J. Jeffery Marshall, MD

• Medical Director
• Cardiac Catheterization Laboratory
• Northeast Georgia Heart Center
• Gainesville, Florida

The two most common types o analyses used to evaluate these observational data are cohort studies and case-control studies eczema antifungal purchase genuine lamisil online. Both groups are then ollowed over time to determine how many in each group develop an adverse e ect o interest fungus lawn buy cheap lamisil 250mg online. While this can be done on a real-time basis fungus on nails generic lamisil 250mg free shipping, more commonly antifungal lozenges otc buy lamisil pills in toronto, exposure (or nonexposure) that occurred in the past is def ned rom an existing database fungus gnats control hydrogen peroxide 250mg lamisil with visa, so that subsequent events can be analyzed retrospectively spore fungus definition order lamisil canada. By contrast, in case-control studies, one f rst specif es the case-def ning outcome event. The controls are patients in the same population who are as similar as possible to the cases but have not had the outcome o interest. In a case-control study, cases are identif ed as patients in a population who have experienced the outcome event o interest. In a cohort study, two groups o patients are identif ed: those who are taking a given drug and another group who are as similar as possible to the exposed group but are not taking the drug o interest. All patients are ollowed over time to determine how many in each group develop a specif ed outcome event o interest. Evaluation of Risk At the most basic level, cohort and case-control studies yield data that can be seen as comprising a 2 2 table def ning the presence or absence o exposure to the drug o interest as well as the presence or absence o the adverse outcome. For cohort studies, this is re erred to as the relative risk; or case-control studies (provided that the case outcome is not common), this is known as the odds ratio. A relative risk (or odds ratio) o 2 means that patients using the drug are twice as likely to have the outcome as patients not using the drug; a relative risk or odds ratio o 0. The 2 2 table is def ned by the presence or absence o exposure to the drug o interest as well as the presence or absence o the outcome o concern. Cells A to D include, respectively, patients who took the drug and had the outcome (A), patients who took the drug but did not have the outcome (B), patients who did not take the drug but had the outcome anyway (C), and patients who did not take the drug and did not have the outcome (D). For case-control studies (provided that the case outcome is not common), this ratio is termed the odds ratio; or cohort studies, this ratio is termed the relative risk. Epidemiologists and statisticians have developed several strategies to correct or this problem o con ounding, which is inherent in observational studies. The goal is to address the possibility that the drug does not cause the outcome o interest but appears associated with it because both are associated with a third con ounding actor. For example, lung cancer is more common among co ee drinkers; this is not because co ee causes lung cancer, but because co ee drinkers are more likely to be smokers. To address con ounding, researchers attempt to learn as much as possible about the characteristics o patients who use each drug regimen under study. Were the patients who were prescribed one drug older than patients given a comparator drug I these characteristics were evenly balanced across the users o the various drugs, there would not likely be a problem. However, i not (or example, i users o ro ecoxib were more likely to be smokers than users o celecoxib, or less likely to take prophylactic doses o aspirin), this would have to be adjusted or in the analysis. Such adjustment can be accomplished by statistical techniques that include multiple regression, propensity scores, or instrumental variable methods. In a randomized trial, subjects are assigned arbitrarily to one treatment versus another. I the study is large enough and the randomization works adequately, di erences in outcomes between subjects in the various study arms are likely to be the result o the di erent treatments they received because they were (by def nition) similar in all other respects. By contrast, in an observational study, the researcher is obliged to study outcomes in patients or whom a physician has already chosen to prescribe one drug versus another versus no drug. It is there ore necessary to move beyond the simple 2 2 ormulation described above, adjusting the observed relationships so as to control or di erences that may have existed be ore the patients took the drugs under study. For example, patients who take antihypertensive medications are likely to have more cardiovascular disease than a group o age- and sex-matched people in the same community who do not take antihypertensive medications. O course, this is not because blood pressure medicines cause heart disease; on the contrary, antihypertensive medications reduce the risk o cardiovascular disease (including heart ailure, myocardial in arction, and stroke) in such patients. But while these medications reduce the risk o heart disease, they do not reduce it to zero. Furthermore, many patients with hypertension start therapy later in li e, or do not adhere adequately to their prescribed regimens. As a result, antihypertensive medication users overall have a higher rate o heart disease than demographically identical individuals who do not take blood pressure medication. However, the early reports o increased risk suggest that selection bias could provide an alternative explanation or suicide in uoxetine users. Thus, a physician would pre er a potentially suicidal patient to have a supply o uoxetine at home rather than a supply o tricyclic antidepressant. Whatever the underlying risk o suicide caused by either drug, these actors alone would combine to create a prof le o higher suicide rates among new uoxetine users compared to tricyclic antidepressant users in an observational assessment. Patients who are regular users o any preventive medication appear to be di erent rom those who do not exhibit this behavior: they are more likely to visit their doctor seeking preventive therapy, or are at least open to receiving it, and their physicians are su f ciently prevention oriented to write such a prescription. Such patients are probably also more likely to engage in other health-promoting behaviors, such as tobacco avoidance, weight control, exercise, and adherence to their other prescribed drug regimens. These characteristics likely exist to an even greater extent among patients who adhere aith ully to the prescribed regimen or a prolonged period o time. Several large randomized trials have proven a similar point: patients randomized to placebo who adhere well to their dummy pill "regimen" have better outcomes (including mortality) than patients who do not adhere well to their placebo "regimen. To address this issue in observational studies, some research groups use only "active controls" as comparator groups- or example, comparing patients adherent to statin regimens with patients adherent to regimens o other preventive drugs rather than simply comparing such patients with patients who are not regular statin users. The solution is not to embrace all di erences in adverse e ect rates regardless o their statistical properties. Instead, it is to consider such rate di erences thought ully and to seek additional evidence to clari y worrisome relationships even i they are not "signif cant" in p-value terms. However, when the data rom all such trials were aggregated (in some cases, years a ter the studies were completed), it became clear that the risk across all studies was clear and consistent (and also met the conventional p 0. The opposite problem arises when considering the statistical signif cance o data rom large population-based epidemiologic studies. Here, sample size (power) is not a limitation, especially when studies employ data on several hundred thousand patients through use o an automated claims database. But here, even i the f nding appears to have statistical signif cance, a di erence o such small magnitude may have little or no clinical importance. As a result, the concept o risk management has become an important theme in drug development and regulation. However, more sophisticated readers o the literature understand that such a cut point is largely arbitrary (compared to , or example, a p value o 0. The situation is even more critical in assessing the statistical signif cance o data about adverse events, whether rom a randomized trial or rom an observational analysis. It is use ul to recall that the p value is determined by both sample size and the magnitude o an observed di erence. Most clinical trials are powered to be large enough to detect a di erence between a study drug and its comparator in producing a clinical outcome that is relatively common. As a result, however, such studies are not likely to have adequate power to f nd a statistically signif cant di erence between groups or outcomes that are much more rare. For drugs with known risks, it is there ore di f cult to know whether an adverse e ect occurs more commonly with a new drug than with another drug in the same class. In this case, however, the absence o head-to-head clinical trials makes it di f cult to make such an evaluation. Thus, in most instances, the individual clinician is le t to make therapeutic decisions without the data needed to make such choices rigorously. A recent development designed to remedy this problem is the movement toward comparative e ectiveness research-a program o publicly unded studies that systematically evaluate therapies against one another. Industry critics have argued that these materials o ten emphasize therapeutic benef ts more persuasively than they communicate risk. As an alternative, several innovative programs have emerged that provide prescribers with noncommercial, publicly unded "marketing" o evidence-based data about drug benef ts, risks, and costs, known as academic detailing. Juries and courts have agreed with this notion; legal settlements exceeded $1 billion or cerivastatin (Baycol) and $21 billion or dex enf uramine (Redux), even in the absence o criminal convictions. These data are being made even more use ul by advanced methodological tools, such as propensity scores and instrumental variables, to improve control or con ounding in observational studies. Pharmacoepidemiologic analyses based on these developments can orm the oundation or decisions-made both at the bedside and at policy levels-based on science rather than on hunches, ear, or hype. These databases and epidemiologic tools also hold potential or def ning comparative drug e ectiveness by using the same tools to measure desired clinical outcomes across agents. Thus, observational studies make possible the head-to-head comparison o medications that is not required by the approval process but that is central to the in ormational needs o prescribers, patients, and payors. From a biological perspective, the systematic detection o adverse e ects will urther benef t rom the development o research tools to predict the toxicities o new compounds more accurately and to ag them or intensive surveillance once a drug is marketed. In addition, pharmacogenomics (see Chapter 7, Pharmacogenomics) is addressing many o these questions rom the perspective o inherited di erences in drug metabolism (pharmacokinetics) and drug responses (pharmacodynamics). Governmental reviews have demonstrated that, even when postmarketing sa ety studies are mandated at the time o approval, they are o ten not completed or even initiated (see above). This helps explain the tardiness with which important adverse e ects have been detected and acted on. Rationalizing the national response to this problem has become a key goal or public policy. Within a ew years, the system was expanded to include data describing the medication use and clinical encounters o more than 100 million (anonymized) patients, making it a valuable tool or the systematic detection o adverse drug e ects ar earlier than had previously been possible. A modular, prospective, semi-automated drug sa ety monitoring system or use in a distributed data environment. High-dimensional propensity score adjustment in studies o treatment e ects using health care claims data. A study with nsul macromolecules in the body, catalyzing biochemical reac- that the average clinical development and approval time was neuroendocrine hormone regulating postprandial tions, constituting receptors and channels in membranes, more than 1 year aster or 33 protein therapeutics approved glucose control) providing intracellular and extracellular sca olding sup- between 1980 and 2002 than or 294 small-molecule drugs port, and transporting molecules within a cell or rom one approved during the same time period. Seventh, many protein therapeutics address unmet post-translational modif cation o proteins. Viewed rom the perspective o disease mecha- tein therapeutics are continuing to trend upward. In the year nisms, these estimates pose an immense challenge to modern 2000, no protein therapeutics were represented in the top 20 medicine, as disease may result when any one o these pro- drugs sold in the United States. In 2013, protein therapeutics teins contains mutations or other abnormalities or is present comprised our o the top ten pharmaceuticals by sales in in an abnormally high or low concentration. Viewed rom the the United States and seven o the top ten pharmaceuticals perspective o therapeutics, however, these estimates repre- by sales worldwide. Second, because the action o tems or recombinant proteins include bacteria, yeast, insect proteins is highly specif c, there is o ten less potential or cells, mammalian cells, and transgenic animals and plants. Fourth, or diseases in glycosylation reactions, and each o the other biological which a gene is mutated or deleted, protein therapeutics can systems listed above produces a di erent type or pattern o provide e ective replacement treatment without the need glycosylation. Darbepoetin- is an erythropoietin analogue that is engineered to contain two additional amino acids that are substrates or N-linked glycosylation reactions. Perhaps the best example o trends in the production and use o protein therapeutics is provided by the history o insulin in the treatment o type 1 and type 2 diabetes mellitus. Untreated, type 1 diabetes is a disease that leads to severe wasting and death due to lack o the protein hormone insulin, which signals cells to per orm numerous unctions related to glucose homeostasis and intermediary metabolism. In 1922, insulin was f rst purif ed rom bovine and porcine pancreas and used as a li e-saving daily injection or patients with type 1 diabetes. At least three problems hindered the widespread use o this protein therapy: f rst, the availability o animal pancreases or purif cation o insulin; second, the cost o insulin purif cation rom animal pancreas; and third, the immunological reaction o some patients to animal insulin. By growing vast quantities o these bacteria, large-scale production o human insulin was achieved. The resulting insulin was abundant, inexpensive, o low immunogenicity, and ree rom other animal pancreatic substances. Recombinantly produced proteins can have several urther benef ts compared with nonrecombinant proteins. First, transcription and translation o an exact human gene can lead to a higher specif c activity o the protein and a decreased chance o immunological rejection. A recombinant orm o -glucocerebrosidase was subsequently developed and introduced, which is not only available in su f cient quantities to treat many more patients with the disease but also eliminates the risk o transmissible. When this protein is made recombinantly, a change o amino acid arginine-495 to histidine allows the addition o mannose residues to the protein. Last, recombinant technology allows the engineering and production o proteins that provide a novel unction or activity, as discussed below. In this chapter, we summarize currently approved protein therapeutics using a classif cation system that is based on their pharmacologic action (Box 54-1). The numbers o therapeutics per group ref ect the relative di culty associated with drug development across the various classes o protein therapeutics. This group has grown as monoclonal antibody technology has matured and will expand urther as signaling pathways and etiologies o disease are more clearly identi ed. As more diseases are linked to deciencies o speci c proteins, this class will continue to grow. Group Ib is dominated by therapies that augment hematological and endocrine pathways and immune responses. The many inter eron and growth actor therapies in Group Ib e ectively treat disease even when their precise pharmacologic mechanism o action is unknown. Group Ic demonstrates the rational use o naturally occurring proteins to modi y the pathophysiology o human diseases.

Anthracyclines fungus gnats yellow leaves purchase 250mg lamisil, natural antitumor antibiotics isolated rom a species o the ungus Streptomyces antifungal kit amazon order generic lamisil, are among the most clinically use ul cytotoxic cancer chemotherapeutic agents fungus resistant fescue order genuine lamisil line. Like many other antineoplastic agents fungus worm discount lamisil uk, anthracyclines cause myelosuppression and alopecia antifungal recipes lamisil 250mg without a prescription. Anthracyclines are excreted in bile xanthone antifungal buy cheap lamisil on-line, and their dose must be reduced in patients with liver dys unction. These agents are major components o chemotherapy regimens or a variety o malignancies, particularly hematologic cancers (such as leukemias and lymphomas) and breast cancer. Daunorubicin is an anthracycline that is commonly used to treat acute myeloid leukemia and acute lymphocytic leukemia. The best known drug in this group, doxorubicin (hydroxydaunorubicin or Adriamycin), remains a key component o regimens used to treat lymphoma and breast cancer, although it has a higher risk o gastrointestinal toxicity than daunorubicin and can be associated with heart ailure. It is thought that doxorubicin acilitates the excessive production o ree radicals in the myocardium and thereby damages cardiac cell membranes. Cardiotoxicity is related to both the peak plasma concentration and the cumulative dose o doxorubicin. Cardiotoxicity can be reduced by coadministration o dexrazoxane, which is thought to inhibit ree radical ormation by chelating intracellular iron and preventing iron-mediated ree radical generation. Liposomal doxorubicin (Doxil) is a specif c ormulation that improves tumor delivery by enhancing penetration o drug into the cell membrane. In addition, liposomal doxorubicin can limit cardiotoxicity by reducing membrane lipid peroxidation and ree radical generation. Tumor cells o ten develop resistance to etoposide by increasing their expression o P-glycoprotein. This protein normally serves as an e ux pump to rid the cell o toxic molecules such as natural metabolic side-products, but it can also remove chemotherapeutic agents derived rom natural products be ore those agents have exerted their cytotoxic e ect. Etoposide is use ul or treating testicular cancer, lung cancer, and leukemia, while both etoposide and teniposide are used to treat various lymphomas. Bone marrow suppression is the chie toxicity o the two epipodophyllotoxins in clinical use. In practice, drugs o these classes are co-administered in many success ul antineoplastic regimens. Its clinical use is generally restricted to the treatment o recurrent leukemia and ovarian cancer. The two major classes o antineoplastic microtubule inhibitors bind to distinct sites on the tubulin heterodimer. Vinca alkaloids bind pre erentially at the end o microtubules and thereby inhibit the addition o new tubulin subunits to the microtubule. Taxanes, which stabilize polymerized microtubules, bind to a di erent site on -tubulin (T). Taxanes may stabilize either the interactions between tubulin subunits or the shape o microtubule protof laments. Colchicine binds to a site located at the inter ace between -tubulin and -tubulin (C). Colchicine is not used in cancer chemotherapy but is used in the treatment o gout (see Chapter 49). Microtubule Inhibitors Microtubules depend on dynamic instability or physiologic unctioning. Without the ability to change length quickly, microtubules can do little other than lend structural support to a quiescent cell. Although microtubules play important roles in many aspects o cellular physiology, drugs that inhibit microtubule unction are pre erentially toxic to M-phase cells. Vinca alkaloids inhibit microtubule polymerization, while taxanes inhibit microtubule depolymerization. Two other inhibitors o microtubule polymerization, griseo ulvin and colchicine, are discussed in Chapter 36, Pharmacology o Fungal In ections and Chapter 49, respectively. Inhibitors of Microtubule Polymerization: Vinca Alkaloids the vinca alkaloids vinblastine and vincristine are natural products originally isolated rom the periwinkle plant, Vinca rosea. The binding o vinca alkaloids to -tubulin at the end o microtubules inhibits tubulin polymerization and thereby prevents microtubule extension. Vincristine causes some myelosuppression, but not to the same degree as vinblastine. Peripheral neuropathy is usually the dose-limiting adverse e ect o vincristine; this toxicity may result rom inhibition o the microtubule tra f cking unction in long peripheral nerves that extend rom the spinal cord to the extremities. Unlike the vinca alkaloids, taxanes promote microtubule polymerization and inhibit depolymerization. Stabilization o the microtubules in a polymerized state arrests cells in mitosis and eventually leads to programmed cell death (apoptosis). Two leading hypotheses have been proposed or the apparent microtubule-stabilizing properties o taxanes. First, taxanes could strengthen the lateral interactions between microtubule protof laments. Increased lateral interactions would decrease the tendency or protof laments to "peel away" rom the microtubule cylinder. In vivo, both o these mechanisms may be important or taxane-mediated stabilization o microtubules; alternative mechanisms are also possible. Paclitaxel is used as an antineoplastic agent in the treatment o many solid tumors, especially breast, ovarian, and non-small cell lung cancer. An acute hypersensitivity reaction occurs commonly in response to paclitaxel, or more likely to the vehicle in which paclitaxel is solubilized; this e ect can be obviated by administration o dexamethasone (a glucocorticoid receptor agonist) and a histamine H1 receptor antagonist be ore treatment with paclitaxel. Many patients experience myalgias and myelosuppression rom paclitaxel, and high doses o the drug can cause pulmonary toxicity. Peripheral neuropathy, typically mani esting as a "stocking and glove" sensory def cit in the extremities, can limit the cumulative amount o drug that can be administered sa ely. Abraxane is an albumin-bound orm o paclitaxel with a mean particle size o 130 nanometers. The albumin-bound paclitaxel nanoparticles do not cause a hypersensitivity reaction, do not require premedication, and cause less myelosuppression than traditional, solvent-based paclitaxel. Abraxane is approved or the treatment o metastatic breast cancer and, in combination with gemcitabine, or the f rstline treatment o pancreatic cancer. Docetaxel is most commonly used in the treatment o breast cancer, non-small cell lung cancer, and prostate cancer. As with paclitaxel, docetaxel causes an acute hypersensitivity reaction that can be obviated by preadministration o glucocorticoids. Docetaxel occasionally exhibits the drug-specif c adverse e ect o uid retention, which likely arises rom increased capillary permeability. The myelosuppression associated with docetaxel is pro ound, however, and is usually dose-limiting. Cabazitaxel is a third taxane that has recently been approved or the treatment o hormone-re ractory prostate cancer a ter ailure o docetaxel-based treatment. The observation that telomerase is expressed in most cancer cells and is key to the process o immortalization highlights this enzyme as an important target in uture cancer therapy. Although telomerase is expressed to some degree in stem cells and normally cycling cells, most normal cells lack telomerase expression. There ore, the dependency o tumor cells on the immortalized state could provide telomerase inhibitors with a avorable therapeutic index. However, e ective agents have yet to be discovered, and one concern is that multiple cell divisions may be required or telomere length to shorten to a level that is critical or cell survival. Combinations o telomerase inhibitors with traditional cytotoxic agents or newer molecularly targeted therapies could yield synergistic e ects. Such strategies, as well as those described in Chapter 40, Pharmacology o Cancer: Signal Transduction, will help to advance cancer therapy by moving beyond general cytotoxic approaches and ocusing treatment instead on the molecular abnormalities responsible or driving oncogenesis. Bendamustine or indolent non-Hodgkin lymphoma in the ront-line or relapsed setting: a review o pharmacokinetics and clinical trial outcomes. Because many normal cells as well as cancer cells are transiting through the cell cycle, these agents are associated with multiple dose-limiting toxicities. However, the therapeutic window o these drugs is narrow, resulting in toxicity to normal stem cells and in hematologic and gastrointestinal adverse e ects. With the impressive advances in basic tumor cell biology over the last several decades and the identif cation o numerous oncogenes and tumor suppressor genes, the potential exists or development o agents that are targeted more specif cally at the molecular circuitry responsible or the dysregulated proli eration o cancer cells. An early example o such a drug was the selective estrogen receptor modulator tamoxifen (see Chapter 30, Pharmacology o Reproduction). Tamoxi en is still one o the most active agents in the treatment o hormone receptor-positive breast cancer, with a relatively modest adverse e ect prof le. This chapter highlights the basic principles and agents o targeted cancer therapy, detailing recent advances and directions or the uture. In general, binding o the growth actor ligand results in receptor oligomerization, a con ormational change in the cytoplasmic domain o the receptor, and tyrosine kinase activation. Intracellular targets are subsequently phosphorylated, propagating a signal that culminates in progression through the cell cycle and cellular proli eration. She develops a skin rash and diarrhea but otherwise tolerates this m edication well. Restaging com puted tom ography scans are per orm ed 2 m onths a ter starting treatm ent with erlotinib. Binding o ligand results in receptor homodimerization (or heterodimerization with other amily members), triggering activation o the tyrosine kinase, autophosphorylation o the receptor on tyrosine (T) residues, and phosphorylation o intracelluyr lar target proteins. Upon ligand-induced receptor dimerization, the associated kinase is activated and autophosphorylated on tyrosine residues, resulting in recruitment and phosphorylation o intracellular target proteins. ErbB receptors are expressed on epithelial cells and are o ten activated or overexpressed in a variety o carcinomas. Signaling through these receptors activates the growth o certain hematopoietic and mesenchymal tissues, and dysregulation o these receptors is requently observed in specif c myeloproli erative disorders, leukemias, sarcomas, and epithelial cancers (Table 40-1). While such signaling cascades might seem unnecessarily complicated, they allow or the integration o diverse extracellular and intracellular signals, the opportunity or multiple points o eedback control, and the tight regulation o critical events such as cellular proli eration. Proteasome Structure and Function Key cellular processes such as cell cycle progression and apoptosis are also regulated at the post-translational level by protein degradation. Ubiquitin is a 9-kDa protein that derives its name rom its widespread distribution in tissues and its conservation across eukaryotes. The second enzyme in the cascade, E2, is a ubiquitin-conjugating enzyme that transiently carries ubiquitin and acts in conjunction with the third enzyme, the ubiquitin ligase E3, to orm a polyubiquitin chain that is trans erred to the target protein on an internal lysine residue. E1 is nonspecif c, and there are a number o di erent E2 ubiquitin-conjugating enzymes with a limited degree o specif city. The E3 ubiquitin ligase component is largely responsible or target protein specif city. Once proteins are selectively ubiquitinated, they are targeted or degradation by the 26S proteasome, which is a cylindrical particle present in both cytoplasm and nucleus. Substrates are cleaved progressively, with one protein being completely degraded be ore the next protein enters. Short peptide segments, on average 6 to 10 amino acids in length, are extruded and subsequently hydrolyzed to individual amino acids in the cytosol. Activated ubiquitin is then passed rom the active-site cysteine o E1 to the active-site cysteine o the ubiquitin-conjugating enzyme E2, which unctions coordinately with the ubiquitin ligase E3 to attach ubiquitin to protein targets. Polyubiquitination o target proteins results in their recognition by the 26S proteasome, which consists o a 19S outer regulatory subunit and a 20S internal core chamber. The proteasome mediates proteolytic degradation o the target protein into short peptide ragments. Bortezomib is a proteasome inhibitor that has been approved or use in multiple myeloma and is under investigation or use in other malignancies. Thus, overexpression o Skp2, which is ound in a number o tumor types, can promote cell cycle progression by degrading p27. Loss o Fbw7 has been implicated in tumor progression due to high levels o cyclin E. Tumor angiogenesis is a complex process involving a number o di erent pro- and antiangiogenic actors. Invasion and migration o endothelial cells is promoted by activation o matrix metalloproteinases and serine proteases and by reorganization o intracellular actin. Thus, the therapeutic window o the newer targeted agents tends to be wider than that o traditional cytotoxic chemotherapy, with a di erent spectrum o adverse e ects. During the course o these studies, it was noted that patients who tended to respond were emale, nonsmokers, Asian, and with adenocarcinoma tumor histology. In vivo, trastuzumab also appears to induce antibody-dependent cellular cytotoxicity and inhibit angiogenesis. The principal adverse e ect o trastuzumab is cardiotoxicity, particularly when used in combination with anthracyclines. Imatinib is relatively well tolerated; its principal adverse e ects are myelosuppression, superf cial edema, nausea, muscle cramps, skin rash, and diarrhea. Imatinib has shown signif cant activity in advanced gastrointestinal stromal tumor, but it has proven largely ine ective in the treatment o systemic mastocytosis. K-ras mutations are requently observed in non-small cell lung cancer, colorectal cancer, and pancreatic carcinoma, while H-ras mutations are ound in kidney, bladder, and thyroid cancers, and N-ras mutations occur in melanoma, hepatocellular carcinoma, and hematologic malignancies. A number o rapamycin derivatives are currently undergoing clinical testing in a wide variety o malignancies, including temsirolimus and everolimus. Both are soluble ester analogues o rapamycin that demonstrate dose-dependent inhibition o tumor cell growth in vitro. Everolimus is approved or treatment o renal cell carcinoma, breast cancer, and pancreatic cancer. Proteasome Inhibitors In light o the importance o ubiquitin-mediated proteasomal degradation in regulating the cell cycle, apoptosis, and other processes involved in neoplastic trans ormation, proteasome inhibitors have been tested in vitro and in vivo or antitumor e ects. Bortezomib induces growth inhibition and apoptosis o tumor cells with relatively ew toxic e ects on normal cells.

One example o this concept involves the treatment o Enterococcus faecalis fungus gnats mycetophilidae cheap lamisil 250 mg without a prescription, a Gram-positive organism that exhibits little susceptibility to aminoglycosides antifungal home remedies for dogs buy 250 mg lamisil fast delivery. Recall that aminoglycosides are thought to kill bacteria by inducing misreading o the genetic code and translation o de ective proteins antifungal pills best order lamisil, which cause urther cellular damage (see Chapter 34) fungus journal buy cheap lamisil 250mg on-line. However xerophilic fungi discount lamisil 250 mg on line, when used in combination with a cell wall synthesis inhibitor such as vancomycin or a -lactam antibiotic fungus ease order lamisil 250mg fast delivery, aminoglycosides are able to reach the bacterial ribosomes and e ectively kill the bacteria (see Chapter 35). The potentiating e ect o the cell wall synthesis inhibitor on the activity o the aminoglycoside is an example o the important pharmacologic concept o synergy. Alternatively, the drugs may not interact, and the e ect o the combination is simply the sum o the e ects o each drug used individually (additivity). The interaction between two antimicrobial drugs is o ten quantif ed by selecting a particular endpoint. Suppose that Drugs A and B inhibit a particular enzyme required or bacterial growth. Comparison of the effects of bacteriostatic and bactericidal drugs on bacterial growth kinetics in vitro. A bactericidal drug kills the target organism, as demonstrated by the time-dependent decrease in the number o live bacteria. Bacteriostatic drugs eradicate in ections by limiting the growth o the in ecting organism or a long enough period o time to allow the host immune system to kill the bacteria. Relationship between rate of microbial killing and drug concentration for time-dependent and concentration-dependent bactericidal drugs. In contrast, concentration-dependent bactericidal agents exhibit increased killing with increasing drug concentration (dashed line). Several generalizations can be made concerning the nature o drug interactions between di erent classes o antimicrobial agents. Finally, the interactions between two bacteriostatic drugs are o ten additive but cannot be predicted in all cases. In the course o this illness, tuberculous bacilli (also called mycobacteria) are inhaled and phagocytosed by alveolar macrophages, in which the bacilli multiply within intracellular vacuoles. Activated macrophages are usually able to keep the in ection under control by killing the multiplying bacilli but are un ortunately unable to eradicate the in ection completely. Tissue damage is caused by the release o neutral proteases and reactive oxygen intermediates rom activated macrophages, with the end result that central necrosis occurs in the tuberculous cavities in the lungs. Inside each o these cavities, as many as 108 to 109 living bacilli may be held in check by macrophages and helper T cells. Success ul cure o tuberculosis in ections typically requires the use o combinations o drugs with antimycobacterial activity. Commonly used drugs include isoniazid, ri ampin, pyrazinamide, and ethambutol (see Chapter 35). M, a standard regimen could consist o 2 months o isoniazid, ri ampin, pyrazinamide, and ethambutol, ollowed by 4 months o isoniazid and ri ampin. Kanamycin and other second-line drugs are sometimes substituted or one or two drugs in this regimen i resistance develops. Isoniazid and ri ampin are o ten the pre erred drugs in such regimens because o their ability to kill intracellular as well as extracellular mycobacteria. As noted in Chapter 35, resistance to antimycobacterial drugs develops primarily through chromosomal mutations, and the requency o resistance to any one o the drugs is about 1 in 106 bacteria. Chapter 35 discusses the implications o the act that a tuberculous cavity contains 108 to 109 bacteria, while the requency o mutants resistant to a single drug is about 1 in 106. On average, then, 100 bacteria will already be resistant to each drug in any single lesion, even be ore that drug is administered. Because o the potentiating e ect o Drug A on Drug B, d[B] is smaller or higher [A]. Because o its intuitiveness and simplicity, the mathematical model described above is o ten used to def ne synergy, additivity, and antagonism. M, his initial 2 weeks o isoniazid treatment likely killed all the isoniazid-susceptible bacilli in his cavity. I he had taken ri ampin as well as isoniazid, only 1 in 1012 bacilli would likely have been resistant to both drugs, and he might have eradicated the in ection. M stopped taking isoniazid, the isoniazid-resistant bacilli remaining in his lungs multiplied, leading to a relapse in his symptoms. O the 108 to 109 isoniazidresistant bacilli in each lesion, again there was a 1 in 106 probability that a bacillus had mutated to acquire ri ampin resistance. By taking ri ampin or 2 weeks, he killed all the ri ampin-susceptible bacilli but selected or ri ampinresistant organisms. Ideally, the regimen should be constructed using drugs that have been shown to be e ective in susceptibility tests. Also, at least initially, drugs that are part o his current treatment plan should be avoided. Ethionamide and clo azimine are second-line drugs that could be included in the regimen. Note that, as a whole, the second-line regimen will be signif cantly more toxic than the f rst-line regimen. Patients with drug-susceptible tuberculosis require access to combination therapy as well as help in adhering to the combination therapy to avoid the emergence o drug-resistant bacilli. Synergistic Combinations A second reason or using a combination drug regimen is to take advantage o the synergy between the actions o the two drugs. This consideration is especially important in the setting o in ections that are not readily handled by the immune de enses o immunocompromised patients. Bactericidal drugs are strongly pre erred, however, in the setting o immunocompromised patients. The reason or using bactericidal combinations in the immunocompromised patient should be obvious-the host does not have su f cient numbers o unctioning lymphocytes and/or neutrophils to eliminate even a nondividing bacterial population. Bactericidal drug combinations are sometimes indicated or meningitis to maximize the probability o overcoming the poor opsonization o bacteria by antibody and complement in the immunologically privileged site o the meninges, especially i the responsible organism is not known (see Chapter 9, Principles o Nervous System Physiology and Pharmacology). As described above, the mechanism o synergy relies on the penicillin inhibiting cell wall biosynthesis, which allows the aminoglycoside to penetrate the thick peptidoglycan layer o this Gram-positive organism. These classic examples illustrate two basic mechanisms whereby one drug can potentiate the activity o another. Amphotericin B has a low therapeutic index when used as a single agent (primarily as a consequence o its nephrotoxicity), but its synergistic e ect in combination with ucytosine allows a reduction in the dose o amphotericin B required to treat a systemic ungal in ection such as cryptococcal meningitis (with a corresponding reduction in toxicity). An analogous combination, sul adoxine and pyrimethamine, is used in the treatment o malaria, toxoplasmosis, and other protozoal inections. These combinations illustrate a second mechanism whereby drugs can exert a synergistic e ect. A combination o drugs with activity against the microbes that are most likely to be involved in the in ection (or that could result in the most serious outcome) is then administered until a positive bacteriologic identif cation is made and drug susceptibility results are obtained. At that point, it may be possible to discontinue unnecessary drugs and implement specif c monotherapy. Un avorable Drug Combinations As mentioned above, antagonistic drug combinations can sometimes be used in combination chemotherapy regimens, although this situation is to be avoided i possible. Antagonism is most commonly observed when static drugs are used in combination with cidal drugs. For example, tetracyclines are bacteriostatic antimicrobials that antagonize the bactericidal activity o penicillins (see Chapter 34). By inhibiting the transpeptidation reaction involved in bacterial cell wall cross-linking, the penicillins create an imbalance between cell wall synthesis and autolysin-mediated cell wall degradation. I the bacterial cell continues to grow, this leads to spheroplast ormation and eventually to osmotic lysis. A protein synthesis inhibitor such as tetracycline, which arrests cell growth, would there ore antagonize the e ect o a -lactam. Similarly, imidazoles and triazoles are ungistatic agents that antagonize the ungicidal activity o amphotericin B (see Chapter 36). The mechanism o antagonism can be appreciated by noting that amphotericin B acts by binding ergosterol and orming pores in the ungal membrane, whereas imidazoles and triazoles inhibit a microsomal cytochrome P450-dependent enzyme, 14 -sterol demethylase, which is involved in ergosterol biosynthesis. Thus, the imidazoles and triazoles oppose the action o amphotericin B by decreasing the concentration o the target or the latter drug. Despite these considerations, static and cidal antimicrobial drugs are sometimes used clinically in combination when no good alternatives exist. The resulting increase in the therapeutic drug concentration(s) can increase the likelihood o adverse e ects. Co-administration of Penicillins with -Lactamase Inhibitors the combination o a -lactam antibiotic and a -lactamase inhibitor. Clavulanic acid is an inhibitor o -lactamase, an enzyme used by many -lactam-resistant Gram-positive and Gramnegative bacteria to inactivate penicillins (see Chapter 35). By preventing the hydrolysis and inactivation o penicillins, clavulanic acid (and other -lactamase inhibitors) greatly increases the potency o penicillins (and other -lactams) against bacteria that express -lactamase. This combination has been e ective in the treatment o in ections due to penicillin-resistant Streptococcus pneumoniae, which is a common cause o otitis media in in ants. Such organisms have typically acquired resistance to penicillins through a plasmid-encoded -lactamase. Polymicrobial and Life-Threatening Infections Combinations o antimicrobial drugs are used not only to prevent the emergence o resistance and to act synergistically against a specif c, known pathogen but also to treat polymicrobial in ections and in ections in which treatment must be initiated be ore the microbe causing the in ection is identif ed. Such an abscess is likely to contain a wide spectrum o microorganisms- much too broad to be targeted e ectively by a single antibiotic. These complete genomic transcripts are eventually packaged into virions that in ect new cells. In the setting o high mutation rates, combination antiviral therapy is benef cial. At such low levels o viral replication, the probability o resistance emerging to any one o the drugs is greatly reduced. Thus, or example, it has been shown that combinations remain e ective or much longer periods o time than does any single agent. Despite these concerns, data rom randomized clinical trials now provide conclusive evidence or the use o combination antiretroviral therapy regardless o the stage o disease. Table 41-2 provides an overview o the major antineoplastic drug classes that are currently available, including their mechanisms o action, cell cycle specif cities, major resistance mechanisms, and dose-limiting toxicities. Note that all these drug classes have been discussed in previous chapters; the ollowing discussion integrates relevant in ormation about the individual drugs in a clinical context. General Considerations To appreciate the challenges that must be aced in treating cancer with drug therapies, it is use ul to examine the current model or oncogenic trans ormation. Normal somatic cells undergo di erentiation as they mature rom a small regenerating stem cell population. Because cells lose the ability to divide as they progress along their di erentiation pathway, malignancies tend to arise in populations o immature or undi erentiated cells. At the molecular level, the process o malignant trans ormation involves multiple steps, including the loss o tumor suppressor gene products. Acquired alterations in genes that regulate the progression o cells through the cell cycle con er a growth advantage on malignant cells, which proli erate in the absence o normal growth regulatory signals. Some o the most aggressive trans ormed cells multiply at a rate o about two divisions a day. At this rate, a single such cell could give rise to a clinically detectable mass o 1 g (109 cells) in just 15 days, and a tumor burden o 1 kg (1012 cells), which is o ten incompatible with li e, could be achieved in 20 days. Fortunately, oncogenesis usually occurs much more slowly than this-a act that supports the concept o screening or many types o cancer. A malignant cell can give rise to a small colony o cells (106 cells) rather quickly, but urther growth is held in check by the limited availability o oxygen and nutrients. Moreover, the continued proli eration o cells at the tumor margins causes a urther decrease in the pO2 in the center o the tumor, and hypoxic tumor cells begin to die (central necrosis). The tumor continues to grow, albeit at a slower rate, because the rate o cell division at the margins exceeds the rate o central necrosis. At some point, hypoxic tumor cells can express or induce the stromal expression o angiogenic actors. Vascularization can be accompanied by a sudden increase in the growth raction as cells are pulled out o G0 phase and into the cell cycle. Because a single malignant cell can expand clonally to give rise to a tumor, it is thought that every malignant cell must be destroyed to e ect a cure o the cancer. Cancer cells can be thought o as "altered sel " cells that maintain similarities to normal, noncancerous cells, o ten making it di f cult to target the cancer cells selectively. These kinetics o tumor cell killing are unlike the time-dependent killing characteristic o many antimicrobial drugs, which ollows zero-order kinetics. Adding to the di f culty o curative cancer treatment is the phenomenon o tumor progression, in which a clonally derived population o malignant cells becomes heterogeneous through the accumulation o multiple genetic and epigenetic alterations. When subjected to immune surveillance or the administration o an antineoplastic agent, subclones o the tumor with relatively nonantigenic or drug-resistant phenotypes are selected. Thus, deletions, gene amplif cations, translocations, and point mutations are not in requent events and can result in antineoplastic drug resistance through any o the mechanisms shown in Table 41-3. With the possible exception o some recently developed classes o antineoplastic therapies directed against molecular targets that are selectively expressed by a malignant clone o cells. Accordingly, neutropenia, thrombocytopenia, anemia, alopecia, nausea, and oral and intestinal ulcerations are common adverse e ects o many cytotoxic antineoplastic agents. Although many rapidly growing lymphomas and leukemias seem to melt away with antineoplastic chemotherapy, more indolent solid tumors must o ten be treated with adjuvant. By the time these tumors come to clinical attention, they may be large and may have metastasized.

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The di erences in the tissue specif cities o mi epristone antifungal agents quiz buy generic lamisil 250mg on line, ulipristal antifungal soap target cheap 250mg lamisil overnight delivery, and asoprisnil are probably due to their di erences in in uencing the binding o transcription co actors to the progesterone receptor complex antifungal qt prolongation buy cheap lamisil 250mg. In combination antifungal for thrush cheap lamisil line, these mechanisms explain the 95% e f cacy o combination oral contraception antifungal and hydrocortisone cream lamisil 250 mg without a prescription. Use o "unopposed" estrogens promotes endometrial growth fungus gnats aloe vera buy generic lamisil on-line, and early studies o estrogen-dominant contraceptives determined that these agents increase the risk o endometrial cancer. Because o this f nding, or a woman with a uterus, estrogen is always co-administered with a progestin to limit the extent o endometrial growth. Ideally, the progestin would possess activity only at progesterone receptors, but almost all currently available progestins also have some androgenic crossreactivity. The development o male contraception is an active area o research; current approaches to this therapy are discussed brie y at the end o the section. Co-administration o estrogen and progestin may also inhibit pregnancy by a number o secondary mechanisms, including alterations in tubal peristalsis, endometrial receptivity, and cervical mucus secretions. Medroxyprogesterone acetate is commonly combined with estrogen or hormone therapy in postmenopausal women. Norethindrone acetate is commonly used in contraceptives; it is metabolized to the parent compound, norethindrone. Drospirenone is a unique synthetic progestin that also has antiandrogenic activity. The steroids are released with zero-order kinetics (see Chapter 3, Pharmacokinetics). The 7-day placebo period removes exogenous hormone stimulation, causing the endometrium to slough and resulting in withdrawal bleeding. The 21-7 cycle ormulation was meant to simulate a 28-day cycle but is relatively arbitrary. By combining pill packs, "long cycles" o 42 active hormone pills ollowed by 7 days o hormone pills, or 63 active hormone pills ollowed by 7 days o hormone pills, can easily be prescribed. An even longer cycle ormulation o ethinyl estradiol and levonorgestrel is available, in which the drug combination is administered or 84 days ollowed by 7 days o placebo. Formulations containing 24 daily hormone pills and 4 days o placebo are also available. Combination oral contraceptive ormulations include monophasic and triphasic hormone schedules. The standard ormulation, used by the majority o women, is a constant (monophasic) dose o estrogen and progestin or 21 days. Triphasic ormulations incorporate a constant dose o estrogen with a dose o progestin that increases each week during the 21 days o the cycle. The main advantage o triphasic administration is that the total amount o progestin administered over each month is reduced. Indeed, the general trend in recent years has been to decrease the quantities o administered estrogen and progestin to the smallest amount necessary or inhibition o ovulation. In general, the lowest e ective dose o ethinyl estradiol is pre erred because low-dose estrogen is thought to minimize the risk o deep vein thrombosis (see below). A number o studies have been per ormed to assess the adverse e ects o long-term contraceptive use. These studies have shown that the incidence o deep vein thrombosis and the incidence o pulmonary embolism are increased with combination oral contraception. These complications occur in requently, and the absolute number o adverse events is low. Interestingly, pregnancy is associated with a greater risk o deep vein thrombosis and pulmonary embolism than treatment with estrogen-containing contraceptives. Use o oral contraceptives is associated with an increase in gallbladder disease because estrogens increase the biliary concentration o cholesterol relative to that o bile salts, and the resulting decrease in cholesterol solubility promotes the ormation o gallstones. Oral contraceptives should not be administered to women over 35 who smoke, because the administration o contraceptives to this population is associated with an increase in thrombotic cardiovascular events. Recent studies have ocused on the benef ts rather than the adverse e ects o oral contraception. Overall, the consensus is that oral contraceptives have more benef cial than harm ul medical e ects. Progestin-Only Contraception In situations where estrogen may be contraindicated, the use o continuous low-dose oral progestins may be warranted. The two progestin-only oral contraceptives available in the United States, commonly re erred to as the mini-pill, are norethindrone and desogestrel. Patients taking these drugs do not typically menstruate, but breakthrough spotting and irregular, light menstrual periods commonly occur during the f rst year o administration. This dosage orm is especially e ective or women who have di f culty remembering to take a daily (pill) or weekly (patch) agent. A silastic implant is also available that releases etonogestrel and is e ective or 3 years. Emergency hormonal contraception is most e ective when administered within 120 hours o the exposure. Both levonorgestrel and ulipristal prevent pregnancy by inter ering with ovulation. Male Contraception the goal o hormonal male contraception is to suppress endogenous production o sperm reversibly, generating a state o azoospermia (absence o sperm in the ejaculate) without suppressing libido or erectile unction. Reliable inhibition o spermatogenesis is a di f cult task, because even a 99% reduction in spermatogenesis could result in a su f cient number o viable sperm or ertilization. Initial studies o male contraception centered on the parenteral administration o testosterone esters such as testosterone enanthate or testosterone undecanoate. As an end product o the hypothalamicpituitary-reproduction axis, testosterone signif cantly suppresses gonadotropin release. In a largescale clinical trial, this approach produced a contraceptive ailure rate o 1 per 100 man-years. The ollowing combinations have been demonstrated to be e ective, reversible male contraceptives: parenteral testosterone enanthate plus daily oral levonorgestrel; parenteral testosterone undecanoate plus injectable medroxyprogesterone acetate; and transdermal administration o testosterone and a synthetic progestin, Nestorone. The main di f culties with this approach have been the large population variability in the degree o spermatogenesis inhibition (on average, only 60% o men become azoospermic) and the signif cant adverse e ects o acne, weight gain, polycythemia, and a potential increase in prostate size. The realization that estrogen loss at menopause has deleterious e ects has led to the development o perimenopausal and postmenopausal hormone replacement therapy (or additional detail, see Chapter 32). The principal indication or such therapy is to suppress hot ashes and treat atrophy o the urogenital tissues, which may mani est as dry vagina. For women with a uterus, estrogen therapy must be combined with progestin therapy to prevent the induction o endometrial cancer. The results o the study, expressed as the relative risk or various endpoints o hormone treatment versus placebo, are presented in Table 30-3. Estrogen treatment did not increase the risk o coronary heart disease or breast cancer, but it did increase the risk o stroke and it decreased the risk o osteoporotic racture. Given the balance o risks and benef ts, the current recommendation or postmenopausal women is to use hormone therapy only to treat bothersome symptoms such as vasomotor symptoms or vaginal dryness and to use the lowest possible dose o hormone therapy or the shortest period o time. Many synthetic progestins are available or use in hormone therapy or menopausal women. Data represent hazard ratios (95% conf dence intervals) o various events during treatment with hormone therapy or placebo. Micronization is a process in which the progesterone crystals are synthesized with a diameter in the nanometer range, thus acilitating their absorption when administered orally. Like contraceptives, hormone therapy is available as oral tablets, transdermal patches, and vaginal rings and tablets. A vaginal ring that elutes estradiol at a controlled dose rate (see Chapter 55, Drug Delivery Modalities) provides local administration o estrogen and minimal systemic absorption o the drug. The vaginal ring is an e ective therapy or postmenopausal vaginal dryness and atrophy. Androgens, estrogens, and progestins are all steroid hormones that exert their physiologic action by binding to intracellular receptors, translocating to the nucleus, and altering gene transcription. Recent evidence suggests that estrogens may also act on membrane receptors to mediate nongenomic e ects. Derangements in the physiologic e ects o reproductive hormones can involve disruption o the hypothalamic-pituitary-reproduction axis, inappropriate growth o hormone-dependent tissue, or decreased activity o gonadal hormones at target tissues. The development o an e ective male contraceptive has met a number o obstacles but should represent a major pharmacologic advance in the uture. Oral testosterone is ine ective because o its high f rst-pass metabolism by the liver. Two esters o testosterone, testosterone enanthate and testosterone cypionate, can be administered intramuscularly. Transdermal testosterone patches have also been developed; this drug delivery system has the advantages that plasma testosterone levels remain relatively constant and f rst-pass hepatic metabolism is bypassed. Testosterone is also available in a topical gel ormulation; using this preparation on a once-a-day application schedule, plasma testosterone levels gradually increase until they reach physiologic replacement levels a ter 1 month o application. Testosterone can also be administered as a tablet that adheres to the buccal mucosa, resulting in rapid systemic absorption o the drug. Aging men sometimes develop symptoms and signs o hypogonadism, such as decreased energy, decreased libido, gynecomastia, decreased muscle mass, and acial hair growth. Recent guidelines recommend that androgen replacement therapy be o ered to men only with consistent symptoms and signs o hypogonadism and low plasma testosterone levels (3. Testosterone should not be administered to men with prostate cancer because it may stimulate growth o the tumor. A novel approach is to combine parenteral testosterone replacement with androgen receptor blockade using utamide. The testosterone replacement stimulates an increase in muscle mass, even in the presence o androgen receptor blockade. However, utamide does block prostate enlargement caused by testosterone replacement. In one survey, approximately 5% o high school athletes reported that they had used androgen supplements. Almost every type o androgen has been abused in an attempt to enhance athletic per ormance, including the adrenal hormone precursors androstenedione and dehydroepiandrosterone. Covert laboratories are continuously inventing new synthetic androgens that have not yet been recognized by standard drug testing programs. These "designer" androgens are meant to enhance athletic per ormance and to be undetectable by sports regulatory authorities. Pharmacologic doses o androgens suppress the hypothalamic-pituitary-reproduction axis, resulting in suppression o testicular unction, decreased sperm production, and impaired ertility. Musculoskeletal and prostate e ects o combined testosterone and f nasteride administration in older hypogonadal men: a randomized controlled trial. Diagnosis and treatment o polycystic ovary syndrome: an Endocrine Society clinical practice guideline. Diabetes mellitus is clinically the most common disease o these endocrine axes, and the majority o the chapter is devoted to the physiology and pharmacology o insulin. Type 1 diabetes mellitus is caused by an absolute def ciency o insulin secretion, and type 2 diabetes mellitus is caused by insu f cient (or dys unctional) insulin secretion to overcome insulin resistance in target tissues. Medical students may be interested to note that Charles Best, a ourth-year medical student in Canada, had a signif cant role in the identif cation o insulin. Along with his mentor, Frederick Banting, Best isolated a pancreatic extract rom dogs that could reduce blood glucose in diabetic dogs and humans. Although the 1923 Nobel Prize in Medicine or Physiology was jointly awarded to surgeon Frederick Banting and physiologist J. Scattered within the exocrine tissue are nearly one million small islands o endocrine tissue that secrete hormones directly into the blood. Energy Homeostasis the storage and subsequent release o nutrients provides a homeostatic mechanism or sustained cellular nutrition in the absence o continuous eeding. What is the etiology of diabetes mellitus, and how is type 1 diabetes mellitus different from type 2 diabetes mellitus In addition to alleviating her polyuria and polydipsia, why is it important to control Mrs. Are there circumstances under which one parameter could be elevated and the other could be normal Insulin promotes the uptake and storage o glucose and other small, energy-containing molecules. The "counterregulatory" hormones oppose the actions o insulin and promote glucose release (Table 31-1).