By S. Chris. University of Colorado, Colorado Springs. 2018.

Most of these adverse experiences are uncommon (occurring in <1% of patients) and dose related order pilex 60caps amex. Gynecomastia has been reported in as many as 4% of patients taking prolonged high doses of cimetidine for hypersecretory conditions (Zollinger-Ellison syndrome) cheap pilex 60caps with amex. Clinical Pharmacology Cimetidine is over 90% absorbed with *50% bioavailability after oral admin- istration 60caps pilex with visa. Ithas relatively low plasma protein binding (13–25%) and is readily removed by hemodialysis. Nearly 50% of the drug is excreted unchanged in urine after an oral Drug-Drug Interactions: Marketing Perspectives 717 dose and 75% is excreted unchanged in the urine after an intravenous dose. The remaining drug after oral dosing is metabolized primarily to cimetidine sulf- oxide and to a lesser extent to 5-hydroxymethyl cimetidine and guanylurea cimetidine, which are excreted in urine. The inhibitory effect of cimetidine on these enzymes is the basis for its drug-drug interaction profile. Market Dynamics Cimetidine was launched in the United States as a first-in-class compound in 1977. The market share of Tagamet decreased steadily from 1983 until it went off patent in 1994 (Fig. Dosing conve- nience (twice a day) made Zantac much more attractive than Tagamet (four times a day) to physicians and patients. Tagamet was eventually approved for twice-daily dosing, but not in time to prevent the market uptake of Zantac. However, the adverse drug-drug interactions attributed to Tagamet also played a prominent role in the marketing strategy and success of Zantac and other competitors. The market share (expressed as percent of total prescriptions dispensed) of the antiulcerant market is shown over the period from 1979 to 1997. Note that the initial increase in market share for Zantac (1983–1986) came exclusively at the expense of Tagamet and that further erosion of Tagamet market share occurred as additional products were introduced into the market. The increasingly competitive marketplace requires that every possible advantage be highlighted, particularly with the more exten- sive use of direct-to-consumer advertising. The potential impact of drug-drug interactions must be considered at all phases of drug development. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant adminis- tration of erythromycin. Risk of developing life-threatening ventricular arrhythmia associated with terfenadine in comparison with over-the-counter anti- histamines, ibuprofen and clemastine. Mibefradil, a review of its pharmacodynamic and phar- macokinetic properties, and therapeutic efficacy in the management of hypertension and angina pectoris. Life-threatening interaction of mibefradil and [beta]-blockers with dihydropyridine calcium channel blockers. Cimetidine: a review of its pharmaco- logical properties and therapeutic efficacy in peptic ulcer disease. See also catalytic site, for, 453 Glucuronidation uses of, 453 Area under plasma concentration-time Autosamplers, 274, 276 curve. See Reaction intestinal segment model, 399 phenotyping membrane vesicles, 398–399 Enzymes, 4, 11 tissue culture transport models, induction 392–398 stabilization, 36 in vivo models for, 403–404 with two binding site, 41, 45, 47 Drug metabolism, 31, 32, 268 in vitro models for assessing, 206 enzymes of Enzyme-selective substrates, 263 cytochrome P450 (P450), 478 Enzyme/transporter phase 1, 478 inducer, 472 phase 2, 478 inhibitor, 472 preclinical, 31, 32 multiplicative effect of, 477 sites of, 471 Epoxide hydrolase, 344. Brown 33 3 Neurotransmitter receptors Classification, labelling, structural analysis, expression and cloning A. Symptoms, therapy and animal models are covered 14 Study and manipulation of neurotransmitter function in humans R. It covers what they do, how they do it and how their activity is involved in brain function and affected by drugs and disease. After an overview of neurotransmitter systems and function and a consideration of which substances can be classified as neurotransmitters, section A deals with their release, effects on neuronal excitability and receptor interaction. The synaptic physiology and pharmacology and possible brain function of each neurotransmitter is then covered in some detail (section B). The final section (D) deals with how neurotransmitters are involved in sleep and consciousness and in the social problems of drug use and abuse. Those studying medicine may also find it useful especially if working in neurology or psychiatry. We have tried to make the book readable rather than just factual and so references have been kept to a minimum, especially in the early chapters on basic neuro- pharmacology and although more are given in the applied sections, they are selective rather than comprehensive. It is often relatively straightforward to identify elements that may be involved and their individual interactions. However, as the accumulation of such studies gradually reveals a complex network of interactions, its output Ð the biological function Ð becomes ever harder to understand and predict. The system is reduced to its elements, but it is not clear how to integrate it again. We have no such pretensions in this book but we do hope to help you to understand how neurotransmitters may be involved in brain function and more particularly how their activity is modified by disease and drugs. As the above quotation implies, this will mean considering the synaptic characteristics of each neurotransmitter, but before we do so, it is important to consider some more general and basic aspects of neuro- transmitter function. What is a neurotransmitter and how did the concept of chemical transmission arise? Which neurons and pathways use which neurotransmitters and how are they organised? Most of these points are considered in detail in subsequent chapters but some will be touched on collectively here. According to the Oxford English Dictionary (2nd edition) it is: A substance which is released at the end of a nerve fibre by the arrival of a nerve impulse and by diffusing across the synapse or junction effects the transfer of the impulse to another nerve fibre (or muscle fibre or some receptor). Acetylcholine released rapidly from vesicles in the nerve terminal, on arrival of the nerve impulse, binds quickly with postsynaptic sites (receptors). When activated these open channels for sodium ions which pass through into the muscle fibre to depolarise its membrane and cause contraction. It is better than having the nerve directly linked to the muscle since the time lost through imposing a chemical at the synapse between nerve and muscle is insignificant and the use of a chemical not only facilitates control over the degree of muscle tone developed, but fortuitously makes it possible for humans to modify such tone chemically. Indeed it was the curare impregnated into the darts used by native South American hunters, so that they could paralyse and then easily kill their prey, that motivated Claude Bernand to investigate its actions at the end of the nineteenth century and so demonstrate the chemical sensitivity of excitable tissue that led to the concept of chemical transmission. He took a sciatic nerve gastrocnemious muscle preparation from a frog (not the actual quest of the hunters), placed the muscle in one dish of appropriate salt solution and extended the nerve into another. Not surprisingly, simple wire electrodes connected to an activated induction coil induced contractions of the muscle whether placed directly on the muscle or on the nerve to it. When, however, curare was added to the dish containing the muscle, direct stimulation of the muscle still induced a contraction, but activation of the nerve was ineffective. This was not due to any effect of curare on the nerve because when curare was added to the nerve rather than the muscle dish, stimulation of the nerve was still effective. Thus there had to be a chemically sensitive site on the muscle, where it was linked with the nerve, which was affected by the curare. Its cardiac effect, change in rate, occurs much more slowly, has nothing to do with the direct opening of any ion channel and is not blocked by curare.

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Such “channelopathies”— abnormally functioning channels duetoinheritable mutations—can affectany electrically active cell and are not limited to the heart cheap pilex 60caps free shipping. For Mechanismsofcardiac tachyarrhythmias 17 instance purchase pilex 60caps with amex, some varieties of migraine buy 60caps pilex mastercard, epilepsy, periodic paralysis, and muscle disorders are apparently duetochannelopathies. While several distinctive cardiac arrhythmias are now thought to be caused by channelopathies, the most clinically relevantand the most commonchannelopathic arrhythmias are those related to triggered activity. Triggered activity Triggered activity is caused by abnormal fluxes of positive ions into cardiaccells. These ionic fluxes producean abnormal “bump” in the actionpotential during late phase 3 or early phase 4 (Figure 1. Inmost if not all cases, afterdepolarizations are thought to be duetoinherited abnormalities in the channels that control the movementofcalcium ionsacross the cell membrane. If the afterdepolarizations are of sufficientam- plitude, they can trigger the rapid sodium channels (which, as noted, are voltage dependent), and thus cause another actionpotential to be generated. Digitalis-toxic arrhythmias, torsades de pointes, and someof the rare ventricular tachycardias that respond to calcium-blocking agents have all been advanced as arrhythmias that are most likely caused by triggered activity. Clinical features of the major tachyarrhythmias Before considering how antiarrhythmic drugs work, it will be help- fultoreview the salient clinical features of the major cardiac tach- yarrhythmias. Automatic supraventricular tachyarrhythmias Automatic supraventricular arrhythmias are seen almost exclusively in acutely ill patients, most of whom have one of the following condi- tions:myocardial ischemia, acute exacerbationsofchronic lung dis- ease, acute alcohol toxicity, or major electrolyte disturbances. Clinically, the heart rate with automatic atrial tachycardias is usu- ally less than200 beats/min. Like all automatic rhythms, the onset and offset are usually relatively gradual; that is, they oftendisplay warm-up, in which the heart rate accelerates over several cardiac cycles. The arrhythmia is usually associatedwith exacerbation of chronic lung disease, especially in patients receiving theophylline. Further, at least three distinctP-wave morphologies are present, which reflects the multifocal ori- gin of atrial activity in this arrhythmia. The basic strategy for treating automatic atrial arrhythmias istoag- gressively treat the underlying illness. Reentrant supraventricular tachyarrhythmias Ingeneral, patients have reentrantsupraventricular tachyarrhyth- mias because they are bornwith abnormal electrical pathways that create potential reentrant circuits. Accordingly (in contrast to pa- tients with automatic supraventricular arrhythmias), these patients most often initially experiencesymptoms when they are young and healthy. Most supraventricular tachyarrhythmias seeninotherwise healthy patients are caused by the mechanism of reentry. The five general categories of reentrantsupraventricular arrhyth- mias are listedinTable 1. Since the beta pathway conducts more rapidly thandoes the alpha pathway, a normal atrial impulse reaches the ventricles via the beta pathway. Most patients with suchbypass tracts do not have overt Wolff-Parkinson–White syndrome, however. Instead, they have concealed bypass tracts, that is, bypass tracts that are incapable of conducting in the antegrade direction (from the atrium to the ventricles), and therefore never display delta waves. Concealed bypass tracts are able to conduct electrical im- pulses only in the retrograde direction (from the ventricles to the atrium). Intra-atrial reentry differs from automatic tachycardiabecause of its sudden onset and termi- nation,and,like all reentrant arrhythmias, it can be induced by pacing. Thus, the bypass tract may be able to conduct the impulse retrogradely back to the atrium. If so, a reentrant impulse may be established, which trav- els antegradely down the normal conducting system and retrogradely up the bypass tract. In atrial flutter, the atrial activity isregular, in excess of 220 beats/min,and usually displays a typical sawtooth pattern (Figure 1. Note the randomly irregular ventricular re- sponse and the absenceofdiscrete P waves. In atrial fibrillation, the atrial activity is continuousand chaotic, and discrete P waves cannot be distinguished (Figure 1. The ventricular response is completely irregular, reflecting the chaotic nature of the atrial activity. Triggered supraventricular tachyarrhythmias The only supraventricular tachycardia commonly attributed to trig- gered activity is that seenwith digitalis toxicity. In fact, the presenceofatrial 26 Chapter 1 tachycardia with block should always make one consider the possi- bility of digitalis toxicity. Atrial flutter and atrial fibrillationcanusually be distinguished by simple inspection. Automatic ventricular tachyarrhythmias Abnormal automaticity accounts for a relatively small proportion of ventricular tachyarrhythmias. As is the case with automatic atrial arrhythmias, automatic ventricular arrhythmias are usually associ- atedwith acute medical conditions, suchasmyocardial ischemia, acid–base disturbances, electrolyte abnormalities, and highadren- ergic tone. Automatic ventricular arrhythmias are most often seen in patients with acute myocardial ischemiaorinfarction,orsome other acute medical illness. Most arrhythmias occurring within the first few hours of an acute myocardial infarction are thought to be automatic. Once the ischemic tissue dies or stabilizes, however, the substrate for automaticity is nolonger present. Ingeneral, the treatmentofautomatic ventricular arrhythmias consists of treating the underlying illness. Reentrant ventricular tachyarrhythmias Most ventricular arrhythmias are reentrant in mechanism. While the conditions producing automatic ventricular arrhythmias are usually temporary in nature (e. Because the intra- atrial reentrant circuit can be located anywhere within the atria, the P-wave morphology can have any configuration. Reentrant circuits within the ventricular myocardium usually arise after scar tissue develops, a conditionmost commonly seenin patients who have myocardial infarctionsorcardiomyopathy. Once the scar tissue gives rise to a reentrant circuit, the circuit persists, and the potential for a ventricular arrhythmiaalways exists. Reentrantventricular arrhythmias are seen only rarely in individuals who have normal ventricles. Most antiarrhythmic drugs affect the ventricular myocardium and,accordingly, most are used to treat ventricular tachyarrhyth- mias. Channelopathic ventricular tachyarrhythmias Channelopathies probably account for several distinctive types of ventricular tachyarrhythmias, at least twoofwhich have now been Mechanismsofcardiac tachyarrhythmias 29 well characterized. These are the ventricular arrhythmias dueto triggered activity and Brugadasyndrome. Triggered activity in the ventricles Because ventricular tachyarrhythmias duetotriggered activity are reasonably common,and because the managementoftriggered ven- tricular arrhythmias is very different from the managementofmore typical ventricular arrhythmias, it is importanttorecognize their characteristics.

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If there is a shift of the curve to either the right or the left buy pilex 60 caps amex, then the noradrenergic response that would be optimal in normal subjects now produces a suboptimal coping response buy discount pilex 60caps online. In the case of a shift to the left buy cheap pilex 60caps line, a reduction in noradrenergic transmission would be required to restore optimal coping whereas for a shift to the right, an increase would be required. One is that the underlying coding is correct but it is the noradrenergic response evoked by the stimulus that is inappropriate. A second is that the amplitude of the noradrenergic response to arousing stimuli is normal but the underlying coding is not. For instance, an early report suggested that there is a positive correlation between the density of (postsynaptic) b-adrenoceptors in rat cortex and behavioural resistance to a mild environmental stress (novelty and frustration) but a negative correlation between these parameters when the stress is intensified (Stanford and Salmon 1992). Evidence suggests that the relationship between these two parameters is described by a bell-shaped curve and so an optimal phasic response is manifest only at intermediate levels of tonic activity (Rajkowski et al. Obviously, it is extremely unlikely that noradrenergic transmission is the sole factor to determine the behavioural response to even simple environmental stimuli. Indeed, a bell-shaped dose±response curve immediately suggests the intervention of one or more additional factors (neurotransmitters? Such interactions with other neurotransmitters could well define the relationship between noradrenergic transmission and the coding of the coping response. Either a reduction or an increase in noradrenergic transmission produces a functional mismatch and diminishes coping. In these normal subjects, optimal coping is attained when the noradrenergic response to a specific stimulus corresponds to that marked (^). If there is a leftward shift of the curve that describes the neurochemical coding of coping, then the (predetermined) noradrenergic response that would be optimal in normal individuals now produces suboptimal coping (*). One remedy for such a dysfunction is to reduce noradrenergic transmission so as to restore optimal coping. Similarly, in the case of a rightward shift of the coping curve (c), a predetermined noradrenergic response to a specific stimulus, that would be optimal in normal individuals, will again produce suboptimal coping (*). In both (b) and (c) an alternative way to restore optimal coping would be to reverse the shift in the noradrenergic transmission/coping curve. Aston-Jones, G, Rajkowski, J, Kubiak, P and Alexinsky, T (1994) Locus coeruleus neurons in monkey are selectively activated by attended cues in a vigilance task. Bonisch, H, Hammermann, R and Bruss, M (1998) Role of protein kinase C and second messengers in regulation of the norepinephrine transporter. Fassio, A, Bonanno, G, Fontana, G, Usai, C, Marchi, M and Raiteri, M (1996) Role of external and internal calcium on heterocarrier-mediated transmitter release. Fillenz, M (1993) Short-term control of transmitter synthesis in central catecholaminergic neurones. Rajkowski, J, Kubiak, P, Ivanova, S and Aston-Jones, G (1998) State-related activity, reactivity of locus coeruleus neurons in behaving monkeys. Russ, H, Staust, K, Martel, R, Gliess, M and Schomig, E (1996) The extracellular transporter for monoamine transmitters exists in cells derived from human central nervous system glia. All these processes, together with some well-known drugs that affect them, are summarised in Fig. Yet, despite this relatively restricted distribution of cell bodies, their processes project more or less throughout the whole neuraxis. For a detailed review of this topic, see Jacobs and Azmitia (1992) but an outline of key features is given here. Despite these changes, all these nuclei are still regarded as forming two major groups. This means that these neurons are well placed for serving a key role in regulation of motor activity, autonomic function and nociception. In addition, there are numerous interconnections between the different Neurotransmitters, Drugs and Brain Function. Although extensive branching of the neuronal processes results in a considerable overlap in the terminal axonal fields of the different nuclei, there is evidence for some topographical organisation of the areas to which different nuclei project (Fig. In any case, species differences in the distribution of co-transmitters is a confounding factor. First, it has an absolute requirement for O2 and the reduced pterin co-factor, tetrahydrobiopterin. Second, hydroxylation of trypto- phan, like that of tyrosine, is the rate-limiting step for the whole pathway (reviewed by Boadle-Biber 1993) (see Chapter 8). Indeed, the activated form of tryptophan hydroxylase has an extremely high Km for tryptophan (50 mM), which is much greater than the concentration of tryptophan in the brain (10±30 mM). Indeed, this has been confirmed in humans to the extent that a tryptophan-free diet can cause a resurgence of depression in patients who were otherwise in remission (see Chapter 20). Although this scheme is rather controversial, it has been suggested as an explanation for the clinical improvement in some patients, suffering from depression or premenstrual tension, when they eat carbohydrates. It has also been suggested to underlie the carbohydrate-craving experienced by patients suffering from Seasonal Affective Disorder (Wurtman and Wurtman 1995). Not a great deal is known about factors that actually activate tryptophan hydroxylase. In particular, the relative contribution of tryptophan supply versus factors that specifically modify enzyme activity under normal dietary conditions is unknown. However, removal of end-product inhibition of tryptophan hydroxylase has been firmly ruled out. Also, it has been established that this enzyme is activated by electrical stimulation of brain slices, even in the absence of any change in tryptophan concentration, and so other mechanisms are clearly involved. So far, it has been established from in vitro studies that the enzyme undergoes phosphorylation, a process that changes the conformation of the enzyme protein and leads to an increase in its activity. Also, when incubated under conditions which are appropriate for phosphorylation, the Km of tryptophan hydroxylase for its co-factor and substrate is reduced whereas its Vmax is increased unless the enzyme is purified from neurons that have been stimulated in vivo, suggesting that the neuronal depolarisation in vivo has already caused phosphorylation of the enzyme. This is supported by evidence that the enzyme activation caused by neuronal depolarisation is blocked by a Ca2‡/calmodulin protein kinase inhibitor. If this is the case, then considerable losses might be incurred from its metabolism by monoamine oxidase before it reaches the storage vesicles. The high affinity of the decarboxylase enzyme for its substrate (10 mM in the brain) makes it unlikely that this stage could ever become rate-limiting for the pathway as a whole. Nevertheless, the Km for this enzyme is considerably higher than tissue concentrations of 5-hydroxytryptophan and so, again, supply of this substrate is likely to be a crucial factor. Steroid hormones also seem to modulate tryptophan hydroxylase gene transcription but research in this area is confounded by the variation in this effect across different tissues and different hormones, with both increases and decreases being reported. Functional disruption of this transporter, either through competitive inhibition (e. These include nicotinic receptors (increase release from striatal synaptosomes), a2A-adrenoceptors (depress cortical release) and H3-receptors (cortical depression).

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Specific Symptomatology—Chronic diarrhoea with general emaciation generic pilex 60caps fast delivery, and a persistent enfeebled condition with dry cheap 60 caps pilex with mastercard, dingy purchase pilex 60caps without prescription, rough, harsh skin. If no great structural change, and no tubercular or cancerous conditions are present, this agent is the most satisfactory remedy we have. It is suggested where the abdomen is contracted, and where the diarrhea is feculent in character with sharp colicky pains. Therapy—It will be curative also in general relaxed, subacute or acute cases of diarrhea, after the stage of inflammation has passed, but is not as reliable a remedy at that time as geranium. In muco-enteritis it is of some service in conjunction with the indicated remedies. It exercises an apparent tonic influence upon the mucous and glandular structures of the entire intestinal canal, overcoming ulceration, and being of material benefit in the more speedy restoration of normal function. In the treatment of chronic eczema, epilobium was strongly advocated by one of our best physicians. In that class of inveterate cases that was at first papular and finally squamous, he got excellent results. He gave it in doses from fifteen to twenty minims, and in persistent cases he would make all infusion of the herb, having the patient drink it freely. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 195 Therapy—A diuretic useful in suppression of urine from any cause. Useful in dropsy and in lithemic conditions, where the urine is scanty, of high specific gravity, and dark-colored. In cases of irritable bladder with much tenesmus, it is soothing in its influence. It is valuable in the treatment of nocturnal incontinence of urine in children, and in incontinence induced by cystic irritation. An infusion made from the green stalks of the plant, is sometimes of more service than other forms, a fact which is true of a large number of diuretics. Some authorities have advised the powdered ashes of this agent in the treatment of certain forms of acid dyspepsia. This influence is probably due to the presence of the potassium or sodium hydrate, or their compounds, in these, ashes, and these substances are readily supplied from more available sources. Equisetum is used where there is suppression of urine or scanty urine, or where there is irritability of the mucous surface of the urinary tract. There is pain at the base of bladder and in the prostate, and there is irritability of the nervous system. Jedlicka of Wisconsin thinks that it influences morbid enlargements within the urinary apparatus. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 196 Ergot is prepared by special processes of purification for hypodermic injection. So used it is immediate in its action and can be so administered when impossible to give it by the stomach. Ergotine in solution in water and glycerine, is excellent for hypodermic administration. Physiological Action—Ergot causes both acute and chronic poisoning when taken in toxic closes. Acute ergotism is characterized by vomiting, purging, headache, dizziness, drowsiness, slowing of the pulse, dilatation of the pupils, dyspnea, pain in the chest and loins, confusion of the senses, formication, coldness, anesthesia, convulsions, swelling of the face. Chronic ergotism is characterized by neuralgic pains, formication and numbness of the extremities, opisthotonos, violent delirium succeeded by exhaustion, death occurring in coma or in convulsions; or the drug may affect nutrition; muscular weakness is followed by gangrene of the limbs or superficial parts, which become blackened, shriveled and hard—a dry gangrene, generally ending fatally. Ergot is classed as a motor excitant by most writers, and yet the evidences, as above described, of its depressing influence upon the nervous system and upon the circulation are most conspicuous. In its influence upon the circulation of the brain and spinal cord, it may be given in sufficient doses to produce anemia, and that it does greatly reduce the excitability of the nervous system, under certain circumstances, none will deny. It acts in perfect harmony with the bromides when there is acute cerebral engorgement with great nervous excitability. There is no doubt that it produces contraction of the arterioles, although there are many evidences to prove that it may permit the venous capillaries to dilate freely. It acts upon the muscular structure of the womb, producing extreme tonic or tetanic spasm of the fibrillae, causing a marked reduction in the size of the organ if enlarged, and rapid emptying of its blood vessels, and consequent anemia. Many prominent writers believe the anemia induced, causes the profound muscular contraction. It is more plainly apparent that a peculiar irritating influence of the agent upon such muscular structure induces its contraction, and that such contraction, assisted by the influence of the agent upon the coats of the arterioles, causes them to become emptied to a marked extent, and thus Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 197 the anemia. Ergot acts upon the heart muscle in much the same manner as upon the muscular structure of the womb, although much less violently. Because of the profound irritation of muscular fibrillae and consequent almost immediate contraction induced by Ergot, it is a most active agent in inducing expulsive pains in labor, in overcoming uterine inertia and in controlling uterine hemorrhage. Specific Symptomatology—Extreme fullness of the circulation of the brain, flushed face, headache, bright, sharp eyes, great restlessness. The indications for its safe use in labor are: first, uterine inertia; muscular relaxation with a more or less general weakness; second, the first stage of labor must be completed, and the ostium vaginae must be fully dilated. The contractions induced by this agent are not smooth, spontaneous, natural, rhythmical contractions, but are irregular and extreme, and if an overdose be given it may induce a tetanic contraction and a single, most violent, continuous expulsive effort which does not cease until the entire contents of the womb are expelled. With such an influence, if there be a rigid, undilated os or perineum, or malposition of the child, or extreme dryness of the parts, serious results, as rupture of the womb or extreme laceration of the perineum, are almost unavoidable. Again, such pronounced action upon the womb structure may result in subsequent muscular paralysis, with great impairment of its contractile power, and if there be no post-partum hemorrhage there may be subinvolution more or less persistent. It will be seen, therefore, that this remedy in parturition is a dangerous one, and if used at all it should be Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 198 used only when every contraindication is absent, and every indication present. Therapy—In labor, when there is threatened post-partum hemorrhage, or when the history of previous labors shows a tendency to such an accident, a full dose of ergot may be given just at the close of the second stage, or after the head has passed the perineum. No harm can come from such a procedure, and it will serve as a positive safeguard. If there is then free hemorrhage and lack of full uterine contraction, the dose may be repeated in perhaps half an hour, but the attendant must be assured that the womb is entirely empty. If the contractions are not firm and continuous, and hemorrhage at all violent should occur, other measures, such as external irritation and compression of the uterine fundus, or the introduction of hot water into the uterine cavity, must be resorted to in addition. If this dose be added to an ounce or two of hot water and drunk, its influence is more immediate and pronounced. In uterine hemorrhage at the menstrual epoch, menorrhagia, or in metrorrhagia, it is a most valuable agent. The dose can be so measured and timed as to reduce the flow to normal time and quantity, while by the use of other agents, a healthy condition is being secured. Its influence, upon the womb structure is at the same time conducive to a sure acting in harmony with other uterine tonics.