Side effectscontraindications
As with other insulin secretagogues, hypoglycemia can occur with administration of repaglinide and nateglinide. Due to the short half-life of these drugs hypoglycemia is usually postprandial and of short duration. Repaglinide and nateglinide are both metabolized in the liver and serum drug concentrations may rise in individuals with hepatic dysfunction. Repaglinide is metabolized by the cytochrome P450 enzyme CYP3A4 and concurrent use with other drugs that induce or suppress this enzyme may...
Mechanistic Macro Models of Arrhythmias
Changes in the normal functioning of the above ion channels, in space and or time as a result of arrhythmogenic stimuli, result in the initiation and maintenance of the two major macro mechanisms of arrhythmogenesis, namely ectopic foci and re-entry. Since regular rhythmic beating requires appropriate pacing, excitability, conduction, and refractoriness, disturbances of any of these four functions can give rise to arrhythmias via either, or both, of the two mechanisms.11 Ectopic foci (errors in...
Benefits of Glycemic Control
Glycemic control is critical to the prevention of diabetic complications. The duration and severity of hyperglycemia correlates with both the development and rate of progression of diabetic retinopathy, nephropathy, and neuropathy. The DCCT and the UKPDS established the effectiveness of glycemic control in the prevention of diabetic complications in T1DM and T2DM, respectively, during the 1990s. The DCCT studied the effect of an intensive insulin regimen on the primary and secondary prevention...
Atherosclerosis
Atherosclerosis refers to the underlying progression in arterial dysfunction and remodeling that restricts blood flow to vessels in the peripheral vasculature.1 Taken from the Greek, athero (gruel or paste) and sclerosis (hardness), atherosclerosis describes the buildup of lipid-laden fatty deposits within the vessel wall that is often called atheroma or atherosclerotic plaques. As illustrated in Figure 1, temporal morphological changes accompany the progression of disease. In its early stages,...
Posttraumatic Stress Disorder
DSM-IV-TR classifies PTSD as an anxiety disorder with the major criteria of an extreme precipitating stressor, intrusive recollections, emotional numbing, and hyperarousal. Individuals at risk for PTSD include, but are not limited to, soldiers and victims of motor accidents, sexual abuse, violent crime, accidents, terrorist attacks, or natural disasters such as floods, earthquakes or hurricanes.7 PTSD has acute and chronic forms. In the general population, the lifetime prevalence of PTSD ranges...
Parkinsons disease
Parkinson's disease16 afflicts 1.5 million Americans with an additional 60 000 cases diagnosed each year (see 6.08 Neurodegeneration). The cardinal symptoms of Parkinson's desease include tremor, bradykinesia, rigidity, and postural instability, the result of the loss of DA-containing cells in the substania nigra. Parkinson's disease patients also suffer from a variety of nonmotor symptoms including sleep disturbance, depression, and dementia. As with AD, Parkinson's disease is a disease that...
Alzheimers disease
AD or dementia of the Alzheimer type (DAT) is a progressive and debilitating disorder characterized by dementia and a loss of cognitive function. Approximately 15 million individuals in developed countries are estimated to currently suffer from AD. Initial symptoms include confusion, loss of initiative, progressive decline in executive function, mood changes, and memory loss. However a decline in cognitive abilities ultimately results in a complete loss of mental function with disease...
Introduction to the Prostate
The prostate is a fibromuscular glandular organ involved in the male reproductive system. It is located between the bladder and pelvic floor, and surrounds the prostatic urethra. It is comprised of a large, nonglandular region and a smaller, glandular region that consists of epithelium and stroma, and can be further subdivided into three main zones the peripheral zone, which constitutes about 70 of the gland the central zone, comprising 25 of the gland and the transitional zone, which...
References
Black, H. R. Cushman, W C. Green, L. A. Izzo, J. L., Jr. Jones, D. W Materson, B. J. Oparil, S. Wright, J. T, Jr. et al. J. Hypertens. 2003, 42, 1206-1252. 2. Lloyd-Jones, D. M. Evans, J. C. Larson, M. G. Levy, D. Hypertension 2002, 40, 640-646. 3. Lloyd-Jones, D. M. Evans, J. C. Levy, D. JAMA 2005, 294, 466-472. 4. Valderrabano, F Gomez-Campdera, F Jones, E. H. Kidney Int. 1998, 68, S60-S66. 5. Lloyd, A. Schmieder, C. Marchant, N. Pharmacoeconomics 2003, 21,...
Glaucoma
Glaucoma is a major cause of vision loss throughout the world.1-3 It represents a heterogeneous group of slow but progressive optic neuropathies that culminate in blindness. Glaucoma involves a triad of tissues comprising Trabecular meshwork Lamina cribrosa Figure 1 The anatomy of the human eye. the trabecular meshwork (TM) in the anterior chamber the optic nerve head (ONH) and the retinal ganglion cells (RGCs) in the posterior chamber of the eye. The exact etiology of glaucoma is unclear, but...
Affective disorders depression and bipolar disease
Major depression (see 6.03 Affective Disorders Depression and Bipolar Disorders) is a chronic disorder that affects 10-25 of females and 5-12 of males. Suicide in 15 of chronic depressives makes it the ninth leading cause of death in the USA. Presenting complaints for depression include depressed or irritable mood, diminished interest or pleasure in daily activities, weight loss, insomnia or hypersomnia, fatigue, diminished concentration, and recurrent thoughts of death. The World Health...
Fear Potentiated Startle
The startle response is an autonomic, reflexive response that is seen across species.45 It consists of a rapid and sequential muscle contraction that is thought to protect the body and facilitate the flight reaction to avoid a sudden attack. The fear potentiated startle (FPS) test can be used to assess differences in startle reactivity and in both animals and humans is thought to represent a form of anticipatory anxiety. The amplitude of the startle reflex can be augmented in the presence of a...
Info
The third line of therapy for ADHD, antidepressants and antihypertensive therapies, is used less frequently than stimulants, but can be effective. These drugs are sometimes used in combination with stimulants in patients with comorbid symptoms. Commonly used agents are tricyclic antidepressants (TCAs), bupropion, or alpha-adrenoceptor agonists (clonidine, guanfacine, etc.). The therapeutic limitations of these diverse compounds include weight loss, sleep disturbances, abuse liability, and...
Approaches to anxioselective GABAa receptor modulators
Two approaches have been taken in the pursuit of improved anxiolytic compounds acting via the BZ receptor. Compounds with partial efficacy as positive allosteric modulators could elicit anxiolytic effects with a reduced propensity for sedation and amnesia. This approach assumes that only a limited degree of GABAA receptor potentiation is required to produce anxiolysis, whereas a greater potentiation is necessary to produce side effects. The second approach is focused on developing a positive...
Chronic inflammatory demyelinating polyradiculoneuropathy
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic demyelinating disease of the PNS that can involve sensory components, motor components, or both. The duration of the onset phase is generally more than 8 weeks however, some CIDP patients show acute onset, as with GBS. It is characterized by progressive or relapsing-remitting weakness and numbness. There is a high incidence of fatigue that may persist for years. Electrophysiological features of CIDP include nerve...
Melanin Concentrating Hormone
The expression pattern of melanin-concentrating hormone (MCH) neurons and receptors in the CNS support a potential role for MCH in a variety of physiological functions including stress, regulation of neuroendocrine processes, and feeding. Of these functions, MCH effects on feeding behavior and energy homeostasis have been most studied,156 but MCHR1 antagonists may be a novel approach to the treatment of anxiety. MCH cell bodies are located in the lateral hypothalamus and zona incerta with...
Affective disorders depression and bipolar disorder
Depressive disorders involve all major bodily functions, mood, and thoughts, affecting the ways in which an individual eats and sleeps, feel about themselves, and think. Without treatment, depressive symptoms can last for weeks, months, or years. Fortunately, however, appropriate treatment can help most individuals suffering from depression. An increasing number of treatment options have become available over the past 20 years for individuals with major depression disorder (MDD), accompanied by...
Surgically Induced Hypertension
One of the major discoveries in hypertension research in the twentieth century was that of Goldblatt and his associates in 1937. They occluded the main renal artery of one kidney in six dogs and found that renin levels in the peripheral blood of these animals substantially increased. Over the next 3-4 days the mean systemic blood pressure in these animals also increased by an average of 104-139 mmHg. The Goldblatt technique was later used in rats and more recently in mice and led to the...
Definition Classification and Diagnosis of Hypertension
Hypertension is a disorder of the cardiovascular system characterized by elevated arterial blood pressure. The blood pressure in the arteries is dependent on the energy of cardiac contractions, elasticity, and contractile state of arterial walls, as well as on the volume and viscosity of the blood. It fluctuates with every heartbeat. The maximal pressure occurs near the end of the stroke output and is termed systolic. The minimal pressure occurs late in ventricular diastole and is termed...
Cyp2c Cyp2j
Regulate vascular tone and blood pressure Figure 4 Pathway and effects of cytochrome P450 metabolites. 6.25.2.5.7 Endothelin in hypertension Endothelin (ET-1) is a potent vasoconstrictor and mitogen that is thought to play a role in the development of hypertension. The vascular endothelium is a major source of ET-1 production. ET-1 is believed to act in a paracrine manner on ETA and ETB receptors on smooth muscle that mediate contraction, cell proliferation, and hypertrophy. Activation of ETB...
Current Treatment
6.30.5.1 Prokinetic Agents 6.30.5.1.1 5HT4 receptor agonists 5HT4 receptors are located on the enteric nervous system within the GI tract of humans and a number of animal species. Activation of these receptors with agonists evokes the release of excitatory and inhibitory neurotransmitters, with the net result of increasing motility and orthograde peristalsis in the GI tract. The first 5HT4 receptor agonist prokinetic, metoclopramide (5), was adopted for clinical use before the target receptor...
Age Related Macular Degeneration
6.12.5.2.1 Dry age-related macular degeneration Perhaps the most significant hurdle for dry AMD clinical trials is that disease onset occurs late in life as a cumulative result of chronic damage to the RPE cells and their dependent photoreceptors. Most dry AMD patients are likely unaware of their disease until visual acuity begins to decline, at which point substantial morphological damage and dysfunction have occurred. It is thus unclear that intervening in a recognized AMD risk-increasing...
The Pathophysiology of Benign Prostatic Hyperplasia
The prostate of aging males can be stimulated to undergo excessive growth. This is characterized by a number of cellular and molecular alterations leading to increased cell proliferation and reduced apoptosis in the prostate epithelium and stroma. The 'remodeling' that occurs as a result of these processes can permanently alter the appearance of the prostate, and may result in symptoms, long-term damage, and prostate cancer. It is not clear why these changes occur in some males, although it has...
Antidepressants 603521 Monoamine oxidase inhibitors
First-generation MAOIs like tranylcypromine (8), iproniazid (9), isocarboxazide (10), phenelzine (11), pheniprazine (12), and nialamide (13) revolutionized the treatment of depression.22 These are generally less utilized in current clinical practice due to their poor side-effect profile and potentially dangerous interactions with other drugs and foods, the latter reflecting the cheese, or tyramine, effect. The current leading MAOIs are tranylcypromine (8), phenelzine (11), and moclobemide (14)....
Oov
Prucalopride (10) is a 5HT4 agonist whose activity in the lower GI tract has attracted attention. In conscious dogs, prucalopride stimulates motor activity in the proximal colon, although distal colon activity is inhibited34 and in healthy human volunteers, prucalopride decreases colonic transit time.35 This prokinetic effect has also been seen in patients with constipation, where prucalopride increased GI transit in the small and large intestine as well as increasing gastric emptying.36...
Defensive Test Battery
This test battery is based on rodent unconditioned behaviors such as freezing, hiding, taking flight, defensive threat attack, and risk assessment56,57 with the flight component being thought to relate to panic. NCEs that are clinically effective in treating panic disorder as well as anxiety are effective in this model. The fear defense test battery developed for rats uses a long (6 m) oval runway apparatus with a human experimenter representing the threat stimulus. When the runway is in the...
Disease Basis
Understanding migraine can be facilitated by grasping the basic neurobiology of head pain, its processing in the brain, and modulation by centers that facilitate or inhibit sensory transmission. In experimental animals the detailed anatomy of the connections of the pain-producing intracranial extracerebral vessels and the dura mater has built on the classical human observations of Wolff9 and others. It is crucial to remember that, while head pain can be an important manifestation of these...
Gr79236
Adenosine antagonists decreased nociceptive thresholds in rats.80 The antinociceptive effects of adenosine are mediated via the A1 receptor.81'82 This has been localized in human trigeminal ganglia,83 suggesting a potential ability of adenosine A1 receptor agonists to inhibit the trigeminal nerve. Selective adenosine A1 receptor agonists, e.g., GR-79236, 11, can inhibit trigeminovascular activation, both in the trigeminal nucleus and by inhibition of release of CGRP in the cranial...
Diuretics
The antihypertensive activity of diuretics was discovered in the clinic. Diuretics do not lower arterial pressure in acute experiments on normotensive animals. Only in chronic experiments on DSS or SH rats can the mild antihypertensive effect of diuretics be detected. The first diuretic found to lower arterial pressure in hypertensive patients was chlorothiazide, discovered by Beyer and his colleagues at Merck. Its discovery was soon followed by the introduction of hydrochlorothiazide, a...
Marmoset Human Threat Test
Several models of fear anxiety can be used in primates,70 one being the human threat test in marmosets. When confronted by a human observer, marmosets exhibit body movements towards the threatening stimulus including tail postures (elevation of tail to expose genital region), slit stares (flattened ear tufts and partial eye closure), scent marking of cage surfaces, and arching of the back with associated piloerection. They also tend to spend less time at the front of their home cage. Diazepam...
Genes and the Metabolic Syndrome Monogenic Disorders
In addition to identifying genes for 'garden-variety' MetS, careful characterization of patients with rare monogenic disorders that recapitulate features of MetS have led to important insights that can be translated to the more common complex form. For instance, familial partial lipodystrophy (FPLD) syndromes are autosomal dominant disorders that occur with a frequency of perhaps 1 100 000 individuals in the general population.37-39 There are three distinct forms FPLD1, FPLD2, and FPLD3, of...
Other Diseases of the Retina
Vision is totally dependent on the ability of the retina to receive images from outside the eye, convert the information through photochemical and biochemical reactions into electrical signals, and transmit these signals to the visual cortex in the brain via the optic nerve. Consequently, the retina is an extremely complex tissue composed of ten different layers of cells that process the visual information and send it on to the brain. Defects and or malfunctions in the physiology of these cells...
Combinations of statins with highdensity lipoprotein cholesterolelevating agents
While statin therapy offers a significant therapeutic benefit to the subset of patients that respond to these agents, typically, more than 60 of the statin-treated patients in controlled trials continued to develop cardiovascular disease and failed to experience a therapeutic benefit.34 Most of these nonresponders also had low HDLc levels. Since statins produce only modest increase of HDLc (< 10 ),34 several studies have been conducted to define the potential benefit using statins in...
Anesthetic Classes
The use of anesthetic agents is dictated in large part by the nature of the surgical procedure. In some cases there is a requirement for the patient to be fully 'asleep' in order to avoid discomfort and interference with the procedure, whereas in other cases, local or regional anesthesia (e.g., pudenal block in pregnancy, dental surgery) may suffice and the patient may remain awake during the procedure. 6.15.2.1 Inhalation or General Anesthetics Inhalation or general anesthetics are...
F3c
NK2, which preferentially bind NKs A and B, are located predominantly on sensory neurons. However, these receptors are also involved in mediating GI motor activity. The NK2 antagonist nepadutant suppressed the stimulatory effects of NKA, but did not affect basal migrating motor complexes. In animal studies, saredutant, another NK2 antagonist, dose-dependently reduced agonist-induced fecal excretion and abdominal contractions in response to colorectal distension. However, no data are available...
Hormonal regulation of bone remodeling
Bone is a metabolically remarkably active tissue that throughout life undergoes constant remodeling by osteoclasts and osteoblasts, as described above. These cellular events are regulated by systemic and local modulators, namely parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, sex and other steroid hormones, calcitonin, prostaglandins, growth factors, and cytokines. Bone is the most important reservoir for body calcium. Ionized plasma calcium, which represents 50 of the total plasma calcium...
Classification of Diabetes Mellitus and the Metabolic Syndrome
In 2003, the American Diabetes Association (ADA) revised the etiologic classification of diabetes mellitus, removing the distinction between primary and secondary causes of diabetes15 (Table 1). The nomenclature now uses Arabic rather than Roman numerals to designate T1DM and T2DM. Terms such as insulin-dependent, non-insulin-dependent, juvenile-onset, maturity-onset, and adult-onset diabetes are eliminated. Thus, diabetes is now classified according to etiology and pathophysiology, without...
Dopamine transporter DAT knockout mouse
A recently developed animal model that may be relevant to ADHD is the DAT knockout mouse, which shows about a 300-fold decrease in the rate of clearance of extracellular dopamine42 due to the lack of the gene that encodes DAT-1. These knockout mice also show evidence of behavioral abnormalities similar to those observed in ADHD, although there remain several important issues regarding dopamine autoreceptor downregulation, serotonergic tone, and activation of trace amine receptors in these...
Markers of Inflammation and Oxidant Stress in Coronary Heart Disease
Currently, there are no validated biomarkers of either inflammation or oxidant stress that can be used predictably for drug intervention in CHD patients. C-reactive protein (CRP), whose biological function is undetermined, has been proposed as a potential marker of inflammation, particularly in patients with acute coronary syndromes (ACS).6 Whether CRP is produced in response to inflammation or contributes directly to an inflammatory response is still unknown. However, elevated plasma CRP...
Neurogenesis creation of new neurons critical to antidepressant action
The seminal studies by Duman and co-workers14 on neurogenesis may help to explain why antidepressants typically take a few weeks to have an effect and may indicate why a rapid-acting antidepressant may not be a viable propositition.14 These workers created a strain of 5HT1A'knockout' mice that as adults show anxiety-related traits, such as a reluctance to begin eating in a novel environment. While unaffected by chronic treatment with the SSRI fluoxetine, the mice became less anxious after...
Thrombolytic Agents used in Trials and Clinical Practice
Thrombolytic drugs lyze preexisting thrombus in both arteries and veins and re-establish tissue perfusion.4 They exert their action through conversion of plasminogen to plasmin, which then degrades fibrin, a major structural component of the thrombus.37 The action of thrombolytic drugs is achieved by either potentiating endogenous fibrinolytic pathways or mimicking natural thrombolytic molecules.1 Currently available thrombolytic agents are derived from bacterial products or manufactured using...
Adult Adhd Animal Model
Attention defect hyperactivity disorder (ADHD) affects 3-7 of school-aged children, and reports suggest similar percentages in adults. Children and adults manifest the symptoms of hyperactivity, impulsivity, and inattention differently, however, and diagnostic criteria are typically oriented around the children's core symptoms. While diagnostic criteria have developed significantly since the 1970s, underdiagnosis is a key issue with regard to adult ADHD. In addition, many of the controlled...
Overall Market Size and Anticipated Growth
The efficiency of eradication of H. pylori infection (around 95-98 ) and the use of antibiotics have completely changed the approach to peptic ulcer therapy, significantly reducing the use of antisecretory compounds. Nonetheless, as shown in Table 1, antiulcer drugs represent the second most frequently sold drug class. Antisecretory compounds are used for the long-term treatment of GERD, a chronic disorder of the esophagus that results a decrease of the low esophageal sphincter (LES) barrier...
Pathophysiology Biochemistry and Genetics of Hypertension
The pathophysiology of essential hypertension has been extensively studied over the last 50 years. Peripheral vascular resistance is usually increased in hypertensive individuals. Normally, the autonomic nervous system, kidneys, adrenal cortex, local hormones, and cytokines regulate vascular resistance. Failure of the normal regulation of vascular resistance leads to hypertension. The failure can theoretically occur in any part of the regulatory system. Initially, overactivity of the...
The Diagnosis of Benign Prostatic Hyperplasia
Several guidelines have been published to aid in the diagnosis of BPH the most prominent ones are those published by the American Urological Association (AUA)9 and by the European Association of Urology (EAU).29 Both of these guidelines recommend that the diagnosis of BPH is based on a medical history, symptomatic assessment using a validated instrument such as the International Prostate Symptom Score (IPSS), which uses eight items to categorize BPH 'urinary' symptoms as mild (IPSS 0-7),...
Myasthenia Gravis
MG is a chronic autoimmune disease of the neuromuscular junction characterized by fluctuating weakness and fatigability of skeletal and extraocular muscles. The natural history is characterized by exacerbations and remissions. Symptoms increase during the day, and may be masked by rest. Patients may have respiratory (and swallowing) difficulties during myasthenic crisis, requiring artificial ventilation and airway protection respiratory compromise is the most common cause of death in MG...
Clinical Trial Issues
Most clinical trials with testosterone replacement treatment have been done in postpubertal males with hypogonadism from various causes. With few exceptions, they have been open-label double-blind studies would be a challenge, although preferable. Total testosterone concentrations have generally been used for the diagnosis of androgen deficiency and for adequacy of replacement testosterone therapy. Free or bioavailable testosterone concentrations may provide a better basis for diagnosis of...
Suicidality in children and adolescents being treated with antidepressant medications
In 2004, the FDA directed manufacturers of all antidepressant drugs to revise the labeling for their products to include a boxed warning and expanded warning statements that alert healthcare providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies.36 The FDA also informed manufacturers that it had determined that a Patient Medication...
Social Anxiety Disorder
The ECNP consensus meeting on SAD72 recommended the conventional double-blind, placebo-controlled, randomized group comparison study to demonstrate efficacy in SAD. Since the latter can be either generalized or nongeneralized, studies investigating efficacy in this disease concentrate on generalized SAD with symptoms of at least four distinct social situations. As in other anxiety disorders, there is a larger drug versus placebo effect seen in patients in the severe to moderate SAD subgroups,...
Animal Models of Attention Deficit Hyperactivity Disorder 605421 The spontaneously hypertensive rat SHR
The most widely accepted animal model of ADHD is the SHR, a strain that was originally developed from Wistar Kyoto (WKY) rats in Japan more than 40 years ago. Unexpectedly, when selecting for hypertension, hyperactivity was also observed. Since then, the SHR has been studied extensively from face, predictive, and construct validity perspectives. SHRs exhibit many behavioral features characteristic of ADHD. Hyperactivity in the SHR strain is observed across multiple behavioral paradigms,...
Definition of Metabolic Syndrome
MetS is a commonly occurring cluster of clinical phenotypes that are individually and collectively strongly related to cardiovascular disease.2 MetS is characterized by disturbed carbohydrate and insulin metabolism, and is clinically defined by threshold values applied to indices of central obesity, dysglycemia, dyslipidemia, and or elevated blood pressure, which must be present concurrently in any one of a variety of combinations.2'3 The cardinal feature of MetS is abdominal obesity, as...
Issues in Preclinical and Clinical Development for Drugs to Treat Osteoporosis
The clinical development of drugs for the treatment of osteoporosis is required to satisfy specific regulatory guidelines prior to approval for marketing. In 1994, the US FDA released draft guidelines covering preclinical and clinical development of osteoporosis drugs of postmenopausal osteoporosis.52 The World Health Organization has developed similar guidelines53 and these are available on its website. The FDA guidelines are under current review and variations may be expected. In addition, as...
Prostate Surgery and Incontinence
Prostate surgery can contribute to transient, short- or long-term incontinence. Radical retropubic prostatectomy is a surgical procedure used in prostate cancer, which involves the removal of adenomatous tissue via an incision in the surgical capsule of the prostate. However, this technique can result in refractory incontinence. One study of 146 prostate cancer patients showed that stress urinary incontinence was evident in the majority of patients (95 ) after surgery, with the main cause of...
Xvp
Figure 3 Various PPIs either on the market or in development. Esomeprazole is the S enantiomer of omeprazole, and all the other compounds are racemates. Different substitutions on the benzimidazole portion alter the pKa of the benzimidazole nitrogen atom, resulting in different acid liability profiles. improve stability. By 1975, Hassle was focusing more on acid secretion, and had available to them, in addition to rats and dogs, the rabbit gastric gland model. They then discovered that...
Figure 2 11cis and 11fransretinaldehyde
A normally functioning Bruch's membrane is sufficiently permeable to allow diffusional exchange of nutrition and waste products between the choroidal capillaries and RPE cells. AMD is a chronic disease resulting from a malfunctioning of this system at several loci. Although there are many gaps in understanding of the disease pathology and progression, a general hypothesis with several variations has emerged, based on consistent clinical and epidemiologic observations in AMD...
Gaba
Figure 3 GABAa receptor. a Horizontal cross-section through the GABAa receptor showing the pentameric arrangement of two a subunits, one p subunit, and one g subunit to form the central chloride permeable channel. Arrows indicate the two recognition sites for GABA at the a p interface and the benzodiazepine Bz binding site at the a g interface. b Vertical cross-section. chlorpromazine, meprobamate, and reserpine . Chlordiazepoxide eventually was tested as a result of a laboratory clean up and...
Sulfonylureas
For nearly 50 years, sulfonylureas, derived from sulfonic acid and urea, have had a central role in oral hypoglycemic therapy of T2DM. Sulfonylureas increase endogenous insulin secretion and can only be used in individuals that have retained significant b-cell function. The combination of efficacy, low incidence of adverse events, and low cost has contributed to their success and continued use. Sulfonylureas are generally safe and are relatively inexpensive. Hypoglycemia is the most common...
I
Stage 4 Deep sleep V more intense Figure 1 Normal nocturnal sleep cycle. NREM, non-rapid eye movement REM, rapid eye movement. stages with a combined duration of 20-40 min that is referred to as slow wave sleep SWS or delta sleep. The early stages of NREM repeat prior to the onset of REM. As sleep progresses, each successive cycle differs from the preceding one in terms of duration and NREM-REM organization. The last cycle is usually the longest with SWS tending to diminish significantly in the...
Conclusions
The adverse physiological, psychological, and economic effects of inadequate pain management have become increasingly recognized in recent years. This has been accompanied by a growing awareness on the part of patients and caregivers that pain need not be tolerated, and an increased emphasis amongst physicians on the proactive treatment of pain. The unmet need for new analgesics remains substantial. Recent advances in the neurobiology of pain, together with the development of new preclinical...
Other Potential Therapeutic Targets
Our understanding about the pathways of insulin action downstream from the insulin receptor is rapidly expanding see Figure 4 . Every step of the insulin receptor pathway has the potential to serve as a target for pharmacological intervention in the treatment of T2DM and obesity. Two such examples are summarized here in GSK-3 and PTP1B. Glycogen synthase kinase 3 GSK-3 is a protein kinase the activity of which is inhibited by insulin.91 GSK-3 serves a regulatory function to phosphorylate...
Future Considerations
Pain is a complex sensory experience, contributed to by cognitive factors, environment setting, society, and culture , experience, and gender, and significantly modulated by the central nervous system. We have focused here on the most tractable aspect of the experience of pain, namely the nociceptor, because most, but not all, pain is associated with activation of a nociceptor in peripheral tissue. The drug receptors ion channels briefly discussed above are all present on nociceptors and thus...
Shortacting insulin regular insulin
Human recombinant DNA produced regular insulin has an onset of action between 30 and 60 min after and a peak effect 2-4 h after injection, with a usual duration of action of 6-8 h. Regular insulin was the shortest acting insulin available prior to the availability of the rapid-acting analogs. Its duration of action extends beyond the duration of digestion and absorption of most meals, thereby increasing the risk of hypoglycemia. insulins Neutral Protamine Hagedorn NPH , lente, and insulin...
Experimental Models of Addiction
In order to identify potential medications for the treatment of drug addiction, animal models have been created that allow the elucidation of the underlying mechanisms of drug-induced behaviors. By its definition, addiction is a unique and complicated human behavior and a single animal model simply cannot predict medication efficacy in humans. Thus most investigators use an arsenal of in vitro and in vivo tests to study neurochemical mechanisms underlying the pharmacological actions and abuse...
Longacting insulins ultralente and insulin glargine
Long-acting insulins are used to provide a basal level of insulin. Ultralente insulin reaches a peak gradually 14-18 h after injection , with a duration of action of up to 24h. Similar to lente insulin, ultralente is a suspension of large, zinc-containing crystals that have been precipitated in an acetate buffer. Insulin glargine Lantus contains two modifications of the human insulin molecule that change both the onset and duration of action. Two arginine residues are added to the carboxyl...
Pharmacodynamics and pharmacokinetics of insulin
Insulin was initially available as a soluble, clear solution. The relatively short duration of action meant that individuals had to take multiple daily injections. Combining insulin with protamine or high concentrations of zinc led to the formation of suspensions that are slowly absorbed with a longer and variable duration of action. Insulin analogs were designed with more predictable characteristics of rapid or attenuated absorption and action. The pharmacodynamic profiles of the different...
Neurochemical Basis of Anxiety
Neurochemical modulators exist at every level within the complex neurocircuitry described above, providing a large number of potential therapeutic targets for the treatment of anxiety. Despite the variations in clinical presentation of the various anxiety disorders, extensive preclinical studies have provided significant evidence for the role of multiple neurochemical systems in the etiology of anxiety, in general, with a significant amount of overlap between the individual disorders...
J A Sikorski Athero Genics Alpharetta Ga Usa 2007 Elsevier Ltd All Rights Reserved
6.20.1.2 Heart Disease Imaging Methods 461 6.20.1.3 Heart Disease Mortality 461 6.20.2.1 Dyslipidemia as a Risk Factor for Coronary Heart Disease 462 6.20.2.2 Lipoproteins Composition, Structure, Function, and Lipid Transport 462 6.20.2.2.1 Very low-density lipoprotein, chylomicrons, and triglyceride transport 463 6.20.2.2.2 Low-density lipoprotein structure and composition 463 6.20.2.2.3 High-density lipoprotein structure and composition 464 6.20.2.3 The Role of Modified Low-Density...
Classification and subclassification of major depression disorder and bipolar affective disorder
6.03.1.1.1.5.1 Major depressive disorder The symptom criteria for major depression in DSM-IV-TR and ICD-10 guidelines are very similar Table 2 , although the coding systems are somewhat different.6'7 One difference is that the ICD-10 has a separate, optional subdiagnosis for depression with and without somatic symptoms. The latter is not present in the DSM-IV system. Both sets of guidelines have depressive disorder subdiagnoses for the following mild, moderate, and major severity single and...
Current Treatment 608251 Cholinesterase inhibitors
The cholinergic hypothesis of AD has led to the development of NCEs that increase ACh, which is lost when neurons of the basal forebrain degenerate. ACh is degraded by cholinesterase activity. Two major forms of cholinesterase exist, acetylcholinesterase AChE and butyrylcholinesterase BuChE , with differential localization. Both enzymes are found in the brain, although AChE predominates 10-fold greater and is in synaptic clefts. BuChE is also found in brain, mainly in glia, but is...
A740003
Figure 13 A-317491 and A-740003, selective P2X3 and P2X7 ligand-gated ion channel antagonists, respectively. primarily to sensory neurons, suggesting a role in pain transmission. The P2X3 messenger RNA mRNA occurs only in the trigeminal, dorsal root, and nodose ganglia, and the receptor is selectively expressed in sensory C-fiber neurons that project to the periphery and spinal cord, and which are predominantly nociceptors. In addition, P2X3 receptors located presynaptically at the central...
Amylin Analogs Pramlintide
Amylin is a 37 amino acid peptide that is formed almost exclusively within pancreatic P-cells and co-secreted with insulin. Amylin acts as a neuroendocrine signal that complements the actions of insulin in postprandial glucose homeostasis via suppression of postprandial glucagon secretion and via inhibition of gastric emptying. Individuals with T1DM have an absolute deficiency of both insulin and amylin, whereas individuals with T2DM have a relative deficiency of both hormones. Pramlintide is...
New Research Areas
The identification clinically useful analgesic targeting nonopioid mechanisms has been challenging as demonstrated by the failure of several novel tachykinin NK-1 receptor antagonists in clinical trials.39 Other novel analgesic agents have either not been advanced or are used in only limited conditions due to mechanism related toxicities. For example, the analgesic efficacy of ziconotide, a selective neuronal calcium channel N-type, Cav2.2 blocker discussed in more detail below is limited to...
Fibrates as highdensity lipoprotein cholesterolelevating agents
Several clinical studies have demonstrated that a reduction in CHD events is positively correlated with treatments that raised HDLc. The controlled Helsinki Heart Trial monitored coronary event rates in over 4000 asymptomatic middle-aged males with dyslipidemia for 5 years and showed that correcting low levels of HDLc with gemfibrozil led to a 34 decrease in coronary events.4'57 For each 1 mg dL _ 1 rise in HDLc among the study subjects, the average response was a 3 decrease in CHD risk....
Models of Acute Pain
Animal models of acute pain allow the evaluation of the effects of potential analgesics on pain sensation transmission in an otherwise normal animal. In addition, the same tests may be used to measure stimulus-evoked pain in animals with chronic inflammation or nerve injury. Usually, these tests rely on an escape behavior withdrawal reflex or vocalization as an index of pain. The animals have control over the duration of the pain, that is, their behavioral response leads to termination of the...
Sleep Switch Hypothalamus
Brainstem Ascending cortical activation REM SWS switch Figure 2 Systems regulating sleep-wake biology. Upper panel a Sleep-wake states are controlled through a delicate balance of activities between the thalamus cortical activation and EEG synchronization , the hypothalamus sleep wake switch , the superchiasmatic nucleus SCN or circadian clock and the brainstem ascending cortical activation, REM SWS switch . Lower panel b Multiple neurotransmitters are involved in sleep-wake regulation. The...
Animal Models of Depression
Animal models of depression26-28 and BPAD have proved to be of considerable value in elucidating basic pathophysiological mechanisms and in developing novel treatments. However, the challenges faced by psychopharma-cologists in modeling human affective disorders in experimental animals are fraught with difficulties. As new targets emerge through hypothesis-driven research or serendipity, the challenge is to link the mechanism to a clinical complex and heterogeneous disorder. Consequently, much...
Selective serotonin reuptake inhibitors SSRIs
While the primary mode of action of TCAs was thought to be inhibition of NE reuptake, a reassessment of the actions of the diverse antihistamines on the reuptake of various biogenic amines, especially 5HT, led to the hypothesis that an increase in brain noradrenergic function caused the energizing and motor stimulating effects of the TCAs, but that an increase in 5HT function was responsible for their mood-elevating effects.42 Structural analogs of diphenhydramine were sought as novel...
Jnj17216498
6.06.6.2 Amphetamine-Like Stimulants Amphetamines including mixed salts have long been first line therapy of hypersomnolence and narcolepsy.64 Amphetamine is a central stimulant that promotes the release of DA, NE, and 5HT. Their primary effects are mediated through reverse efflux of DA via inhibition of the DAT. At higher doses, inhibition of vesicular monoamine transporter VMAT which is involved in amine storage enhances stimulant pharmacology, increasing amine quantities available for...
GABAa subtypeselective benzodiazepine site ligands
No NCEs have yet been reported with a high degree of selective affinity for GABAA receptor subtypes believed to be important for anxiolysis. However, compounds have been identified that, despite having similar affinities, show a degree of functional selectivity for different a-subunit-containing GABAA receptors i.e., they behave as full or partial modulators of certain subtypes and neutral modulators of others . A compound preferentially potentiating a2-subunit-containing GABAA receptor...
The Glutamate Hypofunction Hypothesis
Glutamate is the major excitatory neurotransmitter in the CNS, and antagonists of the NMDA N-methyl-D-aspartate subtype of glutamate receptor, the psychotomimetics, phencyclidine 2 PCP and ketamine 3, mimic the positive, negative, and cognitive symptoms of schizophrenia.13 In the clinic, NMDA receptor antagonists faithfully mimic the symptoms of schizophrenia to the extent that it is difficult to differentiate the two. Controlled human studies of psychosis induced by the NMDA receptor...
Biographies
Michael J Marino, PhD, received his PhD in 1995 from the University of Pittsburgh Department of Neuroscience where he employed behavioral and electrophysiological methods to the study of G-proteins and G-protein coupled receptors. As a postdoctoral fellow with Dr Jeff Conn at Emory University, he performed pioneering work on the role of metabotropic glutamate receptors in regulating the circuitry of the basal ganglia. This work led to the identification of potential targets for the treatment of...
Psychiatric Disorders 601411 Schizophrenia
Schizophrenia see 6.02 Schizophrenia is a complex and debilitating neurodevelopmental psychiatric disorder that affects approximately 1 of the population. It is characterized by diminished drive and emotion during childhood followed by a deviation from reality with hallucinations, and appears to have both genetic and epigenetic causality. Schizophrenia presents with a spectrum of positive, negative, and cognitive symptoms. Positive symptoms include auditory and visual hallucinations, delusions,...
