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...
Selective Adhesion Molecule Inhibitors
Natalizumab is a humanized monoclonal antibody to a4 integrin that was approved by the US FDA in 2004 for the treatment of relapsing forms of MS.23-25 The integrins are a large family of adhesion molecules mediating cell-cell and cell-ECM interactions. Expression of a4 integrin is predominantly on lymphocytes, monocytes, eosinophils, and basophils, but is usually undetectable on neutrophils. It forms heterodimers with either p or P7. One ligand for a4p integrin is VCAM-1 (vascular cell adhesion...
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...
Info
A serious issue with troglitazone, which led to its withdrawal, is hepatotoxicity. Troglitazone both activates the pregnane X receptor, to increase CYP3A4 levels, and is also a CYP3A4 substrate and generates a reactive quinone metabolite. Rosiglitazone is also reported to be associated with liver, cardiovascular, and hematological toxicities as well as edema and weight gain. It is not clear whether any of these clinical adverse effects are mediated by the thiazolidinedione moiety, but many...
References
Zhao, S. Nelson, C. B. Hughes, M. Eshleman, S. Wittchen, H. U. Kendler, K. S. Arch. Gen. Psychiatry 1994, 51, 8-19. 2. American Psychiatric Association DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, IV-TR ed. American Psychiatric Association Washington, DC, 2000. 3. Nutt, D. J. Ballenger, J. C. Sheehan, D. Wittchen, H. U. Int. J. Neuropsychopharmacol. 2002, 5, 315-325. 4. Sartorius, N. Ustun, T B. Lecrubier, Y Wittchen, H. U. Br. J. Psychiatry...
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...
Prepulse inhibition
A disruption in sensory and cognitive gating is hypothesized to be at the core of many of the symptoms of schizophrenia. Prepulse inhibition (PPI) refers to the ability of a low-intensity stimulus, or prepulse, to diminish the startle response elicited by a higher-intensity stimulus. This model has gained significant favor in recent years largely due to the findings that schizophrenic patients exhibit deficits in sensory and cognitive gating. This is particularly evident in studies of...
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...
ReEstablishing Mucosal Tolerance Probiotics Prebiotics Worms and Toll Like Receptor Modulators
The coincidental rise in IBD in the developing world with the decline of helminthic parasitic infection is one aspect of a hygiene hypothesis that suggests that in a sanitary world the mucosal immune system has become functionally less important. An idle GI immune system may not necessarily be desirable. Indeed, reports indicating that administration of the helminths Trichuris suis or Heligmosomoidespolygyrus is effective at reversing the inflammation and inducing clinical remission41 directly...
Unmet Medical Need
Adult ADHD represents a relatively untreated condition. In adults, the hyperactive component is less pronounced and the attention deficit a larger treatment issue than in adolescents. ADHD is not just a lifestyle condition in that inattention and impulsivity result in significant functional impairment and have negative occupational and interpersonal consequences. Impulsivity and the resulting impaired risk assessment also contribute to a higher incidence of illicit drug use among ADHD patients....
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...
Ocular Surface Diseases
The cornea and conjunctiva are exposed to the environment and are thus susceptible to overexposure to light, radiation, chemicals, and airborne pathogens and allergens. Consequently, ocular surface infections, allergies, dryness, and ulcerations represent the major disorders of the cornea and conjunctiva. While these conditions are not blinding by themselves, they severely limit the quality of life for millions of people. Allergic conjunctivitis and perennial conjunctivitis are fairly acute...
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...
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...
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...
Highdensity lipoprotein structure and composition
In contrast to LDL, HDL particles Figure 3 remove excess cholesterol from the periphery and return it to the liver either by the direct uptake of HDL particles via hepatic HDL scavenger receptor type B-1 SR-B1 or indirectly by CETP-mediated transfer of cholesteryl ester from HDL to LDL or VLDL and hepatic uptake of these apoB particles via the LDLr. The process of collecting excess peripheral cholesterol by HDL for disposal via the liver is the reverse cholesterol transport RCT pathway. This is...
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...
Overview and Comparison of Drug Classes
Historically the treatment of ADHD relied on agents affecting monoaminergic neurotransmission, and largely consisted of the stimulants, antidepressants, and antihypertensive agents Table 1 .1'65 The primary pharmacological treatment for ADHD continues to be the use of stimulants, particularly methylphenidate and amphetamines. Methylphenidate has long been the leading treatment for ADHD however it has a short duration of action and a midday dose is required. In schoolchildren, this necessitates...
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...
Trace Amines
In addition to the classical monoamines NE, 5HT, and DA, there exists a class of 'trace amines' that are found in very low levels in mammalian tissues, and include tyramine, b-phenylethylamine b-PEA , tryptamine, and octopamine.74 The rapid turnover of trace amines, as evidenced by the dramatic increases in their levels following treatment with MAOIs or deletion of the MAO genes, suggests that the levels of trace amines at neuronal synapses may be considerably higher than predicted by...
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 Serotonin 5HT Hypothesis
The serotonin 5HT hypothesis of schizophrenia actually pre-dates that of DA. The ability of the hallucinogen lysergic acid diethylamide LSD to antagonize the effects of 5HT on smooth muscle led to the hypothesis that schizophrenia was caused by a decrease in central serotonergic function.11 This theory, largely predicated on the similarities between schizophrenic psychosis and LSD-induced hallucination, was modified with the discovery that LSD could act as a 5HT agonist in some systems. These...
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,...
