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By Z. Vatras. Sherman College of Straight Chiropractic.

On the right of the aromatic core fulvicin 250mg mastercard, a second hydrogen bond acceptor generic 250mg fulvicin free shipping, Acc2 cheap fulvicin 250mg on-line, is located cheap 250 mg fulvicin with visa. General procedure for the preparation of compounds 3a-3k under microwave conditions. The reaction mixture was stirred and heated at 165 °C under microwave conditions for 30 min. As reviewed in chapter 2, substructure-based methods are valuable research tools in cheminformatics and medicinal chemistry research. As already discussed in chapter 2, the analysis of the structural parts that constitute molecules, such as rings and ring systems, is biased towards chemists. In contrast, exhaustive substructure-based methods consider all possible substructures that occur in the molecules, and do not suffer from this bias. This type of large-scale screening of molecular libraries would be virtually impossible without the recent advances in frequent substructure mining algorithms. The algorithm used throughout the first three research chapters, named Gaston, proved very versatile. For instance, the substructures found in the screening library used in Chapter 3, predominantly esters and carboxamide moieties, reflected the synthetic reactions used to construct the library. Hierarchically narrowing down the sets from superfamily, to receptor family, to receptor, and to receptor subtype, revealed well-known motifs as well as new substructural features. These included the imidazole-like substructure common in histamine receptor ligands and the planar ring system consisting of a fused five- and six-membered ring (indole-like substucture) often present in serotonin receptor ligands. As expected, the use of different chemical representations had the effect of finding different sets of characteristic structural features in a library. Varying the chemical representation of a library can be explored further, however, there will always be a trade-off between specificity and diversity. For instance, the normal chemical structure drawing representation was most specific in identifying compounds of a set but performs worse on libraries that are more dissimilar. The work of chapter 3 showed that frequent substructure mining is capable of identifying both well-known and new structural motifs that are characteristic for phylogenetic subsets (e. This tree expresses the structural overlap between ligands of different receptors and therefore which receptors are more likely to share a common ligand. Thus, the tree provides insight into possible side-effects and can be used as a ‘deorphanization’ tool to find new ligands for a receptor by starting with ligands from ‘nearby’ receptors. In this particular case we screened a commercial vendor library for new ligands for the A2A adenosine receptor. New ligands were found and prioritized that were truly different from existing A2A adenosine receptor ligands. This analysis was quite successful, as we learned that many compounds recognized the adenosine receptors when tested in an experimental setting. For reasons of cost-effectiveness we included one vendor only; it is to be expected that the possible inclusion of more libraries would increase the diversity of ligands even further. In chapter 6, our screening concept was extended from screening existing compounds to exploring chemical space. For this we used a derivative of our Molecule Evoluator software, called the Molecule Commander. This prototype was used as a first component in a typical drug design workflow (PipelinePilot®) that combined requirements such as affinity for the desired target (the adenosine A1 receptor in this case) with constraints such as Lipinski’s Rule of Five. This offers the perspective of a chemist formulating a research question and/or drawing one or more molecules, after which the computer is instructed to search compound databases, optimize molecules, and present a range of best possible ideas to the chemist. In particular the use of more abstract substructures as described in Chapter 3 brought significant advantages. In retrospect we have the impression that the vocabulary of the medicinal chemist is largely based on compound features important for chemical reactivity. The explicit use of ‘rings’, ‘bonds’ and ‘functional groups’ as substructures may largely stem from a medicinal chemist’s background in synthetic organic chemistry. For the desired biological effect it would be helpful – and Chapter 3 is proof of that – to focus on the pharmacologically relevant substructures. In the current set-up substructures can be anywhere in the molecule, and lack information about the precise location, e. This also has an impact on the connectivity of an atom, which is essentially lost in this approach. The representation of bonds can also be problematic from the way molecules are represented in databases. For instance, the representation of an aromatic ring system can be quite different in databases, and this may have consequences for the perceived substructure. Likewise, keto/enol tautomerism can cause ambiguity in the process of defining substructures. When the substructures are eventually used for virtual screening purposes – as in Chapter 5 – another question arises: if one substructure is good, would two of the same be better? That is not necessarily the case for a biologically active molecule, but without further precautions a simple summation of fragments may lead to erroneous conclusions, as e. In the world of bioinformatics there has always been the notion that databases holding e. Many compound databases were either prohibitively expensive for academic use or simply not accessible (e. It is a database of drug-like small molecules, with bioactivities abstracted and curated from available scientific literature and patents. As with all databases care should be taken as errors tend to propagate; we noticed several errors ourselves, such as wrong bioactivity data, wrong structures, all probably inevitable in such huge data compilations. In fact, this is the consequence of the transformation from information in published documents such as scientific papers towards data storage. This involves the human mind and possible interpretation errors, the conversion of flat text into structured data such as in databases, and potentially many more ‘conversion’ errors. A better approach would be to remove these intermediate steps of flat text publishing and data extraction and instead make the data directly available in structured format. However, when data is entered in standard databases, most of the context that would normally be provided in an article is lost. Some data providers attempt to offer some context as extra fields in database tables. However, this is done fairly ad-hoc and not in a standardized manner, and these additions therefore lack any real meaning. These shortcomings are increasingly realized nowadays, but aligning and integrating proprietary and public 221 Chapter 7 data sources into a single system is a difficult and time consuming task. Hence it does not come as a surprise that duplication and redundancy are common across companies, institutes and academic laboratories. The members involved in this consortium (both from academia and industry) aim to create an open platform, Open Pharmacological Space, which will be freely accessible for knowledge discovery and verification. Most potent hit compound from the A2A substructure-based screening (Chapter 5) and two examples of hits with roughly the same affinity identified in 1 2 the structure-based screening studies of Katritch et al. In the early phases of the research (2006, 2007) no other structures than rhodopsin were available. That all 222 General Conclusions & Perspectives changed with the elucidation of the 3D structure of the β2-adrenergic receptor, 3 followed by a number of other receptors. Interestingly, some of these receptor structures have been successfully used for virtual screening, by docking commercially available compounds into the ligand binding site and prioritizing them on their energy 1,2,4 score. High ‘hit rates’ were observed and chemical diversity in these hits was also significant. This might suggest that ligand-based methods are obsolete; however, we showed that the hits from the ligand-based approaches are also viable, and, most importantly, different from the ones found in the structure-based screening (see Figure 1). In fact, we also benefitted from the structural knowledge obtained in recent years. Another option would be to feed the compounds stemming from a structure-based search into the ligand-based approach we took in Chapter 6, i. It would be interesting to see whether the combination of the two approaches would also allow us to further expand on all pharmacological characteristics of new compounds. Currently, affinity is the almost exclusive determinant used, whereas ligand efficacy (i. Two recent computational papers are seminal in this respect, and they seem to define a new avenue for research.

Considerable simplification is achieved by avoiding the complex problems of interviewing generic fulvicin 250 mg online, which involve influencing persons to report psychological and social information accurately buy generic fulvicin 250 mg on line, and the infinitely more complex question of what constitutes accurate information on such topics buy fulvicin 250 mg without a prescription. There are various motivations or values which may underlie the resistance of a source to an interrogation attempt fulvicin 250 mg visa. The interest here is in any method through which these bases of resistance may be changed, outweighed, neutralized, or circumvented so that the person comes to behave in a manner he was originally strongly motivated to avoid. The particular form of behavior toward which attention is directed, the imparting of factual information, has various peculiarities. Few experiments, however, have dealt directly with attempts to elicit precisely this form of behavior. The attention of the contributors was broadened of necessity to exploit the relevance of experiments studying interpersonal influence on other forms of behavior. This book does not pretend to examine the processes by which fundamental and lasting alterations of the value system of a subject come about. Nonetheless, in the review of experimentation on interpersonal influence (Chapter 6), it was imperative to consider knowledge developed through experiments that involved theoretical concepts such as "changes in attitude or belief. When a determination is made that later behavior negates some value strongly affirmed earlier in the experiment, or the reverse, the experiment accords sufficiently with the questions being posed here. Although the kind of influence attempt considered here represents a considerably simpler problem than the attitude changes or even attitude reporting used here for some inferences, it nonetheless involves the production and observation of complex, symbolic, learned human behavior. Thus, evidence regarding the manipulations that are possible of the salivary response or other simple responses of either animals or humans would not provide answers to the questions raised by this review. Emphasis has been placed on detailing the scientific implications of both the general and the specific subject matters, and their value for theory and research. The number of relevant questions left unanswered by the study points to the need for further investigation of the problem under consideration. The contributors represent a variety of scientific fields, and their material either separately or in the aggregate will undoubtedly hold interest for specialists in still other fields. The writing style here is akin to the broader style of papers designed for presentation at meetings of representatives from several different scientific disciplines. This work might help the armed forces to offset the lack of knowledge that was in part held responsible for much of the success Communist captors achieved in interrogation of United States prisoners of war in Korea (64). Its value for this purpose is limited in that it assumes an interrogator who pursues his objective of developing information rationally. Past experience indicates that practices encountered by prisoners of war are not determined exclusively by considerations of logic (5). Historically, there has been frequent resort to coercive practices for eliciting information, despite abundant evidence that such measures are relatively ineffective. Some estimates of what an opponent is likely to do, in addition to those based on considerations of what it will be feasible and advantageous for him to do, are required in devising measures for thwarting enemy exploitation attempts against prisoners of war. If the present study also receives the attention of interrogators, it may offset their tendency to adopt the sensational stereotypes of interrogation on which many of them appear to have modeled their practice in the past. Parallel, but secret, investigations can be presumed to have been undertaken by a number of police and intelligence systems. Our contributors have indicated gaps in specially relevant knowledge, many of which would not be pursued intensively in the ordinary course of scientific development. Largely, however, the unanswered questions that are central to the topic of this book also point to critical gaps in present scientific knowledge. The two major sources of information about them are: practitioners of the "art" and their victims. The former are generally required to guard the details of their craft as secrets; the latter may have a limited perception, understanding, and memory of what they have experienced. It is possible that practice in some respects has advanced beyond the level of the inferences and conjectures presented here. In other respects, experience has proven that some potentialities of interrogation have been overestimated. Free access to the guarded handbooks of interrogators everywhere probably would not lead to any substantial modification in the general conclusions of this review. Scope A thorough review has been attempted of the scientific areas that have figured most prominently in speculations concerning "scientific interrogation. Its discussion here illustrates some of the implications of personality evaluation for manipulative situations. Personality evaluation historically has been considered a clinical adjunct to manipulation. Its application requires the manipulation to be "tailor-made" to the specific individual differences encountered in the intelligence source. No comprehensive discussion of this topic has been attempted here for several reasons: (a) most means of personality evaluation require the willing cooperation of the subject, which is not likely to be obtainable from reluctant sources; (b) assessments not requiring the cooperation of the source (e. Published speculations that electrical stimulation of the brain might be employed for purposes of nefarious influence led the editors to believe initially that an examination of this area should also be included in this book. The notion that the action of the brain, and thereby the action of an individual, might be controlled directly is an ancient one. Observations, primarily from animal experimentation, led to the following surmises. First, and earliest, were possibilities suggested by observations of Penfield (46) that cortical stimulation might elicit "memory" and some spontaneous verbalization of information. Second, animal experiments raised the possibility that subjective experiences from subcortical stimulation might be so intense as to provide a basis for the administration of reinforcements of unprecedented strength. Also, the possibility was raised that organisms might be made more "teachable" by direct interventions of this kind. Colonel Marvin found that experimentation had not progressed sufficiently to allow for other than conjectural statements regarding the questions raised. In conclusion it should be said that in its current status: (1) subcortical electrostimulation is strictly in the research stage of development and that information is sketchy and variable, (2) precise implantation of electrodes into a given brain location is possible only within ±0. Also excluded from these pages is a consideration of the role of Pavlovian conditioned reflex theory in interrogation. The notoriety attained by this theory, as explaining the inspiration and effectiveness of Communist techniques of coercive interrogation (20, 32, 36, 52), has prompted studies by other investigators. A number of students of the subject (2, 4, 17, 18, 55, 56) have refuted the contention that Pavlovian theory influenced these practices, whereas Schein (56) and Farber, Harlow, and West (10) indicate the inadequacy of simple conditioning models to account for the kinds of complex behavior patterns produced in the course of interrogation. Contributors have been free to choose eclectically whatever models and theories appeared most adequate to their respective topics. On the whole, matters of length, level of generality, and organization similarly have been left to the judgment of the individual contributors. In those cases where the contributors to this book were not themselves highly conversant with interrogation practices, the editors have drawn on their own experience and on research that they have conducted on interrogation in advising the contributors and in editing the chapters. The editors thus actively sought to increase the relevance of the reviews to the realities of interrogation. Lackland Air Force Base, Texas: Air Force Personnel and Training Research Center, December 1956. Effects of Communist indoctrination attempts: Some comments based on an Air Force prisoner-of-war study. Social-psychological needs and "involuntary" behavior as illustrated by compliance in interrogation. Factors used to increase the susceptibility of individuals to forceful indoctrination: Observations and experiments. Are the Cominform countries using hypnotic techniques to elicit confessions in public trials? Communist interrogation, indoctrination and exploitation of American military and civilian prisoners. Introduction When an interrogation is carried out for the purposes of intelligence, we may assume that it is intended to obtain information and not simply to produce compliant behavior on the part of the man being interrogated. One might describe an interrogator as a man who tries to obtain information from another man who may or may not possess it and who is not necessarily motivated to give the information if he does. The interrogator would like to have this man produce his information rapidly, accurately, completely, and without amendments or additions. In the words of the law, he wants "the truth, the whole truth, and nothing but the truth" — and often he wants this as soon as possible because the information that he seeks has perishable qualities. In the urgency of his need, he may interrogate a man who is injured, fatigued, or in pain. In doing so he incurs the risk that his efforts may produce compliant behavior without eliciting accurate information. The information that the interrogator seeks represents what his source still knows about various events, situations, organizations, devices, etc.

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Passage of a δ-opioid receptor selective enkephalin discount fulvicin 250 mg without prescription, [D-penicillamine2 generic 250mg fulvicin with mastercard,5]enkephalin 250 mg fulvicin visa, across the blood-brain and the blood-cerebrospinal fuid barriers discount fulvicin 250mg line. Exploring ramachandran and chi space: confor- mationally constrained amino acids and peptides in the design of bioactive polypeptide ligands. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Antimicrobial activity and sta- bility to proteolysis of small linear cationic peptides with D-amino acid substitutions. Development of a potent bombesin receptor antagonist with prolonged in vivo inhibitory activity on bombesin-stimulated amylase and protein release in the rat. Solution structure of the all L- and D-amino acid-substituted mucin 2 epitope peptides. Probing the proteolytic stability of β-peptides containing α-fuoro- and α-hydroxy-β-amino acids. The outstanding biological stabil- ity of β-and β-peptides toward proteolytic enzymes: an in vitro investigation with ffteen peptidases. Mimicry of host-defense peptides by unnatural oligomers: antimicrobial β-peptides. The proteolytic stability and cytotoxicity studies of L-aspartic acid and L-diaminopropionic acid derived β-peptides and a mixed /β-peptide. Peptide backbone modifcations: a structure-activity analysis of peptides con- taining amide bond surrogates, conformational constraints, and related backbone replace- ments. Development of novel G-protein-coupled receptor 54 agonists with resistance to degradation by matrix metalloproteinase. Stereoselec- tive formation of a functionalized dipeptide isostere by zinc carbenoid-mediated chain extension. Otaka A, Watanabe J, Yukimasa A, Sasaki Y, Watanabe H, Kinoshita T, Oishi S, Tama- mura H, Fujii N. SmI2-mediated reduction of β, β-difuoro-α, β-enoates with application to the synthesis of functionalized (Z)-fuoroalkene-type dipeptide isosteres. E-olefn dipeptide isostere incorporation into a polypeptide backbone enables hydrogen bond perturbation: probing the requirements for Alzheimer’s amyloidogenesis. Sequential C-Si bond formations from diphenylsi- lane: application to silanediol peptide isostere precursors. Effcient synthesis of trifuoromethyl and related trisubstituted alkene dipeptide isosteres by palladium-catalyzed carbonylation of amino acid derived allylic carbonates. Direct entry to pep- tidyl ketones via SmI2-mediated C-C bond formation with readily accessible N-peptidyl oxazolidinones. Controlled synthesis of (S,S)-2,7-diaminosuberic acid: a method for regioselective construction of dicarba analogues of multicystine-containing peptides. Stereodivergent synthesis of the diamino alcohol core of Ritonavir and its C-2 epimer. Effect of N-methyl substitution of the peptide bonds in luteinizing hormone-releasing hormone agonists. Improving oral bioavailability of peptides by multiple N-methylation: somatostatin analogues. A synthetic enkephalin analog with prolonged parenteral and oral analgesic activity. Stabilization of neurotensin analogues: effect on peptide catabolism, biodis- tribution and tumor binding. N- and C α-methylation in bio- logically active peptides: synthesis, structural and functional aspects. Design in topographical space of peptide and peptidomimetic ligands that affect behavior. Glycopeptide enkephalin analogs produce analgesia in mice: evidence for penetration of the blood-brain barrier. Dermorphin and deltorphin glycosylated analogues: synthesis and antinociceptive activity after systemic administration. Falciani C, Lozzi L, Pini A, Corti F, Fabbrini M, Bernini A, Lelli B, Niccolai N, Bracci L. Synthetic peptides in the form of dendrimers become resistant to protease activity. Infuence of selective fuorination on the biological activity and proteolytic stability of glucagon-like peptide-1. Blood-to-central nervous system entry and stability of biphalin, a unique double-enkephalin analog, and its halogenated derivatives. Benedetti F, Berti F, Budal S, Campaner P, Dinon F, Tossi A, Agrirova R, Gen- ova P, Atanassov V, Hinkov A. Kobayashi K, Oishi S, Hayashi R, Tomita K, Kubo T, Tanahara N, Ohno H, Yoshikawa Y, Furuya T, Hoshimo M, Fujii N. Synthesis and Evaluation of Silanediols as Highly Selective Uncompetitive Inhibitors of Human Neutrophil Elastase. Effcient Routes to Carbon-Silicon Bond Forma- tion for the Synthesis of Silicon-Containing Peptides and Azasilaheterocycles. Kinetic decon- jugation: gateway to the synthesis of Xxx-Gly (E)-alkene dipeptide isosteres. Wangsell F, Gustafsson K, Kvarnstrom I, Borkakoti N, Edlund M, Jansson K, Lindberg J, Hallberg A, Rosenquist A, Samuelsson B. Copper mediated defuorinative allylic alkylation of difuorohomoallyl alchohol deriva- tives directed to an effcient synthetic method for (Z)-fuoroalkane dipeptide isosteres. Diastereoselective syn- thesis of the Leu-Pro type phosphinyl dipeptide isosteres tetrahedron asymmetr. That is, the chapter emphasized on improving the pharmacological activity, that is, potency of peptide drugs. We urge the unfamiliar readers to read our disclaimers and about peptide nomenclature in Sections 5. In this chapter, we will concentrate our discussion on enhancing the pharmacokinetic properties of peptide drugs with an emphasis on membrane permeability. To enhance the oral bioavailability of an active lead drug, one must realize that oral bioavailability involves several factors, such as gastrointestinal transit and absorption, chemical stability in the gastrointestinal tract, and the frst-pass effect of gut wall and liver metabolism. Lipinski formulated a rule of thumb to evaluate if a drug has properties that would make it a likely orally active drug in humans [1]. The rule states that, in general, an orally bioavailable drug should have no more than one violation of the following criteria. Peptide drugs are generally perceived as large molecules and would have diffculty crossing membranes. Most researchers correlate molecular size with molecular weight, and have set out the general rule of thumb that orally bioavailable drugs should be less than 500 g/mol. This description has been further refned by others to orally bioavailable drugs with a molecular weight between 160 to 480 g/mol [2]. As we have described in Chapter 5 we noticed that most orally bioavailable peptide drugs are comprised of three to fve residues that fts into three to fve subsites of the active site. An aspect of our work on β-secretase inhibitors and Alzheimer’s disease will be used to illustrate methods of reducing the molecular size of a peptide design. The subse- quent aggregation of these peptide amyloid β-peptide fragments leads to the pathol- ogy of the disease. In the frst method, we synthesized compounds in which one amino acid was systematically removed at a time from the N-terminal, then from the C-terminal. A nearly complete loss of inhibitory activity on the removal of a residue indicated that the position of the residue was important for active site recognition. Because glycine does not have a side-chain, any near loss of β-secretase inhibition suggested that the interactions between the side-chain of the residue and its associated subsite were important at the affected position. The resulting pentapeptide was optimized at the two end-terminals Universal Free E-Book Store... A wonderful discovery of a potent non-peptide inhibitor of β-secretase by another research group [6] inspired us to shift our focus on non-peptides. As an overall measure of lipophilicity, the log P value can be experimentally determined or esti- mated by calculations, where the partition coeffcient, P, is a ratio of concentrations of an unionized compound between n-octanol and water [9]. As it pertains to passive diffusion across membranes, only the unionized form of the compound will traverse the membrane. Lipinski’s calculated log P rule, in which a drug would most likely be orally bioavailable, was elaborated to a range of −0.

It also recognized that many countries have financial constraints that limit the adoption of third-line regimens generic fulvicin 250mg otc. There are limited data on the use of these newer drugs in infants fulvicin 250mg free shipping, children and pregnancy buy fulvicin 250 mg overnight delivery, including very limited pharmacokinetic and safety data purchase 250mg fulvicin amex. This section provides a brief overview of the most common and important conditions. Sources and links are provided for relevant guidelines, including the evidence base and rationale supporting different recommendations. Existing recommendations cover initiation of co-trimoxazole preventive therapy among adults, adolescents, pregnant women and children for prevention of Pneumocystis pneumonia, toxoplasmosis and bacterial infections, as well as benefits for malaria prophylaxis and discontinuation of co- trimoxazole preventive therapy. Clinical guidance across the continuum of care: Managing common coinfections and comorbidities 157 Key selected existing recommendations Table 8. Recommendations for investigating contact of persons with infectious tuberculosis in low- and middle-income countries. The optimal dosing frequency is daily during the intensive and continuation phases (strong recommendation, high-quality evidence) (2). Clinical guidance across the continuum of care: Managing common coinfections and comorbidities 161 Fig. Infection control measures should be given priority to reduce Mycobacterium tuberculosis transmission in all settings that provide care. Environmental Ventilation (mechanical) Ventilation (natural) Upper-room ultraviolet germicidal irradiation (strong recommendation, low-quality evidence). Personal Spend as much time as possible outside Cough etiquette Sleep alone while smear-positive Avoid congregate settings and public transport while smear-positive (strong recommendation, low-quality evidence). Clinical guidance across the continuum of care: Managing common coinfections and comorbidities 165 Source for recommendation Guidelines for the programmatic management of drug-resistant tuberculosis. The burden of coinfection is greatest in low- and middle-income countries, particularly in South-East Asia and sub-Saharan Africa for hepatitis B. Additional guidance Guidance on prevention of viral hepatitis B and C among people who inject drugs. They will provide detailed guidance on hepatitis C screening, hepatitis C–specifc treatment and general hepatitis C care. Clinical guidance across the continuum of care: Managing common coinfections and comorbidities 167 8. Key interventions to control malaria include prompt and effective treatment with artemisinin-based combination therapies and using insecticide-treated nets and indoor residual spraying with insecticide to control the vector mosquitoes. An additional intervention recommended in areas of high transmission for specific high-risk groups is intermittent preventive treatment during pregnancy and seasonal malaria chemoprophylaxis. Parasitological confirmation should be undertaken for all suspected malaria cases using either microscopy or a rapid diagnostic test. The objectives of diagnosing and managing sexually transmitted infections include identifying the infection and providing appropriate treatment and preventing transmission. Other recent guidelines cover recommendations on periodic screening and periodic presumptive treatment for asymptomatic sexually transmitted infections in sex workers, and periodic testing for asymptomatic urethral and rectal Neisseria gonorrhoeae and Chlamydia trachomatis infections and asymptomatic syphilis infection among female sex workers, men who have sex with men and transgender people. Cervical cancer is a preventable disease and is curable if diagnosed and treated early. Cervical cancer screening leads to early detection of precancerous and cancerous cervical lesions that will prevent serious morbidity and mortality. Global strategy for the prevention and control of sexually transmitted infections: 2006– 2015. Report of the Expert Consultation and review of the latest evidence to update guidelines for the management of sexually transmitted infections. Comprehensive cervical cancer prevention and control: a healthier future for girls and women. Those with more severe immunosuppression may be at higher risk of complications from live vaccines. Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings. Clinical guidance across the continuum of care: Managing common coinfections and comorbidities 171 8. Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. In addition, an altered metabolism, reduced appetite and higher incidence of diarrhoea may lower nutrient intake and absorption and also lead to nutrient losses. If poor growth is identified, then further assessment should be performed to determine the cause, and plan appropriate response. Clinical guidance across the continuum of care: Managing common coinfections and comorbidities 173 8. Care providers should identify and treat the underlying cause when possible, while controlling the pain. Evaluating household water treatment options: health-based targets and microbiological performance specifications. The individual factors may include forgetting doses; being away from home; changes in daily routines; depression or other illness; a lack of interest or desire to take the medicines; and substance or alcohol use. Medication-related factors may include adverse events; the complexity of dosing regimens; the pill burden; and dietary restrictions. Lack of continuity of care is a strong predictor of non-adherence in the longer term. Pregnant and postpartum women The pregnancy and postpartum period presents signifcant biological, social and economic challenges that may affect treatment adherence. Pregnancy-related conditions such as nausea and vomiting may negatively affect treatment adherence. Adolescents Adherence challenges faced by adolescents include a potentially large pill burden if they are treatment-experienced; stigma and fear of disclosure; concerns about safety of medications; adverse effects; peer pressure and perceived need to conform; not remembering to take medications; and inconsistent daily routine. The transition from paediatric to adolescent care presents several challenges that may affect treatment adherence in adolescents. These include assuming increased responsibility for their own care (which may lead to treatment interruptions because of forgetfulness); an inability to navigate the health care system; lack of links between adult and paediatric services; lack of health insurance; and inadequately skilled health care providers (6,7). Depression and substance use have also been shown to present challenges in adolescents. The limited choice of paediatric formulations, poor palatability of liquid formulations, high pill or liquid volume burden, large pill size, frequent dosing requirements, dietary restrictions, loss of primary caregiver, diffculties in swallowing tablets and adverse effects may all affect adherence (3,8,9). Successfully treating a child requires the commitment and involvement of a responsible caregiver. Alcohol and other drug use could be associated with forgetfulness, poor organization and diversion of monetary and time priorities (10,14–16). Service delivery approaches to improve longitudinal care and maintain adherence for most-at-risk populations remains a critical gap in many settings. Experience indicates encouraging results with peer-based interventions that include strong social support such as outreach teams, peer educators and health workers providing multidisciplinary, non- judgemental and respectful care. Incarceration Incarceration may negatively affect continuity of care, diminish trust and predispose individuals to poor fnancial and social support both during and after incarceration. However, excellent outcomes can be achieved with adequate support and structured treatment programmes within the prison setting. The individual-level adherence intervention recommendation in this section relates to the use of mobile phone text messages. There have been simple and robust trials to demonstrate its importance as one of many adherence tools. Adherence interventions, such as text messaging, should clearly be provided as part of a total package of several interventions. Adherence preparation should not delay treatment initiation, when prompt action is necessary. The systematic review identifed very- low-quality evidence from one observational study evaluating opioid substitution therapy for improving adherence. After 12 months, the rates of unsuppressed viral loads were comparable among people who inject drugs using opioid substitution therapy and people who inject drugs without opioid substitution therapy (24). The systematic review also identifed very-low-quality evidence from one randomized trial evaluating the treatment of depression for improving adherence. After 12 months, the risk of non-adherence was similar among those who received depression treatment and those who did not (25).

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Advice to patient • Report symptoms of possible liver dysfunction: jaundice discount fulvicin 250 mg online, anorexia fulvicin 250 mg low cost, dark urine generic fulvicin 250mg online, pale stools cheap 250 mg fulvicin with amex, nausea, vomiting. Clinically important drug interactions • Fluconazole increases effects/toxicity of following drugs: cyclosporine, glipizide, glyburide, phenytoin, theophylline, tolbutamide, warfarin, zidovudine, cisapride. Adjustment of dosage • Kidney disease: Creatinine clearance 20–40 mL/min: adminis- ter q12h; creatinine clearance 10–20 mL/min: increase dosage interval to q24h; creatinine clearance <10 mL/min: increase dosage interval to q24–48h. Warnings/precautions: Use with caution in patients with kidney disease, bone marrow depression (extreme caution). Clinically important drug interactions: Flucytosine increases effects/toxicity of amphotericin B. Therapeutic concentrations are 25–100 µg/mL with peak plasma concentrations between 40 and 60 µg/mL. Editorial comments • Flucytosine is generally administered with amphotericin B to improve its efficacy. Adjustment of dosage • Kidney disease: Guidelines are not available for adjustment of dosage in patients with kidney disease; monitor closely for pos- sible increased toxicity. Warnings/precautions: Use with caution in patients with the fol- lowing conditions: renal insufficiency, fever, infection, bone marrow depression, epilepsy, spasicity, peripheral neuropathy. Advice to patient • Use two forms of birth control including hormonal and barrier methods. Adverse reactions • Common: fatigue, weakness, paresthesia, muscle pain, edema (19%), visual disturbances, nausea and vomiting (36%), cough (44%), rash, fever (69%), chills, infection (44%), stomatitis. Treat with peroxide, tea, topical anesthetics such as benzocaine, lido- caine or antifungal drug. Editorial comments • Use latex gloves and safety glasses when handling cytotoxic drugs. Mechanism of action: Inhibits migration of polymorphonuclear leukocytes; stabilizes lysosomal membranes; inhibits produc- tion of products of arachidonic acid cascade. Contraindications: Systemic fungal, viral, or bacterial infections, myasthenia gravis, severe cardiovascular disease. Increased potassium excretion and retention of sodium and water occur with therapy. Monitoring of serum electrolytes, especially potassium, is required for patients on this medication. Repeat after 45 seconds and thereafter at 60-second intervals if necessary for a maximum of 4 additional times after initial dosing. If no response 5 minutes after 5 mg total drug is administered, it is unlikely that a benzodiazepine is the cause of toxicity and additional drug should not be adminis- tered. Repeat after 45 seconds and at 60-second intervals if necessary to a maxi- mum of 4 additional times. Contraindications: Hypersensitivity to flumazenil or benzodi- azepines, patients receiving a benzodiazepine for life-threatening indications (status epilepticus, controlling intracranial pressure), patient exhibiting severe overdose from tricyclic antidepressant, treatment of benzodiazepine dependence, management of with- drawal syndrome from benzodiazepines. Warnings/precautions • Use with caution in patients with the following conditions: seizure disorder or myoclonic jerking, concurrent sedative–hypnotic withdrawal, recent administration of repeated benzodiazepine, concurrent tricyclic antidepressant overdose, alcohol-dependent patient, head injuries, psychiatric patient, severe liver disease. Flumazenil is only considered as an adjunct to reversing the effects of benzodiazepine overdose. Take steps to enable patient to emerge slowly from benzodi- azepine overdose to avoid withdrawal reaction. Clinically important drug interactions: Drugs that increase toxic- ity of flumazenil: mixed drug overdoses, tricyclic antidepressant overdose. Editorial comments • Flumazenil does not reverse the amnesic effect of benzodi- azepine overdose. Accordingly, the physician should advise patient’s family or caregiver of the need to follow the patient carefully following recovery. Flumazenil should be used cautiously in outpatients and hospitalized patients because of the possibility that patients may have frequent benzodiazepines use or dependence. Mechanism of action: Inhibits elaboration of many of the media- tors of allergic inflammation, eg, leukotrienes and other products of the arachidonic acid cascade. Contraindications: Untreated fungal, bacterial, or viral infec- tions, ocular herpes simplex, septic ulcers, nasal surgery or trauma, untreated infections of nasal mucosa, hypersensitivity to corticosteroids. Warnings/precautions: Use with caution in patients with tuber- culosis of the respiratory tract (active or quiescent), exposure to measles or chicken pox. These should be individualized according to the dis- ease being treated and the response of the patient. This drug should not be used in large amounts or for prolonged periods during pregnancy. Contraindications: Hypersensitivity to corticosteroids, marked impaired circulation, occlusive dressing if primary skin infec- tion; monotherapy in primary bacterial infections (eg, impetigo, cellulitis, rosacea), ophthalmic use, plaque psoriasis (wide- spread). Warnings/precautions • Use with caution in patients with primary skin infection and in those receiving other immunosuppressant drugs. Advice to patient • Avoid long-term application to the following areas of the body: eyes, face, rectum, genitals, skinfolds. These are areas most susceptible to development of skin atrophy and decol- oration. Adverse reactions • Common: itching, burning, skin dryness, erythema, folliculi- tis, hypertrichosis, allergic contact dermatitis, skin maceration, secondary infection, striae, millaria, skin atrophy. Parameters to monitor • Signs of infection: increased pain, purulent exudate, erythema. Organisms most likely to pro- duce intercurrent infection include Candida, Mycobacterium, Toxoplasma, pneumocystis, Nocardi, Ameba. This condition may become clinically significant after 3–4 weeks of drug application. Patients using topical steroids over large areas of the body for prolonged periods are also at risk. Editorial comments: Only 5% strength is suggested for topical treatment of superficial basal cell carcinoma. Mechanism of action: Blocks methylation of deoxyuridylic acid by inhibiting thymidylate synthetase. Warnings/precautions • Use with caution in patients with kidney or liver disease, high- dose pelvic radiation or who are concomitantly using other neoplastic drugs, in particular alkylating agents. Advice to patient • Use two forms of birth control including hormonal and barrier methods. Adverse reactions • Common: dermatitis, alopecia (reversible), stomatitis, nausea, vomiting, diarrhea, anorexia, mucositis. Clinically important drug interactions: Allopurinol, cimetidine increase effects/toxicity of fluorouracil. Treat with peroxide, tea, top- ical anesthetics such as benzocaine, lidocaine or antifungal drug. Editorial comments • Fluorouracil is used alone or in combination with other modalities of treatment, eg, radiation therapy, surgery, other chemotherapeu- tic agents. Warnings/precautions • Use with caution in patients with the following conditions: diabetes mellitus, seizures, liver or kidney disease. Patients should wear a bracelet identifying the condition and possibility of developing hypoglycemia. Adverse reactions • Common: anorexia, body pain, nausea, insomnia, anxiety, tremor, dry mouth. Mechanism of action: Stimulates receptors in androgen-responsive organs, thereby promoting growth and development of male sex organs. Drug should be administered only by physician who is aware of possible adverse effects of drug on bone maturation. Contraindications: Hypersensitivity, males with carcinoma of the breast, known or suspected carcinoma of the prostate, seri- ous cardiac, renal, or hepatic decompensation. Editorial comments • This drug is listed without details in the Physician’s Desk Reference, 54th edition, 2000. Mechanism of action: Inhibits cyclooxygenase, resulting in inhi- bition of synthesis of prostaglandins and other inflammatory mediators. Mechanism of action: Prevents uptake of androgens and blocks nuclear binding of androgens in prostatic tissue. Warnings/precautions • Warn patient not to discontinue therapy without consulting with physician. Advice to patient • To cut down on diarrhea, reduce intake of dairy products, use antidiarrheal agents, and eat foods high in fiber.

Adverse reactions • Common: insomnia best fulvicin 250 mg, drowsiness 250 mg fulvicin visa, nausea discount fulvicin 250 mg, diarrhea buy fulvicin 250mg overnight delivery, dry mouth, male sexual dysfunction. Mechanism of action: Enhances effect of nitric oxide by inhibit- ing phosphodiesterase in corpus cavernosum. Onset of Action Peak Effect Duration 30 min 60–120 min 4 h Food: Take on empty stomach. Contraindications: Concomitant use of nitrates, including patch; hypersensitivity to sildenafil. Advice to patient • Practice safe sex as drug has no effect on disease transmission. Clinically important drug interactions • Drugs that increase effects/toxicity of sildenafil: cimetidine, erythromycin, itraconazole, ketoconazole. Editorial comments • Sildenafil, an extremely popular drug, has proven to provide beneficial responses in patients with impotence associated with diabetes, cardiovascular disease, spinal cord injury, radical prostatectomy and in patients taking drugs for hypertension, depression, or psychosis. Cardiovascular events described with the drug’s use have generally occurred in the setting of preex- isting disease. Warnings/precautions • Use with caution in patients with hypersensitivity to silver sul- fadizine, kidney and liver disease. May have cross-sensitivity with thiaziades, sulfonylaurate, sulfonylureal anhydrase inhibitors. Your physician may recommend coverings over the area being treated with silver sulfadiazine. Clinically important drug interactions: Silver sulfadiazine reduces effects of fibrinolysin, deoxyribonuclease, collagenase, sutilains, papain. Editorial comments: It should be noted that appreciable amounts of silver sulfadiazine may be absorbed and produce systemic adverse reactions. Contraindications: Hypersensitivity to statins, active liver dis- ease or unexplained persistent elevations of serum transaminase, pregnancy, lactation. Warnings/precautions • Use with caution in patients with renal insufficiency, history of liver disease and in alcohol abusers. Values should be obtained prior to and periodically after treat- ment begins to ascertain drug efficacy. It may be advisable to take a liver biopsy if transami- nase elevation persists after drug is discontinued. Onset of Action in Serum Potassium Duration Oral 2–12 h 6–24 h Rectal 2–12 h No data Food: Administer sodium polystyrene sulfonate with water or sor- bitol, not with orange juice. Contraindications: Hypersensitivity to sodium polysterene sul- fonate or components, hypokalemia. Warnings/precautions • Use with caution in patients with sodium intake restriction (severe heart failure, marked edema, hypertension), constipation. Advise patients experiencing constipation to increase intake of fluids and to consume high-fiber foods (bran, wholegrain bread, raw vegetables and fruits). Clinically important drug interactions • Drugs that increase effects/toxicity of sodium polysterene sul- fonate: magnesium hydroxide, aluminum carbonate, other aluminum- and magnesium-containing antacids and laxatives. Mechanism of action: Stimulates linear growth in children with growth hormone deficiency. Contraindications: Growth promotion in children with closed epiphyses (if used for growth stimulation [girls 14–15, boys 15–16]), intracranial lesion with ongoing neoplastic activity, hypersensitivity to m-cresol or glycerin (present in somatropin), critically ill patients. If hypothyroidism develops, it may be nec- essary to use thyroid replacement therapy. Editorial comments • Administration of growth hormone should be undertaken only by a physician who is experienced in diagnosis and treatment of pituitary disorders. Mechanism of action: Competitive blocker of β-adrenergic recep- tors in heart and blood vessels. Adjustment of dosage • Kidney disease: Creatinine clearance >60 mL/min: dosing inter- val 12 hours; creatinine clearance 30–59 mL/min: dosing interval 24 hours; creatinine clearance 10–29 mL/min: dosing interval 36– 48 hours; creatinine clearance <10 mL/min: individualize dose. Editorial comments • Note that this drug is pregnancy category B (most β blockers are category C). Susceptible organisms in vivo: Staphylococcus aureus, Strepto- coccus pneumoniae (penicillin sensitive), Enterobacter cloacae, Hemophilus influenzae, Hemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae, Mycoplasma pneumoniae. Adjustment of dosage • Kidney disease: Creatinine clearance >50 mL/min: loading dose 400 mg on day 1; then 200 mg q48h for ≥8 days. Editorial comments • Sparfloxacin has advantage over levofloxacin of improved Bacteroides fragilis activity. Mechanism of action: Competitively inhibits aldesterone action on distal renal tubules, resulting in excretion of sodium and water and retention of potassium. Adjustment of dosage • Kidney disease: Creatinine clearance 10–50 mL/min: dose q12–24h; creatinine clearance <10 mL/min: do not use. Contraindications: Anuria, hyperkalemia, severe renal insuffi- ciency, serum potassium level >5 mEq/L, patients receiving other potassium-sparing diuretics or potassium supplements, hypersensitivity to spironolactone. Each drug should be titrated sep- arately and the combination used if appropriate. Advice to patient • Change position slowly, in particular from recumbent to upright, to minimize orthostatic hypotension. Sit at the edge of the bed for several minutes before standing, and lie down if feeling faint or dizzy. In particular, avoid those containing significant amounts of sodium or potassium (eg, Alka-Seltzer). If significant changes develop, drug should be stopped regardless of serum potassium. This should be done on the same scale at the same time each day and with the same clothing. Editorial comments • For the treatment of essential hypertension, potassium-sparing diuretics are usually combined with other diuretics or antihy- pertensive drugs. Adjustment of dosage • Kidney disease: Creatinine clearance >50 mL/min: usual dose; creatinine clearance 26–50 mL/min: reduce dose by 50% and administer q12h; creatinine clearance 10–25 mL/min: reduce dose by 50% and administer q24h. Warnings/precautions • Use with caution in patients with kidney disease, peripheral neuropathy, preexisting bone marrow suppression, folic acid or vitamin B12 deficiency. Adverse reactions • Common: headache, insomnia, depression, nervousness, abdo- minal pain, nausea, vomiting, diaphoresis, rash, myalgia, chills, fever, dyspnea. Clinically important drug interactions: Drugs that increase effects/toxicity of stavudine: chloramphenicol, cisplatin, ethamb- utol, hydra- lazine, lithium, metronidazole, phenytoin, vincristine. Drug may be cautiously reintroduced at 50% of prior maintenance dose if symptoms resolve. Editorial comments • Stavudine is used in combination therapy with zidovudine or other nucleoside antiviral drugs. This stimulates the formation of anticoagulant proteins, resulting in dissolution of clot. Adverse reactions • Common: superficial bleeding • Serious: angioneuritic edema, bronchospasm, severe internal hemorrhage, Guillain–Barré syndrome, hypersensitivity reaction. Editorial comments • Streptokinase is probably the most widely used fibrinolytic therapy in the world. The addition of better antiplatelet therapy is a bur- geoning area of research in acute coronary syndromes. Mechanism of action: Binds to ribosomal units in bacteria, inhi- bits protein synthesis. Susceptible organisms in vivo: Mycobacterium tuberculosis, Yersinia pestis, Francisella tularensis, Brucella; synergism against enterococci and streptococcoi. Warnings/precautions • Use with caution in patients with renal disease, neuromuscular disorders (eg, myasthenia gravis, parkinsonism), hearing dis- orders. Parameters to monitor • Peak and trough serum levels 48 hours after beginning therapy and every 3–4 days thereafter as well as after changing doses. Editorial comments • Streptomycin has the greatest activity of all the aminoglycosides against M. It is a first-line drug for tuberculosis though not as effective as isoniazid and rifampin. Mechanism of action: Depolarizes motor endplate at myoneural junction, preventing stimulation by endogenous acetylcholine. Note: Succinylcholine should be reserved for use in children who require emergency intubation, who do not have an accessi- ble vein, and for whom an airway can be readily secured.

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Because a concentration of 7 mg/L is acceptable discount fulvicin 250mg with amex, we only need to hold the next scheduled dose for an additional 13 hours before beginning the new dose of 800 mg every 24 hours order 250 mg fulvicin mastercard. He has been treated with 750 mg of vancomycin every 16 hours for the last 10 days buy generic fulvicin 250mg on line. His most recent Cpeak was 26 mg/L (drawn 2 hours after a 1-hour vancomycin infusion) discount fulvicin 250 mg otc, and his most recent Ctrough was 9 mg/L. You are asked to determine if it is possible to obtain a Cpeak of approximately 25 mg/L and a Ctrough of around 5 mg/L with a once-a-day dose. Before answering this question, we must be sure we know what the question is asking. By substituting the above values, we obtain: Next, we use our general equation to solve for K0 (maintenance dose) with our predetermined 24- hour dosing interval: where: Cpeak(steady state) = desired peak concentration at steady state (25 mg/L), K0 = drug infusion rate (also maintenance dose you are trying to calculate, in milligrams per hour), V = calculated volume of distribution (33. By substituting the above values, we obtain: This dose could be rounded up or down to 800 or 900 mg given every 24 hours. Remember that the desired peak concentration of 25 mg/L will be slightly higher or lower if the dose is rounded up or down, and the adjusted desired peak can be calculated as shown in previous cases. Finally, we must check to see that our Ctrough concentration with this dose is acceptable (assume a dose of 900 mg was given for a desired peak of 26. Even though once-daily dosing is convenient for this patient, we need to consider whether the trough concentration will be adequate for this patient with endocarditis. Examples of such recommendations can be found in Morbidity and Mortality Weekly Report (e. Individualization of theophylline dosage maximizes therapeutic benefit while minimizing adverse effects. Theophylline is used less frequently in the treatment of asthma as beta-2 agonists and anti-inflammatory agents (corticosteroids) have become the first-line therapies. However, theophylline is still occasionally used for treatment of nocturnal or mild persistent asthma, and dosage individualization is 1 2 necessary. Although theophylline was once thought to have primarily a bronchodilator effect, it is now recognized to have anti-inflammatory effects as well. The therapeutic range is now generally accepted to be 5-15 mg/L, a decrease from the previously accepted range of 10-20 mg/L. This newer range is probably more relevant to bronchodilator effects; anti-inflammatory effects may be achieved at lower concentrations. Theophylline is eliminated from circulation through hepatic oxidative metabolism (cytochrome P450) and has a low intrinsic clearance (see Lesson 9). Therefore, total hepatic clearance of theophylline is determined by the intrinsic clearance of the liver and is not dependent on liver blood flow. Theophylline may undergo nonlinear, or Michaelis-Menten, pharmacokinetics (see Lesson 10) even within the therapeutic range, but this is more likely to occur at concentrations above the 4 therapeutic range. Diseases that affect liver blood flow, such as cirrhosis and heart failure, may reduce theophylline clearance. Drugs that alter hepatic oxidative metabolism can also dramatically 5 6 affect theophylline clearance. Some drugs, such as cimetidine and erythromycin, will decrease theophylline clearance and cause increased plasma theophylline concentrations (Table 14-1). Suppository and rectal solution forms of the drug are available but are not commonly used. Intravenous infusion involves administration of theophylline itself or in a salt form (such as aminophylline). When theophylline derivatives are used, the theophylline dose equivalent should be calculated. Therefore, to obtain the theophylline dose equivalent, the aminophylline dose should be multiplied by 0. Others are designed to slowly release drug in the gastrointestinal tract for up to 24 hours after administration. Determine an appropriate loading dose of aminophylline to produce a theophylline concentration of 15 mcg/mL. In this case, the desired plasma theophylline concentration is 15 mcg/mL, the aminophylline salt equivalent (S) is 0. In patients more than 7 50% above ideal body weight, volume of distribution should be calculated using ideal body weight. The basic loading dose equation can be derived from the plasma concentration equation we learned in Lesson 1. This 650-mg aminophylline loading dose will produce a serum concentration slightly less than 15 mcg/mL. Note: Remember, aminophylline is a salt form of theophylline and contains approximately 80% theophylline equivalents. In this situation, we will slightly modify the loading dose Equation 14-2 to the following: (See Equation 14-2. This 450-mg aminophylline loading dose will result in a serum concentration slightly less than 15 mg/L. The loading dose is to be given over 30 minutes, and a maintenance infusion is to be started immediately. Suggest an aminophylline infusion rate to achieve a plasma theophylline concentration of 13 mcg/mL. Figure 14-1 demonstrates the relationship between serum levels achieved with the loading and maintenance doses of theophylline or aminophylline. A theophylline level is ordered immediately and is reported by the laboratory as 22 mcg/mL. Now that we have his actual clearance, we can calculate a new maintenance dose that will give us the desired theophylline serum concentration of 13 mcg/mL: (See Equation 14-4. Next we can determine the time we need to wait by using the following equation: -Kt C = C0e (See Equation 3-2. Clinical Correlate The most significant side effects from theophylline occur at serum concentrations higher than 20 mcg/mL. At concentrations higher than 35 mcg/mL, major adverse effects include hyperglycemia, hypotension, cardiac arrhythmias, seizures, brain damage, and death. Plasma concentrations with a loading dose and continuous infusion of theophylline or aminophylline. She has a history of heavy marijuana and tobacco use but no other medical problems. Suggest an oral dosage regimen that will produce a pss average of approximately 12 mcg/mL, using a sustained released product dosed every 12 hours. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute; 1997. Recent advances in our understanding of the use of theophylline in the treatment of asthma. Theophylline: pooled Michaelis-Menten behavior of theophylline and its parameters (Vmax and Km) among asthmatic children and adults. Cimetidine inhibition of theophylline elimination: influence of adult age and time course. Phenytoin is usually administered either orally or intravenously and exhibits nonlinear or Michaelis-Menten kinetics (see Lesson 10). Unlike drugs undergoing first-order elimination (Figure 15-1), the plot of the natural logarithm of concentration versus time is nonlinear with phenytoin (Figure 15-2). Consequently, as the phenytoin dose increases, a disproportionately greater increase in plasma concentration is achieved. This enzyme saturation process can be characterized with an enzyme-substrate model first developed by the biochemists Michaelis and Menten in 1913. In this metabolic process, drug clearance is constantly changing (in a nonlinear fashion) as dose changes. To describe the relationship between concentration and dose, a differential equation can be written as shown below: (See Equation 10-1. Next, this differential equation can be expressed algebraically by assuming that we are at steady state and dX/dt is held constant. Then dX/dt, the change in the amount of drug (X) over time (t), can be expressed as X0/τ (dose over dosing interval), as shown in the following equation: (See Equation 10-1. The oral bioavailability of phenytoin is considered to be 100%, so an F factor is not needed in these calculations. Other pertinent clinical data include: weight, 75 kg; height, 5 feet, 11 inches; serum creatinine, 1. What intravenous loading dose and oral maintenance dose would you recommend to achieve and maintain a phenytoin concentration of approximately 20 mg/L?

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