By Z. Urkrass.
Dextroam- phetamine can help persons maintain satisfactory job performance while being Dextroamphetamine 107 deprived of sleep discount aurogra 100 mg visa erectile dysfunction icd 9 code. Some pilots called the substance crucial for top performance of respon- sibilities order aurogra us impotence under 30. Outside evaluation concluded that efﬁciency and safety improved when pilots were under the drug’s inﬂuence purchase aurogra 100 mg online impotence caused by medication. Athletic performance may be enhanced by the drug, but amphetamine class substances are generally banned by sports regulatory authorities. Tests on healthy volunteers found that taking enough dextro- amphetamine to produce euphoria was also enough to produce mania. The drug may cause stroke and is normally avoided if patients have heart disease, hardening of the arteries, high blood pressure, glaucoma, hyperthyroidism, restlessness, and former or current drug abuse. Heart trouble has been attrib- uted to several years’ abuse of the drug, and brain damage has been noted. Lack of dependency has been noted among juveniles receiv- ing medical doses of dextroamphetamine. Another study found that adults with medical authorization to use dextroamphetamine for obesity or depres- sion often found it no more appealing than a placebo. These results are con- sistent with the fact that any drug’s potential for abuse depends on the needs it satisﬁes in a user; if a medical need is the only one satisﬁed, then the person will have no interest in continuing the drug once the afﬂiction is cured. Among persons inclined toward abuse, that inclination can be increased by taking dextroamphetamine with morphine. Those two substances can cancel out some of each other’s unpleasant physical sensations while retaining the psychological pleasures of both drugs. Abusers may interpret the situation as “gain without pain,” but combining stimulants with depressants can give the human body quite a beating. Moreover, researchers ﬁnd that abusers can ac- quire tolerance to the psychological effects of dextroamphetamine while effects on blood pressure remain strong. Therefore, boosting the dose to maintain the level of psychic high may pose as much danger to a habituated user as to someone unaccustomed to the drug. Although the antimania medicine lithium reduces central nervous system stimulation caused by amphetamine, experiments have not shown lithium reducing either mania or heart rate and blood pressure in- creases caused by dextroamphetamine. Such foods include beer, some wines, cheese, chocolate, bananas, raisins, avocados, salami, and soy sauce. Tricyclic antidepressants make a dose of dextroamphetamine last longer and can increase amphetamine blood levels produced by dextroamphetamine. Although extrapolation of animal studies to human conditions must always be cautious, it is known that dextroamphetamine’s effects become stronger in rats if they take caffeine at the same time. Rat and human experiments also indicate that dextroamphetamine will improve pain relief provided by mor- phine. Animal experiments indicate that dextroamphetamine interferes with alcohol absorption, suggesting that achieving alcohol intoxication might re- 108 Dextroamphetamine quire a dextroamphetamine user to drink more than normal. Upon taking dextroamphetamine, tobacco cigarette smokers use more cigarettes and report greater pleasure from smoking. Combining marijuana smoking with dextroamphetamine does not seem to affect physical coordination (walking and the like) more than just using mar- ijuana alone. Each of those two drugs raises heart rate and blood pressure but do not seem to have a multiplier effect when used together—the increase in cardiac effects is simply the amount caused by dextroamphetamine plus the amount caused by marijuana; one does not make cardiac effects of the other more potent. One instance of serious birth defects is reported from a woman who used dextroamphetamine in the ﬁrst trimester, but the meaning of that one instance is uncertain because she also used lovastatin (a drug for reducing cholesterol in persons at serious risk of heart attack), and lovastatin by itself is considered highly dangerous to fetal development. A statistical association has been re- ported between maternal dextroamphetamine use and infant heart defects. Dextroamphetamine has been prescribed for use in pregnancy without ap- parent ill effect on infants but is considered potentially hazardous. Biphetamine is used recreationally to boost men- tal quickness and physical activity and to create euphoria. The compound can facilitate hallucinations, raise blood pressure, and prevent sleep. Dexedrine’s oral capsule is designed to deliver some of the drug immedi- ately, followed by gradual delivery of the remaining drug. In this context “inactive” means an ingredient that does not promote a drug’s medical purpose, not that the ingredient has no pharmaceutical effect. Experimenters found that the product can allow satisfactory performance by airplane pilots on continuous simulator ﬂight duty for 64 hours straight without sleep. Because the drug is an opiate analogue and is related to levor- phanol, for convenience this book lists dextromethorphan as an opioid. Nal- oxone, a chemical used to provoke withdrawal symptoms in persons who have dependence with opiates and opioids, can bring forth those symptoms in addicts who have switched from methadone to dextromethorphan. That ﬁnding is consistent with dextromethorphan being an opioid; nonetheless, the substance is not generally classiﬁed as an opioid. The drug resembles codeine but is considered weaker in humans, although a cat experiment measured dextromethorphan as three times stronger than codeine. Body processes break down dextromethorphan into other substances including dextrorphan. Urinalysis comparing the amounts of dextromethorphan and its break- down product dextrorphan can identify a person’s susceptibility to lung can- cer. Case reports tell of dextromethorphan’s success in treating infants’ brain seizures. One experiment found the substance to be a useful supplement in treating older epileptics, but another study detected no improvement. Parkin- son’s disease patients have shown encouraging response to treatment with the drug, but using it against Huntington’s disease and Lou Gehrig’s disease has brought disappointment. A mice experiment in France tested whether dextro- methorphan can protect against the effects of the chemical warfare agent so- Dextromethorphan 111 man, but the results were negative. Army experiment with guinea pigs also found dextromethorphan to have little value as protection against soman poisoning. Most persons ﬁnd the drug unpleasant if the medically rec- ommended dosage is exceeded, with unwanted effects such as easy excitabil- ity, memory trouble, nausea, itching, interference with male sexual function, slurred speech, trouble with thinking, and difﬁculty with moving arms and legs. Nonethe- less, one study of cough medicines found that volunteers preferred dextro- methorphan to other remedies that were effective, leading the researchers to speculate that the drug was providing pleasure unrelated to effectiveness in relieving cough. In one instance, the com- pound allowed a lawyer to work industriously for weeks with little sleep, followed by mental collapse requiring hospitalization. This individual had engaged in manic episodes and drug abuse in the past, however. Persons without such a history may well be susceptible to manic reactions from over- use of dextromethorphan, but the examples just cited raise the question of whether persons prone to drug abuse are particularly susceptible. Investigators examining dextromethorphan’s potential for treating juvenile bacterial meningitis called off the experiment when patients began developing diabetes after receiving high doses of the drug (possibly because of action on the pancreas inhibiting insulin production), and reports exist about other in- stances of juveniles developing diabetes when being treated with the com- pound. Accounts of persons abusing dextromethorphan began ap- pearing in science journals during the 1960s. In the 1990s news media reports described the substance as popular among teenagers, who sometimes referred to this drug use as “robo-copping.
It is evident that the relative contribution of the high-Km enzyme increases (and that of the low-Km enzymes decreases) as the substrate concentration is increased 100mg aurogra sale erectile dysfunction icd 9 code wiki. The Hill equation is: n Vmax Á ½S v ¼ n ð9Þ S50 þ ½S where S50 is analogous to (but not identical to) Km (i aurogra 100 mg on-line erectile dysfunction after radiation treatment for rectal cancer. When n is greater than 1 purchase aurogra 100mg without prescription erectile dysfunction doctors in nj, it indicates positive cooperativity (substrate activation); when n is less than 1, it indicates negative cooperativity (substrate inhibition) (109). A Hill coefficient of 2 implies the presence of two discrete (nonoverlapping) substrate-binding sites on the enzyme, whereas a Hill coefficient of, say, 1. Correlation Analysis: Sample-to-Sample Variation in the Metabolism of the Drug Candidate Correlation analysis is one of the four basic approaches to reaction phenotyping. The experimental conditions for examining the in vitro metabolism of the drug candidate by a bank of human liver microsomes are based on the results of experiments described in Steps 2 and 3 (i. In order to obtain clinically relevant results, the metabolism of the drug candidate by human liver microsomes must be examined at pharmacologically relevant concentrations of the drug candidate, as illustrated for lansoprazole 5-hydroxylation in Figure 20. In our laboratory, reaction phenotyping is carried out with a bank of human liver microsomal samples (e. Banks of human liver microsomes intended for correlation analysis are commercially available as kits (e. The latter determination also provides a measure of the statistical significance of any correlations. Correlation analysis provides valuable information on the extent to which the metabolism of a drug candidate will potentially vary from one subject to the next (i. However, when two or more enzymes contribute to metabolite formation, corre- lation analysis may lack the statistical power to establish the identity of each enzyme. Statistically significant correlations should always be confirmed with a visual inspection of the graph because there are two situations that can produce a misleadingly high correlation coefficient: (1) the regression line does not pass through or near the origin and (2) there is an outlying data point that skews the correlation analysis, as illustrated in Figure 25. Correlation analysis works particularly well when a single enzyme dominates the formation of a particular metabolite. This approach success- fully identifies the enzymes involved when each enzyme contributes 25% or more to metabolite formation, but it will likely not identify an enzyme that contributes only approximately 10%. A graphical representation of the application of multivariate analysis to the results of a reaction phenotyping experiment is shown in Figure 26, on the basis of an examination of the sample-to-sample variation in the 1-hydroxylation of bufuralol (12 mM) by a panel of human liver microsomes. The sample-to-sample variation in bufuralol 1-hydroxylation correlates reasonably well with In Vitro Study of Drug-Metabolizing Enzymes 327 Figure 25 Common pitfalls in correlation analysis. Correlation analysis is suspected when the regression line is unduly affected by a single outlying data point, or when the regression line does not pass near the origin. When two enzymes contribute significantly to metabolite formation, their identity and relative con- tribution can be established by performing correlation analysis in the presence and absence of an inhibitor of one of the participating enzymes (preferably the major contributor). This approach works even when one of the enzymes contributes substantially less than 25% to metabolite formation, as was demonstrated by 328 Ogilvie et al. Chemical and Antibody Inhibition Chemical and antibody inhibition represent the second and third approaches to reaction phenotyping. As in the case of correlation analysis, chemical and antibody inhibition experiments must be conducted with pharmacologically relevant concentrations of the drug candidate in order to obtain clinically relevant results. Therefore, appropriate solvent and preincubation controls should be included in all chemical inhibition experiments. The lack of specificity can complicate the interpretation of chemical inhibition experiments. If a drug candidate is metabolized by a high-affinity enzyme, the con- centration of a competitive chemical inhibitor must be increased with increasing concentration of the drug candidate in order to achieve a high degree of inhi- bition. A good rule of thumb is to use multiples (generally up to 10-fold) of the lowest inhibitor concentration, which is calculated from the following equation: ½DrugÁKiðinhibitorÞ Lowest½Inhibitor¼ ð10Þ KmðDrugÞ where [Drug] is the intended final concentration of the drug candidate added to the microsomal incubation, Ki is the inhibition constant of the inhibitor for a given enzyme, and Km is the Michaelis constant of the drug candidate (as determined in Step 3). This method of calculating of the lowest concentration of inhibitor is applicable to competitive inhibitors but not to noncompetitive or metabolism-dependent inhibitors. A range of inhibitor concentrations is rec- ommended to demonstrate concentration dependence. For example, if the lowest concentration of the chemical inhibitor were calculated to be 1 mM (from the above equation), then the range of inhibitor concentration should span at least 10-fold (e. If both enzymes contribute to metabolite formation, the inhibitory effect of the chemical on one enzyme may be offset by its activating effect on the other enzyme. When chemical inhibition experiments are conducted with a relatively metabolically stable drug candidate (one that must be incubated with relatively high concentrations of human liver microsomes for a relatively long time in order to generate quantifiable levels of metabolite), it is important to take into account the metabolic stability of the inhibitors themselves. Lack of metabolic stability makes some compounds poor choices as chemical inhibitors despite their selectivity. Finally, appropriate controls should be included in each chemical inhibi- tion experiment to evaluate whether any of the chemical inhibitors interfere with the chromatographic analysis of the metabolites of interest and whether metabolite formation is inhibited by any of the organic solvents used to dissolve the chemical inhibitors. Unfortu- nately, the utility of this method is limited by the availability of specific inhibitory antibodies and by nonspecific effects associated with the addition of antiserum and ascites fluid to the microsomal incubation. The use of antiserum (for polyclonal antibodies) and ascites fluid (for monoclonal antibodies) rather than purified antibodies often necessitates adding a large amount of albumin and other proteins to the micro- somal incubation. For this reason, control (preimmune) serum and ascites fluid should be included as negative controls in antibody inhibition experiments. These issues are lessened when purified antibodies are used instead of antisera and ascites fluid. As in the case of chemical inhibition, a lack of specificity can complicate the interpretation of antibody inhibition experiments. A lack of specificity and the nonspecific effects outlined above likely account for the majority of cases where the sum of the inhibitory effects of a panel of inhibitory antibodies adds up to greater than 100%. If an antibody inhibits the metabolism of a marker substrate by 80%, and if the same antibody inhibits the metabolism of drug candidate by 80%, there is uncertainty as to whether the inhibited enzyme contributes 80% or 100% to the metabolism of the drug candidate. Genetic or drug- mediated loss of an enzyme that accounts for 80% of a drug’s clearance will cause a fivefold increase in systemic exposure, whereas loss of an enzyme that accounts for 99% of a drug’s clearance will cause a 100-fold increase in exposure. In both cases, cytochrome b5 increases Vmax/Km, which is a measure of in vitro intrinsic clearance. The kinetic constants are only determined for those enzymes that were shown in preliminary experiments to be capable of metabolizing the drug candidate. Unfortunately, this method is complicated by the empirical observation that Km, 334 Ogilvie et al. The Relative Merits of the Four Approaches to Reaction Phenotyping Many of the potential pitfalls and advantages or disadvantages of the four approaches to reaction phenotyping have been mentioned in the preceding sec- tions, and they are summarized in Table 10. Establishes the degree of inter- microsomes (n ¼ 10 or more) individual variation in metabolic formation or substrate disappearance. An outlying data point or a regression line that does not intersect near the origin can produce misleading results. Metabolite formation by high activity samples may violate initial rate conditions (<10% substrate loss). Lack of antibody specificity may reflect cross- fluid or purified antibody) reactivity or an artifact of adding albumin (present at high concentrations in serum and ascites fluid). Solvent controls for all chemical inhibitors and preincubation controls for metabolism-dependent inhibitors must be included.
Unlike brandy or strychnine or digitalis order aurogra 100 mg with visa impotence divorce, the immediate and sharp purchase cheap aurogra online impotence questionnaire, stimulating purchase aurogra visa erectile dysfunction drugs walmart, or whipping-up effects do not appear in the same way to be lost when the effect of the medicine is gone. The improvement on all conditions is plainly marked, but the restoration is nearly that of a full normal condition obtained in a smooth and satisfactory manner. It is more like an increase of vital force, which remains to a large extent, in the improved condition of all the functions after the remedy has had time to be fully eliminated. From my own personal observations and from the conclusions I have drawn from the observations of others, I would say that lobelia seems at once to supply a subtle but wholly sufficient force, power, or renewed vital influence, by which the nervous system and the essential vital force within the system again reassert themselves and obtain complete control of the functional action of every organ. From this influence, in a natural and sufficient manner, a complete harmonious operation of the whole combined forces is at once resumed, in some cases in an almost startling manner. Other agents stimulate, prop up, whip up or temporarily increase the force and power of one or another function, while this remedy with this peculiar power at once assumes control of the whole, and succeeds against all the opposing influences. Specific Symptomatology—This remedy is specific given in irritable, Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 278 spasmodic and oppressed breathing, and in respiratory disorders from exalted nerve force and nerve irritation. It is contraindicated in general relaxation and in dyspnea from enlarged or fatty heart, or from hydropericardium, or enfeebled heart, with valvular incompetence. It is specific in threatened spasm with exalted nerve action—a high degree of nerve tension with great restlessness and excitability, flushed face and contracted pupils. Therapy—In spasmodic asthma, if given in a dose of from thirty minims to one dram during the paroxysm, the benefit is apparent almost immediately. This full dose may be once repeated, but this is seldom necessary, and a single dose seldom produces vomiting. When continued with other agents it must be given in doses not to exceed ten minims three or four times a day. It is a reliable expectorant, and either alone or in combination with other indicated remedies, is useful in all cases of dry, hard, barking cough, or where the expectoration is difficult to raise, in spasmodic croup, and in membranous croup without depression. It is not so commonly used at the present time for that purpose as ipecac, as the irritation, nausea and general depression are usually greater than is necessary. It resembles tobacco in this and in many other particulars, producing a burning sensation in the fauces which is persistent and unpleasant. Either alone or combined with tincture of capsicum, it has long been used to overcome spasms of all characters, from infantile convulsions to puerperal eclampsia and epilepsy. It has been given in tetanus with benefit, and with success in the spasm of hydrophobia and of strychnia poisoning. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 279 Because of the great importance placed upon this remedy by Thompson, and the violent opposition which followed his endorsement, it has been openly decried by the profession at large, and denounced because of its inactivity in small doses, and declared to be a profound poison in full doses. If it had been given fearlessly in full, large, single doses, the best of results would have occurred. As a remedy for hysteria, hysterical paroxysms and hysterical convulsions, the combined tinctures of this remedy and capsicum have no superior. It will immediately terminate many paroxysms and quickly control convulsive attacks. This agent has in the past been exceedingly popular as a relaxant in rigid os uteri. Very many cases are on record of almost immediate relaxation and rapid termination of labor. Ernst Jentzsch, sitting one night at the bedside of his only son in the throes of death, from fulminating diphtheria, after antitoxin to the extreme limit had been used, and all other available measures, claims that in answer to prayer, with a peculiar confidence that he could not account for, gave the boy, without any precedent, a hypodermic injection of one-half dram of specific medicine, lobelia. He made the following statement as to results: “All the fatal symptoms gave way to those of returning health, the patient passing from a death struggle into a peaceful slumber, from which he awoke after three hours, somewhat weak. Another dose was given, which was followed by a still more pronounced reaction for the better. The patient from that time continued to convalesce, and, with the exception of a post-diphtheritic pharyngeal paralysis, he made a rapid recovery. At first there was some doubt from the reports received, but later and more recently reports are quite uniformly favorable in encouraging the belief that it will be found to be fully as useful a remedy as the serum antitoxin. It not only removes the membranes, but it Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 280 destroys the germs of disease, and at once puts the patient in the best possible physical condition to resist its inroads. It preserves intact the functions of the body, and preserves or restores the functions of the nervous system. It is nontoxic, has not only no anaphylaxis following, but a single dose restores a patient suffering from anaphylaxis from the serum antitoxin. The latest report at this writing received found nine children in a hovel with no care, all with diphtheria and only one with the disease mildly. Using nothing whatever except lobelia, the physician lost one case out of the nine, putting them, however, into as good condition as possible in their surroundings from the beginning of his treatment. The dose for diphtheria varies from ten minims to forty, and is administered according to the demands of the patient from one hour at first to six hour intervals, with one or two injections a day for any subsequent paralysis. An occasional case however will show unfavorable results, and in some cases where there are serious heart lesions, there has been prostration, depression, and threatened death which were combated only by vigorous measures. The smaller dose should be used in these cases until no evidence of idiosyncrasy or susceptibility are known to occur. This agent is equally satisfactorily in the treatment of diphtheritic- membranous—croup. In the treatment of tonsillitis, it will not be needed except in the severer forms, in which it will promote satisfactory results. In the treatment of coughs, those due to pneumogastric irritation, are quickly relieved as well as the pain accompanying. In the treatment of whooping cough, but few cases are reported at this time, but the suggestion is that it be given just preceding the attack of Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 281 cough and repeated if possible on two or three consecutive attacks. In the treatment of bronchial coughs and acute bronchitis, especially if the bronchial tubes are loaded with mucus and there is a sense of tightness with some difficulty in breathing, the agent is directly indicated. If with pneumonia or broncho-pneumonia there should be rapid shallow breathing with anxious expression of the countenance and a tendency to cyanosis, this agent is clearly indicated. It is well known that in the treatment of pneumonia in the later stages, symptoms occur frequently which seem to threaten an almost immediate fatal termination. When from any cause, usually from heart complications, the patient complains of shortness of breath, especially if there be any sense of oppression in the chest, or tightness around the chest, a medium dose of lobelia hypodermically will give full freedom and in many cases a careful properly timed repetition of the injection will give permanent relief. In the treatment of nausea, persistent vomiting, and a generally disturbed condition of the stomach, if ten drops of lobelia be added to half a glass of water and a teaspoonful be given by the mouth every ten or fifteen minutes, it will often give prompt relief. It is also useful adjusted in the same manner as the above for sick headaches and given over a period of time with reference to the conditions that induce the disease and also to any possible periodical recurrence of the disease, it will be found curative. In the treatment of acute spasm in the stomach, in the pylorus or cardiospasm, this agent is of immediate benefit. Some obstinate Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 282 cases having been cured with it. It quickly relieves certain cases of chronic constipation, and is positively indicated in obstipation and where the obstruction of the bowels seem certain. No depression is observed, no erratic action, even when what would seem to be unnecessarily large doses have been given. Heart conditions depending upon feebleness or lack of tone or of muscular power should have occasional regular doses of this agent. In chronic heart disease with dilatation—hypertrophy—the consequent valvular deficiency and other structural defects, the agent must be given with caution as in a few cases untoward results have been seen.
Compounds of this group include tubocurarine generic aurogra 100 mg impotence brochures, metocurine purchase generic aurogra line erectile dysfunction caused by high cholesterol, gallamine buy aurogra 100mg fast delivery impotence zantac, pancuronium, vecuronium, and atracurium. Tubocurarine is used mainly in anesthesiology as a myorelaxant, causing prolonged muscle relaxation during an operation. Small doses are successful at causing temporary relaxation of skeletal muscle without any vital change of primary body functions. It is used particularly in endotracheal intubation or orthopedic surgery for repositioning fractures, resetting compound dislocations, and so on. Metocurine: Metocurine, 6,6 ,7 ,12 -tetramethoxy-2,2,2 ,2 -tetramethyltubocuraranium dichloride (15. Pancuronium: Pancuronium, 1,1 -(3α,17β-diacetoxy-5α-androstan-2β,16β-ylene)-bis- (1-methylpiperidinium) dibromide (15. It is used in anesthesiology as a myorelaxant, causing prolonged muscle relaxation during surgical interventions of the thoracic and abdominal cavities, in proctology, ophthalmology, ortho- pedic practice, and in heart surgeries. Only the piperidine substituent on C16 of the steroid skeleton is transformed into a quaternary salt [15,16]. Atracurium: Atracurium is 2,2 -[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]] bis [1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquino- linium] dibenzene sulfonate (15. Two molecules of a secondary amine, tetrahydropapaverine, are joined to the product in a Michael reaction, forming compound (15. Then both nitrogen atoms are methylated by methylbenzenesulfonate, giving atracurium (15. However, since these drugs are inactivated slower than acetylcholine, they act longer in the synapse, causing a more stable depolarization. In this manner, the process of receptor repolarization is blocked and skeletal muscles relax. Succinylcholine has a lot of very practical value in medicine as a neuromuscular blocker. Muscle Relaxants Succinylcholine: Succinylcholine, 2,2 -[(1,4-dioxo-1,4-butanediyl)bis(oxy)]bis[N,N,N- trimethylethanaminium(diacetylcholine)] dichloride, which can be viewed as a dimeric mol- ecule of acetylcholine (diacetylcholine), is synthesized by reacting succinic acid dichloride with 2-dimethylaminoethanol and subsequent transformation of the resulting bis-(2-dimethy- laminoethyl)succinate (15. Unlike nondepolarizing substances, succinylchloride is not a competitive antagonist; con- versely, it is a more stable agonist than acetylcholine. In this manner, succinylcholine dif- fers from acetylcholine only in duration—it lasts longer, causing a more stable depolarization. During this period, muscles that cause fine movement (ocular, facial, neck) are the most sensitive and are blocked first, after which muscles of the extremities are blocked, and finally the most stable respiratory muscles. Therapeutic use of succinylcholine consists of preventing involuntary patient move- ment. It is used for brief operations, intubation of the trachea, and other endoscopic pro- cedures. Unlike other muscle relaxants, it has a direct effect on the contractile mechanism by interfering in the process of calcium ion release from the sarcoplasmic reticulum. This results in a lack of coordination in the mechanism of excitation––contraction of skeletal muscle, which has a greater effect on fast muscle fibers than on slow muscle fibers. Dantrolene is used for controlling the onset of clinical spasticity resulting from serious clinical cases such as wounds, paralysis, cere- bral palsy, and disseminated sclerosis. Of course, neuromuscular blockage reduces spasms; however, it is accompanied by loss of voluntary movement. In conditions of muscle spasticity, there need to be drugs capable of relieving painful muscle spasms that do not take away the ability of voluntary muscle contraction and that do not hamper brain function. Among these it is noteworthy to mention alcohol and barbiturates, which, however, are not used for this purpose because they cause sig- nificant sedation and other effects. Included is a large het- erogenic group of chemical compounds that have an effect on the spinal cord and suppress monosynaptic and polysynaptic reflexes. Among these are baclofen, cyclobenzaprine, cariso- prodol, methocarbamol, chlorphenesin, chlorzoxazone, orphenadrine, and diazepam. According to the first, 4-chlorobenzaldehyde is condensed with two moles of acetoacetic ester, giving the product (15. Reacting this with an alkaline solu- tion of a halogen (Hofmann rearrangement) gives baclofen (15. Adding nitromethane to this in the presence of base gives ethyl ester of β-(4-chlorophenyl)-γ- nitrobutyric acid (15. Signs of muscle spasticity have been shown in disseminated sclerosis and other spinal disorders. It may be useful to patients with muscle spasms resulting from spinal cord injuries. It is used as an adjuvant agent for relieving muscle spasms associated with severe diseased conditions of the muscle. It is used as an adjuvant drug for loss of flexibility of skeletal muscle as well as for relieving pain caused therein. It is used for reliev- ing spasms and skeletal muscle pain as well as for treating tetanus. The discovery and synthesis of histamine was a great achieve- ment in pharmacology, medicine, and immunology. This natural, powerful, biogenic amine is widely distributed in practically all tissues of mammals and is involved in various physio- logical processes. The body’s reaction to histamine is characterized by contraction of smooth muscle, signs of inflammation, constriction of vessels, and symptoms characteristic of shock. It is certain that histamine plays a central role in allergic reactions, hypersensitivity reactions, and is part of the body’s response mechanism in the inflammatory process. Histamine can enter the organism with food; it also can be generated by bacteria of the gas- trointestinal tract. However, these sources do not create additional reserves of histamine since exogenous histamine is easily catabolized in the organism. Histamine is dispersed and stored in mast cells in the majority of organs, in which it is preserved in secretory cytoplasmic granules in the form of a heparin-proteasic matrix mak- ing up over 10% of their mass. Histamine is also found in interstitial fluid such as digestive juices, blood, and urine. It is primarily metab- olized by two enzymes by deamination with deaminoxidase and methylating histamine with N-methyltransferase. Upon being secreted from the tissue, histamine can cause a large number of physiolog- ical effects. Its role in various pathological processes associated with severe and chronic allergic reactions and hypersensitivity reactions has been uniquely proven. At the same time, functions of endogenous histamine (in development of nerve transmission, secretion of digestive juices, tissue growth and restoration) remain inconclusive. Despite the fact that a number of various factors can cause the release of endogenous histamine, it is believed that the most important reason is an immunological response of the organism. Accepted knowledge states that during anaphylaxis and allergies, a specific 219 220 16.