cancer: Cyclophosphamide, etoposide, ifosfamide, tamoxifen, vinblastine, vincristine
Cough: Dextromethorphan (found in many over-the-counter cold medicines)
HIV: Agenerase, Crixivan, Viracept, Norvir, Fortovase
Prostate enlargement: Proscar
Heart disease/High blood pressure: Coreg, Cardizem, Plendil, Cardene, Adalat, Procardia, Nimotop, Sular, Covera, Calan, Verelan
Erectile dysfunction: Viagra, Cialis
Asthma/Emphysema: Theophylline
High cholesterol: Lipitor, Lescol, Mevacor, Zocor
Pain: Alfenta, Duragesic, Actiq, Sufenta
Infection: Biaxin, Sporanox, erythromycin, troleandomycin
Most importantly, check with your doctor about specific interactions between grapefruit juice and medication to ensure your health and safety.
Source
August 20, 2010 10:17 AM
If you enjoy a glass of grapefruit juice with your breakfast, you should check to make sure that it doesn't interact with your prescription medications. Unfortunately, many Americans learn this lesson the hard way. Take, for example, Lucas King, a 59-year-old retiree who suffers from heart disease and is on prescription heart medication to treat his condition.
King's heart disease is attributable to many factors: he is obese, inactive, and has a family history of the health condition. In addition, his LDL or "bad" cholesterol level was too high: 225 mg/dL. However, even after following his doctor's advice to get more exercise and change his unhealthy diet, his numbers just wouldn't budge. So, to help King, his doctor prescribed the drug Lipitor, along with continued diet and exercise. Over time, King's doctor raised the dosage to the maximum, which helped him to lose over 36 pounds and bring his LDL cholesterol down to 104.
Feeling much healthier, King decided to travel to his winter home in Florida. Naturally, he took advantage of the grapefruit tree growing in his yard and drank at least 2 glasses of juice each day from the fruit. But just two months after receiving the good news about his health, King was rushed to a Florida emergency room with muscle pain, fever, and fatigue. Subsequently, King was diagnosed with rhabdomyolysis, a severe muscle reaction that can cause death.
While King's diagnosis might seem bizarre and unusual, it is actually more common for individuals who take prescription cholesterol-lowering medications than you might think. Prescription statins can already cause rhabdomyolysis, which is indicated on the warning label and the fact sheet that patients receive with the medication. What most patients don't realize, however, is that grapefruit juice slows the activity of the liver enzyme responsible for metabolizing the drugs. In fact, the Florida Department of Citrus acknowledges that grapefruit juice interacts with some cholesterol-lowering drugs. Thankfully, not all prescription statins interact with the fruit juice, so if you enjoy a glass or two with your morning meal, there are other statins that you could take instead. King did just that: he switched to Pravachol and is doing much better. Read below for a list of prescription drugs that interact with grapefruit juice, including some for other health problems:
Anxiety: Xanax, Buspar, Versed, Halcion
Depression: Luvox, Zoloft
Allergies: Allegra
Abnormal heart rhythm: Cordarone, quinidine
Heart disease/stroke/blood clots: Coumadin
Epilepsy: Tegretol
Cancer: Cyclophosphamide, etoposide, ifosfamide, tamoxifen, vinblastine, vincristine
Cough: Dextromethorphan (found in many over-the-counter cold medicines)
HIV: Agenerase, Crixivan, Viracept, Norvir, Fortovase
Prostate enlargement: Proscar
Heart disease/High blood pressure: Coreg, Cardizem, Plendil, Cardene, Adalat, Procardia, Nimotop, Sular, Covera, Calan, Verelan
Erectile dysfunction: Viagra, Cialis
Asthma/Emphysema: Theophylline
High cholesterol: Lipitor, Lescol, Mevacor, Zocor
Pain: Alfenta, Duragesic, Actiq, Sufenta
Infection: Biaxin, Sporanox, erythromycin, troleandomycin
Most importantly, check with your doctor about specific interactions between grapefruit juice and medication to ensure your health and safety.
Source
6 Studies on Hypercoagulation relations to Fatty Liver, Metabolic syndrome, and Increased Cardiovascular Risks
August 21, 2010 posted by Denise Nichols
Hypercoagulation’s relationship to nonalcoholic fatty liver disease, metabolic syndrome, increase risk in Cardiovascular disease, diabetes, cadium toxicity, osteomalacia, anemia, increase risk of thrombosis, cellular thrombosis are discussed in these 6 studies.
Gulf War Veterans have you been diagnosed with Liver problems? You must realize that the liver is important in order to detoxify the body and is damaged by chemicals, heavy metals , and viruses. Gulf War veterans need to not be using alcohol, need to be aware to follow and watch liver function values that the doctors should be monitoring, and also the pharmacist and the gulf war veteran patient should closely monitor other drugs that are prescription that might have adverse effects or side effects related to the liver.
Symptoms of Liver problems include:
1. See if the patient has discoloration of skin. The skin and eyes acquire a yellowish tinge and the urine turns dark yellow. It is called jaundice and this is considered to be the primary sign of liver disease.
2. Track the patient’s diet. Loss of appetite leading to weight loss is indicative of liver dysfunction. The patient may become anemic and have a nauseating feeling.
3. Check for light colored stools as it indicates the beginning of liver disorder. A liver patient may also complain of irritable bowels or irregular bowel movements.
4. Find out if there is distended abdomen. Swelling under the right lower ribs is a common complaint of liver patients. It can put severe pressure on the diaphragm that results in painful breathing.
5. Examine the shape and appearance of the nails. Curved and whitish look of nails also suggests a liver problem.
6. Notice nose bleeding and easy bruises as it shows liver abnormality and deficiency of proteins.
7. Test for polydipsia and polyuria-excessive thirst and frequent urination can occur in case of a liver disease.
8. Frequent headaches, dizziness, spasms, irritability, depression and so on are also indicative of liver problem.
9. Other items to watch for:
--Itchy skin that doesn’t seem to go away
--Dark urine color
--Bloody or tar-colored stool
--Chronic fatigue
Here are the 6 research studies:
1. Clin Liver Dis. 2009 Feb;13(1):109-16.
Hypercoagulation in liver disease.
Northup PG. Division of Gastroenterology and Hepatology, University of Virginia Health System, JPA and Lee Streets, MSB 2142, Charlottesville VA 22908-0708, USA. pgn5qs@virginia.edu
Abstract
The coagulopathy of liver disease is complex and often unpredictable. Despite clear evidence of an increased tendency for bleeding in patients who have cirrhosis, many circumstances also promote local and systemic hypercoagulable states. The consequences of hypercoagulability include the obvious morbidity and mortality of portal vein thrombosis, deep vein thrombosis, and pulmonary embolism, but possibly also include other end-organ syndromes, such as portopulmonary hypertension, hepatorenal syndrome, and spontaneous bacterial peritonitis. A more subtle contribution also could be responsible for progression of early fibrosis to decompensated cirrhosis. Future research is needed to elucidate specific mechanistic pathways that might lead to local hypercoagulation and the clinical interventions that might prevent morbidity and mortality related to hypercoagulation in patients who have cirrhosis.
PMID: 19150315 [PubMed - indexed for MEDLINE]
2. Semin Thromb Hemost. 2009 Apr;35(3):277-87. Epub 2009 May 18.
Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome.
Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M. Department of Biomedical and Surgical Sciences, University of Verona, Italy. giovanni.targher@univr.it
Comment in:
Semin Thromb Hemost. 2009 Apr;35(3):257-9.
Abstract
Nonalcoholic fatty liver disease (NAFLD), comprising its whole spectrum of conditions ranging from simple steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH) and cirrhosis, is the most frequent liver disease in developed countries and is now regarded as the liver manifestation of the metabolic syndrome. Several studies indicate that NAFLD, especially in its necro-inflammatory form (NASH), is associated with a systemic proinflammatory/prothrombotic state, independently of shared metabolic risk factors. This suggests that NAFLD/NASH is not simply a marker of the proinflammatory/prothrombotic state in the metabolic syndrome but is actively involved in its pathogenesis, possibly through the systemic release of proinflammatory and procoagulant factors from the steatotic liver (C-reactive protein, plasminogen activator inhibitor-1, interleukin-6, fibrinogen, and other proinflammatory cytokines). The clinical impact of NAFLD on the proinflammatory/prothrombotic risk profile deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.
PMID: 19452403 [PubMed - indexed for MEDLINE]
3. Diabetologia. 2008 Nov;51(11):1947-53. Epub 2008 Sep 2.
Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?
Targher G, Marra F, Marchesini G.
Department of Biomedical and Surgical Sciences, University of Verona, Ospedale Civile Maggiore, Verona, Italy. giovanni.targher@univr.it
Abstract
Non-alcoholic fatty liver disease (NAFLD), comprising a spectrum of conditions ranging from pure steatosis to steatohepatitis and cirrhosis, has reached epidemic proportions and represents the most common cause of chronic liver disease in the community. The prevalence of NAFLD has been estimated to be between 20% and 30% in the general population, but this value is much higher ( approximately 70-80%) in type 2 diabetic patients, who are also at higher risk of developing advanced fibrosis and cirrhosis. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development of cardiovascular disease (CVD). Several epidemiological studies indicate that NAFLD, especially in its more severe forms, is linked to an increased risk of CVD, independently of underlying cardiometabolic risk factors. This suggests that NAFLD is not merely a marker of CVD, but may also be actively involved in its pathogenesis. The possible molecular mediators linking NAFLD and CVD include the release of pro-atherogenic factors from the liver (C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 and other inflammatory cytokines) as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia, in turn favouring CVD progression. The clinical impact of NAFLD on CVD risk deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.
PMID: 18762907 [PubMed - indexed for MEDLINE]
4. J Thromb Haemost. 2008 Jan;6(1):2-9. Epub 2007 Sep 24.
Hypercoagulation and thrombophilia in liver disease.
Northup PG, Sundaram V, Fallon MB, Reddy KR, Balogun RA, Sanyal AJ, Anstee QM, Hoffman MR, Ikura Y, Caldwell SH; Coagulation in Liver Disease Group. Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA 22908-0708, USA. pgn5qs@virginia.edu
Abstract
A complex balance exists between endogenous procoagulants and the anticoagulant system in liver disease patients. Hypercoagulable events occur in cirrhosis patients despite the well-known bleeding diathesis of liver disease. These events may be clinically evident, such as in portal vein thrombosis or pulmonary embolism, but these conditions may also be a silent contributor to certain disease states, such as portopulmonary hypertension or parenchymal extinction with liver atrophy as well as thrombosis of extracorporeal circuits in dialysis or liver assist devices. Moreover, liver disease-related hypercoagulability may contribute to vascular disease in the increasingly common condition of non-alcoholic fatty liver disease. Despite the incidence of these problems, there are few widely accessible and practical laboratory tests to evaluate the risk of a hypercoagulable event in cirrhosis patients. Furthermore, there is little research on the use of commonly accepted anticoagulants in patients with liver disease. This article is a result of an international symposium on coagulation disorders in liver disease and addresses several areas of specific interest in hypercoagulation in liver disease. Critical areas lacking clinical information are highlighted and future areas of research interest are defined with an aim to foster clinical research in this field.
PMID: 17892532 [PubMed - indexed for MEDLINE]
5. Pathophysiol Haemost Thromb. 2006;35(6):411-6.
The effects of chronic cadmium toxicity on the hemostatic system.
Koçak M, Akçil E. Department of Pathophysiology, Faculty of Medicine, Ankara University, Ankara, Turkey. mkocak@epdk.org.tr
Abstract
Cadmium, a highly toxic heavy metal, is distributed widely in the general environment. The characteristic clinical manifestations of chronic cadmium intoxication include renal proximal tubular dysfunction, osteomalacia and anemia. Accumulating evidence suggests that cadmium toxicity may also affect various organs such as the liver, lung, testis and hematopoietic system. The aim of this study was to determine the effect of chronic cadmium exposure on the anticoagulant system in rats. Fourty-five adult Wistar albino rats were randomly allocated into 2 groups. While the control group was given tap water, the animals in the cadmium group were treated with 15 ppm CdCl(2) for 4 weeks. Blood cadmium concentration, prothrombin time, activated partial thromboplastin time, plasma protein C and antithrombin activity, and platelet count were determined in the rats. Blood cadmium concentrations increased in the experiment group compared to the control group (p < 0.001). Results also show that cadmium exposure shortened prothrombin time (p < 0.05) and activated partial thromboplastin time (p < 0.01) in rats. Protein C (p < 0.001) and antithrombin (p 0.05). In conclusion, when the parameters of the hemolytic system are considered, the decrease in protein C and antithrombin activities and the shortening of prothrombin time and activated partial thromboplastin time suggests the presence of a hypercoagulable state during chronic cadmium intoxication. Therefore, it may be stated that chronic cadmium toxicity sets the stage for hypercoagulation and hence increases the risk of thrombosis.
PMID: 17565233 [PubMed - indexed for MEDLINE]
6. Cell Biochem Funct. 2006 Mar-Apr;24(2):173-92.
Tissue factor upregulation drives a thrombosis-inflammation circuit in relation to cardiovascular complications.
Chu AJ. Surgery Department, Wayne State University, Detroit, MI 48201, USA. ajchu91@hotmail.com
Abstract
The extrinsic coagulation is recognized as an ‘inducible’ signalling cascade resulting from tissue factor (TF) upregulation by exposure to clotting zymogen FVII upon inflammation or tissue injury. Following the substantial initiation, an array of proteolytic activation generates mediating signals (active serine proteases: FVIIa, FXa and FIIa) that lead to hypercoagulation with fibrin overproduction manifesting thrombosis. In addition, TF upregulation plays a central role in driving a thrombosis-inflammation circuit. Coagulant mediators (FVIIa, FXa and FIIa) and endproduct (fibrin) are proinflammatory, eliciting tissue necrosis factor, interleukins, adhesion molecules and many other intracellular signals in different cell types. Such resulting inflammation could ensure ‘fibrin’ thrombosis via feedback upregulation of TF. Alternatively, the resulting inflammation triggers platelet/leukocyte/polymononuclear cell activation thus contributing to ‘cellular’ thrombosis. TF is very vulnerable to upregulation resulting in hypercoagulability and subsequent thrombosis and inflammation, either of which presents cardiovascular risks. The prevention and intervention of TF hypercoagulability are of importance in cardioprotection. Blockade of inflammation reception and its intracellular signalling prevents TF expression from upregulation. Natural (activated protein C, tissue factor pathway inhibitor, or antithrombin III) or pharmacological anticoagulants readily offset the extrinsic hypercoagulation mainly through FVIIa, FXa or FIIa inhibition. Therefore, anticoagulants turn off the thrombosis-inflammation circuit, offering not only antithrombotic but anti-inflammatory significance in the prevention of cardiovascular complications.
PMID: 15617024 [PubMed - indexed for MEDLINE]
————–
- ISAC Panel (Fibrinogen Activity, Prothrombin Fragment 1+2, Thrombin/Antithrombin Complex, PA by Flow)320020 – Hypercoagulation Panel (No Meds) (Antithrombin Activity, Protein C Activity, Protein S Activity, Activated Protein C Resistance, Fibrinogen Activity, Prothrombin Time/INR, Activated Partial Thromboplastin Time, Dilute Russell’s Viper Venom Time Screen, Dilute Russell’s Viper Venom Time Confirm, Lipoprotein (a), Homocysteine, Factor II Mutation, Platelet Activation by Flow) Note: May include PNP, PT Mixing Study, and/or aPTT Mixing Study
Source
Also See: Original Hypercoagulation Study on Gulf War Veterans
Hypercoagulation’s relationship to nonalcoholic fatty liver disease, metabolic syndrome, increase risk in Cardiovascular disease, diabetes, cadium toxicity, osteomalacia, anemia, increase risk of thrombosis, cellular thrombosis are discussed in these 6 studies.
Gulf War Veterans have you been diagnosed with Liver problems? You must realize that the liver is important in order to detoxify the body and is damaged by chemicals, heavy metals , and viruses. Gulf War veterans need to not be using alcohol, need to be aware to follow and watch liver function values that the doctors should be monitoring, and also the pharmacist and the gulf war veteran patient should closely monitor other drugs that are prescription that might have adverse effects or side effects related to the liver.
Symptoms of Liver problems include:
1. See if the patient has discoloration of skin. The skin and eyes acquire a yellowish tinge and the urine turns dark yellow. It is called jaundice and this is considered to be the primary sign of liver disease.
2. Track the patient’s diet. Loss of appetite leading to weight loss is indicative of liver dysfunction. The patient may become anemic and have a nauseating feeling.
3. Check for light colored stools as it indicates the beginning of liver disorder. A liver patient may also complain of irritable bowels or irregular bowel movements.
4. Find out if there is distended abdomen. Swelling under the right lower ribs is a common complaint of liver patients. It can put severe pressure on the diaphragm that results in painful breathing.
5. Examine the shape and appearance of the nails. Curved and whitish look of nails also suggests a liver problem.
6. Notice nose bleeding and easy bruises as it shows liver abnormality and deficiency of proteins.
7. Test for polydipsia and polyuria-excessive thirst and frequent urination can occur in case of a liver disease.
8. Frequent headaches, dizziness, spasms, irritability, depression and so on are also indicative of liver problem.
9. Other items to watch for:
--Itchy skin that doesn’t seem to go away
--Dark urine color
--Bloody or tar-colored stool
--Chronic fatigue
Here are the 6 research studies:
1. Clin Liver Dis. 2009 Feb;13(1):109-16.
Hypercoagulation in liver disease.
Northup PG. Division of Gastroenterology and Hepatology, University of Virginia Health System, JPA and Lee Streets, MSB 2142, Charlottesville VA 22908-0708, USA. pgn5qs@virginia.edu
Abstract
The coagulopathy of liver disease is complex and often unpredictable. Despite clear evidence of an increased tendency for bleeding in patients who have cirrhosis, many circumstances also promote local and systemic hypercoagulable states. The consequences of hypercoagulability include the obvious morbidity and mortality of portal vein thrombosis, deep vein thrombosis, and pulmonary embolism, but possibly also include other end-organ syndromes, such as portopulmonary hypertension, hepatorenal syndrome, and spontaneous bacterial peritonitis. A more subtle contribution also could be responsible for progression of early fibrosis to decompensated cirrhosis. Future research is needed to elucidate specific mechanistic pathways that might lead to local hypercoagulation and the clinical interventions that might prevent morbidity and mortality related to hypercoagulation in patients who have cirrhosis.
PMID: 19150315 [PubMed - indexed for MEDLINE]
2. Semin Thromb Hemost. 2009 Apr;35(3):277-87. Epub 2009 May 18.
Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome.
Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M. Department of Biomedical and Surgical Sciences, University of Verona, Italy. giovanni.targher@univr.it
Comment in:
Semin Thromb Hemost. 2009 Apr;35(3):257-9.
Abstract
Nonalcoholic fatty liver disease (NAFLD), comprising its whole spectrum of conditions ranging from simple steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH) and cirrhosis, is the most frequent liver disease in developed countries and is now regarded as the liver manifestation of the metabolic syndrome. Several studies indicate that NAFLD, especially in its necro-inflammatory form (NASH), is associated with a systemic proinflammatory/prothrombotic state, independently of shared metabolic risk factors. This suggests that NAFLD/NASH is not simply a marker of the proinflammatory/prothrombotic state in the metabolic syndrome but is actively involved in its pathogenesis, possibly through the systemic release of proinflammatory and procoagulant factors from the steatotic liver (C-reactive protein, plasminogen activator inhibitor-1, interleukin-6, fibrinogen, and other proinflammatory cytokines). The clinical impact of NAFLD on the proinflammatory/prothrombotic risk profile deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.
PMID: 19452403 [PubMed - indexed for MEDLINE]
3. Diabetologia. 2008 Nov;51(11):1947-53. Epub 2008 Sep 2.
Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?
Targher G, Marra F, Marchesini G.
Department of Biomedical and Surgical Sciences, University of Verona, Ospedale Civile Maggiore, Verona, Italy. giovanni.targher@univr.it
Abstract
Non-alcoholic fatty liver disease (NAFLD), comprising a spectrum of conditions ranging from pure steatosis to steatohepatitis and cirrhosis, has reached epidemic proportions and represents the most common cause of chronic liver disease in the community. The prevalence of NAFLD has been estimated to be between 20% and 30% in the general population, but this value is much higher ( approximately 70-80%) in type 2 diabetic patients, who are also at higher risk of developing advanced fibrosis and cirrhosis. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development of cardiovascular disease (CVD). Several epidemiological studies indicate that NAFLD, especially in its more severe forms, is linked to an increased risk of CVD, independently of underlying cardiometabolic risk factors. This suggests that NAFLD is not merely a marker of CVD, but may also be actively involved in its pathogenesis. The possible molecular mediators linking NAFLD and CVD include the release of pro-atherogenic factors from the liver (C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 and other inflammatory cytokines) as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia, in turn favouring CVD progression. The clinical impact of NAFLD on CVD risk deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.
PMID: 18762907 [PubMed - indexed for MEDLINE]
4. J Thromb Haemost. 2008 Jan;6(1):2-9. Epub 2007 Sep 24.
Hypercoagulation and thrombophilia in liver disease.
Northup PG, Sundaram V, Fallon MB, Reddy KR, Balogun RA, Sanyal AJ, Anstee QM, Hoffman MR, Ikura Y, Caldwell SH; Coagulation in Liver Disease Group. Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA 22908-0708, USA. pgn5qs@virginia.edu
Abstract
A complex balance exists between endogenous procoagulants and the anticoagulant system in liver disease patients. Hypercoagulable events occur in cirrhosis patients despite the well-known bleeding diathesis of liver disease. These events may be clinically evident, such as in portal vein thrombosis or pulmonary embolism, but these conditions may also be a silent contributor to certain disease states, such as portopulmonary hypertension or parenchymal extinction with liver atrophy as well as thrombosis of extracorporeal circuits in dialysis or liver assist devices. Moreover, liver disease-related hypercoagulability may contribute to vascular disease in the increasingly common condition of non-alcoholic fatty liver disease. Despite the incidence of these problems, there are few widely accessible and practical laboratory tests to evaluate the risk of a hypercoagulable event in cirrhosis patients. Furthermore, there is little research on the use of commonly accepted anticoagulants in patients with liver disease. This article is a result of an international symposium on coagulation disorders in liver disease and addresses several areas of specific interest in hypercoagulation in liver disease. Critical areas lacking clinical information are highlighted and future areas of research interest are defined with an aim to foster clinical research in this field.
PMID: 17892532 [PubMed - indexed for MEDLINE]
5. Pathophysiol Haemost Thromb. 2006;35(6):411-6.
The effects of chronic cadmium toxicity on the hemostatic system.
Koçak M, Akçil E. Department of Pathophysiology, Faculty of Medicine, Ankara University, Ankara, Turkey. mkocak@epdk.org.tr
Abstract
Cadmium, a highly toxic heavy metal, is distributed widely in the general environment. The characteristic clinical manifestations of chronic cadmium intoxication include renal proximal tubular dysfunction, osteomalacia and anemia. Accumulating evidence suggests that cadmium toxicity may also affect various organs such as the liver, lung, testis and hematopoietic system. The aim of this study was to determine the effect of chronic cadmium exposure on the anticoagulant system in rats. Fourty-five adult Wistar albino rats were randomly allocated into 2 groups. While the control group was given tap water, the animals in the cadmium group were treated with 15 ppm CdCl(2) for 4 weeks. Blood cadmium concentration, prothrombin time, activated partial thromboplastin time, plasma protein C and antithrombin activity, and platelet count were determined in the rats. Blood cadmium concentrations increased in the experiment group compared to the control group (p < 0.001). Results also show that cadmium exposure shortened prothrombin time (p < 0.05) and activated partial thromboplastin time (p < 0.01) in rats. Protein C (p < 0.001) and antithrombin (p 0.05). In conclusion, when the parameters of the hemolytic system are considered, the decrease in protein C and antithrombin activities and the shortening of prothrombin time and activated partial thromboplastin time suggests the presence of a hypercoagulable state during chronic cadmium intoxication. Therefore, it may be stated that chronic cadmium toxicity sets the stage for hypercoagulation and hence increases the risk of thrombosis.
PMID: 17565233 [PubMed - indexed for MEDLINE]
6. Cell Biochem Funct. 2006 Mar-Apr;24(2):173-92.
Tissue factor upregulation drives a thrombosis-inflammation circuit in relation to cardiovascular complications.
Chu AJ. Surgery Department, Wayne State University, Detroit, MI 48201, USA. ajchu91@hotmail.com
Abstract
The extrinsic coagulation is recognized as an ‘inducible’ signalling cascade resulting from tissue factor (TF) upregulation by exposure to clotting zymogen FVII upon inflammation or tissue injury. Following the substantial initiation, an array of proteolytic activation generates mediating signals (active serine proteases: FVIIa, FXa and FIIa) that lead to hypercoagulation with fibrin overproduction manifesting thrombosis. In addition, TF upregulation plays a central role in driving a thrombosis-inflammation circuit. Coagulant mediators (FVIIa, FXa and FIIa) and endproduct (fibrin) are proinflammatory, eliciting tissue necrosis factor, interleukins, adhesion molecules and many other intracellular signals in different cell types. Such resulting inflammation could ensure ‘fibrin’ thrombosis via feedback upregulation of TF. Alternatively, the resulting inflammation triggers platelet/leukocyte/polymononuclear cell activation thus contributing to ‘cellular’ thrombosis. TF is very vulnerable to upregulation resulting in hypercoagulability and subsequent thrombosis and inflammation, either of which presents cardiovascular risks. The prevention and intervention of TF hypercoagulability are of importance in cardioprotection. Blockade of inflammation reception and its intracellular signalling prevents TF expression from upregulation. Natural (activated protein C, tissue factor pathway inhibitor, or antithrombin III) or pharmacological anticoagulants readily offset the extrinsic hypercoagulation mainly through FVIIa, FXa or FIIa inhibition. Therefore, anticoagulants turn off the thrombosis-inflammation circuit, offering not only antithrombotic but anti-inflammatory significance in the prevention of cardiovascular complications.
PMID: 15617024 [PubMed - indexed for MEDLINE]
————–
- ISAC Panel (Fibrinogen Activity, Prothrombin Fragment 1+2, Thrombin/Antithrombin Complex, PA by Flow)320020 – Hypercoagulation Panel (No Meds) (Antithrombin Activity, Protein C Activity, Protein S Activity, Activated Protein C Resistance, Fibrinogen Activity, Prothrombin Time/INR, Activated Partial Thromboplastin Time, Dilute Russell’s Viper Venom Time Screen, Dilute Russell’s Viper Venom Time Confirm, Lipoprotein (a), Homocysteine, Factor II Mutation, Platelet Activation by Flow) Note: May include PNP, PT Mixing Study, and/or aPTT Mixing Study
Source
Also See: Original Hypercoagulation Study on Gulf War Veterans
FDA extends review on Acetadote for non-acetaminophen acute liver failure
21. August 2010 00:42
Cumberland Pharmaceuticals Inc. (Nasdaq: CPIX) today announced the U.S. Food and Drug Administration (FDA) has extended its review of the supplemental new drug application (sNDA) for the use of Acetadote® (acetylcysteine) Injection in patients with non-acetaminophen acute liver failure. The review has been extended by three months resulting in a new Prescription Drug User Fee Act (PDUFA) goal date in December 2010.
"We look forward to continued discussion with the FDA regarding this potentially life-saving treatment for patients who have few alternatives," said A.J. Kazimi, Chief Executive Officer of Cumberland Pharmaceuticals.
Acute liver failure is a rare syndrome associated with a high mortality rate and frequent need for liver transplantation. Approximately 50 percent of acute liver failure cases are caused by acetaminophen poisoning. Other causes of acute liver failure not induced by acetaminophen overdose include hepatitis B disease, autoimmune hepatitis, Wilson disease, fatty liver of pregnancy, and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Currently, transplantation of the liver is the only treatment for patients with liver failure not caused by acetaminophen overdose. In March 2010, Cumberland submitted the sNDA to the FDA for the use of Acetadote in patients with non-acetaminophen acute liver failure. The FDA formally accepted the application for review and designated the review classification as Priority in May 2010.
Acetadote was launched by Cumberland in 2004 as the first U.S.-approved injectable drug to treat acetaminophen overdose. In 2006, the FDA approved Acetadote for use in pediatric patients. The Company also received FDA approval for updated labeling regarding the safety of Acetadote in 2008 based on new information from a post-marketing safety study reporting a lower-incidence of side effects compared to previously reported data.
Source: Cumberland Pharmaceuticals
Source
Cumberland Pharmaceuticals Inc. (Nasdaq: CPIX) today announced the U.S. Food and Drug Administration (FDA) has extended its review of the supplemental new drug application (sNDA) for the use of Acetadote® (acetylcysteine) Injection in patients with non-acetaminophen acute liver failure. The review has been extended by three months resulting in a new Prescription Drug User Fee Act (PDUFA) goal date in December 2010.
"We look forward to continued discussion with the FDA regarding this potentially life-saving treatment for patients who have few alternatives," said A.J. Kazimi, Chief Executive Officer of Cumberland Pharmaceuticals.
Acute liver failure is a rare syndrome associated with a high mortality rate and frequent need for liver transplantation. Approximately 50 percent of acute liver failure cases are caused by acetaminophen poisoning. Other causes of acute liver failure not induced by acetaminophen overdose include hepatitis B disease, autoimmune hepatitis, Wilson disease, fatty liver of pregnancy, and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Currently, transplantation of the liver is the only treatment for patients with liver failure not caused by acetaminophen overdose. In March 2010, Cumberland submitted the sNDA to the FDA for the use of Acetadote in patients with non-acetaminophen acute liver failure. The FDA formally accepted the application for review and designated the review classification as Priority in May 2010.
Acetadote was launched by Cumberland in 2004 as the first U.S.-approved injectable drug to treat acetaminophen overdose. In 2006, the FDA approved Acetadote for use in pediatric patients. The Company also received FDA approval for updated labeling regarding the safety of Acetadote in 2008 based on new information from a post-marketing safety study reporting a lower-incidence of side effects compared to previously reported data.
Source: Cumberland Pharmaceuticals
Source
In Practice: Dr. Google has mixed results
Using the search engine can be a boon for physicians — if they do it right.
By Rahul K. Parikh, Special to the Los Angeles Times
August 23, 2010
During an otherwise unremarkable afternoon at the office, I was sitting at my desk plowing through paperwork when a colleague came knocking — and forever changed how I practice medicine.
"Hey, Rahul, what's McMurray's sign?" he asked.
It is said that a physician needs to carry some 2 million facts to practice medicine. Though I knew that McMurray's sign had something to do with examining a patient's knee, it was one of the 2 million facts that, like some tattered scraps of paper pushed to the back of a file cabinet, I had long since forgotten.
I shrugged and turned toward my bookshelf to pull down a decade-old volume of Nelson's Textbook of Pediatrics. Somewhere in that tome was the definition of McMurray's sign and how to elicit it on exam.
Just as I was reaching for the book, I had another idea. I turned back to my workstation, clicked on that little "e" to bring up my Internet browser and went to Google. I typed "McMurray's sign" in the search box and hit "enter," and up popped several links to YouTube videos. We clicked on one and, like two medical students learning the basics of our craft, watched the short mini-lecture that showed an instructor moving the knee joint to check for a positive McMurray's sign. And with that, my colleague was off to try it on his own patient.
Eureka. No more pencils, no more books. With a computer and Google (sorry, Bing, statistics show that Google is where we go first and frequently) in your office and your exam rooms, it's a whole new world — for better or worse.
I've used Google regularly in my practice for the last four to five years, and statistics suggest I'm not alone (though it's Google's data, so it's perhaps best taken with a grain of salt): Eighty-six percent of doctors say they now regularly use the Internet on the job. Of that group, the majority start at Google, which they use as a springboard to look for general information about diseases and drugs.
And why not? As writer and physician Atul Gawande likes to point out, in medicine today there are 13,000 diseases, 6,000 drugs and 4,000 medical and surgical procedures. Even for the best and most motivated of physicians, it's a Sisyphean battle to keep up. Having the Internet at my fingertips makes me a better doctor, though I'll admit that sometimes it feels a bit like cheating on an exam.
Use it judiciously
I was sitting with the parent of a new patient a while back. As she was filling me in about her son's medical history, she told me his father has a history of retinitis pigmentosa. Like McMurray's sign, it was a distant but familiar phrase. As I was nodding my head listening, I stopped typing into his chart, brought up Google and typed in "retinitis pigmentosa."
A mere 0.36 seconds later, I got links 1-10 of 866,000. I clicked on a Medline link and glanced over some bullet points to see if I needed to send this child for any screening tests. Because, as I read, the "signs and symptoms often first appear in childhood, but severe vision problems do not usually develop until early adulthood," I knew I just had to make sure I did his vision test annually. Didn't miss a beat.
Most doctors seem to agree that using Google to educate yourself or patients makes sense (for a pediatrician like me, that means showing parents pictures of different diaper rashes and kids pictures of poison oak so they don't walk into a plant for the ninth time this summer). But things get trickier — and more controversial — when doctors start using Google to make diagnoses.
There's a now famous story first told in the New England Journal of Medicine about a trainee in allergy and immunology who was presenting a case to some colleagues. The audience included a visiting distinguished professor in the same field. The case was of an infant with diarrhea, an unusual rash and multiple immunologic abnormalities. The attending physicians and house staff discussed several diagnostic possibilities, but no consensus was reached. They were stumped. Finally, the visiting professor asked the trainee if she had made a diagnosis. She reported that she had: The child had a rare syndrome known as IPEX.
The distinguished physician asked the young trainee how she'd figured this out.
"Well, I had the skin biopsy report, and I had a chart of the immunologic tests. So I entered the salient features into Google, and it popped right up," she was quoted as saying. The author of that letter to the New England Journal, who was present at the meeting, wondered: "Are we physicians no longer needed? Is an observer who can accurately select the findings to be entered in a Google search all we need for a diagnosis to appear, as if by magic?"
He needn't worry. It turns out that we're not all as good at Googling as that young doctor was.
In a 2006 study published in the British Medical Journal, researchers had physicians read the histories of 26 tricky cases published in the New England Journal of Medicine and enter search terms into Google to see if they could make the diagnosis. They nailed it 58% of the time. Not bad, but not much better than the flip of a coin, either.
I tried this experiment myself with a handful of those New England Journal cases — I didn't get a single one right. So my advice is: Unless you're Internet savvy enough and have time to scan pages and pages of websites, skip Googling for diagnoses and just call your nearest specialist for help.
How scholarly?
Another of Google's potential pitfalls has to do with Google Scholar — a product the company launched in 2004 that searches academic publications and websites.
A colleague of mine recently declared that this was now his go-to site for medical research. And, in fact, more visitors were led to biomedical journal websites by Google Scholar within a year of its release than by PubMed, the free Internet database published by the National Library of Medicine and the standard-bearer for doctors and others looking for academic publications.
But at least one study, in the Journal of the Medical Library Assn. in 2007, suggests that Google Scholar may not be the best choice. In a head-to-head comparison of Google Scholar and PubMed, Scholar searches yielded significantly more total citations of primary research articles than did PubMed, suggesting it's less specific than PubMed.
Researchers also found that Google Scholar brings older articles to the top of the results. This is fine if you want a history lesson but problematic if you're looking for cutting-edge clinical data. (It turns out Google Scholar places more weight on studies that are cited more, regardless of their validity.)
Plus, the researchers concluded, users often don't search more than five pages to answer a question, leaving knowledge susceptible to the most popular articles, not necessarily the best.
This study raises an important point about Google, and really all search engines. These are businesses whose success largely rests on proprietary math and technology — algorithms, which in Google's case, are trade secrets, no different than the formula for Coca-Cola. As such, what you find on the top of the page depends on an often mysterious process.
That doesn't mean Google is doing something bad (the company's motto is "Don't be evil"). But it does mean users lack the kind of transparency some of us need when we place our professional faith in a search engine.
The solution for doctors (and everyone), I suspect, is best answered by taking note of that lack of transparency and by making it a professional priority to become search savvy. A growing number of medical professionals have suggested this as well.
Searchers also can use Google — and other sites — more narrowly. That little "advanced search" button next to the big search box, for example, can narrow the results, as can using quotation marks for exact phrases and excluding words by putting a minus sign in front of them. There are lots of tips about how to do this floating around on the Web (just Google "tips to using Google").
This little bit of expertise, especially in a world in which medical knowledge exponentially outpaces our ability to know it all, is a valuable skill set for young doctors to gain.
Parikh, a Walnut Creek, Calif., physician, writes the Vital Signs medical column for Salon.com. http://www.rahulkparikh.com/.
Source
By Rahul K. Parikh, Special to the Los Angeles Times
August 23, 2010
During an otherwise unremarkable afternoon at the office, I was sitting at my desk plowing through paperwork when a colleague came knocking — and forever changed how I practice medicine.
"Hey, Rahul, what's McMurray's sign?" he asked.
It is said that a physician needs to carry some 2 million facts to practice medicine. Though I knew that McMurray's sign had something to do with examining a patient's knee, it was one of the 2 million facts that, like some tattered scraps of paper pushed to the back of a file cabinet, I had long since forgotten.
I shrugged and turned toward my bookshelf to pull down a decade-old volume of Nelson's Textbook of Pediatrics. Somewhere in that tome was the definition of McMurray's sign and how to elicit it on exam.
Just as I was reaching for the book, I had another idea. I turned back to my workstation, clicked on that little "e" to bring up my Internet browser and went to Google. I typed "McMurray's sign" in the search box and hit "enter," and up popped several links to YouTube videos. We clicked on one and, like two medical students learning the basics of our craft, watched the short mini-lecture that showed an instructor moving the knee joint to check for a positive McMurray's sign. And with that, my colleague was off to try it on his own patient.
Eureka. No more pencils, no more books. With a computer and Google (sorry, Bing, statistics show that Google is where we go first and frequently) in your office and your exam rooms, it's a whole new world — for better or worse.
I've used Google regularly in my practice for the last four to five years, and statistics suggest I'm not alone (though it's Google's data, so it's perhaps best taken with a grain of salt): Eighty-six percent of doctors say they now regularly use the Internet on the job. Of that group, the majority start at Google, which they use as a springboard to look for general information about diseases and drugs.
And why not? As writer and physician Atul Gawande likes to point out, in medicine today there are 13,000 diseases, 6,000 drugs and 4,000 medical and surgical procedures. Even for the best and most motivated of physicians, it's a Sisyphean battle to keep up. Having the Internet at my fingertips makes me a better doctor, though I'll admit that sometimes it feels a bit like cheating on an exam.
Use it judiciously
I was sitting with the parent of a new patient a while back. As she was filling me in about her son's medical history, she told me his father has a history of retinitis pigmentosa. Like McMurray's sign, it was a distant but familiar phrase. As I was nodding my head listening, I stopped typing into his chart, brought up Google and typed in "retinitis pigmentosa."
A mere 0.36 seconds later, I got links 1-10 of 866,000. I clicked on a Medline link and glanced over some bullet points to see if I needed to send this child for any screening tests. Because, as I read, the "signs and symptoms often first appear in childhood, but severe vision problems do not usually develop until early adulthood," I knew I just had to make sure I did his vision test annually. Didn't miss a beat.
Most doctors seem to agree that using Google to educate yourself or patients makes sense (for a pediatrician like me, that means showing parents pictures of different diaper rashes and kids pictures of poison oak so they don't walk into a plant for the ninth time this summer). But things get trickier — and more controversial — when doctors start using Google to make diagnoses.
There's a now famous story first told in the New England Journal of Medicine about a trainee in allergy and immunology who was presenting a case to some colleagues. The audience included a visiting distinguished professor in the same field. The case was of an infant with diarrhea, an unusual rash and multiple immunologic abnormalities. The attending physicians and house staff discussed several diagnostic possibilities, but no consensus was reached. They were stumped. Finally, the visiting professor asked the trainee if she had made a diagnosis. She reported that she had: The child had a rare syndrome known as IPEX.
The distinguished physician asked the young trainee how she'd figured this out.
"Well, I had the skin biopsy report, and I had a chart of the immunologic tests. So I entered the salient features into Google, and it popped right up," she was quoted as saying. The author of that letter to the New England Journal, who was present at the meeting, wondered: "Are we physicians no longer needed? Is an observer who can accurately select the findings to be entered in a Google search all we need for a diagnosis to appear, as if by magic?"
He needn't worry. It turns out that we're not all as good at Googling as that young doctor was.
In a 2006 study published in the British Medical Journal, researchers had physicians read the histories of 26 tricky cases published in the New England Journal of Medicine and enter search terms into Google to see if they could make the diagnosis. They nailed it 58% of the time. Not bad, but not much better than the flip of a coin, either.
I tried this experiment myself with a handful of those New England Journal cases — I didn't get a single one right. So my advice is: Unless you're Internet savvy enough and have time to scan pages and pages of websites, skip Googling for diagnoses and just call your nearest specialist for help.
How scholarly?
Another of Google's potential pitfalls has to do with Google Scholar — a product the company launched in 2004 that searches academic publications and websites.
A colleague of mine recently declared that this was now his go-to site for medical research. And, in fact, more visitors were led to biomedical journal websites by Google Scholar within a year of its release than by PubMed, the free Internet database published by the National Library of Medicine and the standard-bearer for doctors and others looking for academic publications.
But at least one study, in the Journal of the Medical Library Assn. in 2007, suggests that Google Scholar may not be the best choice. In a head-to-head comparison of Google Scholar and PubMed, Scholar searches yielded significantly more total citations of primary research articles than did PubMed, suggesting it's less specific than PubMed.
Researchers also found that Google Scholar brings older articles to the top of the results. This is fine if you want a history lesson but problematic if you're looking for cutting-edge clinical data. (It turns out Google Scholar places more weight on studies that are cited more, regardless of their validity.)
Plus, the researchers concluded, users often don't search more than five pages to answer a question, leaving knowledge susceptible to the most popular articles, not necessarily the best.
This study raises an important point about Google, and really all search engines. These are businesses whose success largely rests on proprietary math and technology — algorithms, which in Google's case, are trade secrets, no different than the formula for Coca-Cola. As such, what you find on the top of the page depends on an often mysterious process.
That doesn't mean Google is doing something bad (the company's motto is "Don't be evil"). But it does mean users lack the kind of transparency some of us need when we place our professional faith in a search engine.
The solution for doctors (and everyone), I suspect, is best answered by taking note of that lack of transparency and by making it a professional priority to become search savvy. A growing number of medical professionals have suggested this as well.
Searchers also can use Google — and other sites — more narrowly. That little "advanced search" button next to the big search box, for example, can narrow the results, as can using quotation marks for exact phrases and excluding words by putting a minus sign in front of them. There are lots of tips about how to do this floating around on the Web (just Google "tips to using Google").
This little bit of expertise, especially in a world in which medical knowledge exponentially outpaces our ability to know it all, is a valuable skill set for young doctors to gain.
Parikh, a Walnut Creek, Calif., physician, writes the Vital Signs medical column for Salon.com. http://www.rahulkparikh.com/.
Source
Hepatitis C, Hispanic Ethnicity Linked to HCC Mortality
Those with HCV infection have 18-fold higher risk of hepatocellular carcinoma mortality
Publish date: Aug 20, 2010
FRIDAY, Aug. 20 (HealthDay News) -- Hepatitis C infection and Hispanic ethnicity are associated with a higher risk of hepatocellular carcinoma (HCC)-related mortality, according to research published in the August issue of Clinical Gastroenterology and Hepatology.
Zobair M. Younossi, M.D., and Maria Stepanova, Ph.D., of the Inova Fairfax Hospital in Falls Church, Va., analyzed data from 15,866 participants in the Third National Health and Nutrition Examination Survey from 1988 to 1994.
The researchers found that, over a median follow-up of 160 months, 14.55 percent of the subjects had died, with 25 of the deaths related to HCC and 58 deaths non-HCC liver related. Factors that predicted mortality related to HCC were hepatitis C infection (hazard ratio [HR], 18.12), Hispanic ethnicity (HR, 5.14), and age (HR, 1.10). Factors predicting non-HCC liver-related mortality included hepatitis C (HR, 27.00), nonalcoholic fatty liver disease (HR, 11.56), alcoholic liver disease (HR, 10.81), and iron overload (HR, 6.18).
"Although early diagnosis and treatment of all liver diseases and diabetes mellitus may favorably impact all liver-related mortality, screening and treatment of hepatitis C virus may specifically improve the rate of HCC-related mortality. In addition, screening and treatment programs must target all individuals at risk for HCC, including Hispanic Americans," the authors conclude.
Abstract
Full Text (subscription or payment may be required)
Source
Publish date: Aug 20, 2010
FRIDAY, Aug. 20 (HealthDay News) -- Hepatitis C infection and Hispanic ethnicity are associated with a higher risk of hepatocellular carcinoma (HCC)-related mortality, according to research published in the August issue of Clinical Gastroenterology and Hepatology.
Zobair M. Younossi, M.D., and Maria Stepanova, Ph.D., of the Inova Fairfax Hospital in Falls Church, Va., analyzed data from 15,866 participants in the Third National Health and Nutrition Examination Survey from 1988 to 1994.
The researchers found that, over a median follow-up of 160 months, 14.55 percent of the subjects had died, with 25 of the deaths related to HCC and 58 deaths non-HCC liver related. Factors that predicted mortality related to HCC were hepatitis C infection (hazard ratio [HR], 18.12), Hispanic ethnicity (HR, 5.14), and age (HR, 1.10). Factors predicting non-HCC liver-related mortality included hepatitis C (HR, 27.00), nonalcoholic fatty liver disease (HR, 11.56), alcoholic liver disease (HR, 10.81), and iron overload (HR, 6.18).
"Although early diagnosis and treatment of all liver diseases and diabetes mellitus may favorably impact all liver-related mortality, screening and treatment of hepatitis C virus may specifically improve the rate of HCC-related mortality. In addition, screening and treatment programs must target all individuals at risk for HCC, including Hispanic Americans," the authors conclude.
Abstract
Full Text (subscription or payment may be required)
Source
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