By B. Vandorn. West Chester University of Pennsylvania.
Finally micronase 2.5 mg discount, there are the relatively rare published investigations on the use of drugs for purposes of interrogation in police or security procedures; these are reviewed carefully because of their direct relevance purchase micronase 5mg with mastercard. No published reports have come to the attention of this author detailing the scientific application of drugs by intelligence agencies of any nation as a means of obtaining information. Apparently, what knowledge is available, whether derived from haphazard experience or systematic study, is not accessible in open sources. Rolin (112) casually claims that the Nazis used mescaline to get information from prisoners at Dachau. In discussing the methods of communist indoctrination of Americans who have fallen into the hands of communists or communist-controlled countries, Hinkle (62) has stated that the methods of Russian interrogation and indoctrination are derived from age-old police methods that have been systematized, and are not dependent on drugs, 1 hypnotism, or any other special procedure designed by scientists. Methodological Problems in Determining the Applicability of Drugs to Interrogation Procedures: Nonspecific Effects of Drugs on Verbal Behavior One of the crucial questions arising in evaluating the use of a drug for interrogation techniques is what responses are related to the pharmacologic activity of the drug administered and what responses are related to some other aspects of the transactions taking place when a person receives medication from another person. A large variety of nonpharmacologic factors can affect the responses of an individual after getting a dose of medication (see also Masserman and Pechtel, 102). In fact, one of the major problems plaguing investigators of 1 Popular literature contains a number of accounts alleging the use of drugs in interrogations. Recent well-publicized examples include the alleged use of mescaline against Cardinal Mindszenty (S. Ryan, I came back from a Red death cell, Saturday Evening Post, January 17, 24, 31, and February 7, 1953); and the account by the Communist editor, Henri Alleg, of an alleged use of sodium pentothal in interrogations he received while held by French forces in Algeria (H. A series of nonpharmacologic factors within the total transaction of a person giving another person a drug has been found to be more or less capable of contributing to the responses occurring with administration of the drug. These factors may be listed and what is known about each will be taken up separately. Reactions to attitudes or motivations of the person administering the medication and interacting with the informant. The studies of Beecher and his group (7, 8) indicate that 30 to 50 per cent of individuals are placebo reactors, that is, respond with symptomatic relief to taking an inert substance. If one is interested in the pharmacology of a new drug and tries it out on a group of patients, a third to a half of this group will be relieved of their symptoms by a placebo; they react favorably to the syringe, pills or capsule, regardless of what it contains. Thus they dilute the significant data derived from the half or two-thirds of the group that react only to the active ingredient in the syringe or capsule. In studying a new drug-whether one is interested in applying its pharniacologic effect toward the alleviation of pain, amelioration of emotional distress, or the facilitation of communication of covert information-the scientist is not primarily interested in the subjective and behavioral effects of syringes and pills. Thus the scientist is obliged to take into account the placebo reactors, who must be screened out if one is to get an accurate idea of what the drug itself does. Of course, to relieve pain or facilitate communication in a patient or prisoner, the "placebo phenomenon" can be made use of itself and -99- the investigator can expect that in 30 to 50 per cent of trials pain may be relieved or interrogation may be facilitated. Some additional factors are known which increase the likelihood of a placebo effect: 1. A sympathetic woman investigator can obtain a higher percentage of pain relief from various niedicatimis than can a colder, more remote male (7). Clinical psychiatric findings in the same study regarding placebo reactors found greater responsiveness characteristic of individuals who are more anxious, more self-centered, more dependent on outside stimulation than on their own mental processes; persons who express their needs more freely socially, who are talkers, and who drain off anxiety by talking and relating to others. In contrast to the placebo reactors, the nonreactors are clinically more rigid and more emotionally controlled than average for their age and background. If one is interested in ascertaining whether a drug produces a given effect to a degree greater than a placebo, it becomes obvious that the effect produced by the drug must exceed the chance variations of the placebo effect to a reliable extent. In experimental investigations exploring the usefulness of drugs for various purposes, the placebo and other nonspecific reactions to medicaments must be separated from the effects specific to the active drug. Devising an experimental study using infrahuman animals to assess the pharmacologic effect of a drug only postpones the assessment of the complicated responses likely to occur when the drug is given to a human being. For the researcher interested in discriminating specific from nonspecific effects of drugs, Beecher (7) has outlined a series of principles and practices on the basis of seventeen drug studies in which he has participated, as follows: • 1. Subjective responses are the resultant of the action of the original stimulus and the psychic modification of that stimulus. Man is the essential experimental subject for a definitive answer to questions in this field, and men are easier to work with than women, for with men the controls are simpler. The agents tested and the time they are tested are unknown not only to the subjects but to the observers as well. When a new agent is to be compared with the agents of past experience, and this is nearly always the case, a standard of reference is required (morphine in standardized dosage is used as the standard for analgesics, etc. Significant comparisons of side actions of agents can be made only on the basis of equal strength in terms of their primary therapeutic effect. Mathematical validation of supposed difference in effectiveness of the two agents is necessary. The subjective (and behavioral) effects of drugs can be quantified accurately and rapidly only when placebo reactors are screened out. Silent Administration The obverse of placebo administration, the deliberate administration of an inert material, is silent administration, the unknown administratiou of a pharmacologically potent substance. The act of administering a medication usually potentiates its effect since it invokes the status of a professional person and the prestige of social institutions and organizations that are a part of the setting. A general recognition of this fact has made the control of the placebo effect a routine feature of all carefully designed drug studies.
Depending on the parasite specie the clinical manifestations vary from localized ulcerative skin lesions to disseminated visceral infection buy micronase 5mg without a prescription. The latter is the most severe form of the disease proven micronase 5 mg, which is fatal when left untreated. However the recommended therapy is far from satisfactory due to the emergence of resistances, severe side effects and the limited efficacy owing to disease exacerbation, mainly associated with compromised immune capability (e. Depending on the parasite specie the clinical manifestations vary from localized ulcerative skin lesions to disseminated visceral infection. The latter is the most severe form of the disease, which is fatal when left untreated. A vertebrate host becomes infected with Leishmania, through the bite of an infected sandfly (Phlebotomus and Lutzomya spp) along with its blood meal, by the inoculation of infective flagellated promastigotes that invade or are phagocytosed by local or recruited host cells. In the phagolysosomes, the promastigotes will differentiate into non-flagellated amastigotes that multiply and are able to infect other adjacent or distant macrophages. The disease control is dependent on drug therapy once no approved human vaccine is available. Pentavalent antimonials, represented by sodium stibogluconate and meglumine antimoniate, have been the first-line treatment in many endemic areas for more than 7 decades (Chappuis et al. Among the antimonials severe adverse effects, are the life-threatening acute pancreatitis and cardiac arrhythmia. Amphotericin B has replaced antimonials as first-line treatment in many areas of the Bihar State in India, where treatment unresponsiveness is more than 60% (Sundar et al. Although, it administration requires close medical supervision due to high toxicity (fever with rigor and chills, thrombophlebitis and occasional serious toxicities like myocarditis, severe hypokalaemia, renal dysfunction and even death) (Sundar et al. The toxic events were substantially reduced by the emergence of Amphotericin B lipid formulations (Sundar et al. Indeed, these formulations allowed a targeted drug delivery to parasites, once they are preferentially internalised by the reticuloendothelial cells. Even these formulations are used as first-line treatment in Europe and United States, its use in endemic areas was precluded due to economic reasons (Gradoni et al. It is highly effective (adults and children’s) and well tolerated, with limited side effects that are usually mild and temporary (Sundar et al. However, miltefosine is teratogenic, being its use strictly forbidden in pregnant women’s or in women’s who could become pregnant within two months of treatment (Sindermann et al. Non internalized parasites were removed and serial dilutions of each drug were added. Parasite load quantification The parasite load in the liver and spleen was determined by the limiting dilution method as previously described (Buffet et al. The organs were then submitted in quadruplicate, to the serial 2-fold dilutions in a 96 well microtitration plates. The plates were incubated at 27ºC for 15 days and then each well was inspected for the presence or absence of promastigotes. The final titter was the last dilution for which, at least one 5 promastigote was recorded. The number of parasites per gram of organ (parasite load) was calculated as follows: parasite load= [(geometric mean of reciprocal titter from each quadruplicate cell culture/weight of homogenized organ) x reciprocal fraction of the homogenized organ inoculated into the first well]. Blood analysis Uncoagulated blood samples were used to obtain a complete blood evaluation, including total red blood cell, haemoglobin, hematocrit, total white blood cells, and granulocyte, monocyte, lymphocyte counts. The inhibition of the parasites growth induced by each drug were evaluated by measuring the activity of the reporter protein, luciferase. Indeed, this assay was previously validated to be used in drug screening experiments (Roy et al. The possibility to culture some species of Leishmania amastigotes, under axenic conditions, represented a major advance in drug screenings, which were usually performed with the parasite insect stage, the promastigotes (Bates, 1994; Balanco et al. Meanwhile differences in drug sensitivity between axenic and intracellular amastigotes were already reported, supporting the necessity of evaluate drugs efficacy against the intracellular forms (Ephros et al. Indeed, some explanations could be attributed to such differences, including an antileishmanial effect mediated by the host cell or alternatively, an interference with the high concentration of serum used in the axenic amastigotes culture medium. All the animals were treated during 3 consecutive days and the drug efficacy was evaluated 3 days after the last drug administration. The administration of amphotericin B also slightly reduced the liver parasite load to -1 3. A different scheme of treatment through the administration of the several drugs at 1mg/kg twice a day and during the same period of time as the above treatments (3 consecutive days), was also conducted. However no increased reduction of the parasite load was detected (data not shown). Blood samples were collected 3 days after the last treatment for haematological toxicity analysis. Uncoagulated blood samples were used to obtain a complete blood evaluation, including red blood cells, total white blood cells, haemoglobin, hematocrit, and lymphocyte, neutrophil and monocyte count.
By the late 1960’s purchase micronase 5mg mastercard, analysts invariably used to have the bliss of excellent experience of achieving the goal of superb separations of complex mixtures in seconds rather than in minutes purchase micronase 2.5 mg with visa, with the aid of electronic integrators to get an exact access of areas under elution bands, and above all the ‘computer-printouts’ of the complete analysis with the flick of a finger. In many favourable instances the smallest possible quantities ranging from nanogram to picogram* could be detected with utmost ease and convenience. Hence, either a stable vapour from the mixture is obtained directly or indirectly converting the substance in it to such derivatives that are thermally stable. Furthermore, the spectrum of these selective interactions may also be enhanced by an appropriate chemical modification of the silica surface i. These silica particles are mostly uniform, porous, with spherical or irregular shape, and having diameter ranging from 3. Bonded-Phase Supports : The bonded-phase supports usually overcome plethora of the nagging prob- lems which is mostly encountered with adsorbed-liquid phases. The nature of the R group of the silane solely determines the surface polarity of the bonded phase. Note : The exact mechanism by which the respective bonded phases actually alter the nature of the sorption mechanism is still not yet clear. When such microparticulate-bonded-phases are packed compactly into a column by means of a suit- able device, the small size of these particles offers a significant resistance to solvent flow ; therefore, the mobile phase has to be pumped through the column under a high positive pressure. In-line Detector : It broadly helps to sense the separated solutes, after they exit through the column. Invariably the detector is an electrical signal whose variation is displayed on a potentiometer recorder or a computing integrator or a video-screen. Therefore, such component(s) have to be appropriately converted into their corre- sponding detectable form once they emerge from the column. All these vital components will be discussed with adequate details, wherever necessary, in the various sections that follow : Solvent reservoir Flow Sample splitting valve injection port Degassers Separation column Guard column Mixing valve Equilibration Constant pump and coil temperature gradient system chamber To waste Recorder Vacuum pump Data processing Detector Time Figure 30. The mobile phase, that may be either a single liquid or a mixture of two or more liquids, is pumped at high pressure into a temperature controlled oven, where it first, gains its entry into an equilibration coil to bring it to the operating temperature, and secondly, through a ‘guarded column’ specially designed and strategically positioned to protect the analytical column from impurities and ultimately extend its lifetime. The pressures mentioned above correspond to mobile-phase flow rates of approximately 1-5 cm3 min–1 through the column. Flow : The flow can be measured periodically at the column outlet by collecting the liquid for a known period, and thereafter, either measuring the volume or weighing it physically. Temperature : In reality, the maintenance of strict ‘temperature control’ plays a vital role in measuring the retention-data correctly and precisely. They are : (a) Constant Pressure Pump : A constant-pressure pump acts by applying a constant pressure to the mobile-phase. The flow rate through the column is determined by the flow resistance of the column. Importantly, in a constant-pressure pump the flow rate will change if the flow resistance changes. Whereas in the constant flow pumps the changes in flow resistance are compensated duly by a change of pressure. The piston is moved in and out of a solvent chamber by an eccen- tric cam or gear. The forward-stroke closes the inlet-check value while the outlet valve opens and the respective mobile phase is duly pumped into the column. Consequently, the return-stroke-closes the outlet valve and it refills the chamber. Mobile-phase outlet Seals Check valves Piston Solvent chamber Eccentric cam Mobile-phase inlet Figure 30. The stage-A depicts the drive while the refill zone is vacant ; while the stage-B evidently shows the two-heads functioning simultaneously thereby the drive and the refill both zones could be visualized. The major drawback associated with this type of injec- tors is ‘leaching effect’ of the mobile-phase just in contact with the septum, thereby resulting in the formation of ‘ghost peaks’ or ‘pseudo peaks’. The flow of the mobile-phase through the column is stopped for a while, and when the column reaches an ambient pressure the top of the column is opened and the sample introduced at the top of the packing. These valves enable samples to be introduced reproducibly into pressurized columns without causing the least interruption of the mobile-phase flow. Here, the sample is loaded at atmospheric pressure into an external loop in the microvolume- sampling valve, and subsequently injected into the mobile-phase by a suitable rotation to the valve. However, the volume of sample introduced usually ranges between 2 µl to over 100 µl ; but can be varied either by altering the volume of the sample loop or by employing specific variable-volume sample valves. Mobile phase To column Mobile phase To column Adjustable Sample in Sample out Sample in Sample out length sample loop (a) Sampling mode (b) Injection mode Figure 30. Therefore, it is always preferred for most quantitative work by virtue of its very high degree of precision and accuracy.
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