Cholinergic Neuroeffector Junction • Choline is accumulated in cholinergic presynaptic nerve endings via an active trans- port mechanism linked to a Na+ pump order 200 mg celecoxib free shipping diet arthritis sufferers. Properties ofIndirect-Acting Cholinomimetics Late-onset dementia with progressive memory loss Drug Characteristics Clinical Uses and cognitive decline order celecoxib american express treating arthritis of the spine. Nicotine acts as a cholinomimetic on nicotinic receptors discount celecoxib 100 mg without prescription rheumatoid arthritis leg pain, whereas bethanechol and pilocarpine are cholinomimetic drugs that act on muscarinic receptors. Those acting on the end-plate nicotinic receptors (N ) are tubocurarine, atracurium, and succinylcholine. Those acting on muscarinic (M) receptors M include atropine, benztropine, and scopolamine. All M-receptor activators are nonspecific (they act on Ml-3), and, in general, M-receptor activation decreases cardiovascular function and increase secretions and smooth muscle contraction. Table 11- 2-1 summarizes the type of M receptor involved and the specific end-organ responses to M-receptor activators. Table 11-2-2summarizes the effects of nicotinic receptor activation on the adrenal medulla, the autonomic ganglia, and the neuromuscular junction. The effect of autonomic ganglia stimulation depends upon the transmission system used to connect the ganglia to the end organ. Table 11-2-3summarizes the receptor mechanisms used by the various receptor types. Table 11-2-4summarizes the activity, properties, and clinical uses for the direct-acting cholinomimetics, and Table 11-2-5 does the same for the indirect-acting ones. Although these are less toxic for humans, they still provide a hazard, causing poisoning with both acute and chronic symptoms caused by both muscarinic and nicotinic hyperactivity ("dumbbelss"). In simple terms, increasing doses of atropine progressively decreases secretions and causes mydriasis, blurred vision, tachycardia, constipation, and urinary retention. Overdoses of over-the-counter medications containing M blockers are common causes of toxicity. Management is largely symptomatic, although physostigmine may be useful because it helps counteract both central and peripheral effects. The clinical uses and properties of the M-blocking drugs are summarized in Table 11-2-6. Table 11-2-7summarizes specific effects of ganglionic blocking agents and the transmission system employed for various specific organs. Drugs and uses: donidine and methyldopa (mild to moderate hypertension) • See Cardiovascular section. Effect of High-dose Epinephrine Is Similar to Norepinephrine Dose-dependent effects: - Low-dose. Table 11-3-1summarizes the distribution and physiologic effects associated with the activation of alpha 1 and 2, beta 1 and 2, and D] receptors. The cardiovascular effects of epinephrine (E) are betalike at low doses and alphalike at high doses. The properties, clinical uses, and adverse effects of the nonselective beta receptor antagonist propranolol are described. A comparison of beta adrenoceptor antagonists that are cardioselective and those that have intrinsic sympathomimetic activity is made (Table 11-3-3). Emergency drug management prior to surgery usually involves cholinomimetics, carbonic anhydrase inhibitors, and/or mannitol. Note Drug Drug Class Mechanism of Action Antimuscarinic drugs and Pilocarpine, Cholinomimetic Activation of M receptors causes contraction echothiophate of ciliary muscle, which increases flow (;(1 agonists are contraindicated through the canal of Schlemm; echothiophate in closed-angle glaucoma. Figure 11-4-8 Arterial contraction Heart rate t t Time 1 2 3 4 5 Given the following information: o Contractile force is measured in an isolated arterial preparation, and heart rate is measured in an isolated heart preparation. The effects of autonomic drugs affecting the cardiovascular system are summarized visually in Figures 11-4-2through 11-4-11. Which one of the following effects is not caused by the ingestion of mushrooms that contain pilocarpine? An increase in the cytosolic concentration of norepinephrine in sympathetic nerve end- ings leads to A. A 5-year-old child becomes ill while visiting relatives who have a farm in Arkansas. His symptoms include severe abdominal cramps with vomiting and diarrhea and profuse lacrimation and salivation. If these symptoms are due to chemical toxicity, the most likely cause is exposure to A. The activation of muscarinic receptors in bronchiolar smooth muscle is associated with A. Overuse of certain decongestants that are indirect-acting sympathomimetics can lead to a diminished response. With this principle in mind, one can anticipate that hexa- methonium will cause A. The presumptive diagnosis was drug toxicity due to the ingestion of a compound similar to A. Reflex tachycardia is most likely to occur after the systemic administration of A. Which one of the following sites is characterized by adrenergic neurohumoral transmis- sion? Activation of prejunctional 0:2 receptors on sympathetic nerve endings is associated with A. The data in the table below show the effects of four drugs (#1-4) on mean blood pressure administered as individual agents before and after treatment with prazosin. Ocular effects that include mydriasis and fixed far vision are characteristic of A. Following a myocardial infarct, a 40-year-old male patient is being treated prophylacti- cally with propranolol. In terms of adverse effects of the drug, which of the following is most likely to occur with use of this specific beta blocker? A 45-year-old Nobel Prize-winner in chemistry has recently been the recipient of a heart transplant. Patient education has included both verbal and written descriptions of the potential cardiovascular effects of pharmacologic agents. Which one of the following drugs is least likely to cause tachycardia in this patient? Because you know about the problem of distinguishing between cholinergic excess and under- treatment in the myasthenic patient, you would probably recommend that your colleague be given A. A number of pharmacologic treatments can slow the progression of the dis- ease, which can ultimately lead to complete blindness if left untreated. Beta blockers cause ciliary muscle contraction, increasing aqueous humor outflow B. Labetalol is an effective antihypertensive agent that, like propranolol, is capable of block- ing beta receptors. Antagonist Pretreatment Agonist 1 Agonist 2 Agonist 3 J, J, None r Atropine r - r Prazosin i - r J, J, Propranolol - Mecamylamine t - r Identify the agonist drugs from the following list: A. Bradycardia due to vagal stimulation is elicited by activation of muscarinic receptor in the heart.
It is our policy to explain that there are two distinct phases involved in the growth of a baby purchase genuine celecoxib line arthritis back medication, as shown in Fig celecoxib 100mg line arthritis medication uk. The first phase is the embryonic development generic 100 mg celecoxib free shipping arthritis knee lubricant, and it is dur- ing this period that the structure or architecture for the baby is laid down. Embryonic age should be differentiated from menstrual age, which is 2 weeks greater than embryonic age. Briefly, we explain to our patients that organs take shape and the body assumes the form it will have thereafter by day 58 postconception. All major structures, such as the heart, brain, liver, kidneys, and limbs, have formed by this time. Fetal development dur- ing the remainder of pregnancy, the second phase of development, is primarily devoted to the growth of these organs and structures, and to augmenting their function. It is through this heuristic approach to counseling that the patient understands that most congenital anomalies are caused by early exposures, often before the pregnancy was recognized. This component is included early in the consultation; patients then understand why certain questions are important and having such knowledge increases their cooperation and rapport. Preconceptional counseling Ideally, all counseling regarding drug or medication use during pregnancy should occur before conception, because the opportunity to prevent possible adverse effects is then optimal. Preconceptional counseling should include all the components of a consultation during the pregnancy, with one exception. Recommendations regarding medication or drug use during pregnancy will be prospective for a preventive purpose, and only med- ically indicated drugs and medications known to be safe will be recommended for con- tinued use while attempting to conceive. The concept of background risk for major congenital anom- alies should be explained in a manner tailored to the patient’s level of understanding. This concept is especially important because it conveys to the patient that, even if the drug exposure is harmless, no guarantee can be given that the fetus she carries will not have a congenital anomaly. Notwithstanding other risk factors, the risk for major con- genital anomalies is approximately 3. Other identified risks are generally considered to be additive to background risk. A usual component of counseling is the determination of exactly what drugs were taken, the dosage, the timing and duration of the exposure(s), the patient’s health history and present state of health. A thorough physical examination should be used to deter- mined the present state of health. No No further action although Yes ultrasound may reassure Confirm gestational age by ultrasound Drug taken Drug taken during critical outside of period of organogenesis embryogenesis Rule out Refer for Other possible targeted prenatal adverse fetal ultrasound and tests as effects advice indicated Counseling and evaluation of the drug-exposed pregnant patient 17 parents as well as the baby’s father’s parents, brothers and sisters, and nieces and nephews, should be constructed. The current state of health of all people in the pedigree should also be elicited. For those individuals in the pedigree who are no longer living, whether death was due to a birth defect or to a heritable disorder should be determined. It is also important to ask whether the patient’s family or the baby’s father’s family has any member who was mentally retarded, or has a chromosomal abnormality, Down syn- drome, congenital heart disease, spina bifida or another neural tube defect, or any other inherited disease. When such risk factors are discovered, it is important to explore these avenues further. It is desirable to refer the patient for a medical genetic consultation and evaluation when a risk increase above background is other than zero. The next step in the consultation is to determine whether or not the agent(s) has known teratogenic potential. This is the most difficult part of the evaluation because there is insufficient information to make such a determination for more than 60 percent of medications. The Effects of Neurologic and Psychiatric Drugs on the Fetus and Nursing Infant: A Handbook for Health Care Professionals. If it can be documented that the agent has no terato- genic risks or adverse fetal effects associated with its use during pregnancy, then no fur- ther action is required except to document this in the medical record and counsel the patient accordingly. Some patients may benefit from reassurance offered by high-resolu- tion ultrasound to confirm fetal well-being, and this procedure should be offered if the patient’s anxiety is not relieved through counseling. The limitations of diagnostic ultra- sound should also be included in the consultation. If the drug is known not to be safe for use during pregnancy, or if there are reasons to suspect that a drug with unknown risks is associated with congenital anomalies, then gestational age should be confirmed by ultrasound. It is of utmost importance to base the risk assessment and counseling upon embryonic age, not menstrual age. If the expo- sure occurred during embryogenesis, then it is necessary to undertake high-resolution ultrasound in an attempt to detect damage to specific organ systems or structures that were being formed during the time of the exposure. If the ultrasound scan is normal, then it is reasonable to reassure the patient of normal fetal structure within the limits of the sensitivity and specificity of ultrasound, which range from 40 to 90 percent for gross structural abnormalities when the procedure is performed by an experienced sonogra- pher. If the exposure occurred during the fetal period, it is likewise important to evalu- ate the possible fetal effects of the medication. If defects are detected, it is necessary to describe them in detail to the patient and to give a prognosis, as far as available medical knowledge will allow, regarding the out- come of pregnancy and postnatal development. To assist the patient in making a deci- sion on the disposition of the pregnancy, prognostication should include medically doc- umented risk figures. Ethically, pregnancy termination should not be a recommendation made to the patient and her family and significant others. This option should be dis- cussed, but the ultimate decision of whether to continue the pregnancy should be left to the patient and her family and significant others. The role of teratogen counseling is ulti- mately to provide the patient with as much information as possible and encourage her to make her own decision regarding whether to continue the pregnancy. Drug- or chemical-related causes of maternal complications, congenital anomalies, and fetal toxicity are almost unique among adverse pregnancy outcomes because they are potentially preventable, given the window of opportunity to do so. These problems are also exceptional among obstetric complications in that they are often the focus of malpractice litigation. Attorneys recognize that such adverse outcomes could have been prevented, and litigation ensues despite the fact that the window of opportunity to inter- vene prudently may not have existed for the physician and, more importantly, the drug exposure may not be teratogenic at any time during the pregnancy. The major drawback with such disclaimers was that there existed little to no information upon Informed consent and post-exposure counseling 19 which to ‘weigh the possible hazards’. Such disclaimers would make defense of a litiga- tion case involving a drug or medication extremely difficult for the physician because benefits are not easily weighed against unknown possible hazards. With no scientific data relating a specific malformation to a given drug, it is nearly impossible to ‘prove’ in the courtroom that a drug is not a teratogen and is safe for use during pregnancy. Thus a jury may be asked to consider the important question of why a physician would utilize a medication that carried the warning ‘safe use in pregnancy has not been estab- lished’. The disclaimer itself implies that a medication may indeed be a teratogen, although the warning is actually little more than legally formulated rhetoric designed to protect the pharmaceutical company (Brent, 1982). Five risk categories that addressed potential adverse fetal effects, including congenital anomalies, were developed. Although an improvement over the previous labeling disclaimers, this classification is less than perfect (Brent, 1982). These authors pointed out that ‘any classification of agents according to teratogenic risk is incomplete because the risk to a given patient is determined by all of the conditions of exposure’. Paramount importance must also be ascribed to drug dose, route of administration, and timing of exposure, as well as expo- sure to multiple agents during the pregnancy (Friedman et al. Even if an agent is a potential teratogen of significant risk or even a proven teratogen such as thalidomide, the actual risk to the fetus may be minimal to none if the timing of exposure occurred during late pregnancy or after the period of organogenesis.
Increasing the concentration of K in the medium infused via the probe increases noradrenaline efflux whereas removing Ca2 reduces it is needed for analysis: i buy 200 mg celecoxib with amex rheumatoid arthritis wrist. In any case buy celecoxib 200 mg fast arthritis relief genuine health review, the efficiency of the probe membrane limits the net influx (or efflux)of solutes to about 10± 20% of the theoretical maximum cheap generic celecoxib canada arthritis in knee elderly. It should also be borne in mind that the microdialysis probe is not sampling the transmitter in the synapse: only that transmitter which escapes metabolism in, or reuptake from, synapses will migrate towards the probe. In the drug-free state, any change in the transmitter concentration in the dialysis samples is usually assumed to indicate a change in its rate of release from nerve terminals; this is supported by the spontaneous efflux of transmitters being Ca2-dependent and K- sensitive (Fig. However, efflux does not always reflect release rate, especially if experimental interventions (e. Voltammetry This can be carried out in vitro (in brain slices, cultured cell preparations)or in vivo and involves penetrating the experimental tissue with a carbon-fibre electrode of 5±30 mmin diameter (Fig. This serves as an oxidising electrode and the Faradaic current generated by the oxidation of solutes on the surface of the electrode is proportional to their concentration. Obviously, only neurotransmitters which can be oxidised can be measured in this way so the technique is mainly limited to the study of monoamines and their metabolites. Changes in the concentration of transmitters are monitored by rapid cycles of voltage scans (e. Since a complete scan takes only about 20 ms, the time resolution with voltammetry is much better than with microdialysis and is suitable for studying rapid, transient changes in transmitter release. One difficulty with this method is that all oxidisable solutes in the external medium will be incorporated into the voltammogram and interfering peaks can be a problem. In fact, the concentration of monoamine metabolites and oxidisable solutes can be considerably greater than those of the parent amines which can be difficult to distin- guish as a result. Ascorbic acid and uric acid are particularly problematic in this respect, although recent work suggests that an increase in the concentration of extracellular ascorbic acid could be a marker for the early phase of cerebral ischaemia. In general, voltammetry is most useful for measuring rapid (subsecond)changes in monoamine release. Under these circumstances, slower changes in the metabolites and other compounds do not interfere. The trace is a plot of the oxidation peak height against time, calibrated for dopamine. One of the earliest biosensors was the dorsal wall muscle of the leech which contracts in the presence of nM concentrations of acetylcholine. Others are the bioluminescent proteins, such as aequorin, which fluoresce in the presence of Ca2. Within a reasonable range, the fluorescence intensity is pro- portional to the cation concentration and so it can be used to monitor the increase in the intracellular concentration of Ca2 during excitation of nerve terminals. More recently, biosensors have been developed which comprise electrodes coated with glucose oxidase or lactate oxidase. The activity of these enzymes generates a current that can be used to quantify the concentration of glucose and lactate on the surface of the electrode. This work is playing an important part in research on brain metabolism during neuronal activity. Two separate lines of research led to the proposal that transmitter released in response to neuronal excitation is derived from a vesicle-bound pool rather than from the neuronal cytoplasm. Using differential centrifugation, these vesicles were soon identified as the major storage sites for neurotransmitters. The second was electrophysiological evidence that the effect of neuronal release of acetylcholine on the postsynaptic membrane potential at the neuromuscular junction was quantal in nature, suggesting that this transmitter, at least, was released in discrete packets. Early neurochemical investigations of the source of released transmitter measured noradrenaline release from chromaffin granules in the adrenal medulla. Chromaffin granules are considerably larger (250 nm diameter)than the storage vesicles in noradrenergic nerve terminals (40±100 nm)and so their experimental use avoided the constraint imposed by the low sensitivity of early assay techniques (see Winkler 1993). Yet, like noradrenergic neurons, the adrenal medulla is derived from the developing neural crest and noradrenaline release is activated by stimulation of preganglionic cholinergic neurons. Chromaffin granules therefore provide a useful model for pro- cesses involved in the storage and release of noradrenaline from neurons. Subsequent refinements of assays for noradrenaline enabled studies of noradrenaline release to be extended to stimulated sympathetic nerve/end-organ preparations. These experiments confirmed that noradrenaline was released from vesicle-bound packets of transmitter contained within the terminal vesicles. Experiments of this kind have provided a great deal of evidence in favour of exocytotic release of vesicular noradrenaline. For example, by administering reserpine (which causes noradrenaline to leak out of the vesicles into the cytoplasm)together with an inhibitor of the enzyme monoamine oxidase (which will prevent metabolism of cytoplasmic noradrenaline), it is possible to redistribute the noradrenaline stored within nerve terminals because it leaks from the vesicles but is preserved within the neuronal cytoplasm. Under these conditions, the total amount of transmitter in the terminals is unchanged but impulse-evoked release rapidly diminishes. Different evidence, mainly based on histological studies, suggested that acetylcholine is also released by vesicular exocytosis. It is then possible to fracture axolemma membranes in a way that separates their lipid bilayer. Electron microscopy reveals numerous pits in the membranes which are thought to reflect the vesicle/axolemma fusion pore of vesicles in the process of exocytosis. Subsequent studies, combining immunocytochemistry with electron microscopy, showed that proteins in the membranes of vesicles become incorporated into the axolemma during transmitter release. Furthermore, when neurons are stimulated in a medium containing an electron-dense marker, that does not penetrate the neuronal membrane, the marker later appears in vesicles inside the nerve terminals (Basbaum and Heuser 1979). This suggests that such markers are incorporated into the vesicles when they come into contact with the extracellular fluid during exocytosis. For instance, impulse-evoked release of this transmitter is prevented by the drug, vesamicol, which blocks uptake of acetylcholine from the cytoplasm into the terminal vesicles (Searl, Prior and Marshall 1991). Although most evidence supports vesicular exocytosis of acetylcholine (see Ceccarelli and Hurlbut 1980), some researchers contest this view. According to this scheme, opening of the pore is triggered by an increase in the concentration of intracellular Ca2 and allows gated release of aliquots of cytoplasmic acetylcholine. The vesicles are thought to serve merely as a reserve pool of transmitter and for sequestration of intracellular Ca2 (Dunant 1994). They are delivered to the terminals by fast axoplasmic transport and are the only type of vesicle to be found in axons (see Calakos and Scheller 1996). This suggests that they have different functions and regulatory processes which, since they contain peptides, agrees with the finding that their release requires higher frequencies of nerve stimulation than does that of the classical neurotransmitters. Electron microscopy certainly shows that their membranes are recovered after fusion with the axolemma but precisely how this occurs is unresolved. One possibility is that they are retrieved intact from the active zone, immediately after release has taken place. Alternatively, they could become incorporated into, and mix with, the components of the axolemma but are reformed after sorting of the different membrane elements (see Kelly and Grote 1993).
In spermatorrhea with irritability and considerable sexual weakness and plethora purchase 200mg celecoxib with mastercard arthritis in feet at young age, it will cure when other agents fail purchase genuine celecoxib on line rheumatoid arthritis depression, if given in half-dram doses after meals cheap celecoxib online arthritis exclusion diet. The pure alkaloids of cinchona are not employed in medicine, but their salts, formed from acid and basic combinations, are in common use. In the consideration of the therapeutic properties of the various alkaloids of cinchona there is but little difference observed in their action. There is almost no influence exercised by any one of them that is not exercised to an equal extent by quinine, and except where otherwise specified, the Sulphate. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 126 Quinine Sulphate. Physiological Action—In doses of five grains three or four times a day for a few days, it produces fullness of the capillary circulation of the brain, throbbing in the head, suffusion of the face, ringing in the ears, with dullness of hearing, headache, mental confusion and nervous excitement. If the above doses be given every three hours continuously there is muscular feebleness, with general impairment of motility, increasing debility, great restlessness, with wakefulness, dilated pupils and partial loss of sight. A single dose of sixty grains of quinine sulphate, given to an adult male caused extreme depression, with feeble circulation, coldness of the surface and extremities, respiration slow and sighing; pulse slow and almost imperceptible, pupils widely dilated, sight and hearing almost extinct, voice very feeble; thirst great, tongue pale and moist, breath cold. While in some cases blindness from quinine has continued for some time in no case has it been permanent. In some cases death has followed the administration of the remedy in disease, a result fairly attributed to the drug. In small doses it is tonic, in large doses stimulant, and in still larger doses sedative, acting on the cerebro-spinal nervous system and through the ganglionic nervous system on the heart. Besides the above named effects, large and repeated doses may cause gastric irritation, eructations, chill and fever paroxysms headache, perspiration, vertigo, staggering and delirium— the condition known as cinchonism. Specific Symptomatology—Quinine will act favorably upon the system if the skin be soft, if the mucous membranes of the mouth are moist, and if the tongue is moist and inclined to clean, if the pulse is full and soft and the temperature declining or at normal. In other words, when the secretory functions of the body are in a working condition, quinine will produce no unpleasant results. It will overcome malarial periodicity, especially if the above named conditions are present when the agent is administered. It is profoundly tonic; under limited conditions it is antipyretic and also antiseptic. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 127 Quinine destroys the plasmodium malariae readily, even in the minute quantity of one part to twenty thousand of water. Therapy—In the administration of quinine as an antiperiodic, the beneficial influences are not altogether in proportion to the size of the dose. Enormous doses may abort a chill if given during its course, or during the course of the fever. They are very likely, however, to increase the nervous erethism and the temperature; whereas, if proper doses be given during the intermission, from one to three hours preceding the anticipated attack, or at the time when the temperature has reached its lowest point, small doses will accomplish positive results. In continued fever, with a sufficiently marked remission occurring at a given time each day, or on each alternate day, the agent should be given during the remission, provided the temperature declines to a point sufficiently low to admit of a temporary restoration of the suspended secretions. As a result the temperature does not run quite as high as on the previous day, and the next remission is more marked and of longer duration. The fever is still lower and the remission so marked by the third day that the agent, in reasonable doses, may be continued through the exacerbation, the temperature at no time, probably, rising above 101 degrees and not increasing above normal after the third day. The writer has adopted this course for so many years, with perfectly satisfactory results, that the method is confirmed in his mind as the proper one in all cases where malaria is the cause, Where continued fever exists, quinine is of no benefit if there is no marked remission or other evidence of malaria. It is thus of no use during the progress of typhus, typhoid and other protracted fevers. In such cases it causes nerve irritation and increased temperature, especially if there is deficient secretion. When the fever is broken and there is a tendency toward a restoration of secretion, and the temperature is normal or subnormal, then this agent is a vitally important one. Here the bisulphate, being readily absorbed, Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 128 produces the happiest results. In intermittent fevers it is excellent practice to give the remedy in broken doses during the intermission. The absorption of the sulphate of quinine takes place so slowly that a period of between four and six hours is required, under favorable circumstances, to develop the full effect of the remedy. A dose of from three to five grains, given five hours before the expected paroxysm, will exercise its full influence upon the paroxysm when it should appear. If another dose of two and one-half grains be given two hours after the first dose, and a third dose of the same size be administered after another period of two hours, or one hour before the chill will occur, the effect of the agent will be uniformly continued during the time in which both the chill and the fever would have reached their highest point. The repetition of this course on the second and third days will usually be sufficient to overcome the most severe. It is well to adopt the same course on the seventh, fourteenth and twenty-first days following the attack. The following formula is of excellent service in those cases in which the liver and other glandular organs have been profoundly influenced by the disease, and where the nervous system shows considerable depression: Rx— Quiniae Sulphat, xl grains. When the paroxysms no longer appear, two or three grains of quinine may be given regularly every three hours during the day. In the treatment of congestive chill, and in malignant conditions of malarial origin, quinine is specific, but should be given in much larger doses, and usually with some direct stimulant and in conjunction with the use of external heat. It may be given in doses of twenty grains preceding the attack, or with stimulants during the attack. If a severe attack is fully anticipated, large doses should be repeated every two or three hours during the entire remission. It was once considered of Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 129 essential importance in the reduction of high temperatures, but the conditions and character of its action were so imperfectly understood that it often did harm, and caused an increase in the temperature instead of a reduction. As a restorative after pneumonia, where hepatization has been extensive, this agent is an important one. Two grains of the bisulphate of quinine, with one-fourth of a grain of ipecac, and perhaps the one-fourth of a grain of nux vomica, will rapidly improve the function of the nervous system and of the circulation, and as rapidly overcome the hepatization and other results of inflammatory action. The influence upon the stomach and intestinal canal, and thus upon the digestion and assimilation of food, is marked and immediate. Its influence is exercised to the best possible advantage when there is impaired or deficient nerve force. It is indicated as a restorative after prostrating disease, especially after continued and inflammatory fevers. It strengthens the action of the heart, improving the character of the circulation of every organ. It stimulates the liver and kidneys, and thus assists in the rapid elimination of the waste products of the disease. It stimulates the respiratory function, promoting oxygenation of the blood, thus assisting in the restoration of the character of that fluid.