By B. Sulfock. Point Park University.
It is used in several ﬁxed combina- tions with rifampicin and with other tuberculostatic drugs cheap 25mg atarax with mastercard anxiety symptoms treated with xanax, such as pyrazinamide and ethambutol (see later in the chapter) order atarax 25 mg anxiety funny. It is used to counteract the development of resistance according to the general arguments given earlier in the chapter, as well as for rifampicin resistance. To exercise its effect, it has to be activated to isonicotinic acid (9-3) in the bacterial cell. This acti- vation is effected by a mycobacteria-speciﬁc catalase-peroxidase, which normally protects the bacterial cell against peroxides by degrading them to free oxygen and water but which also seems to be able to oxidize isoniazid to its active form. Resistance against isoniazid occurs and is a threat to treat- ment, since the lowered susceptibility to one of the components of the drug combination therapy affects the total therapeutic effect and could contribute to the development of multiresis- tance (see Chapter 10). Isoniazid resistance could be caused by mutations in the katG gene expressing the catalase-peroxidase enzyme, inactivating its enzymic effect and thus preventing it from activating to its antibacterially active form any isoni- azid administered. Another form of isoniazid resistance, caused by spontaneous mutations in the gene expressing the mycolic acid–synthesizing enzyme, has been observed. This enzyme is the target of the activated form of isoniazid, and the mutations make it less susceptible to the drug. Pyrazinamide Another speciﬁcally acting tuberculostatic agent, pyrazinamide (9-4), is often used in a ﬁxed combination with rifampicin. The exact mechanism of action for this drug is not known, but it has been shown that it must be converted enzymically inside the cell to pyrazinoic acid (9-5), which is the active antibacterial agent. The logical solution to this clinical resistance problem would then be to use pyrazinoic acid as a tuberculostatic drug. Compared to pyrazinamide, however, pyrazinoic acid is taken up very poorly in the bacterial cell. Ethambutol The ethylenediamine derivative ethambutol (9-6)isanother agent used as a component in ﬁxed tuberculostatic drug com- binations containing, for example, rifampicin, isoniazide, and pyrazinamide. Ethambutol is a speciﬁc tuberculostatic drug which has been used for this purpose since the beginning of the 1960s. Despite many years of clinical use of ethambu- tol, its mechanism of action has not been known until relatively recently. The ethambutol-mediated interference with mycobacterial cell wall formation is regarded as being able to increase the per- meability for other antimycobacterial agents and thus contribute to that valuable clinical synergism, observed for example at the combination of ethambutol with rifampicin, which is a large molecule whose size interferes with permeability. Resistance to ethambutol has been observed, and was in many cases, but not all, shown to be caused by spontaneously occurring mutational changes in the synthesis regulation of the enzymes involved in the polymerization of arabinose. Cycloserine Cycloserine was used as a remedy against tuberculosis, but is not used much clinically nowadays because of the central ner- vous system disturbances that were sometimes experienced by patients. It is a true antibiotic in the sense that it was originally isolated from several Streptomyces species, among them S. D-Cycloserine (9-7)has a simple chemical conﬁguration and is a structural analog of D-alanine. D-Cycloserine is a broad-spectrum antibiotic with a particularly good effect on mycobacteria, among them M. One is L-alanine racemase, forming D-alanine from L-alanine; the other is D-alanine-D-alanine synthetase. It should be mentioned that D-cycloserine has a 100-fold higher afﬁnity for D-alanine-D-alanine synthetase than does the normal D-alanine substrate. The ﬁnal effect of D-cycloserine is similar to that of betalactams, of glycopeptides, and also of phosphomycin, in that the bacterium affected is unable to form the crucial transpeptidase cross-links for murein stability and thus for a stable cell wall. It is caused by spontaneous mutations in the genes expressing L-alanine racemase and D-alanine-D-alanine synthetase to lower the afﬁnity of D-cycloserine for these enzymes. Also, changes in the alanine permease transporting D-cycloserine into the cell have been shown to mediate resistance to the drug. Finally, we note that the side effect of D-cycloserine causing disturbances in the cen- tral nervous system has recently been turned into an advantage in that when it is administered as a drug, it functions as an adjuvant to cognitive behavioral therapy in the treatment of obsessive-compulsive disorder. It works as an analog of p-aminobenzoic acid and inhibits folic acid synthesis in M. It has been used as a standard remedy since 1946, often in combination with streptomycin mitigating the selection of resistance against the latter.
In the sparsely populated northern areas cheap atarax 10mg on line 0800 anxiety, antibiotics consumption is just about 70% of that seen in the more densely populated southern areas order atarax 10mg amex anxiety zone dizziness. Taken into account that the Swedish population is relatively homogeneous, these large differences cannot reﬂect differences in the infection panorama but must be related to variations in prescription patterns for many non- medical reasons. Further analysis of these reasons ought to be useful in efforts to curb the overconsumption of antibiotics in general. Similar differences in the consumption of antibiotics can also be observed in hospitals, where typically, 30 to 60% of inpatients are treated with antibiotics. As speciﬁc examples, the consumption of tetracyclines could vary sixfold and cephalosporins almost fourfold between hospitals. These differences imply overconsumption and are so large that they could not be explained by differences in the panorama of infectious diseases, given that all the hospitals investigated included clinics for infectious diseases. International comparisons also give the impression that antibiotics are overconsumed. A comparison between Canada (British Columbia) and the European average showed that the Canadian consumption of antibiotics was comparable to that in Sweden but that the European average was more than 10% higher. Data on antibiotic use are now available from most European Union countries (see European Surveillance of Antibi- otic Consumption, http://www. From this and other investigations it was observed that antibiotic sales could vary more than fourfold between European countries. All these data on antibiotics consumption speak for stricter control of antibiotics use. This ought to limit overconsump- tion and diminish the total selection pressure toward resistance development. This is the most obvious and immediate way of at least slowing down the increase in antibiotics resistance among pathogenic bacteria. It is connected to higher care costs when antibiotic therapy fails because of resistance, higher infection control costs, and the necessity of using more expensive antibiotics. There are cal- culations of these costs by health care economists, who report them to be very high. It is then important to curb the use of antibiotics by using them only for the urgent treatment of pathogens causing infections. As a speciﬁc example, in the Stockholm (Sweden) area, amoxicillin and trimethoprim can no longer be used for empirical therapy for urinary tract infections with Escherichia coli before the resistance determi- nations are in from the bacteriological laboratory, because of widespread resistance. This bacterium is the pathogen found most commonly in these infections and is now very frequently resistanttothedrugsmentioned. Thisisagreatlosssinceamox- icillin and trimethoprim are inexpensive and efﬁcient medicines and easy to handle. Earlier, a large part of the antibiotics consumption was used as feed additives in husbandry and to some extent also in plant agriculture. The use in animals was based on the empirical but not completely under- stood observations that meat animals gained weight faster when given antibiotics in their fodder. It soon became clear, however, that this practice led to the spread of antibiotic resistance through the food chain into the general population. An example of this was the use of avoparcin, a glucopeptide, an analog to van- comycin (see Chapter 5). It soon became clear that this practice led to a widespread dissemination of vancomycin- resistant enterococci into the general population through the food chain. This was all the more frightening since vancomycin was looked upon as a drug of last resort in many cases of infectious disease. It is the drug of choice for the treatment of infections by methicillin-resistant staphylococci. In monitoring the effect of the ban, a dramatic drop in the occurrence of vancomycin-resistant enterococci was seen in chickens and supermarket chicken meat. This could also be seen in stool samples from patients in which the prevalence of a key vancomycin resistance gene dropped from 5. There is another interesting example of the consequences of using antibiotics for growth promotion in animal husbandry. It regards streptothricin, found in the Streptomyces screening efforts performed in Selman Waksman’s laboratory described in Chapter 1. Streptothricin was found to be too toxic for human use but was used under the name nourseothricin for growth promotion in pig farms in the earlier East Germany. Soon after the introduction of streptothricin use, plasmid-borne resistance to streptothricin was observed in E.
In between these two layers atarax 10mg with mastercard anxiety symptoms of going crazy, however quality 25mg atarax anxiety xanax dosage, the composition and design of the device varies considerably. Adhesive patches The adhesive patches are simplest in concept, consisting only of a layer of drug-containing adhesive polymer which serves, therefore, as a reservoir of the compound and the means by which the device is held to the skin. These systems can hold substantial amounts of the active agent, often in considerable excess of that delivered during the designated application of the patch (e. Not infrequently, the degree of control offered by these systems is relatively small (see below), and it is the stratum corneum that ultimately regulates the absorption rate of the drug into the body. It should be noted that these representations of the patches greatly exaggerate their real thicknesses, which are in fact similar to that of a normal Band-Aid The layered devices are a little more complex than the simple adhesive systems in that they use different polymer compositions or different polymers to provide the functions of drug-containing matrix and adhesive. It should also be noted that some layered systems have been developed in which the drug-containing matrix contacts the skin directly and the patch is held to the skin by a peripheral adhesive. While effective, these devices suffer from the drawback that the area of contact between patch and skin is significantly greater than the “active” area, i. These devices are characterized by two particular features: first, an enclosed reservoir of the drug, which may be liquid in nature; and, second, a polymeric membrane separating the reservoir from the adhesive layer, itself made from a different polymer. The idea, naturally, behind this design is that the membrane acts as a rate-controlling element for drug delivery to and across the skin (i. There are, in fact, situations for which this claim is true; however, it must also be noted that there are others where the control lies, at least in part, elsewhere (see below). The essential components of a transdermal system are the drug, one or more polymers, the “vehicle”, and other excipient(s). Polymers are used in transdermals as pressure-sensitive adhesives, release liners, backings and laminates, and for speciality films and supports. A pressure-sensitive adhesive may be defined as a solvent-free, permanently tacky, viscoelastic substance, capable of adhering instantaneously to most solid surfaces with application of slight pressure, and removable without leaving perceptible residue. Release liners are usually silicone and fluorocarbon coatings on paper, polyester or polycarbonate films. Backing and other membranes are fabricated with diverse polymers including ethylene vinyl acetate, polypropylene, polyester, polyethylene, polyisobutylene and polyvinyl chloride. Special films in current use include foams, non- wovens, micro-porous membranes, etc. Additional excipients, present for stability and other purposes, may be lactose, silicon dioxide, cross-linking agents, and hydroxyethylcellulose. The manufacture of a transdermal drug delivery system is a complex and sophisticated process requiring specialized equipment and facilities. In the most basic and generic sense, two procedures can be identified, one for “solid-state” patches (adhesive and layered systems), the other for reservoir devices. In the former case, the important steps are: (a) Mixing of drug, excipients, polymers and solvent to make a coating solution (or solutions), (b) Casting the coating solution(s) onto the protective liner, evaporating the solvent, and laminating the backing film, (c) Die-cutting the drug laminate to the desired patch size, (d) Packaging. For reservoir systems, the components of the reservoir (drug, excipients, viscous liquid) are first mixed. Separately, the adhesive polymers and solvent are mixed to make a solution, which is then cast onto a protective liner. The system is then assembled by forming the backing film, pumping in the drug reservoir, and then heat-sealing the laminate to the backing. That is, if the delivery system truly controls the rate of absorption of drug into the body, then only the variability in clearance remains as a factor to influence the resulting plasma concentration achieved (Equation 8. Given, however, that there now exist on the market many different patches for one specific drug, all of which are approved for the same therapeutic indication (and the same delivered dose), it is appropriate to ask to what extent does the control of delivery rest with the patch as opposed to the skin. To illustrate this point, consider three of the presently marketed nitroglycerin systems that are labeled to deliver drug at 0. First of all, it should be noted that, despite the differences in design, drug loading and surface area, these patches are considered to be bioequivalent. Thus, one cannot use drug content nor mechanism of release as useful parameters with which to assess the comparability of different transdermal systems (by contrast, for oral delivery, a generic Table 8. In the first (Experiment A), drug release from the patch directly into 202 Figure 8. In left panel, drug release from the patch into an aqueous receptor is measured (“Experiment A”).