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It was originally termed a ‘major tranquiliser’ due to its calmative effects in addition to dramatically reducing psychotic symptoms amongst agitated patients (Jones & Buckley generic 200mg cefixime fast delivery antibiotics for bladder infection while pregnant, 2006; Schulz & McGorry purchase cefixime 200 mg mastercard virus image, 2000; Weiden et al. The introduction of Chlorpromazine represented the first effective medical management strategy for schizophrenia and was, thus, deemed one of the great medical advances of the twentieth century (Sharif et al. Typical antipsychotics were breakthrough medications, as they provided therapy for psychosis, which had previously been almost impossible to treat (Conley, 2000). The effectiveness of antipsychotics in reducing the intensity of consumers’ positive symptoms- has permitted the outpatient treatment of schizophrenia and was associated with a dramatic reduction in mental hospital populations (Freedman, 2005; Schulz & McGorry, 2000). The typical antipsychotic medications currently in use include: Haloperidol, Thieridaxine, Thiothixene, Fluphenazine, Trifluoperazine, Chlorpromazine and Perphenazine. Over one hundred clinical trials have demonstrated the effectiveness of typical antipsychotic medications, including a series of double-blind placebo studies (Sharif et al. Research that has not supported the effectiveness of typical medications is generally restricted to poorly designed studies that involved ineffective dosages (Sharif et al. Although typical antipsychotic medications substantially reduce the positive symptoms of schizophrenia in some people, they have been documented as having no appreciable effect on cognitive dysfunction, and as having only a limited effect on, and even worsening, negative and depressive symptoms (Conley, 2000; Jones & Buckley, 2006; 19 Mueser & Gingerich, 2006; Weiden et al. Contradictory evidence exists, however, which points to clinical trials that indicate that all symptoms associated with schizophrenia improve with typical antipsychotic medication although, in general, positive symptoms respond to a greater degree and more consistently than negative symptoms (Sharif et al. Extensive evidence indicates that typical antipsychotic medications are essentially similar in efficacy profiles, however, individual consumers may respond better to one drug than another due to their different side effect profiles (Sharif et al. For example, while Chlorpromazine is quite sedating, Haloperidol is not (Mueser & Gingerich, 2006). The side effects of typical antipsychotic medications are frequently distressing and prominent and in addition to sedation, include: slowed thinking, dizziness, sexual dysfunction and sensitivity to sunlight. Anticholinergic side effects are also associated with typical antipsychotics, which include dry mouth, blurry vision, constipation, difficulty urinating and memory problems (Mueser & Gingerich, 2006). Tardive dyskinesia typically 20 emerges several months after the commencement of treatment and is potentially a lifelong condition (Weiden et al. It usually consists of involuntary movements of the head, tongue, lips, hands and feet and can affect speech, posture and sometimes breathing (Birchwood & Jackson, 2001; Jones & Buckley, 2006; Mueser & Gingerich, 2006). Typical presentations of the conditions involve protruding tongue, facial grimaces, and slow rhythmical movements of the hands and feet, sometimes even without the person knowing it (McEvoy et al. The chances of developing tardive dyskinesia can reportedly be reduced by using the lowest possible effective dose of medication (McEvoy et al. Since the development of the new, atypical antipsychotic medications, indications for typical antipsychotic medications are shrinking. McGorry (1992) posits that typical antipsychotic medications, in low dosages, may still have a role amongst a small proportion of consumers, who demonstrated a positive response to typical schedules including remission and good tolerability. They have also been indicated in the acute management of aggression or violence in some patients in the past (McEvoy et al. Advantages of typical antispychotic medications over atypical antipsychotic medications include greater medication familiarity for some consumers and clinicians and they are less expensive (Weiden et al. The development of atypical antipsychotic medications has also increased the probability of finding a suitable drug for individuals with schizophrenia, as there are now more options available to consumers and practitioners (Janssen et al. The wider choice offered by the advent of atypical medications, in addition to their increased tolerability, have been associated with more sustained adherence to prescriptions (Liberman & Kopelowicz, 2005). Clozapine, the first atypical antipsychotic medication, manufactured in 1959, was first tested in the 1970s and was discontinued due to serious blood reactions (Weiden et al. It was reintroduced for use in 1989 in the United States, followed by the introduction of the other atypical antipsyhotic medications in the 1990s or after 2000 (Weiden et al. The atypical antipsychotic medications currently available are: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, sertindole, zotepine and amisulpiride. With the exception of clozapine, these atypical antipsychotic medications were developed following years of scientific research aimed at understanding how typical antipsychotic medications work and trying to make more effective medications with fewer serious side effects (Mueser & Gingerich, 2006). Several studies have historically supported, and continue to support, the efficacy of atypical antipsychotic medications for treating positive symptoms of schizophrenia amongst treatment-responsive, recurrent- episode consumers, when compared with placebo (eg; Buchanan et al. A recent systematic review revealed some evidence that olanzapine, 22 ziprasidone and zotepine were more effective at reducing relapse rates over 12 months than placebo (Smith et al. A vast number of double-blind studies comparing the acute treatment effects of atypical antipsychotic medications with typical antipsychotic medications have been conducted.

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This process cefixime 100mg line antimicrobial nail solution, known as transcytosis discount cefixime 100mg mastercard antibiotic xifaxan cost, represents a potentially useful and important pathway for the absorption of high molecular weight drugs such as peptides and proteins. Indeed, some peptides and proteins are known to enter intestinal mucosal cells through pinocytosis; furthermore, a few peptides and proteins (including immunoglobulin G, nerve growth factor and epidermal growth factor) have been reported to reach blood vessels in the lamina propria and the portal venous circulation. This process may be facilitated by serum proteins knows as opsonins, which cover the particulate and promote adsorption and ingestion. The extent and pattern of opsonization depends highly on antigen surface characteristics such as charge and hydrophilicity. When digestion is complete, the lysosomal membrane may rupture, discharging its contents into the cytoplasm. Fixed macrophages are found lining certain blood and lymph-filled spaces, such as the sinusoids of the liver (these cells are commonly referred to as Kuppfer cells), bone marrow and spleen. For the purpose of completeness, the process of phagocytosis has been described briefly here. The process of phagocytosis is of particular relevance when particulate delivery systems, such as microspheres, liposomes and other advanced delivery systems (described in Chapter 5), are used. Phagocytic processes are also finding applications in oral drug delivery and targeting. Specialized epithelial cells known as M cells, which overly lymphoid sections of the gastrointestinal tract, may be involved in the phagocytic uptake of macromolecules and microparticles from the gut (see Section 6. Pore transport A further mechanism of transcellular transport is via the aqueous pores which exist in many lipid membranes. However, most drugs are generally much larger (≥1 nm in diameter) than the pore size, and this route is therefore of minor importance for drug delivery. These properties will influence the route and mechanism of drug absorption through the mucosa. For example, it is not unreasonable to assume that: • low molecular weight hydrophilic compounds would tend to be absorbed via the paracellular route, moving between the epithelial cells; • lipid-soluble drugs would usually absorbed via transcellular passive diffusion, diffusing through the lipidic membrane barrier; • macromolecules may be absorbed via endocytic processes; • drugs bearing structural similarities to endogenous nutrients may be absorbed via carrier-mediated mechanisms. However, this is a rather simplistic view and it is important to realize that these considerations are only broad generalizations. Thus although a drug molecule may be predominantly absorbed via one particular route/mechanism, it is also likely that suboptimal transport will occur via other routes and mechanisms. In particular, drugs that are absorbed via active mechanisms are often also absorbed, to a (much) lesser extent, via passive diffusion mechanisms. A brief description of the effect of the physicochemical properties of the drug on the absorption process is given below and is discussed in more detail in the relevant chapters. A measure of the lipid solubility of a drug is given by its oil/water equilibrium partition coefficient. This is determined by adding the drug to a mixture of equal volumes of a lipophilic liquid (often octanol, but other solvents also used) and water and shaking the mixture vigorously to promote partitioning of the drug into each phase. For a given drug: if log P=0, there is equal distribution of the drug in both phases if log P>0, the drug is lipid soluble if log P<0, the drug is water soluble 19 Table 1. Thus in general, the higher the log P, the higher is the affinity for lipid membranes and thus the more rapidly the drug passes through the membrane via passive diffusion. Values of log P that are too high (>6) or too low (<3) may be associated with poor transport characteristics. Drugs with very high log P values have poor aqueous solubility, which is partly the reason for their poor absorption properties, as some degree of aqueous solubility is required for drug absorption (see Section 1. Furthermore, if a drug is too lipophilic, it will remain in the lipidic membrane and never partition out again into the underlying aqueous environment. Very polar compounds (with very low log P values) are not sufficiently lipophilic to be able to pass through lipid membrane barriers. If a drug molecule forms hydrogen bonds with water, desolvation and breaking of the hydrogen bonds is required, prior to partitioning into the apical membrane of the epithelial cell. If the number of hydrogen bonds between the drug and water is > 10, too much energy is required and there will be minimal drug transport across the membrane. The number of hydrogen bonds a drug forms with water can be estimated by inspection of the drug structure (Table 1.

 

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