By Q. Riordian. Faulkner University. 2018.
Does a need exist for further empiric studies on alternative nonspecific sites that may lead primarily to mild suppression of diffuse cortical dysfunction? Pursuing a specific therapy that may function on a subclinical level with a feedback or demand loop would seem to be © 2005 by CRC Press LLC more logical quality 25mg fildena erectile dysfunction bp meds, particularly with the goal of arresting a local positive feedback loop before a significant region of the brain is involved purchase 50 mg fildena with visa erectile dysfunction treatment in kl. Methods to arrest local development of a seizure could also include local paren- chymal, intracerebroventricular or system delivery of drugs although few drugs are approved for intrathecal or parenchymal delivery and diffusion is limited. Electrical stimulation of a focal region is attractive, but it would exert a limited field of effectiveness, and if ill-timed could heighten hyperexcitability and thus aggravate seizure activity. Cardiac demand systems in current clinical use appear to be highly effective at detecting abnormal rhythms and generating sufficient electrical pulses to abort abnor- mal rhythms and restart more normal beats. It is tempting to suggest that some of this technology could also be applied to pre-ictal detection of seizures. Other modes of diffuse stimulation could include cranial nerve inputs such as trigeminal30 or the current vagus nerve stimulation, but in intermittent stimulation mode. Magnetic stimulation to some regions may also be inhibitory, as may many of the current sites in thalamus, STN, or hippocampus. Many proprietary systems in development, which are neither publicized nor published, may overcome some of these difficult chal- lenges. However, many of these systems may not become general knowledge unless they are effective or FDA approval is gained. Many patients undergoing video EEGs also have implanted depth electrodes, and stimulation of the depth electrodes is currently underused as a possible method for seizure control. Such research studies would have to be added after sufficient clinical information is garnered to localize seizures. However, pre-ictal detection could be determined post hoc with application of known algorithms to optimal EEG or depth electrode signals. The cortical effects and clinical effects of stimulation or medication at different sites could also be determined on a short-term level, with possible targets: 1. The trigeminal nerve if a suitable location could be found for stimulation within or adjacent to the nerve 4. Rapid systemic medication delivery In addition to short-term studies, a combination of detection, processing, and suppression methods could be tested using a number of types of seizures. It is difficult now to argue for long-term implantation of stimulation electrodes at any of these © 2005 by CRC Press LLC sites until short-term data on clinical effects and side effects can be obtained. In addition, the stimulation level at which seizures can be suppressed will be critical as will the feasibility of suppression prior to clinical expression of a seizure in a subconscious pre-ictal state. Clearly, one long-term goal is to design, develop, and clinically test an “intelli- gent brain-pacemaker” device to detect neural activity preceding clinical manifes- tations of an epileptic seizure and disrupt this pathological brain state through intermittent electrical stimulation of a brain region or a peripheral cranial nerve. Additionally, childhood and neonatal seizures and status epilepticus are more aggressively treated early now, as better protocols for status are now in use. As episodes of febrile seizures and status decline, significantly fewer patients may experience later complex partial seizures because in many instances mesial temporal sclerosis appears to have arisen from early episodes of febrile seizures that terminated in status epilepticus. Thus, better early medical treatment may prevent the development of later intractable epilepsy, and could eventually decrease the population for whom surgical therapy of any type is considered. Despite a number of new modalities of treatments on the horizon, an ideal system would consist of pre-ictal seizure detection in a critical area of the brain, and then a counteracting influence (local or systemic drug injection, local or diffuse electrical stimulation, etc. From a clinical perspective, the only effective surgery is one that completely prevents seizure, avoids social stigmas attached to patients with the disorder, and maintains optimal neurological function- ing. The concept stems from clinical concerns about functional independence and integration of indi- viduals into society and far-reaching visions of direct interactions of the brain and mind and external events. Conceptually, all devices such as typewriters and cars can be considered brain–machine interfaces (BMIs). In many disease situations, the brain is preserved but its output mechanisms in the periphery are neither functional nor attached, making interaction with the outside world impos- sible. Reestablishing a means of interacting with the world by directly connecting to the source — the brain — is the essence of BMI development.
For instance order fildena 50 mg on line buying erectile dysfunction pills online, while recording single units from the digit-wrist area of caudal M1 and the magnocellular red nucleus as rats perform this task generic fildena 150 mg with visa erectile dysfunction doctor prescription, we have found that many neurons in both areas that code the overt arm-movement phases are strongly modulated by olfactory information taken in during the ﬁnal sniff of the food target just prior to lifting the paw12 (Figure 7. In fact, the caudal M1 in rats is distinguished by having layer IV somatosensory inputs,5 whereas most motor regions in mammals lack layer IV sensory inputs. Correspondingly, we have found that many rat M1 units are partic- ularly active during phases of the reaching task in which somatosensory information is being evaluated, such as lifting the paw off the ground, brushing the paw against M1 cell, FINAL SNIFF mRN cell, FINAL SNIFF sig001c sig019a 80 20 60 15 40 10 20 5 0 0 -1 -0. The percentages below each graph show the proportion of single units recorded in each area that displayed such signiﬁcant modulation on the ﬁnal sniff. M1 cell, LIFT M1 cell, ONSHELF M1 cell, CONTACT sig011a sig012c sig005a 40 60 30 40 30 40 20 20 10 20 10 0 0 0 -1 -0. However, in one study we conducted, the inadequacy of that model was strikingly illustrated. As animals became more proﬁcient at the task, roughly one third of all recorded S1 units developed much longer latencies consistent with motor processing, and roughly one third of all recorded M1 cells developed early, somatosensory latencies. PRINCIPLE II: INFORMATION FROM MULTIPLE SPATIAL SCALES IS PROCESSED SIMULTANEOUSLY Three or four decades ago, many researchers advocated the view that mammalian sensory systems represent their sensory surfaces topographically and with high resolution, and that the high resolution, body centered information gained at the sensory surface was gradually transformed at higher levels of the nervous system by cells with progressively larger receptive ﬁelds into object-centered representa- tions. However, it is now widely recognized that information is processed at multiple spatial scales simultaneously. For instance, at the somatosensory surface, Type I cutaneous recep- tors process mechanical somatosensory data with high spatial resolution, while Type II receptors have larger, less well deﬁned receptive ﬁelds. For instance, it has recently been discovered that in many thalamic nuclei, a matrix of calbindin-immunoreactive cells projects diffusely throughout the cortex, irrespective of sensory topography or even sensory domain. For example, the relay nucleus for body somatosensory afferents, VPL, contains both parvalbumin-positive, precisely projecting, somatotopically organized afferents to layer IV of cortical area SI, with correspondingly small receptive ﬁelds, as well as much more widely pro- jecting, calbindin-staining cells whose axons target the superﬁcial cortical layers in multiple sensory modalities. It is now hypothesized that these diffusely projecting cells play a critical role in coordinating activity across brain regions, particularly in view of evidence that many layer IV corticothalamic feedback neurons target these transcortically projecting matrix cells. For example, much like the thalamic relay nuclei, the striatum of the basal ganglia contains topographically more ordered regions that process information with high spatial resolution (striosomes), as well more diffusely orga- nized regions26 (matrix cells). And the relative lack of topographical ordering in the cerebellum, where instead distant regions of the body surface are adjacently located in the cerebellar cortex,19 is thought to promote sensorimotor learning across the whole body. Behavioral tasks therefore either need to be extremely well controlled if they are to be based primarily on the hypothesis of high resolution, topographic processing (e. PRINCIPLE III: LABORATORY ANIMALS ARE CONSTANTLY EVALUATING INFORMATION ACROSS MULTIPLE TIME SCALES IN ORDER TO MORE ACCURATELY PREDICT WHAT WILL HAPPEN IN THEIR WORLD It is now widely agreed that mammals – like nearly all species with nervous systems – are constantly re-evaluating the past at different time scales and com- bining the resulting knowledge with their current perceptions in order to predict the future at different time scales. The sample appears to gain skill in a linear fashion over the course of the ﬁrst six training days, when it then begins to asymptote at its highest performance level. Many older task models were based on the simplifying assumption that tasks were learned and maintained as a simple function of the number of training trials up through reaching an asymptotic performance level, and degraded as a simple function of lack of practice or interference by new memories. For example, rats in a recent study of ours12 were trained daily on the skilled reach-to-grasp-food task39 described earlier. On day one of training the sample of rats grasped the target correctly on 27% of trials, and improved daily and linearly in their perfor- mance until day six, when their success rate began to asymptote at approximately 68% correct (Figure 7. Consistent with this view of task learning, it was recently shown that the caudal digit-wrist motor cortex, which contains an overlapping somatosensory representation of the forepaw, expands and grows new synapses during the learning of this task, whereas no similar changes were detected in the (more strictly motor) rostral M120 (note that this ﬁnding also underscores Principal I). Moreover, the degree of long term potentiation in M1 synapses has been found to correlate with reaching skill acquisition. PARALLEL PROCESSING AT MULTIPLE TIME SCALES However, other neuroscientiﬁc data suggest that the information processing relevant to task learning and performance ﬂows in a more complex manner, as rats or other animals attempt to better understand their past and better predict the future. These processes occur at multiple time scales throughout different levels of the nervous system. For example, at the somatosensory periphery, slowly adapting versus rapidly adapting cutaneous receptors in the mammalian glabrous skin38 allow simultaneous perception of different aspects of the tactile world. In the ﬁgure, C stands for a comparator component, which compares the current behavioral output with the ideal output and then feeds that information back to the adaptive ﬁlter. Modiﬁcation of neural processing by evaluative feedback is seen at longer time scales as well, e. Animals are also constantly using their current experience to develop better models of what might occur to them.
The sequential activation Upon vascular injury buy fildena 100 mg low cost erectile dysfunction treatment new delhi, the coagulation of several enzymes allows the afore- system is activated: thrombocytes and mentioned reactions to “snowball” order 150 mg fildena visa erectile dysfunction pills, cul- fibrin molecules coalesce into a “plug” minating in massive production of fibrin (p. Unnecessary Progression of the coagulation cas- formation of an intravascular clot – a cade can be inhibited as follows: thrombosis – can be life-threatening. If 1) coumarin derivatives decrease the clot forms on an atheromatous the blood concentrations of inactive fac- plaque in a coronary artery, myocardial tors II, VII, IX, and X, by inhibiting their infarction is imminent; a thrombus in a synthesis; 2) the complex consisting of deep leg vein can be dislodged, carried heparin and antithrombin III neutraliz- into a lung artery, and cause complete es the protease activity of activated fac- or partial interruption of pulmonary tors; 3) Ca2+ chelators prevent the en- blood flow (pulmonary embolism). In addition, at- ble complexes with Ca2+; oxalate pre- tempts are directed at inhibiting the ag- cipitates Ca2+ as insoluble calcium oxa- gregation of blood platelets, which are late. Chelation of Ca2+ cannot be used prominently involved in intra-arterial for therapeutic purposes because Ca2+ thrombogenesis (p. For the thera- concentrations would have to be low- py of thrombosis, drugs are used that ered to a level incompatible with life dissolve the fibrin meshwork! There are two ways to initiate the cascade (B): 1) conversion of factor XII into its active form (XIIa, intrinsic system) at intravas- cular sites denuded of endothelium; 2) conversion of factor VII into VIIa (extrin- sic system) under the influence of a tis- sue-derived lipoprotein (tissue throm- boplastin). Some activated factors require the presence of phos- pholipids (PL) and Ca2+ for their proteo- lytic activity. Conceivably, Ca2+ ions cause the adhesion of factor to a phos- pholipid surface, as depicted in C. Phos- pholipids are contained in platelet fac- tor 3 (PF3), which is released from ag- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Antithrombotics 143 XII XIIa Synthesis susceptible to inhibition by coumarins XI XIa Reaction susceptible to inhibition by heparin- antithrombin complex IX IXa VIIa VII VIII + Ca2+ + Pl Ca2+ + Pl (Phospholipids) X Xa V + Ca2+ + Pl Prothrombin II IIa Thrombin Fibrinogen I Ia Fibrin A. Inhibition of clotting cascade in vivo Platelets Endothelial Clotting factor defect COO– COO- XII – COO ++ Tissue thrombo- ++ kinase – – XIIa – – – PF3 VIIa VII – Phospholipids e. Inhibition of clotting by removal of Ca2+ Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Carbox- iologically by complexing with anti- yl groups are required for Ca2+-mediat- thrombin III (AT III), a circulating gly- ed binding to phospholipid surfaces (p. There are several vitamin K de- ting by accelerating formation of this rivatives of different origins: K1 (phy- complex more than 1000-fold. Heparin tomenadione) from chlorophyllous is present (together with histamine) in plants; K2 from gut bacteria; and K3 the vesicles of mast cells; its physiologi- (menadione) synthesized chemically. Therapeutically used All are hydrophobic and require bile ac- heparin is obtained from porcine gut or ids for absorption. Structurally chains of amino sugars bearing -COO– related to vitamin K, 4-hydroxycouma- and -SO4 groups; they contain approx. Antico- min K from vitamin K epoxide, hence agulant efficacy varies with chain the synthesis of vitamin K-dependent length. Synthesis of The numerous negative charges are clotting factors depends on the intrahe- significant in several respects: (1) they patocytic concentration ratio of cou- contribute to the poor membrane pe- marins to vitamin K. The dose required netrability—heparin is ineffective when for an adequate anticoagulant effect applied by the oral route or topically on- must be determined individually for to the skin and must be injected; (2) at- each patient (one-stage prothrombin traction to positively charged lysine res- time). Subsequently, the patient must idues is involved in complex formation avoid changing dietary consumption of with ATIII; (3) they permit binding of green vegetables (alteration in vitamin heparin to its antidote, protamine K levels), refrain from taking additional (polycationic protein from salmon drugs likely to affect absorption or elim- sperm). For effective thromboprophylaxis, a The most important adverse ef- low dose of 5000 IU is injected s. With low dosage of can be counteracted by giving vitamin heparin, the risk of bleeding is suffi- K1. Coagulability of blood returns to ciently small to allow the first injection normal only after hours or days, when to be given as early as 2 h prior to sur- the liver has resumed synthesis and re- gery. In urgent cases, deficient factors bleeding, other potential adverse effects must be replenished directly (e. K3 Menadione Acenocoumarol Carboxylation of glutamine residues II, VII, IX, X 4-Hydroxy- Vit. Vitamin K-antagonists of the coumarin type and vitamin K Activated clotting factor Inacti- Inacti- vation vation Mast cell AT III AT III + + + + + + + + - - - - Heparin 3 x 5000 IU s.
Theophylline also may exert an antiinﬂamma- Theophylline should be used with caution in pa- tory effect through its ability to modulate inﬂammatory tients with myocardial disease discount 25mg fildena with amex sudden onset erectile dysfunction causes, liver disease cheap fildena 150mg with visa erectile dysfunction medication online, and acute mediator release and immune cell function. The half-life of theophylline is Inhibition of cyclic nucleotide phosphodiesterases is prolonged in patients with congestive heart failure. Phos- is warranted when coadministering drugs, such as cime- phodiesterases are enzymes that inactivate cAMP and tidine or zileuton, that may interfere with the metabo- cyclic guanosine monophosphate (GMP), second mes- lism of theophylline. Indeed, coadministration of zileu- sengers that mediate bronchial smooth muscle relax- ton with theophylline is contraindicated. It is also used to treat the reversible compo- nent of airway obstruction associated with chronic ob- The parasympathetic cholinergic pathway emanating structive pulmonary disease and to relieve dyspnea as- from the vagus nerve exerts the main neuronal control sociated with pulmonary edema that develops from in human airways. The most prevalent peripheral side effects are dry mouth, headache, nervousness, dizzi- Basic Pharmacology ness, nausea, and cough. Unlike atropine, ipratropium The airway effects of released acetylcholine are medi- does not inhibit mucociliary clearance and thus does ated via activation of three distinct muscarinic receptor not promote the accumulation of secretions in the lower subtypes: M1, in parasympathetic ganglia, mucous glands airways. ANTIINFLAMMATORY AGENTS Although atropine and related compounds possess The medical and scientiﬁc communities have recog- bronchodilator activity, their use is associated with the nized that asthma is not simply a disease marked by typical spectrum of anticholinergic side effects (see acute bronchospasm but rather a complex chronic in- Chapter 13), and they are no longer used in the treat- ﬂammatory disorder of the airways. To improve the clinical utility of anti- knowledge, antiinﬂammatory agents, particularly corti- cholinergics, quaternary amine derivatives of atropine costeroids, are now included in the treatment regimens were developed. Corticosteroids A major breakthrough in asthma therapy was the intro- Clinical Uses duction in the 1970s of aerosol corticosteroids. Ipratropium has a slower onset of action markedly reduced systemic absorption, they are associ- (1–2 hours for peak activity) than 2-adrenoceptor ago- ated with a greatly reduced incidence and severity of nists and thus may be more suitable for prophylactic side effects. Compared with 2-adrenoceptor agonists, iprat- substantial reduction in the use of systemic cortico- ropium is generally at least as effective in chronic ob- steroids. Inhaled corticosteroids, along with 2-adreno- structive pulmonary disease but less effective in asthma. Side All corticosteroids have the same general mechanism of effects are much more prevalent with systemic adminis- action; they traverse cell membranes and bind to a spe- tration than with inhalant administration. The steroid-receptor complex consequences of systemic administration of the corti- translocates to the cell nucleus, where it attaches to nu- costeroids include adrenal suppression, cushingoid clear binding sites and initiates synthesis of messenger ri- changes, growth retardation, cataracts, osteoporosis, bonucleic acid (mRNA). The novel proteins that are CNS effects and behavioral disturbances, and increased formed may exert a variety of effects on cellular func- susceptibility to infection. The precise mechanisms whereby the cortico- side effects can be reduced markedly by alternate-day steroids exert their therapeutic beneﬁt in asthma remain therapy. At the mo- inhaled agents are either poorly absorbed or rapidly lecular level, corticosteroids regulate the transcription of metabolized and inactivated and thus have greatly di- a number of genes, including those for several cytokines. The The corticosteroids have an array of actions in sev- most frequent side effects are local; they include oral eral systems that may be relevant to their effectiveness candidiasis, dysphonia, sore throat and throat irritation, in asthma. Some regulation of -adrenoceptor numbers, inhibition of studies have associated slowing of growth in children IgE synthesis, attenuation of eicosanoid generation, de- with the use of high-dose inhaled corticosteroids, al- creased microvascular permeability, and suppression of though the results are controversial. In addition, al- Clinical Uses lergic conditions, such as rhinitis, conjunctivitis, and The corticosteroids are effective in most children and eczema, previously controlled by systemic corticos- adults with asthma. They are beneﬁcial for the treat- teroids, may be unmasked when asthmatic patients are ment of both acute and chronic aspects of the disease. Inhaled corticosteroids, including triamcinolone ace- Caution should be exercised when taking cortico- tonide (Azmacort), beclomethasone dipropionate (Beclo- steroids during pregnancy, as glucocorticoids are terato- vent, Vanceril), ﬂunisolide (AeroBid), and ﬂuticasone genic. Systemic corticosteroids are contraindicated in (Flovent), are indicated for maintenance treatment of patients with systemic fungal infections. Systemic corticosteroids, including pred- ALTERNATIVE THERAPIES nisone and prednisolone, are used for the short-term A number of medications useful in the treatment of treatment of asthma exacerbations that do not respond asthma are neither strictly bronchodilators nor antiin- to 2-adrenoceptor agonists and aerosol corticosteroids. They are classiﬁed as alternative Systemic corticosteroids, along with other treatments, asthma therapies (Table 39. Because of phylactically to decrease the frequency and severity of the side effects produced by systemically administered asthma attacks, are not indicated for monotherapy. They corticosteroids, they should not be used for maintenance are used along with adrenomimetic bronchodilators, therapy unless all other treatment options have been corticosteroids, or both. A ﬁxed combination of inhaled ﬂuticasone and sal- meterol (Advair) is available for maintenance antiin- Leukotriene Modulators ﬂammatory and bronchodilator treatment of asthma. Until the late 1990s, nearly 3 decades had passed since the introduction of a truly new class of antiasthma drugs hav- Adverse Effects and Contraindications ing a novel mechanism of action. This situation changed The side effects of corticosteroids range from minor to with the introduction of zaﬁrlukast (Accolate) and severe and life threatening.