Mark Corson

By W. Sugut. Campbell University. 2018.

Like oxaze- pam it is primarily elimated after glucuronidation purchase ofloxacin 200mg amex, and both are highly protein bound buy cheap ofloxacin 200 mg line. When oxazepam was given before and after 7 d of 2/d treatment with diflunisal buy discount ofloxacin 200 mg line, the Cmax of oxazepam was decreased and its oral clearance increased. The authors conclude that the interaction resulted from the displacement of oxazepam from its protein-binding sites and by inhibition of the tubu- lar secretion of the oxazepam glucuronide. The authors concluded that these find- ings were consistent with the induction of P450 and/or glucuronidation (360). Five daily “small” doses of dexamethasone were found to have no significant effect on the pharma- cokinetics or pharmacodynamics of triazolam in normal volunteers (361; Table 30). The authors did detect a significant decrease in the percentage of diazepam plus metab- olites excreted in urine over a 96-h period (362). The findings suggest that paracetamol may decrease the glucuronidation of diazepam metabolites. The effect of probenecid on the elimination of benzodiazepines was first studied 1. Drug Interactions with Benzodiazepines 65 Table 31 Key to Drug Interaction Tables Interacting drug The route is oral, unless stated otherwise. An indication of the duration of treament is given, and when different the benzodiazepines considered are noted separately in parentheses (e. Benzodiazepines The benzodiazepine of interest is indented 1/4 inch; if a metabolite was also studied, it is listed directly below with a 1/2-inch indentation. The abbreviations for route of administration are: or, oral; iv, intravenous; im, intramuscular. N For cross-over studies only one group of subject numbers are provided; if gender was specified, females are noted with an “f”; males with an “m” (e. For comparisons between groups, a ‘/’ separates the groups; the one receiving the interactant is listed first (50/40, refers to a study where 50 subjects recieved the interactant and 40 did not). Pharmacokinetics Are presented as the ratio of the interactant to the control group. Cl Clearance for iv administration; apparent oral clearance for oral administration. PhDyn qualitative assessment of the results of pharmacodynamic measures recorded in the study. This was both an assessment of the degree of change and the number of measures that changed: 0 – no effect; - to ----, a dimunition in the pharmacodynamics ranging from slight to loss of all effect; + to ++++, an enhancement of the pharmacodynamics ranging from slight to toxic. The t1/2 of lorazepam was significantly increased and its clearance significantly decreased. This result suggested not just inhibition of ex- cretion, but also inhibition of glucuronide formation (363). With temazepam there was no significant effect on plasma pharma- cokinetics, but there was reduced urinary content of the temazepam glucuronide (300). This was associated with potentiation of the psychomotor effects of the benzodiaz- epine (Table 30). The authors suggest that the major effect is on the elimination of the metabolite (364). Probenecid does effect the renal elimination of many benzodiazepines; it may also have an effect on glucuronidation and possibly P450 mediated reactions. The effect of modafinal on the pharmacokintics of triazolam (and ethinyl estradiol) was studied in females taking daily birth control medication con- taining ethinyl estradiol (366). In a group of woman given triazolam before and after 28 d of treatment with modafinal, there was a significant induction of the elimination of triazolam (Table 30). John’s wort, garlic oil, Panax ginseng, Ginkgo biloba) on a P450 phe- notyping “cocktail” designed to measure 1A2, 2D6, 2E1, and 3A4 activities. Individuals had the phenotyping cocktail before and after a 28-d period of use of the supplement; each supplement use was separated by a 30-d washout period. When an inhibition of metabolism is also encountered, the effect may be synergistic. Interactions with other drugs and dietary substances are generally based upon an interaction at the site of metabolism. Most often this reflects the involvement of P450 3A4, but in some instances the involvement of 2C19 in diazepam metabolism, and glucuronidation are also sites of interaction. A few examples of displacement from protein binding and inhibition of renal tubular secre- tion also exist. These metabolic interactions can vary from having little or no effect on the pharmacodynamics to inhibitions that produce toxic side effects and inductions that essentially negate the pharmacodynamics of the benzodiazepine. A misadventure with either or both interactant is likely to magnify the end result. Though I have tried to achieve a thorough review of the peer-reviewed literature, many papers were not 1. Authors who feel I have missed their studies are asked to send the pertinent reprints. Should this article be updated in the future, I will make my best effort to include those studies at that time. Adinazolam pharmacokinetics and behavioral effects fol- lowing administration of 20–60 mg doses of its mesylate salt in volunteers. Enantiomer resolution of camazepam and its derivatives and enantio- selective metabolism of camazepam by human liver microsomes. Investigation of the metabolites of tofizopam in man and animals by gas-liquid chromatography-mass spectrometry. In vitro methods for assessing human drug metabolism: their use in drug development.

Although the different Starling-Sarnoff curves defined different degrees of contractility buy ofloxacin 400mg amex, the work of the heart was measured exclusively as external work: systolic pressure x stroke volume buy 200mg ofloxacin overnight delivery. With measurement of work during ejection alone buy 400mg ofloxacin free shipping, Sarnoff had been measuring only isotonic work, whereas the heart was doing isometric and isotonic work. However, with reference to the Starling curves, the point is that since the work of Sarnoff, cardiac performance was seen as a function of filling pressure. Since reexamination of the heart as a muscle, it is clear that the change in myofibril length by preload is the variable which correlates best with subsequent stroke work. Since fiber length and filling pressure do not vary linearly, measurement of one cannot entirely substitute for the other. Thus a given ventricle, filled to a given end-diastolic pressure and volume would produce some specified stroke work with each beat. If, by some pathologic process, the ventricle would become stiffer during diastole (i. Measurement of Starling curves for the right heart and left heart differ (see Figs. Since both ventricles pump the same volume output, the stroke work differences are due to lower arterial pressure in the pulmonary artery than in the aorta. After all, in the human the thickness of the ventricular wall will be appropriate to the work (esp. Since the left ventricular peak systolic pressure (120 mm Hg) is 5- 6x higher than right ventricular peak systolic pressure (20 mm Hg), the left ventricular wall (10-12 mm) is 5-6x thicker than the right ventricular wall (1-2 mm). Similarly, the thicker wall will be less compliant, so that filling pressures for the left ventricle (5-12 mm Hg) are 5-10 x higher than filling pressures for the right ventricle (1- 2 mm hg) in the normally functioning heart. Although volume measurement would permit better correlation with fiber length, it is commoner to measure pressures in clinical situations. Reasons include the fact that it is easier to measure pressure (fluid-filled catheters are left in the atria or pulmonary artery) than volume; measurements are usually made over relatively short periods of time (minutes-days) and as a rule no important changes in compliance or heart size occur during such short times and compliance is difficult to measure precisely. For the right side of the heart clinical measurements usually utilize right atrial pressures, since these are in equilibrium with right ventricular end-diastolic pressures. For the left ventricle, pulmonary artery diastolic (sometimes pulmonary capillary, or "wedge") pressures are used. These approximate pulmonary venous pressures which are, in turn, in equilibrium with mean left atrial, and therefore, left ventricular pressures. For any stable compliance (or stiffness) a reduction in filling pressure would reflect a decrease in filling volume. A very high filling pressure might signal hypervolemia and the need for addition of an inotropic drug (e. Repeated measurements of cardiac output by indicator-dilution techniques may be made throughout such a series of pressure measurements and medical interventions. Peripheral resistance can then be calculated (Peripheral Resistance = Mean Arterial Pressure/Cardiac Output) and it, too, can be modified to maintain output at optimum levels. Some examples of different situations may help to clarify the changes in the Starling curves: Starling Curve and Venous Return - Jim Wong, M. Heart failure    (-) inotropic* •* Means that this variable is the “initial” cause of the altered physiology. To understand the bases of measurement of intracardiac pressures, their significance and their normal range. The net volume of blood propelled from the heart in one beat is denoted the stroke volume. Even though the actual flow is pulsatile with instantaneous flow rate changing rapidly with time, constant demand on the heart to pump blood leads to a constant average flow rate, the cardiac output, which remains stable. If blood flowed in a simple tube and in discrete mass elements, one could flag one or more elements then watch the flag move to compute the flow rate. The Fick method follows directly from a statement of conservation of mass, assuming the subject remains in a constant physiological state. To obtain accurately measured cardiac output, the oxygen concentration in the blood entering and leaving the lungs as well as the cardiac output itself must remain constant during the period of measurement. Under these conditions the mass flow rate of oxygen away from the lungs equals the rate at which it is being carried in by - venous blood plus the rate of absorption from the air in the alveoli (Fig. In addition to requiring that the patient be in physiological steady state (especially constant respiratory activity and cardiac output), the indicator substance (generally oxygen) must be thoroughly mixed with the blood to truly represent the average concentration at each sampling point. Only passing through the heart assures adequate mixing; therefore, the Fick method requires obtaining blood samples in the heart or an artery beyond its mixing chambers. Typically, one takes blood samples to measure for oxygen saturation from any systemic artery (all arterial blood has the same oxygen concentration as the aorta) and from the pulmonary artery (equivalent to mixed venous blood). Furthermore, since the actual flow is highly pulsatile, the sample should be taken slowly, over 5-10 seconds, to insure measuring the average oxygen concentration (averaged over time, i. Having found Ci , Co , and O, one can use the Fick formula to compute cardiac output, F. If we inject a marker such as cardiogreen dye, radioactive tracer or cold saline solution, which the blood carries, then watch how the marker passes a downstream point, some blood will move quickly in large arteries and veins while other moves slowly through longer, smaller parts of the vasculature Different blood particles, and the markers moving with them, require different times to move between two points within the vasculature. This effect spreads out the initial injected indicator marker as it moves through the vascular system with the blood. Eventually the indicator which moves through the vasculature faster than average will reach the sensor which in turn will detect increasing concentrations of indicator*. As time progresses the bulk of the indicator will pass, the concentration curve will peak, then return to zero as the slowest moving indicator- carrying blood passes the sensor. As with the Fick method, this equation’s accuracy critically depends on the cardiac output remaining constant from the time of indicator injection until the curve has been measured. Since the definite integral equals the area under the curve, this equation says: the cardiac output equals the amount of indicator injected divided by the area under the concentration vs. The major limitation inherent in this method arises from the circulation being a closed system.

Whitford gave iris and hyoscyamus with a very small dose of podophyllin for headaches in the back part of the head generic ofloxacin 400 mg line. Laws reports the use of iris in a bad case of eczema where the attacks lasted six months 400mg ofloxacin with mastercard, each worse than the previous one cheap ofloxacin 200 mg fast delivery. Both have great confidence in it in the treatment of goiter, and in the treatment of syphilis where they do not expect to have to use the iodides with it. Physiological Action—This agent is a gastric tonic and one of the typical stomach bitters. It is believed to increase the flow of the saliva and of the gastric juice, and increases also the appetite and the power of digestion. It is similar in action to hydrastis canadensis, but does not extend its influence so positively to the nervous system. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 267 Therapy—It is indicated when there is atonicity of the digestive apparatus, especially when there is any irritation whatever. It is restorative in fevers, improving the general nutrition by the improvement of the tone of the organs of digestion and assimilation. It is useful after protracted diarrheas and dysentery, after cholera infantum when a non-irritating tonic is needed, and in cholera morbus, being of benefit in promoting restoration in these cases. It will relieve the vomiting of this disease, and a few drops of the tincture will also relieve vomiting in seasickness, and has been beneficial in the vomiting of pregnancy. It is useful in overcoming intestinal flatus, an infusion in inflamma-tory intestinal disease being most satisfactory. Dose, from one-third to one minim; prescribed from ten drops to one-half dram in four ounces of water, a teaspoonful every one, two or three hours. Physiological Action—Experiments with the drug have ascertained that it influences, with great energy, the liver, small intestines, colon and rectum, causing an increased manufacture and elimination of bile, as well as increased activity of the glands of the intestinal tract. Full doses produce large bilious evacuations, without much pain or griping, in which respect its action very much resembles that of iris versicolor. Therapy—It is said to be a valuable remedy in duodenal catarrh, with Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 268 torpidity of the liver and chronic jaundice. Small doses have been successfully employed in dysentery, bilious diarrhoea, and in intestinal diseases, with symptoms indicating irritability, hyperemia, or a tendency to inflammation. Chronic constipation can be successfully corrected by medium doses of the extract, if the affection depends upon defective elimination of bile, causing the stools to be clay-colored and dry from a lack of biliary and glandular secretion. Combined with other agents, as hyoscyamus, belladonna, nux vomica, leptandra or capsicum, a most excellent pill can be made, which will cure many cases the above conditions, and will stimulate the stomach and intestinal tract, in those atonic or debilitated conditions which induce chronic dyspepsia. In the skin disorders named under dandelion, pustular and eczematous, it will act in the same manner as dandelion, and may be advantageously combined with that agent. It is specifically adapted to skin diseases associated with some abnormal condition of the intestinal tract. Eczema, herpes circinatus, acne, impetigo, pemphigus, rupia, prurigomoluscum, lichen and chronic scaly skin diseases, yield to its influence with appropriate auxiliary measures. Irritation of mucous membranes, chronic inflammation of the throat, eruption over the body like that of scarlatina, noli me tangere, scrofulous enlargement of glands, congestion and irritation of the respiratory and gastric mucous membranes, nursing sore mouth, ulcers in the mouth with constipation, rheumatism of the muscles in the lumbar region, yield to its influence. Juglans cinerea has proved to be curative of a great variety of skin diseases, whether scaly or pustular, whether characterized by papules or bullae, as stated above, so long as the lesion is associated with some disorder of digestion and assimilation It is analogous to arsenic in its action in squamous affections, and to Sulphide of calcium in pustular diseases of the skin. It may be used to advantage, both locally and internally, in chronic and illconditioned ulcers, stimulating waste and improving nutrition. In the treatment of skin diseases with Juglans, a saturated tincture of the fresh inner bark should be employed in small doses, at the same time that the remedy is used as a local application. In obstinate cases of chronic Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 269 eczema, the local use of the juice of the fresh inner bark has hastened the cure. In bowel complaints of infants and children, in the constipation of nursing women, and in the commencing stages of diarrhea and dysentery the syrup may be used, while the extract is the best form of the remedy as a cathartic in intermittent fever, and whenever the remedy is employed as a cathartic. Juglans may be given in conjunction with berberis, phytolacca, or podophyllin when there are disorders that are induced by occipital headaches. This is a volatile oil obtained from juniper berries by distillation, and is of a pale greenish or yellowish color, and of a warm, terebinthinate taste. This is an empyrheumatic oil obtained from the wood of Juniperus Oxycedrus, a shrub resembling common juniper, by dry distillation, and is a dark-colored, thick liquid with a tarry odor, and a burning, bitter taste. Therapy—Juniper has long been in use as a general diuretic and soothing kidney remedy. It is indicated in feeble or aged patients with persistent dragging or weight across the kidneys. It will quickly relieve many cases of simple renal hyperemia, preventing the development of structural change, or the advancement of nephritis. After acute nephritis, whether from direct causes, or subsequent to scarlet fever, diphtheria, or other severe disease, when active inflammation has subsided, it will restore the secretory power of the Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 270 epithelium of the renal tubules and readjust the secretory function to the blood pressure, restoring normal action. It is useful in strangury, and in some dropsies where there is absence of acute inflammation. It may be applied directly, but is quite severe upon an irritable or sensitive surface. It is a useful agent in psoriasis, and as a parasiticide it will destroy psora and cure favus. It was at one time in common use as an application to skin diseases and parasites in domestic animals. Physiological Action—In Kalmia we have a remedy acting in a manner somewhat like veratrum viride, both in controlling fevers and in inflammations, as well as in its influence as an alterative, it having been successfully used both in primary and secondary syphilis. Like veratrum it has also been employed hypodermically in the treatment of neuralgia of the face, and sciatica.

Isotopes used as tracers A radioactive isotope attached to an important molecule can tell where it is generic ofloxacin 200mg with mastercard. Isotopes emitting g-rays are easily observed purchase ofloxacin 400mg without prescription, but also pure b-emitters like H–3 (tritium) and C–14 can be used cheap 400mg ofloxacin otc. Thus, Melvin Calvin used C–14 to the exploration of photosynthetic carbon dioxide reduction. The Hershey – Chase experiment A very well known experiment with radioactive tracers was the Hershey– Chase experiment from 1952. Alfred Hershey and Martha Chase used the isotopes P–32 (b-emitter with half-life 14 days) and S–35 (b-emitter with half-life 87 days). Alfred Hershey (1908 – 1997) was the principal investiga- Numerous experiments within bio- tor, whereas Martha Chase (1927 – 2003) was the lab. Isotopes in radiation therapy In radiation therapy the purpose is to irradiate cancer cells to death and let the normal cells survive. Radium (Ra–226) was used from the beginning, both for teletherapy and as im- plants in brachytherapy. Attached to compounds (monoclonal antibodies) the isotope can be transported to the the cancer cells. Isotopes for diagnostic purposes Several isotopes emitting g-rays can, and have been used for diagnostic purposes. For example, I–131 will be accumulated in the thyroid and can via a gamma camera give information about sicknesses in the thyroid. We have pointed out before that the isotope most often used for medical information is Tc–99m. Thus, after the b-particle emission the newly formed technetium isotope is in a socalled “meta- stable” state. If we could isolate this metastable isotope it would be perfect for medical use, since the isotope would only emit a g-photon with no contamination from b-particles. Decay scheme for Mo-99 Mo–99 67 h The decay of Mo–99 results in a metastable nucleus – de- noted Tc–99m. By emitting a g- photon it ends up in Tc–99 which is radioactive with a Tc–99 halfife of 213 000 years. The compound is rinsed with physi- ological saline, and the Tc-99m that has been formed follows the water – it is like “milking”. The next step is to hook on this isotope to compounds that can bring it to particular places in the body that can be studied. More than 30 compounds based on Tc-99m have been made for imaging and functional studies of the brain, myocardium, thyroid, lungs, liver, gallbladder, kidneys, skeleton, blood and tumors. Tc-99m emits γ-radiation with an energy of 140 keV, which readily escapes the body and is easily measurable. From a physicists point of view it is probably the technique developed to observe the distribution of radioactivity that is the most interesting – whereas from a medical point of view it is the diagnostic power that is the most interesting. Ben Cassen and Hal Anger The technique with the radioactive isotopes in medical diagnostics started in the 1950s when Benedict Cassen invented the rectilinear scanner and in 1958 with the g-camera (or Anger camera). Blahd A picture of Hal Anger (1920 – 2005) and Benedict Cassen (1902 – 1972) at the International Confer- ence on Peaceful Uses of Atomic Energy in Geneva, Switzerland, in 1955. It can be mentioned that the “Society of Nuclear Medicine” every second year since 1994 give out a prize in honor of Benedict Cassen (The Benedict Cassen prize) for outstanding achievements in nuclear medicine. The illustration to the right demonstrate the technique introduced by Benedict Cassen. He assembled the frst auto- mated scanning system that was com- prised of a motor driven scintillation de- tector coupled to a relay printer. After the ini- tial studies, it was an extensive use of the scanning system for thyroid imaging during the early 1950s. Cassen’s devel- opment of the rectilinear scanner was a defning event in the evolution of clinical nuclear medicine. In 1956, Kuhl and his colleagues developed a photographic attachment for the Cassen scanner that improved its sensitivity and resolution. With the development of organ-specifc radio pharmaceuticals, a commercial model of this system was widely used during the late 1950s until the early 1970s to scan the major body organs. The decline of the rectilinear photoscanner began in 1973 with the advent of computed axial tomography. As its name suggests (single photon emission), ordinary g-ray emission is the source for the information. The camera or detector rotates around the patient, and the detector will observe the tracer distribution for a variety of angles. After all these angles have been observed, it is possible to reconstruct a three dimensional view of the isotope distribution within the body. A computer is used to apply a tomo- graphic reconstruction algorithm to the multiple projections, yielding a 3-D dataset. An example with Tc–99m In the example shown (to the right), Tc-99m was added to methylene- diphosphonate, which is absorbed by the bone-forming cells (the osteo- blasts). The picture makes it possible to study diseases of the skeleton, such as bone cancer. In order to un- derstand this we refer to chapter 2 where we discussed the different ways an unstable nucleus could attain a more stable state. We mentioned that in the ordinary b-decay, a neutron was transformed into a proton and an electron, which was emitted. This is a favorable reaction since the neutron mass is lager than the proton mass. The opposite reaction where a proton is transformed into a neutron is how- ever, a more diffcult process.