Abstract: The authors evaluated the effect of air pollution on the occurrence of birth defects ascertained by the California Birth Defects Monitoring Program in neonates and fetuses delivered in southern California in 1987-1993. By using measurements from ambient monitoring stations of carbon monoxide (CO), nitrogen dioxide, ozone, and particulate matter <10 microm in aerodynamic diameter, they calculated average monthly exposure estimates for each pregnancy. Conventional, polytomous, and hierarchical logistic regression was used to estimate odds ratios for subgroups of cardiac and orofacial defects. Odds ratios for cardiac ventricular septal defects increased in a dose-response fashion with increasing second-month CO exposure (odds ratio (OR)(2nd quartile) CO = 1.62, 95% confidence interval (CI): 1.05, 2.48; OR(3rd quartile) CO = 2.09, 95% CI: 1.19, 3.67; OR(4th quartile) CO = 2.95, 95% CI: 1.44, 6.05). Similarly, risks for aortic artery and valve defects, pulmonary artery and valve anomalies, and conotruncal defects increased with second-month ozone exposure. The study was inconclusive for other air pollutants. The authors' results are supported by the specificity of the timing of the effect and some evidence from animal data; however, this is the first known study to link ambient air pollution during a vulnerable window of development to human malformations. Confirmation by further studies is needed.

Abstract: Abnormal accumulation of β-amyloid (Aβ) in Alzheimer's disease (AD) is associated with prominent brain inflammation. Whereas earlier studies concluded that this inflammation is detrimental, more recent animal data suggest that at least some inflammatory processes may be beneficial and promote Aβ clearance. Consistent with these observations, overproduction of transforming growth factor (TGF)-β1 resulted in a vigorous microglial activation that was accompanied by at least a 50% reduction in Aβ accumulation in human amyloid precursor protein (hAPP) transgenic mice. In a search for inflammatory mediators associated with this reduced pathology, we found that brain levels of C3, the central component of complement and a key inflammatory protein activated in AD, were markedly higher in hAPP/TGF-β1 mice than in hAPP mice. To assess the importance of complement in the pathogenesis of AD-like disease in mice, we inhibited C3 activation by expressing soluble complement receptor-related protein y (sCrry), a complement inhibitor, in the brains of hAPP mice. Aβ deposition was 2- to 3-fold higher in 1-year-old hAPP/sCrry mice than in age-matched hAPP mice and was accompanied by a prominent accumulation of degenerating neurons. These results indicate that complement activation products can protect against Aβ-induced neurotoxicity and may reduce the accumulation or promote the clearance of amyloid and degenerating neurons. These findings provide evidence for a role of complement and innate immune responses in AD-like disease in mice and support the concept that certain inflammatory defense mechanisms in the brain may be beneficial in neurodegenerative disease.

Abstract: Azathioprine (AZA) and its active metabolite, 6-mercaptopurine (6-MP), are purine analogues that interfere with the synthesis of adenine and guanine ribonucleosides. These ribonucleosides are important precursors of DNA and RNA. Because AZA and 6-MP act predominantly on rapidly dividing cells such as the T lymphocytes, these drugs are not only cytotoxic but also immunosuppressive and anti-inflammatory. The effects are dose-related, small doses of either drug are anti-inflammatory, but larger doses are immunosuppressive and cytotoxic (Goldstein, ’87). 6-MP has been used in cancer chemotherapy, primarily in childhood and adult leukemias and usually in combination with other drugs. 6-MP is also used to treat autoimmune diseases, such as inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) (Bermas and Hill, ’95; Ramsey-Goldman and Schilling, ’97). Initial oral doses for treatment of leukemia range between 2.5–5 mg/kg/d. For maintenance therapy of leukemia, doses range between 1.5–2.5 mg/kg/d. Similar doses (1.5–2.5 mg/kg/d) are used to treat IBD (Present et al., ’80; Botoman et al., ’98; USP DI, ’01), but the use of 6-MP as an immunosuppressant has been largely superseded by AZA, which has been shown to possess a better therapeutic index (Van Scoik et al., ’85; Goldstein, ’87; Chabner et al., ’96). AZA is no longer used as an antineoplastic agent (Ostensen, ’92), but is employed in the treatment of autoimmune disorders at doses between 1–2.5 mg/kg/d and at doses between 1–5 mg/kg/d as part of immunosuppressive regimens to prevent transplant rejection (Botoman et al., ’98; USP DI, ’01). The majority of patients affected by autoimmune diseases are women, in whom the peak incidence occurs between 16 and 55 years of age (Weterman, ’89; Brent et al., ’97; Esplin and Branch, ’97). Successful treatment with cytotoxic and immunosuppressant drugs such as AZA has greatly improved the feasibility of pregnancy in affected women, many of whom must continue to take the medications throughout gestation to prevent relapse. Similarly, women who become pregnant after organ transplantation continue immunosuppressive therapy to prevent rejection if they have been on immunosuppressive therapy before pregnancy. In some patients who become ill with an immunopathic or malignant disease while pregnant, treatment with 6-MP or AZA may be initiated during gestation. The use of cytotoxic immunosuppressants during pregnancy raises concern about possible adverse effects in the developing embryo or fetus, but the potential teratogenicity of AZA and 6-MP is difficult to evaluate in humans. These agents are used to treat patients who have severe illness, and it is often impossible to determine if adverse effects that occur in the embryo/fetus resulted from a particular treatment, the maternal illness, or some other factor (Brent et al., ’97). Also, because of the severity of the illness and the complications that ensue, combination therapy is common. Use of drug combinations as well as variations in dose further hamper efforts to attribute an observed adverse effect to a particular treatment. This article will review human and animal data regarding the pharmacology of 6-MP and AZA and their adverse effects on the embryo and fetus.

Abstract: A growing number of animal data strongly suggest that a hyporeactive hypothalamus-pituitary adrenal (HPA) axis may be pathologically significant by increasing the susceptibility to chronic inflammation. Following this line of evidence, the specific goal of the present study was to investigate the HPA axis in patients with atopic dermatitis (AD), a chronic allergic inflammatory disease. In addition, the sympathetic adrenomedullary (SAM) system as a second potent immunoregulatory and anti-inflammatory stress-response system has been examined. AD patients (n = 36) and nonatopic control subjects (n = 37) were exposed to a standardized laboratory stressor consisting of a free speech and mental arithmetic task in front of an audience. Cortisol, ACTH, and catecholamine concentrations were assessed before and after the stressor. To investigate feedback sensitivity of the HPA axis, a low dose (0.5 mg) dexamethasone suppression test was also performed. AD patients showed significantly attenuated cortisol and ACTH responses to the stressor, whereas catecholamine levels were significantly elevated in atopic patients. No difference between the experimental groups was found in basal cortisol and ACTH concentrations, whereas basal catecholamine levels were significantly elevated. Analysis of cortisol levels after dexamethasone treatment suggested an intact feedback sensitivity in AD sufferers at the pituitary level. The present findings suggest that patients with AD demonstrate a blunted HPA axis responsiveness with a concurrent overreactivity of the SAM system to psychosocial stress. Considering the important immunoregulatory role of the HPA axis and the SAM system, especially under stressful conditions, an aberrant responsiveness of these neuroendocrine systems may increase the susceptibility to (allergic) inflammation and may be one psychobiological mechanism of stress-related aggravation of the disease.

Abstract: One of the oldest questions in epilepsy is whether seizures are a cause or a result of brain damage. Animal data have provided us with insights into the relationship between seizures and subsequent brain damage. It is now recognized that seizures can be caused by brain injury and that, in certain conditions, can cause brain damage. Whether seizures result in brain damage depends on a number of variables, including age of the animal, seizure type and duration, etiology of the seizures, and genetic substrate on which the seizures occur. Seizures lasting for hours can cause injury to the brain regardless of whether they are generalized or focal in onset. The cell loss that occurs after the seizure is secondary to excessive excitability, with seizures causing massive depolarization of neurons leading to excessive glutamate release. This glutamate release results in increased intracellular calcium, causing a cascade of changes that ultimately result in cell death. Hypoxia and ischemia can exacerbate the injury. However, even in animals that are well ventilated and oxygenated, prolonged seizures can lead to cell loss and subsequent reorganization of synaptic networks. Although prolonged seizures at any age can result in cell loss, the immature brain fares much better than the mature brain with regard to cell loss after a prolonged seizure. Evidence that prolonged seizures result in neuronal loss is firmly established. It is less clear how detrimental recurrent seizures are. Although cell loss and synaptic reorganization have been reported in recurrent seizure models, such as kindling, it is generally modest compared to status epilepticus. When seizure-induced changes do occur, the pathologic patterns in the brain differ from those in status epilepticus.

Abstract: Animals are predominantly risk prone toward reward delays and risk averse toward reward amounts. Humans in turn tend to be risk-seeking for losses and risk averse for gains. To explain the human results, Prospect Theory postulates a convex utility for losses and concave utility for gains. In contrast, Scalar Utility Theory (SUT) explains the animal data by postulating that the cognitive representation of outcomes follows Weber's Law, namely that the spread of the distribution of expected outcomes is proportional to its mean. SUT also would explain human results if utility (even if it is linear on expected outcome) followed Weber's Law. We present an experiment that simulates losses and gains in a bird, the European Starling, to test the implication of SUT that risk proneness/aversion should extend to any aversive/desirable dimension other than time and amount of reward. Losses and gains were simulated by offering choices of fixed vs. variable outcomes with lower or higher outcomes than what the birds expected. The subjects were significantly more risk prone for losses than for gains but, against expectations, they were not significantly risk averse toward gains. The results are thus, in part, consistent with Prospect Theory and SUT and show that risk attitude in humans and birds may obey a common fundamental principle.

Abstract: Objective: To review stress during the postpartum and the research supporting that a unique, protective biology exists in breastfeeding mothers that may reduce reactivity to stress. Data Sources: Publications from nursing and biomedical literature. Study Selection: Studies reviewed were those that have contributed to concurrent conceptualizations of postpartum stress. Additionally, studies with sufficient participants were analyzed for common findings. Animal literature was reviewed for studies on the stress response in lactating and nonlactating animal models. Data Extraction: Stress during the postpartum may be conceptualized as physical, intrapersonal, and interpersonal. Animal data and a few recent human studies suggest that the neuroendocrinology of the lactating mother may down-regulate the magnitude of the stress response. Data Synthesis: A diminished stress response may serve to protect the breastfeeding maternal-infant dyad from environmental stimuli and to direct the physiology of the mother toward milk production, energy conservation, and nurturance. Conclusion: Nurses understand the benefits of breastfeeding for optimal infant health, but new research suggests that maternal health may also be benefited in a biologic and as yet unexplored way. JOGNN, 31, 411–417; 2002.

Abstract: Contributors Preface Chapter 1 A Brief History of Cancer Chemotherapy Summary 1. Introduction 2. Genotoxic (Cytotoxic) Therapy 3. Growth Control Pathways 4. Host-Tumor Interactions 5. Conclusions References Chapter 2 Novel Targets in the Cell Cycle and Cell Cycle Checkpoints Summary 1. Introduction 2. Molecular Regulation of Cell Cycle Progression 3. Molecular Regulation of Cell Cycle Checkpoints 4. Rationale for Targeting Cyclin-Dependent Kinases and Cell Cycle Checkpoint Pathways 5. Agents and Strategies for Therapeutic Interference 6. Conclusions References Chapter 3 Growth Factor and Signal Transduction Targets for Cancer Therapy Summary 1. Introduction 2. The ErbB Family of Receptor Tyrosine Kinases (RTKs) 3. The Ras-Raf-MEK-ERK Signaling Pathway 4. c-Src Kinase, Signal Transduction, Transformation, and Cancer 5. Akt 6. Nuclear Hormone Receptors as Targets for Cancer Therapy 7. Implications for Drug Discovery and Development References Chapter 4 Cell Death Pathways as Targets for Anticancer Drugs Summary 1. Introduction 2. Two Main Pathways for Drug-Induced Apoptosis 3. Modulation of Drug-Induced Cell Death by Bcl-2 and Related Proteins 4. The Central Role of Caspases in Drug-Induced Apoptosis 5. Synergy between Death Receptors and Cytotoxic Drugs 6. The Rel/NF-kB/IkB Proteins 7. Conclusion References Chapter 5 Drug Resistance Pathways as Targets Summary 1. Introduction 2. Targeting Drug Transport 3. Targeting Cellular Stress Responses 4. Targeting DNA Repair Systems 5. Conclusions References Chapter 6 Role of Matrix Metalloproteinases and Plasminogen Activators in Cancer Invasion and Metastasis: Therapeutic Strategies Summary 1. Introduction 2. The Extracellular Matrix 3. Cancer Invasion and Metastasis 4. Cell Adhesion in Cancer 5. Cancer Cell Motility 6. Inflammatory Response to Cancer 7. Proteolytic Enzymes Implicated in Cancer Invasion 8. MMPIs as Novel Anticancer Agents 9. Sheddases 10. The uPA System: Proteolytic Control of MMP Activation References Chapter 7 Tumor Vasculature as a Target Summary 1. Introduction 2. How to Inhibit Tumor Angiogenesis 3. Concluding Remarks References Chapter 8 Gene-Directed Enzyme Prodrug Therapy Summary 1. Introduction 2. Background 3. Enzyme-Prodrug Systems 4. Tailored Prodrugs for GDEPT 5. The Activation Process 6. Augmenting the Effect 7. Exploiting the Bystander Effect and Acquired Immunity 8. Conclusions References Chapter 9 Tumor Antigens as Targets for Anticancer Drug Development Summary 1. Introduction 2. Antigen Targets for Cancer Vaccines 3. Tumor Antigens as Targets for Antibody-Based Therapeutics References Chapter 10 Structure-Based Drug Design and its Contributions to Cancer Chemotherapy Summary 1. Introduction 2. Antimetabolites 3. Protease Inhibitors 4. Protein Kinase Inhibitors 5. Other Targets 6. Novel Methods in Structure-Based Drug Design 7. Conclusions and Current Questions References Chapter 11 The Contribution of Synthetic Organic Chemistry to Anticancer Drug Development Summary 1. Introduction 2. Early Rationality 3. The Random Screening Era: Directly from Screen to Clinic 4. Organic Synthesis Catches Up: Development of National Product Leads 5. Development of Synthetic Compounds: Structure-Activity Relationships 6. Immunotoxins: Synthetic Organic Chemistry Applied to Large Molecules 7. Organic Synthesis in Rational Design: Tumor-Activated Prodrugs of Cytokines 8. Early Genomics: Inhibitors of Transmembrane Tyrosine Kinases 9. The Genomics/Proteomics Era: Combinatorial Chemistry 10. Conclusion References Chapter 12 Biosynthetic Products for Anticancer Drug Design and Treatment: The Bryostatins Summary 1. Introduction 2. Background to the Bryostatins 3. Comprehensive Review of Bryostatin Scientific and Medical Reports References Chapter 13 DNA-Encoded Peptide Libraries and Drug Discovery Summary 1. Introduction 2. Methods for DNA-Encoded Peptide Display 3. Applications for DNA-Encoded Peptide Libraries 4. Conclusions References Chapter Mechanism-Based Highthroughput Screening for Novel Anticancer Drug Discovery Summary 1. Importance of Mechanism-Based Targets in Postgenomic Drug Discovery 2. High-Throughput Screening 3. Assay Technologies 4. Assay Performance and Downstream Evaluation of Bits 5. Compounds for HTS 6. Examples of Compounds Identified Through Screening Approaches 7. Future HTS Developments 8. Concluding Remarks References Chapter 15 Tumor Cell Cultures in Drug Development Summary 1. Introduction 2. Growth Inhibition Assays 3. Clonogenic Assays 4. Three-Dimensional Cell Cultures: Modeling Extravascular Drug Transport 5. Modeling of in Vivo Activity by in Vitro Assays 6. Perspective References Chapter 16 Screening Using Animal Systems Summary 1. Introduction 2. Choice of in Vivo Systems for Large-Scale Drug Development 3. Combined in Vitro/in Vivo Testing Procedure Using Human Tumor Xenografts-The Freiburg Experience 4. Use of Transgenic Animals in the Search for New Drugs 5. Screening for Angiogenesis Inhibitors References Chapter 17 Relevance of Preclinical Pharmacology and Toxicology to Phase I Trial Extrapolation Techniques: Elevance of Animal Toxicology Summary 1. Introduction 2. Historical Perspective 3. Special Toxicity Evaluations 4. Recent Examples of Drug Development at NCI 5. Predictability of Nonclinical Animal Data 6. Conclusions References Chapter 18 Clinical Trial Design: Incorporation of Pharmacokinetic, Pharmacodynamic, and Pharmacogenetic Principles Summary 1. Introduction 2. Rationale for Chemotherapy Optimization 3. Pharmacokinetic-Pharmacodynamic Relationships 4. Pharmacogenetics 5. Strategies to Improve Therapeutic Index 6. Conclusion and Perspectives References Chapter 19 Tumor Imaging Applications in the Testing of New Drugs Summary 1. Introduction 2. Positron Emission Tomography 3. PET in New Drug Evaluation 4. Conclusions References Chapter 20 Mechanistic Approaches to Phase I Clinical Trials Summary 1. Introduction 2. Mechanism-Based Studies of Established Anticancer Agents to Assess Target Inhibition 3. Mechanistic Trial Perspectives on Anticancer Agents with Novel Mechanisms 4. Potential of PET Scanning in the Assessment of Pharmacodynamic End Points 5. Conclusion References Index

Abstract: The bryostatins are a group of novel macrocyclic lactones derived from the marine bryozoan, Bugula neritina. In vitro evidence indicates that their main mechanism of action is modulation of protein kinase C (PKC) activity. Phase I studies suggested significant antineoplastic activity against several tumor types and defined the main dose-limiting toxicity as myalgia. Bryostatin-1 has subsequently been investigated extensively in phase II clinical trials as a single agent, although trial design has been hampered by lack of human pharmacokinetic data. Results have been generally disappointing but in vitro and animal data suggests an important role for bryostatin-1 in combination with cytotoxic agents. Preliminary results of phase I studies support these observations but further work needs to be done to define the future role of the bryostatins in the clinic.

Abstract: Seizures have a partial onset in approximately two-thirds of epilepsy patients. In most of these cases epilepsy is a consequence of a brain-damaging insult such as head trauma, stroke, brain infection, brain surgery, or status epilepticus. The epileptic process consists of three phases: initial insult U27AA; latency period (epileptogenesis) U27AA; recurrent seizures (symptomatic epilepsy). The treatment of epilepsy focuses exclusively on preventing or suppressing seizures, which are the end products of the epileptic process. The challenge is whether epileptogenesis can be prevented by therapeutic intervention. If not, can the disease process be modified in such a way that epilepsy will be easier to treat? Achieving these goals is becoming more realistic now that there is a better understanding of the neurobiology of the epileptic process and the factors that predict the risk for progression in individual patients. These data provide new opportunities for the design of neuroprotective and antiepileptogenic treatments for patients who, if untreated, could develop drug-refractory epilepsy associated with cognitive decline. Here we review the available data on neuroprotective, antiepileptogenic, and disease-modifying effects of antiepileptic drugs and other treatments at different phases of the epileptic process. Analysis of these data suggests that by using compounds currently available, beneficial effects on the outcome can be achieved by modification of the epileptogenic insult at the acute phase and by modification of circuitry reorganization that is induced/maintained by brief seizures after the diagnosis of epilepsy. Discontinuation or modification of epileptogenesis in patients who experienced an epileptogenic insult months or years before is more complicated. However, molecular screening of candidate epileptogenesis-related genes has revealed novel mechanisms underlying network reorganization and will undoubtedly provide exciting avenues for the development of true antiepileptogenic and disease-modifying agents.

Abstract: Although experimental animal data have implicated ornithine decarboxylase, a key regulatory enzyme of polyamine biosynthesis, in brain development and function, little information is available on this enzyme in normal or abnormal human brain. We examined the influence, in autopsied human brain, of postnatal development and aging, regional distribution, and Alzheimer's disease on the activity of ornithine decarboxylase. Consistent with animal data, human brain ornithine decarboxylase activity was highest in the perinatal period, declining sharply (by approximately 60%) during the first year of life to values that remained generally unchanged up to senescence. In adult brain, a moderately heterogeneous regional distribution of enzyme activity was observed, with high levels in the thalamus and occipital cortex and low levels in cerebellar cortex and putamen. In the Alzheimer's disease group, mean ornithine decarboxylase activity was significantly increased in the temporal cortex (+76%), reduced in occipital cortex (-70%), and unchanged in hippocampus and putamen. In contrast, brain enzyme activity was normal in patients with the neurodegenerative disorder spinocerebellar ataxia type I. Our demonstration of ornithine decarboxylase activity in neonatal and adult human brain suggests roles for ornithine decarboxylase in both developing and mature brain function, and we provide further evidence for the involvement of abnormal polyamine system activity in Alzheimer's disease.

Abstract: Experimental and clinical data indicate that epilepsy and seizures lead to neuronal cell loss and irreversible brain damage. This neurodegeneration results not only in the central nervous system dysfunction but may also be responsible for the decreased efficacy of some antiepileptic drugs (AEDs). The aim of this review was to assemble current literature data on neuroprotective properties of AEDs. The list of hypothetical neuroprotectants is long and consists of substances which act via different mechanisms. We focus on AEDs since this heterogeneous group of pharmaceuticals, as far as mechanisms of their action and mechanisms of neuronal death are concerned, should provide protection in addition to antiseizure effect itself. Most studies on neuroprotection are based on animal experimental models of neuronal degeneration. Electrically and pharmacologically evoked seizures as well as different models of ischemia are frequently used. Although our knowledge about properties of AEDs is still not complete and discrepancies occasionally occur, the group seems to be promising in terms of neuroprotection. Some of the drugs, though, turn out to be neutral or even have adverse effects on the central nervous system, especially on immature brain tissue (barbiturates and benzodiazepines). Unfortunatelly, we cannot fully extrapolate animal data to humans, therefore further well designed clinical trials are necessary to determine neuroprotective properties of AEDs in humans. However, there is a hope that AEDs will have a potential to serve as neuroprotectants not only in seizures, but perhaps, in other neurodegenerative conditions in humans as well. The novel AEDs (especially lamotrigine, tiagabine, and topiramate) seem particularly promising.

Abstract: Although the available information is limited, a survey of the literature concerning the effect of ageing on endothelium-dependent responses in animal blood vessels suggests that the release of endothelium-derived relaxing factors (nitric oxide and endothelium-derived hyperpolarizing factor) is reduced, whereas that of endothelium-derived vasoconstrictor prostanoids is augmented. The very few in vitro data on isolated human blood vessels and a number of studies conducted in intact people concur with the animal data. Taken in conjunction, these findings suggest that ageing is accompanied by progressive endothelial dysfunction, which sets the scene for development of atherosclerosis.

Abstract: The recently identified adipocytokine adiponectin has been shown to improve insulin action and decrease triglyceride content in skeletal muscle (by stimulating lipid oxidation) in mice. In the present study, we tested the hypothesis that high serum concentrations of adiponectin are associated with lower intramyocellular (IMCL) fat content by promoting lipid oxidation in humans. IMCL-content in predominantly non-oxidative tibialis anterior muscle and oxidative soleus was determined by proton magnetic resonance spectroscopy in a cross- sectional study involving 63 healthy volunteers. In a second set of experiments, changes in IMCL in both muscles were measured after a three days dietary lipid challenge (n = 18) and after intravenous lipid challenge (n = 12) with suppressed lipid oxidation under hyperinsulinemia. Adiponectin serum concentrations were found to be negatively correlated with IMCL in the oxidative soleus muscle (IMCL [sol]) (r = - 0.46, p < 0.001) independent of measures of obesity, but not with IMCL in the non-oxidative tibialis anterior muscle (IMCL [tib]) (p = 0.40). Adiponectin serum concentrations were negatively correlated with the observed increase in IMCL load after dietary lipid challenge in the tibialis (r = 0.53, p = 0.03) but not in the soleus muscle. During suppression of lipid oxidation by hyperinsulinemia, no effect of adiponectin on IMCL was observed in either soleus or tibialis muscle. Overall, the presented findings are consistent with the hypothesis that adiponectin promotes lipid oxidation in humans resulting in lower intracellular lipid content in human muscle. These results are consistent with animal data, where adiponectin could be shown to enhance lipid oxidation and reduce muscle triglycerides.

Abstract: The dramatic increase in the prevalence of obesity is a global phenomenon associated with increased risk of the development of cardiovascular and renal disease. Changes in renal structure and function that occur early in the development of obesity may lead to urine outflow obstruction and increased intrarenal pressure, mechanisms sufficient to shift the pressure-natriuresis relation to higher blood pressure levels. Another important alteration that may lead to hypertension with obesity is the increase in sympathetic nervous system activity. Several studies point to higher leptin levels associated with hypertension in humans, and animal data now convincingly suggest that leptin has direct central effects that increase sympathetic outflow to the kidneys, associated with increases in blood pressure. Although understanding of the pathophysiology of obesity-associated hypertension has made substantial progress during the past years, treatment of obese hypertensives remains largely empirical and clearly deserves to be addressed in larger randomized, controlled trials.

Abstract: Recent animal studies have led us to reconsider the mechanism of action of antidepressant and mood stabilizing drugs. Whereas effects on neurotransmitter systems and intracellular signalling pathways continue to amass, studies now suggest that these drugs may act to prevent neuronal damage and cell loss that may occur in the brain of patients with mood disorders. Animal studies suggest that antidepressant and mood stabilizing drugs are neuroprotective and may also lead to neurogenesis in selected brain regions. Although the mechanisms through which neuroprotection occurs and the experimental conditions differ for these 2 classes of drugs, the net effects are clearly relevant to the pathophysiology of mood disorders. In rat hippocampus and cerebral cortex, long-term treatment with a range of antidepressants, including tricyclics, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors and electroconvulsive shock, increases the expression of several target genes including brain-derived neurotrophic factor (BDNF).1,2 In addition, infusion of BDNF blocks depressive-like behaviours in rats. Conversely, stress, which is important in the pathogenesis of depression, can decrease the expression of BDNF in key brain regions. Treatment with antidepressants has been found to enhance neurogenesis in the dentate gyrus region of rat hippocampus, and this may be linked to an increase in the expression of BDNF.3 One study found that long-term lithium treatment also increased neurogenesis in mouse hippocampus.4 A compelling series of studies has shown that long-term treatment with lithium and anticonvulsants such as divalproex sodium increases the expression of several other neuroprotective factors.5,6,7,8,9 Treatment with these mood stabilizing drugs protects primary neuronal cultured cells and stable neuronal cell lines from excitotoxicity and a large number of other pharmacologic insults. Some evidence even suggests that lithium may protect against ischemic changes in rat brain.10 Although the targets of mood stabilizers may be different from those of antidepressants and the data to support the potential neuroprotective effects of these classes of drugs have only recently been reported, the results emanating from a number of laboratories in North America and Europe are remarkably consistent. How relevant are these results from animal studies for the clinical management of patients with mood disorders? Clinicians are justifiably cautious when prescribing psychotropic drugs to patients with compromised central nervous system (CNS) function for risk of toxicity. Indeed, prescribing lithium to patients with CNS dysfunction has long been avoided because of a clear worsening of neurologic symptoms in patients with pre-existing neurologic disease. Fears that psychotropic drugs cause “brain damage” are commonplace in patients and have presented a therapeutic challenge for psychiatrists. Several mood stabilizing drugs have the risk of serious CNS teratogenicity, including neural tube defects, when taken by pregnant women, and most should be avoided during pregnancy and breast-feeding.11,12 These clinical guidelines, which are well accepted and based on substantial clinical experience and data, must be considered when evaluating the recent animal data demonstrating the neuroprotective effects of antidepressant and mood stabilizing drugs. There are increasing reports of cell loss, both neuronal and glial, in key cerebral cortex regions and layers in patients with major depression and bipolar disorder.13,14,15,16 The changes are often subtle, limited to key regions and cortical layers and detected only by careful nonbiased stereologic cell-counting techniques. Changes in the size of key regions such as the hippocampus and amygdala have also been reported in patients with mood disorders,17,18,19,20 and these cellular and volumetric changes may be related to the persistent cognitive deficits that appear resistant to treatment in these patients. Additional evidence obtained from the examination of brain tissue of patients with mood disorders supports the proposed targets of these drugs. For example, as measured in postmortem tissue of depressed patients, antidepressants may increase the levels of BDNF in hippocampus.21 As well, lithium treatment may lead to small but potentially relevant increases in gray matter volume in patients with bipolar disorder.22 Enthusiasm and excitement about the neuroprotective effects of these psychotropic drugs is warranted, but more evidence is needed before clinicians can use this data to influence practice. Neither antidepressants nor mood stabilizers can reverse pre-existing brain lesions or treat neurodegenerative diseases. In the same manner, patients do not experience enhanced memory after treatment with either class of drugs. Studies designed to measure neuroprotective effects of these commonly prescribed drugs in patients with psychiatric disorders, with careful measurement of CNS function and structure, are needed to assess the impact these data will have in clinical psychiatry.

Abstract: It is apparent that the sequence of events that has been followed in the approach to the discovery and development of a new beta-lactam prodrug has been similar in many of the case histories we have studied and indeed similar to the approach we have followed. Initially, we select a suitable series of prodrug moieties, which either comprises totally novel structures or is deduced from the data bases available (bearing in mind reports of potential toxicity) or both. The successful preparation of these prodrugs and the studies undertaken to ensure they are of known purity and stability is not easy and, as would be expected, is the initial go/no-go decision. Usually, the next stage has involved the assessment of whether or not bioavailability of the parent molecule is increased after administration of the prodrug ester by gavage to laboratory animal species. The selection of which species to use has very often been made according to which has the most information available in those particular laboratories and in the literature. It is this process that can be dishearteningly misleading as was demonstrated in Table IV and Fig. 1. Increasing the range of animal species does not lead to a better ability to predict bioavailability in humans. Hydrolysis studies are important to ensure that any novel prodrug will hydrolyze in human tissues, and also in the clarification of why a particular prodrug is not performing as expected in animals. After selection, it is essential to determine where and how rapidly hydrolysis takes place in the animal species to be used for safety evaluation prior to the first bioavailability studies in humans. The assessment of absolute oral bioavailability has not always been undertaken. This would seem critical for studies in not only the selected animal species but also in humans. In the absence of these data it is difficult to judge whether oral uptake can be increased further by modifying the ester moieties and at the development stage to determine whether or not modifications in formulation could increase bioavailability. When the prodrug is being developed for an injectable beta-lactam already available for humans, there would be no problem, but it would be an important consideration during the development of an entirely novel beta-lactam antibiotic for which no parenteral data are available in humans. Animal data are not totally predictive. The development of prodrugs is not easy, as a consequence of species differences in the properties of the prodrug superimposed on those of the parent compound during the evaluation. However, technical advances have enabled us to assay concentrations more precisely, determine basic physicochemical properties more efficiently, understand absorption processes by the use of in vitro systems, and analyze data far more comprehensively by the use of ever-evolving computer software. The prodrug approach to increasing the oral bioavailability of beta-lactam antibiotics has provided clinically valuable agents and continues. Despite the inherent difficulties, knowledge gained over the years, of the relationships between physicochemical and biological properties of the parent compound and the intact prodrug ester, has contributed to the design of novel prodrugs and a number of novel auxiliaries have been developed.

Abstract: Basic life support and rapid defibrillation for ventricular fibrillation or pulseless ventricular tachycardia are the only two interventions that have been shown unequivocally to improve survival after cardiac arrest. Several drugs are advocated to treat cardiac arrest, but despite very encouraging animal data, no drug has been reliably proven to increase survival to hospital discharge after cardiac arrest. This review focuses on recent experimental and clinical data concerning the use of vasopressin, amiodarone, magnesium, and fibrinolytics during advanced life support (ALS). Animal data indicate that, in comparison with epinephrine (adrenaline), vasopressin produces better vital organ blood flow during cardiopulmonary resuscitation (CPR). These apparent advantages have yet to be converted into improved survival in large-scale trials of cardiac arrest in humans. Data from two prospective, randomized trials suggest that amiodarone may improve short-term survival after out-of-hospital ventricular fibrillation cardiac arrest. On the basis of anecdotal data, magnesium is recommended therapy for torsades de pointes and for shock-resistant ventricular fibrillation associated with hypomagnesemia. In the past, CPR has been a contraindication to giving fibrinolytics, but several studies have demonstrated the relative safety of fibrinolysis during and after CPR. Fibrinolytics are likely to be beneficial when cardiac arrest is associated with plaque rupture and fresh coronary thrombus or massive pulmonary embolism. Fibrinolysis may also improve cerebral microcirculatory perfusion once a spontaneous circulation has been restored. A planned, prospective, randomized trial may help to define the role of fibrinolysis during out-of-hospital CPR.

Abstract: The objective of this study was to test the interspecies scaling approach for a wide variety of drugs to predict oral clearance in humans from animal data. This study is an attempt to evaluate whether the rule of exponents of Mahmood and Balian for the prediction of systemic clearance can also be applied for the prediction of oral clearance in humans. Three different methods were used to generate log-log plots to scale up the clearance values: (1) clearance versus body weight (simple allometric equation), (2) the product of clearance and maximum life-span potential (MLP) versus body weight, and (3) the product of clearance and brain weight versus body weight. Data from 32 drugs were analyzed, and it was concluded that the oral clearance of drugs could be best predicted using one of the allometric equations.

Abstract: Purpose: To examine the incidence of radiation-induced late rectal complications by analyzing the data of measured rectal doses in patients with cancer of the uterine cervix treated with high-dose-rate intracavitary brachytherapy. Methods and Materials: We measured doses to the rectum in 105 patients with cancer of the cervix during high-dose-rate intracavitary brachytherapy with a semiconductor dosimeter that can measure five points in the rectum simultaneously. On the basis of these measurements, equivalent doses, to which the biologically equivalent doses were converted as if given as fractionated irradiation at 2 Gy/fraction, were calculated as components of the cumulative dose at five rectal points in intracavitary brachytherapy combined with the external whole pelvic dose. Results: The calculated values of equivalent doses for late effects at the rectum ranged from 15 to 100 Gy (median 60 Gy for patients who did not develop complications and 76 Gy for patients who subsequently developed Grade II or III complications). When converted to a graph of absolute rectal complication probability, the data could be fitted to a sigmoid curve. The data showed a very definite dose-response relationship, with a threshold for complications at approximately 50 Gy and the curve starting to rise more steeply at approximately 60 Gy. The steepest part of the curve had a slope equivalent to approximately 4% incidence/1 Gy increase in equivalent doses. Conclusion: The radiation tolerance dose, 5% and 50% complication probability, was about 64 and 79 Gy, respectively. Our data almost agree with the prescribed dose for the rectum for the radiation tolerance doses on the basis of the recorded human and animal data. The probability of rectal complications increased drastically after the maximal rectal dose was >60 Gy.

Abstract: Nitric oxide synthase is expressed in the sino-atrial node and animal data suggests a direct role for nitric oxide on pacemaker activity. Study of this mechanism in intact humans is complicated by both reflex and direct effects of nitric oxide on cardiac autonomic control. Thus, we have studied the direct effects of nitric oxide on heart rate in human cardiac transplant recipients who possess a denervated donor heart. In nine patients, the chronotropic effects of systemic injection of the nitric oxide synthase inhibitor N G -monomethyl-L-arginine (L-NMMA) (3 mg kg _1 ) or increasing bolus doses of the nitric oxide donor, sodium nitroprusside (SNP), were studied. Injection of L-NMMA increased mean arterial pressure by 17 ± 2 mmHg (mean ± S.E.M.; P < 0.001) and also had a significant negative chronotropic effect, lengthening the R–R interval by 54 ± 8 ms (P < 0.001). This bradycardia was not reflex in origin since injection of the non-NO-dependent vasoconstrictor, phenylephrine (100 mg) achieved a similar rise in mean arterial pressure (18 ± 3 mmHg; P < 0.001) but failed to change R–R interval duration (DR–R = _3 ± 4 ms). Furthermore, no change in levels of circulating adrenaline was observed with L-NMMA. Conversely, injection of sodium nitroprusside resulted in a positive chronotropic effect with a dose-dependent shortening of R–R interval duration, peak DR–R = _25 ± 8 ms with 130 mg (P < 0.01). These findings indicate that nitric oxide exerts a tonic, direct, positive chronotropic influence on the denervated human heart. This is consistent with the results of animal experiments showing that nitric oxide exerts a facilitatory influence on pacemaking currents in the sino-atrial node.