Lsv

Based on the unequivocal role of Ado in eliciting sleep, an obvious target for the development of new hypnotics would appear to be the Ai receptor agonists. However, while adenosine is a highly effective paracrine neuromodulator, its widespread distribution has confounded efforts in NCE discovery given the sedative effects of agonists in the CNS and the hypotensive actions of the purine nucleoside. Despite 30 years of research, the only Ado agonist approved for human use is Ado itself for the...

Lbb

Based on the strength of the evidence implicating the 5-HT2C receptor in the control of feeding behavior, as well as other CNS pathways, there has been much interest in developing selective, druggable 5-HT2C receptor agonists. The patent literature suggests that a number of companies have been involved in this effort, including Bayer, Biovitrum, Bristol-Myers Squibb, Eli Lilly, Pfizer, Vernalis, Wyeth, Yamanouchi, and Arena. At least two relatively selective 5-HT2C receptor agonists have been...

Glaucoma

Many drugs that are being used to lower and control IOP and thus slow down the progression of glaucomatous damage and vision loss. As with most drugs the side effects need serious consideration prior to prescription. Topical ocular use of FP-class PG analogs causes mild but protracted hyperemia burning and stinging iridial hyperpigmentation orbital skin color pigmentation and eyelash thickening and growth. The major side effect of topical ocular use of b blockers is transient stinging, burning,...

Glitinides nonsulfonylurea secretagogues

Glitinides, like sulfonylureas, act at the K+-ATP channels to augment glucose-stimulated insulin secretion. Glitinides differ from sulfonylureas by having a more rapid onset and shorter duration of action, primarily lowering postprandial glucose levels. They are only effective in individuals with viable pancreatic b-cells and are therefore not suitable for individuals with T1DM. Repaglinide and nateglinide (Figure 7) are the two glitinides approved by the FDA for use in the USA. Repaglinide is...

Unmet Medical Needs

6.22.6.1 Precautions of Androgen Therapy in Aging Males Androgen replacement therapy has been reported to cause water retention, polycythemia, hepatotoxicity, sleep apnea, prostate enlargement, and to reduce HDL cholesterol.3 Hepatic toxicity is associated with derivatives of testosterone rather than pure testosterone. Polycythemia is observed more commonly in males receiving injectable testosterone. Thus, hematocrit should be measured periodically to minimize the risk of polycythemia. HDL...

Hyperplasia Prostate Dysfunction

M G Wyllie and S Phillips, Urodoc Ltd, Herne Bay, UK 6.24.1 Introduction to the Prostate 551 6.24.1.1 The Aging Prostate 552 6.24.2 The Definition of Benign Prostatic Hyperplasia 554 6.24.3 The Pathophysiology of Benign Prostatic Hyperplasia 555 6.24.3.2 Cellular Changes 556 6.24.3.3 Changes in Proliferation, Apoptosis, and Senescence 556 6.24.3.5 Androgen-Related Changes 558 6.24.3.7 Impact on Bladder Pathophysiology 559 6.24.3.8 Impact on Lower Urinary Tract Symptoms 560 6.24.4 The Diagnosis...

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...

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...

Introduction to the Prostate

Tgf Beta And Fgf

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...

Experimental Disease Models

Drug discovery in depression has been hampered by the lack of a universally accepted animal model(s) that can be used to screen NCEs for antidepressant effects. Although there are several animal models that reproduce some features of depression in the context of stress and or separation, it is questionable as to whether these are relevant to the human disorder MDD or BPAD. The advantages and disadvantages of animal models for depression are summarized in Table 6. In all cases, the behavioral...

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...

Muscarinic Agonists

Activation of muscarinic receptors may exert antipsychotic-like activity in animals and humans. The first indication that activation of muscarinic receptors might have antipsychotic activity in humans arose from the use of cholinesterase inhibitors to treat behavioral disturbances in demented individuals, particularly those with dementia with Lewy bodies (DLBs) (see 6.08 Neurodegeneration).64 These patients exhibit visual hallucinations, delusions, apathy, agitation, dementia, and mild...

Rp67580

Figure 13 Small-molecule NK1 receptor antagonists. NK receptor antagonists have shown mixed effects in clinical trials.162 The initial target for NK antagonists was pain. Despite robust activity in numerous preclinical models, none of the NK1 antagonists advanced to the clinic showed efficacy.163 Based on the efficacy of MK-869 in the guinea pig vocalization model it was advanced to clinical trials in anxiety and at 300 mg showed initial improvements in depression and anxiety symptoms...

Benzodiazepine site ligands

Since the allosteric potentiation of GABAa receptor function was first elucidated using BZs, this site is commonly referred to as the 'BZ site' however, compounds of different chemical classes, 'non-BZ' ligands, have been discovered that also bind to the BZ site and produce similar therapeutic effects. These compounds provided the first evidence for heterogeneity of BZ sites and for subtypes of GABAA receptors that mediate the different pharmacological actions of BZ site ligands. Other...

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...

A71623

The regulation of food intake by opioids is complex, involving five major peptide classes ( -endorphin, dynorphin, enkephalins, endomorphans, and nociceptin (NOP Orphanin FQ)) and four GPCRs m opioid (MOP), delta opioid (DOP), k opioid (KOP), and NOP receptors.27 The interest in the opioid system and feeding began with the observation that the mixed MOP, DOP, and KOP antagonist, naloxone, decreased deprivation-induced feeding in rats. Subsequent studies documented the efficacy of mixed and...

Biguanides

Biguanides have been used in the treatment of T2DM since the1950s. Derived from the French lilac, Galega officinalis, phenformin was the initial biguanide available for clinical use. It was taken off the market in the 1970s after numerous cases of lactic acidosis were found to be associated with its use. The etiology of the lactic acidosis was related to impaired hydroxylation of phenformin in a subset of individuals. In contrast, individuals taking metformin are at very low risk of developing...

Mcab

MCAB to TNF-a, chimeric MCAB to TNF-a, H Soluble fusion P of CTLA4 Random, synthetic peptide mix dsDNA-based bioconjugate Oligonucleotide Approved by the US Off-label Clinical trials INJ RRMS GIDP, CIS, SPMS with relapses IV Relapsing MS Crohn's disease, RRMS INJ Refractory RA GIDP, MG PPMS, RRMS, SLE IV Crohn's disease Crohn's disease Pravascacin Acorvascacin Simvascacin Minocycline Mycophenolace mofecil Cyclophosphamide Micoxan crone Azachioprine Mechocrexace Albucerol sulface (salbucamol...

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...

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...

Mechanism of Thrombolysis

Fibrinolysis Diagram

Under normal circumstances there is no plasminogen activation occurring in plasma, the action of the fibrinolytic system is confined to fibrin. When fibrin is formed, a small amount of plasminogen activator and plasminogen adsorb to it and plasmin is created in situ to catalyze the degradation of fibrin Figure 3 .20 Naturally occurring plasminogen Figure 3 Schematic diagram showing the process of fibrinolysis and its control. D-dimers, breakdown product of fibrin. Figure 3 Schematic diagram...

Tenecteplase TNKtPA

Tenecteplase, a genetically engineered t-PA, was assessed for pharmokinetics, safety, and efficacy in humans in the Thrombolysis in Myocardial Infarction 10A TIMI 10A trial.66 It was administered over 5-10 s as a single bolus of 5-50 mg and had a half-life of 17 min, nearly five times longer than t-PA. Subsequently, the TIMI 10B trial, a phase II dosing trial,67 was carried out to identify a specific bolus dosing regimen of TNK-t-PA that would achieve similar rates of TIMI-3 flow on 90-min...

Renin Inhibitors

The first and rate-limiting step in RAS, the conversion of angiotensinogen to Ang I, is catalyzed by renin. Several renin inhibitors have been synthesized, but low efficacy, poor oral bioavailability, high cost of synthesis, and the availability of highly successful ARBs prevented their development. One of the first clinically tested renin inhibitors was enalkiren ABT-64662 Figure 4 . More recently developed, aliskiren42 is currently in advanced clinical evaluation. At 75, 150, or 300 mg single...

Glycoprotein IIbIIIa Receptor Antagonists

Activation of platelets by several agonists results in the expression of specific functional receptors for fibrinogen on the platelet surface, referred to as GP IIb IIIa receptors. The GP IIb IIIa receptor is a member of the integrin family of receptors.76 When platelets are activated by a variety of stimuli including thrombin, collagen, ADP, and epinephrine, the GP IIb IIIa receptor changes its conformation to be receptive to one end of a fibrinogen dimer. Occupancy of a GP IIb IIIa receptor...

Dexanabinol HU211

The cannabinoid analog dexanabinol, which demonstrated protective efficacy in preclinical TBI models,28 has been tested in a phase II clinical trial in severe TBI patients. The new compound entity was found to be safe and showed that patients treated within 6 h tended to have better control of intracranial and cerebral perfusion pressures.29 This new compound entity is unique in that it combines antioxidant and weak NMDA receptor antagonist properties along with selected anti-inflammatory...

Multiple sclerosis

MS is a chronic disease of the CNS, characterized by cell-mediated inflammation, demyelination, and variable degrees of axonal loss.3'4 MS is also characterized by lesions in the white matter of brain, brainstem, optic nerve, or spinal cord that are visible by MRI, and formed by infiltration of CNS parenchyma by monocytes and lymphocytes. Degeneration of postmitotic oligodendrocytes and oligodendrocyte progenitors is also a hallmark of MS lesions and an impediment to remyelination. The lesions...

Lanoteplase nPA

The Intravenous nPA for Treatment of Infarcting Myocardium Early InTIME -1 study compared a single bolus dose of lanoteplase 15-120 kU kg 1 with an accelerated regimen of alteplase in patients and found that coronary patency at 90 min 83 versus 71 and frequency of TIMI grade III flow were greater with the highest doses of lanoteplase compared to alteplase.71 The InTIME-1 study was followed by InTIME-2, which assessed mortality at 30 days in patients with acute myocardial infarction randomized...

Classification Systems for Antiarrhythmic Drugs

There are two accepted classification systems for antiarrhythmic drugs. The first, and most widely used, was created by Vaughan Williams and Singh,19 and modified by Harrison and others. The second is known as the Sicilian Gambit.20 1. The Vaughan Williams-Singh classification has a number of advantages in that all drugs in a particular class tend to have the same clinical utility and similar, if not identical, actions on particular ion channels. The classification system has been found to be...

New Antiarrhythmics Classes

There is still muted interest in developing more effective and safer drugs to prevent and revert atrial and ventricular arrhythmias. The identification of new ion channels, enhanced knowledge regarding existing channels, new information on pathology, and the identification of putative new arrhythmogens provide the basis for ongoing research. Programs are ongoing to identify new class 1 antiarrhythmics, although there is little residual interest in this field because of the assumption that the...

Reteplase

The Recombinant Plasminogen Activator Angiographic Phase II International Dose-Finding Study RAPID-1 was an angiographic study that compared reteplase r-PA with alteplase t-PA .45 Patients were randomized to 1 t-Pa 100 mg i.v. over 3h 2 r-PA as a 15 MU single bolus 3 r-PA as a 10 MU bolus followed by 5MU 30min later or 4 r-PA as a 10 MU bolus followed by another 10 MU 30 min later. Coronary angiography was then performed at 30, 60, and 90 min after treatment and then again at discharge....