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1. |
Kinetic and Dynamic Models of Diving Gases in Decompression Sickness Prevention |
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Clinical Pharmacokinetics,
Volume 41,
Issue 6,
2002,
Page 389-402
Robert Ball,
Sorell L. Schwartz,
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摘要:
Decompression sickness is a complex phenomenon involving gas exchange, bubble dynamics and tissue response. Relatively simple deterministic compartmental models using empirically derived parameters have been the mainstay of the practice for preventing decompression sickness since the early 1900s. Decades of research have improved our understanding of decompression physiology, and the insights incorporated in decompression models have allowed people to dive deeper into the ocean. However, these efforts have not yet, and are unlikely in the near future, to result in a ‘universal’ deterministic model that can predict when decompression sickness will occur. Divers using current recreational dive computers need to be aware of their limitations. Probabilistic models based on the estimation of parameters using modern statistical methods from large databases of dives offer a new approach and can provide a means of standardisation of deterministic models. Future improvements in decompression practice will depend on continued improvement in understanding the kinetics and dynamics of gas exchange, bubble evolution and tissue response, and the incorporation of this knowledge in risk models whose parameters can be estimated from large databases of human and animal data.
ISSN:0312-5963
出版商:ADIS
年代:2002
数据来源: ADIS
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2. |
Pharmacokinetics of the Carmustine Implant |
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Clinical Pharmacokinetics,
Volume 41,
Issue 6,
2002,
Page 403-419
Alison B. Fleming,
W. Mark Saltzman,
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摘要:
Controlled release delivery of carmustine from biodegradable polymer wafers was approved as an adjunct to surgical resection in the treatment of recurrent glioblastoma multiforme after it was shown in clinical trials to be well tolerated and effective. Given the localised nature of the drug in the brain tissue, no direct pharmacokinetic measurements have been made in humans after implantation of a carmustine wafer. However, drug distribution and clearance have been extensively studied in both rodent and non-human primate brains at various times after implantation. In addition, studies to characterise the degradation of the polymer matrix, the release kinetics of carmustine and the metabolic fate of the drug and polymer degradation products have been conducted bothin vitroandin vivo.GLIADEL®1wafers have been shown to release carmustinein vivoover a period of approximately 5 days; when in continuous contact with interstitial fluid, wafers should degrade completely over a period of 6 to 8 weeks. Metabolic elimination studies of the polymer degradation products have demonstrated that sebacic acid monomers are excreted from the body in the form of expired CO2, whereas 1,3-bis-(p-carboxyphenoxy)propane monomers are excreted primarily through the urine. Carmustine degradation products are also excreted primarily through the urine.Pharmacokinetic studies in animals and associated modelling have demonstrated the capability of this modality to produce high dose-delivery (millimolar concentrations) within millimetres of the polymer implant, with a limited penetration distance of carmustine from the site of delivery. The limited spread of drug is presumably due to the high transcapillary permeability of this lipophilic molecule. However, the presence of significant convective flows due to postsurgical oedema may augment the diffusive transport of drug in the hours immediately after wafer implantation, leading to a larger short-term spread of drug. Additionally, in non-human primates, the presence of significant doses in more distant regions of the brain (centimetres away from the implant) has been shown to persist over the course of a week. The drug in this region was presumed to be transported from the implant site by either cerebral blood flow or cerebrospinal fluid flow, suggesting that although drug is able to penetrate the blood-brain barrier at the site of delivery, it may re-enter within the confines of the brain tissue.
ISSN:0312-5963
出版商:ADIS
年代:2002
数据来源: ADIS
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3. |
Clinical Pharmacokinetics of Leflunomide |
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Clinical Pharmacokinetics,
Volume 41,
Issue 6,
2002,
Page 421-430
Blaž Rozman,
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摘要:
Leflunomide is the first disease-modifying antirheumatic drug to be approved for rheumatoid arthritis in the past 10 years. Orally administered leflunomide is almost completely converted into its active metabolite A77 1726 (hereafter referred to as M1). M1 displays linear pharmacokinetics at the dosages of leflunomide used in clinical practice. It has a long elimination half-life (approximately 2 weeks), reaching a steady state after approximately 20 weeks. M1 is highly bound to plasma proteins. The pharmacokinetics of M1 are not affected by food intake, and dosage requirements are not influenced by age or gender. Approximately 90% of a single dose of leflunomide is eliminated, 43% in urine, primarily as leflunomide glucuronides and an oxalinic acid derivative of M1, and 48% in faeces, primarily as M1. Elimination can be dramatically increased by using charcoal or cholestyramine.In vitrostudies have shown no major influence of leflunomide on the metabolism of analgesics, nonsteroidal anti-inflammatory drugs and methotrexate, drugs usually used in the treatment of rheumatoid arthritis. In clinical studies with a limited number of patients using these drugs concomitantly, no safety problems appeared. Nonspecific inducers of cytochrome P450 (CYP) and some drugs metabolised by CYP2C9 affect the metabolism of M1, and caution should be used in patients cotreated with them.Additionalin vitroandin vivopharmacokinetic studies are needed to better understand the nonenzymatic and enzymatic metabolism of leflunomide. Additional clinical trials should be performed in order to find new indications for leflunomide in other autoimmune diseases, and new combination therapeutic strategies in rheumatoid arthritis. This review is a summary of current knowledge of the pharmacokinetics of leflunomide, focusing primarily on humans and in particular on patients with rheumatoid arthritis.
ISSN:0312-5963
出版商:ADIS
年代:2002
数据来源: ADIS
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4. |
Pharmacokinetic-Pharmacodynamic Relationships of the Anthracycline Anticancer Drugs |
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Clinical Pharmacokinetics,
Volume 41,
Issue 6,
2002,
Page 431-444
Romano Danesi,
Stefano Fogli,
Alessandra Gennari,
Pierfranco Conte,
Mario Del Tacca,
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摘要:
The anthracycline glycoside antibiotics represent a group of potent anticancer agents with a wide spectrum of activity against solid tumours and haematological malignancies, and are the mainstay of a large number of clinical protocols for the treatment of adult and childhood neoplastic diseases. Their clinical activity is limited, however, by acute and chronic adverse effects. Myelosuppression, predominantly neutropenia and leucopenia, is the dose-limiting toxicity; in addition to this, mucositis, nausea, vomiting and alopecia are frequent, whereas hepatopathy, characterised by elevated bilirubin concentrations, occurs less frequently. Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and can be acute or chronic; in the acute setting, electrocardiographic abnormalities may be seen, including ST-T elevations and arrhythmias, but chronic cardiotoxicity represents a serious adverse effect that may be lethal due to the development of irreversible, cumulative dose−dependent, congestive cardiomyopathy.The occurrence of toxicity displays a marked interindividual variation, and for this reason the pharmacokinetics and pharmacodynamics of anthracyclines have been extensively investigated in order to identify integrated models that can be used in the clinical setting to prevent the development of serious toxicity, mainly leucopenia, and maximise tumour exposure. Pharmacokinetics has been recognised to influence both the toxicity and the activity of anthracyclines; in particular, there is increasing evidence that the mode of administration plays an important role for cumulative cardiotoxicity and data indicate that bolus administration, rather than continuous infusion, appears to be an important risk factor for anthracycline-induced cardiomyopathy, thus implying that this type of toxicity is maximum concentration-dependent. On the contrary, exposure to the drug, as measured by area under the curve, seems best related to the occurrence of leucopenia. Finally, the development of pharmacokinetic-pharmacodynamic models allows the simulation of drug effects and ultimately dose optimisation in order to anticipate important toxicities and prevent their occurrence by the administration of prophylactic treatments.
ISSN:0312-5963
出版商:ADIS
年代:2002
数据来源: ADIS
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5. |
Comparison of Pharmacokinetics of Lanoteplase and Alteplase During Acute Myocardial Infarction |
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Clinical Pharmacokinetics,
Volume 41,
Issue 6,
2002,
Page 445-452
John B. Kostis,
Randy C. Dockens,
Udho Thadani,
Vasnath Bethala,
Carl Pepine,
Wayne Leimbach,
Nimish Vachharajani,
Ralph H. Raymond,
Bruce C. Stouffer,
Lee K. Tay,
Wen Chyi Shyu,
Wei-chi Liao,
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摘要:
ObjectiveLanoteplase is a rationally designed variant of tissue plasminogen activator. The aim of this study was to examine the pharmacokinetics and functional activity of a single intravenous bolus dose of lanoteplase with those of a bolus plus two-step infusion of alteplase.DesignSeven-centre substudy of the InTIME-I angiographic trial in patients presenting within 6 hours of onset of suspected acute myocardial infarction.Patients and ParticipantsA total of 31 patients (28 males, 3 females) enrolled in this substudy [mean age 59 (range 26 to 76) years].MethodsTwenty-three patients randomised to lanoteplase received single bolus doses of 15 kU/kg (n = 5), 30 kU/kg (n = 3), 60 kU/kg (n = 9), or 120 kU/kg (n = 6). Eight patients received alteplase ≤100mg as a bolus followed by a two-stage 90 min infusion. Blood samples were analysed for antigen concentration and plasminogen activator (PA) activity.ResultsThe distribution plasma half-life of approximately 35 min for lanoteplase was at least five times longer than that of alteplase. Lanoteplase plasma clearance averaged 3 L/h (50 ml/min), whereas the mean plasma clearance of approximately 24 L/h (400 ml/min) for alteplase approaches hepatic blood flow following acute myocardial infarction. PA activity after lanoteplase 120 kU/kg remained for 6 hours, compared with less than 4 hours after alteplase 100mg.ConclusionsThe longer antigen and activity half-lives, slower clearance and less complicated administration of lanoteplase compared with alteplase suggest that it may offer advantages for use as a single intravenous bolus to achieve reperfusion after myocardial infarction.
ISSN:0312-5963
出版商:ADIS
年代:2002
数据来源: ADIS
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