By S. Givess. New England Conservatory of Music. 2019.

No wonder this large molecule poses entirely different challenges for research order sildigra 120mg with mastercard, devel- opment and production buy sildigra 25mg without prescription. Each of the amino acid residues in the protein erythropoietin is comparable to an aspirin molecule in size generic 120 mg sildigra with amex. Drugs from the fermenter 27 Proven methods The most important consequence of the size dif- for small molecules ference between traditional and biotechnological drugs relates to their structure. The three-dimen- sional shape of simple organic molecules, known in chemical parlance as small molecules, is essentially determined by fixed bonds between the individual atoms. As a result, traditional drugs are usually highly stable compounds that retain their three-dimensional shape in a wide range of ambient conditions. Traditional drugs are usual- ly easy to handle and can be administered to patients conve- niently in various forms such as tablets, juices or suppositories. It is true that many traditional drugs were originally derived from natural products. For example, healers used an extract of the leaves or bark of certain willow species to treat rheumatism, fever and pain hundreds of years before the Bayer chemist Felix Hoffmann reacted the salicylate in the extract with acetic acid in 1897 to form acetylsalicylic acid, a compound that is gentler on the stomach. The methods have been tried and tested for decades, and the drugs can be manufactured anywhere to the same standard and in any desired amount. Ster- ile conditions, which pose a considerable technical challenge, are rarely necessary. On the other hand, preventing the organic solvents used in many traditional production processes from damaging the environment remains a daunting task. Unstable structure Biopharmaceuticals require a far more elaborate of proteins production process. Most drugs manufactured by biotechnological methods are proteins, and pro- teins are highly sensitive to changes in their milieu. Their struc- ture depends on diverse, often weak, interactions between their amino-acid building blocks. These interactions are optimally coordinated only within a very narrow range of ambient condi- tions that correspond precisely to those in which the organism from which the protein is derived best thrives. Because of this, even relatively small changes in the temperature, salt content or pH of the ambient solution can damage the structure. This, in turn, can neutralise the function of the protein, since this de- pends on the precise natural shape of the molecule. Most of these mole- cules act as vital chemical Detecting signals: interferon gamma and its receptor messengers in the body. The target cells that receive and translate the signals bear special receptors on their surface into which the cor- responding chemical mes- senger precisely fits. If the three-dimensional shape of The signal protein interferon gamma (blue) is recognised by a the chemical messenger is specific receptor (left and right) located on the surface of its even slightly altered, the target cells. Interferon gamma as a biopharmaceutical is used to treat certain forms of immunodeficiency. The situation is similar for another group of therapeutic proteins, the antibodies. Their function is to recognise foreign structures, for which purpose they have a special recognition region whose shape pre- cisely matches that of the target molecule. Changing just one of the several hundred amino acids that make up the recognition region can render the antibody inactive. It is possible to produce antibodies to target any desired foreign or endogenous sub- stance. Modern biotechnology makes use of the technique to block metabolic pathways in the body involved in disease pro- cesses. Like other therapeutic proteins, antibodies must there- fore assume the correct molecular arrangement to be effective. Biopharmaceuticals: This structural sensitivity also causes problems biological instead of because proteins do not always automatically as- chemical production sume the required structure during the produc- tion process. Long chains of amino acids in solu- tion spontaneously form so-called secondary structures, arranging themselves into helical or sheetlike structures, for ex- ample. However, this process rarely results in the correct overall shape (tertiary structure) especially in the case of large pro- teins where the final structure depends on the interactions of several, often different, amino acid chains. During natural biosynthesis of proteins in the bodys cells, a se- ries of enzymes ensure that such protein folding proceeds cor- rectly. The enzymes prevent unsuitable structures from being Drugs from the fermenter 29 Diverse and changeable: the structure of proteins primary structure } A chain of up to twenty different amino acids (primary struc- ture the variable regions are indicated by the squares of dif- ferent colours) arranges itself into three-dimensional struc- secondary tures. The position of these secondary structures in rela- tion to one another determines the shape of the protein, i. Often, a number of proteins form func- tional complexes with quaternary structures; only when arranged in this way can they perform their intended func- tions. When purifying proteins, it is extremely difficult to retain such protein complexes in their original form. These strictly controlled processes make protein production a highly complex process that has so far proved impossible to replicate by chemical means. Instead, proteins are produced in and isolated from laboratory animals, microorganisms or special cultures of animal or plant cells. Natural sources limited Biological production methods do, however, have several disadvantages. The straightforward ap- proach, isolating natural proteins from animals, was practised for decades to obtain insulin (see article Beer for Babylon). But the limits of this approach soon became apparent in the second half of the 20th century. Not only are there not nearly enough slaughtered animals to meet global demands for insulin, but the animal protein thus obtained differs from its human counter- part. The situation is similar for virtually every other biophar- maceutical, particularly since these molecules occur in animals in vanishingly small amounts or,as in the case of therapeutic an- tibodies, do not occur naturally in animals at all. Most biopharmaceuticals are therefore produced in cultures of microorganisms or mammalian cells. Simple proteins can be 30 Little helpers: the biological production of drugs The bacterium Escherichia coli is relatively easy to cultivate. For complicated substances consisting of several proteins or for substances that have to be modified by the addition of non-protein groups such as sugar chains, mam- malian cells are used. To obtain products that are identical to their human equivalents, the appropriate human genes must be inserted into the cultured cells. These genetically manipulated cells then contain the enzymes needed to ensure correct folding and processing of the proteins (especially in the case of mam- malian cells) as well as the genetic instructions for synthesising the desired product. In this way a genetically modified cell is obtained which produces large quan- tities of the desired product in its active form. Biotech production: each But multiplying these cells poses a technological facility is unique challenge, particularly when mammalian cells are used to produce a therapeutic protein. Cells are living organisms, and they react sensitively to even tiny changes in their environment. From the nutrient solution to the equip- ment, virtually every object and substance the cells touch on their way from, say, the refrigerator to the centrifuge can affect them.

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Safety and efficacy of tramadol in the treatment of premature ejaculation: a double-blind order 120 mg sildigra with visa, placebo-controlled buy sildigra 120 mg without a prescription, fixed-dose order sildigra with amex, randomized study. It is very important that the physician warns the patient that sexual intercourse is a vigorous physical activity, which increases heart rate as well as cardiac work. Any successful pharmacological treatment for erectile failure demands a degree of integrity of the penile mechanisms of erection. Further studies of individual agents and synergistic activity of available substances are underway. The search for the ideal pharmacological therapy for erectile failure aims to fulfil the following characteristics: good efficacy, easy administration, freedom from toxicity and side-effects, with a rapid onset and a possible long-acting effect. Premature ejaculation is another very common male sexual dysfunction, with prevalence rates of 20% to 30%. Physical examination and laboratory testing may be needed in selected patients only. Behavioural techniques may be efficacious as a monotherapy or in combination with pharmacotherapy, but they can be difficult to perform. This information is publically accessible through the European Association of Urology website. This guidelines document was developed with the financial support of the European Association of Urology. E1, which affect penile blood flow, can result in Impotency remains largely unrecognized simply prolonged erections necessitating other drug therapy because most men do not discuss sexual problems to counter act its efects. In addition, many physicians do can cause burning and eventual fbrosis of the penis. Primary causes are rare and may be belief, ageing is not an inevitable cause of impotency. Sex disorders of the male are classifed into disorders of A man may have a sexual problem if he: sexual function, sexual orientation and sexual behaviour. Such factors include Is unable to have an erection sufcient for pleasurable neural activity, vascular events, intracavernosal nitric oxide intercourse system and androgens. Sexual dysfunction in men refers to repeated inability to achieve normal sexual intercourse. While sexual dysfunction rarely threatens physical health, it can take a heavy psychological Disorders of Desire toll, bringing on depression, anxiety and debilitating Disorders of desire can involve either a deficient or feelings of inadequacy. Dysfunctions that can neglected by the healthcare team who strive more with the occur during the desire phase include: technical and more medically manageable aspects of the i. It results in a complete or females and thus, it is conventional to focus more on male almost complete lack of desire to have any type of sexual sexual difculties. Generally, wide range of complex sexual behaviours that have a prevalence of about 10% occurs across all ages. These have contributed in no small measure to everything else) and sexual impulsivity (failure to resist prevalence of sexual dysfunction in the aged. These changes Disorders of Ejaculation were highly correlated with both weight loss and activity There exists a spectrum of disorders of ejaculation ranging levels. However, it should be emphasized that controlled from mild premature to severely retard or absent ejaculation. This procedure may lead to treatmentspecifc sequelae afecting healthrelated QoL. Cavernosal impact on the quality of life (QoL) of suferers and their nerve injury induces pro-apoptotic (loss of smooth muscle) partners and families. These changes may also be caused by Epidemiology poor oxygenation due to changes in the blood supply to Recent epidemiological data have shown a high prevalence the cavernosa. Although further studies are hyperprolactinaemia), which can be potentially cured with needed to make clear the role of lifestyle changes in the specifc treatment. Testosterone is associated with the preservation of smooth muscle within replacement is contraindicated in men with a history the human corpora cavernosa. Daily sildenafl also resulted of prostate carcinoma or with symptoms of prostatism. Adverse events are generally mild in nature, surgery for veno-occlusive dysfunction is no longer selflimited by continuous use. The recommended starting dose is 10 mg and should be adapted according to the patients Firstline Therapy response and sideefects. Afer 12 weeks in a doseresponse arterial blood fow leading to smooth muscle relaxation, study, improved erections were reported by 66%, 76% and vasodilatation and penile erection. Efcacy initiators of erection and require sexual stimulation to was confirmed in post-marketing studies. To date, no data are available from double or tripleblind The recommended starting dose is 50 mg and should be multicentre studies comparing the efcacy and/or patient adapted according to the patients response and sideefects. Adverse events drug will depend on the frequency of intercourse (occasional are generally mild in nature and self-limited by continuous use or regular therapy, 3-4 times weekly) and the patients use. Afer 24 weeks in a doseresponse study, improved is short- or long-acting, possible disadvantages and how erections were reported by 56%, 77% and 84% of men taking to use it. It is administered in 10 and carried out of both studies in 234 patients for 1 year and 20 mg doses. Tadalafl, 5 mg once daily, was | April-June 2012 | International Journal of Green Pharmacy 114 Saxena, et al. Blood- placebo plus ondemand vardenafl 10 mg for 24 weeks, fowinduced fuid shear stress in the penile vasculature followed by 4 weeks of wash-out. Most potent herbal aphrodisiacs are available and have Other studies (open-label, randomised, cross-over studies litle or very litle side efects [Table 1]. However, when patients have the choice, it seems that with various mechanisms of action,[27] but today there is no they prefer on-demand rather than continuous therapy. Table 1: Herbal approaches in the treatment of erectile dysfunction name of plant common name Family Part used Reference Allium sativum L. Ex Heim Black aphrodisiac Rubiaceae Stem [35] Myristica fragrans Houtt Nutmeg Myristicaceae Seed [36] Panax ginseng Ginseng Araliaceae Root [37] Turnera aphrodisiaca Damiana Trneraceae Areal part [38] Withania somnifera Linn. Psychosexual dysfunction in chronic renal failure: An depressant) associated with prolonged erections and overview. Impotence and its medical and psychosocial mechanism of action (though it may possibly act as a correlates: Results of the Massachusets Male Aging Study. Modifable risk factors and erectile dysfunction: Can yohimbine and trazodone have a similar efcacy to lifestyle changes modify risk. Erectile dysfunction afer radical prostatectomy: intercourse) of about 50%, but possible carcinogenesis in Hemodynamic profles and their correlation with the recovery of erectile function. Venous impotence: Pathophysiology, data on Red Korea ginseng suggested it might have a diagnosis and treatment. Modifable risk factors and erectile dysfunction: Can lifestyle changes modify risk.

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Eur Neurol comparison of the effects of nebivolol and atenolol 1994 sildigra 50mg with visa;34(3):155-157 purchase 120mg sildigra visa. The reliability of clinical and biochemical assessment in symptomatic late-onset Brake M buy sildigra 25 mg on-line, Loertzer H, Horsch R et al. Eur J effective treatment for lower urinary tract symptoms secondary Endocrinol 1997;137(1):34-39. Erectile dysfunction and of idiopathic erectile dysfunction in men with the priapism. A comparative review of apomorphine formulations for erectile dysfunction: Recommendations for use in the elderly. Hyperprolactinemia and sexual function in phosphodiesterase type 5 inhibitors for erectile dysfunction. Am J Cardiol associated with testosterone replacement in middle- 2003;92(9A):26M-36M. Relationship between patient self-assessment of erectile dysfunction and the sexual health inventory Brooks D P, Giuliano F. Sexual function does testosterone administration and visual erotic stimuli on not change when serum testosterone levels are nocturnal penile tumescence in normal men. Systematic review of randomised controlled trials of sildenafil (Viagra) in the treatment of male Carey M P, Johnson B T. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: A randomized Carey Michael P, Wincze John P, Meisler Andrew W. Erratum: Erectile response with vardenafil in sildenafil nonresponders: A Chen J, Greenstein A, Kaver I et al. Effect of evaluation better predicts the degree of erectile dysfunction than oral administration of high-dose nitric oxide donor L- the response to intracavernous alprostadil testing. The additive erectile recovery effect of brain-derived Cawello W, Schweer H, Dietrich B et al. Pharmacokinetics of neurotrophic factor combined with vascular prostaglandin E1 and its main metabolites after intracavernous endothelial growth factor in a rat model of neurogenic injection and short-term infusion of prostaglandin E1 in patients impotence. Vacuum constriction Efficacy and safety of on- demand oral tadalafil in the device and topical minoxidil for management of impotence. Cavernous nerve Prevalence of erectile dysfunction in Asian reconstruction to preserve erectile function following non-nerve populations: A meta-analysis. Prevalence of hypogonadism in the aging Chatterjee R, Andrews H O, McGarrigle H H et al. Cavernosal male and male erectile dysfunction in Asia-Pacific arterial insufficiency is a major component of erectile countries. Management of erectile dysfunction by combination therapy with testosterone and sildenafil in recipients of high-dose Chew K K, Stuckey B G A. Nuclear penogram: Non-invasive technique to monitor and record effect of Chew K K, Stuckey B G A, Thompson P L. Erectile pharmacologically-induced penile erection in impotence dysfunction, sildenafil and cardiovascular risk. Management of premature ejaculation -- a (Viagra) in patients with cardiovascular disease. Circulation comparison of treatment outcome in patients with and 1999;99(1):168-177. Efficacy and after medical therapy for prolactin and adrenocorticotropic safety of sildenafil citrate in the treatment of erectile hormone co-producing pituitary macroadenoma without dysfunction in patients with ischemic heart disease. Effect of sildenafil on renin secretion in Contreras L N, Masini A M, Danna M M et al. Ann Chir Gynaecol Canadian Journal of Psychiatry - Revue Canadienne de 1996;85(3):247-250. Randomized clinical trial hyperprolactinemia in male patients consulting for comparing transurethral needle ablation with transurethral sexual dysfunction. Br J Sex Med 2007;4(5):1485 resection of the prostate for the treatment of benign prostatic 1493. Can Pharm J screening of hypogonadism in patients with sexual 2004;272(7299):608-610. Tolerability and safety profile of sildenafil citrate (Viagra) in Latin American patient populations. Caverject, a new licensed prostaglandin preparation for use in erectile dysfunction. Patient-partner satisfaction with intracavernous medication supported Collazos J, Martinez E, Mayo J et al. Journal of Acquired Immune Deficiency Syndromes: Urology & Nephrology 1999;31(2):257-262. Comparison of the New erectile dysfunction by an external ischiocavernous Cardioselective Beta-Blocker Nebivolol with Bisoprolol in muscle stimulator. Acute and prolonged effects of sildenafil on brachial artery flow- Dang G, Matern R, Bivalacqua T J et al. Treatment of male intracavernous injections and penile prostheses in impotence: a new option. Influence of the method of papaverine and phentolamine intracavernosal intracavernous injection on penile rigidity: a possible injection. Design and auto-injector system: a multicentre double-blind evaluation of nitrosylated alpha-adrenergic receptor antagonists placebo-controlled study. Dutasteride: A novel dual inhibitor of 5a-reductase for benign prostatic Degirmenci B, Acar M, Albayrak R et al. Expert Opin Pharmacother citrate (Viagra) on renal arteries: An evaluation with Doppler 2005;6(2):311-317. Time/duration sildenafil, vardenafil and tadalafil in erectile effectiveness of sildenafil versus tadalafil in the treatment of dysfunction. Expert Opin Pharmacother 2005;6(1):75 erectile dysfunction in male spinal cord-injured patients. Int J Impot subjective and physiological measures of mechanically produced Res 1993;5(2):97-103. Beneficial effects of switching from beta-blockers to nebivolol Denisov M F, Davis J M, Brecher M. Asian adverse events in patients treated with risperidone [8] (multiple J Androl 2006;8(2):177-182. Visual loss associated with erectile dysfunction Ende A R, Lo Re V, DiNubile M J et al. Acupuncture in the treatment of psychogenic erectile dysfunction: first Durackova Z, Trebaticky B, Novotny V et al.

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The Academy promotes research on issues important for our future society as well as on fundamental scientific problems purchase 25 mg sildigra visa. Stimulating the dialogue between scholars and the public is of utmost importance to the Academy buy sildigra 25 mg visa. The Academy of Sciences and Humani- ties in Hamburg is member of the Union of German Academies of Sciences and Humanities discount sildigra 25 mg amex. The Leo- poldina represents the German scientific community in international committees and pursues the advancement of science for the benefit of humankind and for a better future. Publishers Akademie der Wissenschaften in Hamburg Edmund-Siemers-Allee 1, 20146 Hamburg Deutsche Akademie der Naturforscher Leopoldina e. Elke Senne Composition/Layout: Hubert Eckl, KommunikationsDesign Foreword "Why do we need new antibiotics (and dont get them)? Fewer and fewer antibiotics are available for an increasing number of infections caused by antibiotic-resistant bacteria. With the statement "Antibiotics research: problems and perspectives", the Academy of Sciences and Humanities in Hamburg and the German National Academy of Sciences Leopoldina take up this topic, which is relevant to society at large and to both human and veterinary medicine. How can future research contribute to solving the problem of resistance and the lack of new antibiotics? What regulatory and nancial framework conditions are required to ensure that research results nd their way into widespread application more quickly? They also encourage measures to respond effectively to the challenges of increasing antibiotic resis- tance. The focus is on aspects of research, but societal and legal issues are also mentioned. Jrg Hacker President of the Academy Spokesman of the working group President of the German of Sciences and Humanities in "Infection Research and Society", National Academy of Hamburg Academy of Sciences and Humanities Sciences Leopoldina in Hamburg Contents Foreword 5 Summary 9 1 Introduction 13 2 Antibiotic resistance and development status quo 17 2. They are the foundation for the treatment of bacterial infections in humans as well as animals. However, two developments are making it more and more difcult to treat bacterial infections successfully. On the one hand, in recent years there has been an increasing number of antibiotic- resistant pathogens, both in human medicine as well as veterinary medicine. On the other hand, the number of new antibiotics developed since the 1970s has steadily decreased. The search for new active agents and targets can only succeed if research continues on the causes and mechanisms of antibiotic resistances and if measures for the responsible use of antibiotics are effective. To reduce the spread of resistances and to develop new antibiotics, rstly more research must be carried out and, secondly, framework conditions are necessary which will allow research discoveries to be implemented effectively. Amongst other things, the recommendations emphasise the importance and the potential of innovative technologies for researching antibiotic resistances and of new active agents. Clinical studies and translational approaches should be pur- sued more intensively and the prerequisites for their execution and nancing must be improved. In view of the urgency of the resistance problem, a rethinking of the certication conditions for new active agents is needed. Last but not least, socio-economic aspects should form an integral part of the research. Increased basic research: A broad range of basic research on the origin, spread and pre- ven-tion of resistance as well as on the development of new antibiotics is indispensable. Improvement of the structural conditions for innovations: Of particular importance is the development of a stable product pipeline. One necessary condition is the maintenance and expansion of infrastructure for the research and development of new antibiotics. In addition, it is vital to facilitate and strengthen cooperation between industry and acade- mic research in order to more effectively link basic research resources with the diverse re- quirements of pharmaceutical product development. It is also essential to continue the international coordination of measures between governments and industry. Facilitation for clinical research: Clinical studies on the duration of effective antibiotic therapies, on the use of different therapy regimes and the effect on the development of re- sistances should be increased and funded. Further development of regulatory framework conditions: Due to the development of re- sistances, the proof of superiority of new antibiotics versus currently available substances is too high a treatment aim. In future, a certificate of efficacy should be sufficient as the treatment aim for approval of new therapy principles and new substance classes in particular. Restriction of antibiotics use in veterinary medicine and plant protection: Antibiotics should, if possible, only be allowed for targeted use after clinical diagnosis and based on the results of resistance tests. Consistent implementation of surveillance and antibiotics consumption records and re- duction as well as promotion of education and training: Regular surveillance of the resis- tance rates of important pathogens should be carried out on all levels: locally to globally and across the hospital, outpatient and animal husbandry sectors. Increased socio-economic research: The socio-economic, legal and ethical framework con- ditions for the development of new antibiotics should be investigated more, hindrances should be identified and solutions found. Measures should be evaluated more on a for- ward-looking as well as a retrospective basis. Research activities should cover a wide range of topics and methods in order to approach the prob- lems of antibiotics resistances from various sides and to allow the widest possi- ble approach to the search for new active agents. They are the foundation for the treat- ment of bacterial infections in humans as well as animals. Without antibiotics, many of the now widely used therapies and medical procedures such as chemotherapy, organ transplants, joint operations or the provision of care to premature babies would not be possible. On the one hand, in recent years we have seen an increasing number of antibiotic-resistant pathogens, both in human medi- cine as well as veterinary medicine. On the other hand, the number of new an- tibiotics developed since the 1970s has decreased. In particular, there are not enough antibiotics for multidrug-resistant gram-negative pathogens for every- day clinical use. It is to be feared that this decit will become more and more problematic in the years to come. Current estimates suggest that around 25,000 patients die of the consequences of an antibiotic-resistant bacterial infection. There is the fear that the lack of ef- fective antibiotics seriously threatens further progress in many areas of medi- cine such as in intensive care, transplant medicine, oncology and surgery. Box 1: Antibiotic resistance and its causes Antibiotics are substances that inhibit the growth of bacteria by blocking vital metabolic path- ways or the synthesis of macromolecules. Due to genetic, structural and metabolic charac- teristics of individual bacterial families, there is no omnipotent antibacterial active principle. Many antibiotic-specific gene clusters are located in close pro- ximity to areas of genes that encode resistance. Both the genes for antibiotic production as well as the resistance-specific genes are often transferred through horizontal gene transfer within bacterial species, but also across species boundaries. How often and how quickly resistance is selected varies greatly between the different bacte- rial species. Some species that are already equipped with a so-called intrinsic resistance to many antibiotics acquire new resistance genes very easily. This is why multiple-resistant pa- thogens arise as described increasingly for staphylococci or pseudomonads.

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Many patients will describe their stool as constipated buy sildigra 100mg with amex, meaning that the stool is hard or in pellets (scybalous) purchase genuine sildigra line, while other patients may have a stool frequency that falls within the normal range yet feel that their bowels have not completely emptied purchase 50 mg sildigra amex. In Western culture the most frequent cause of constipation is an inadequate intake of dietary fiber. The concept of fiber has become quite confusing to many persons, with the increased emphasis on oat fiber for elevated cholesterol treatment. Cereal grain fibers that have more insoluble fiber (as opposed to soluble oat bran fiber) are best to increase stool frequency. The insoluble fiber should be added gradually over 8 to 12 weeks up to a maximum daily dose of about 30 g. Many patients who are constipated continue to pass dry, hard stool, despite an increase in dietary fiber, because they do not increase the water content of their diet. This possibility of organic disease should always be considered in a patient with the new onset of constipation after the age of 40 years (when the incidence of colon cancer rises). Not infrequently, patients with an underactive thyroid will present with the primary symptom of constipation. Hypercalcemia rarely reaches levels that produce constipation, but should always be considered, since this electrolyte disturbance can be a life-threatening disorder. Constipation in this setting is always resistant to therapy until the hypercalcemia is treated. This is due to the functional obstruction from spasm caused by the inflammation First Principles of Gastroenterology and Hepatology A. The colon more proximally continues to produce formed stool, which cannot pass easily through the inflamed rectum. Proctitis will usually be associated with excess mucus production, with or without blood in the stool, and proctosigmoidoscopy will diagnose this entity. Another cause of constipation is diabetes mellitus, which results in impaired colonic motility due to dietary factors, as well as autonomic neuropathy of the enteric nervous system, seen with long-standing diabetes mellitus. Patients with diabetes may also develop diarrhea, which again has been linked to the autonomic neuropathy. This is presumed to be secondary to reduced colonic activity due to a low fiber intake. Severe cardiopulmonary diseases of whatever cause that limit activity can also result in constipation. Neurologic disorders that cause the patient to have a reduced ability to ambulate can have constipation as a feature. Some patients with diseases of the nervous system may have impaired awareness of rectal distention to signal a need to defecate, and nerve dysfunction (both peripheral and central) may impair normal colonic propulsion. Although constipation with fecal impaction occurs they may complain of diarrhea or soiling due to overflow incontinence of stool from the fecal impaction of the rectum inhibiting the normal resting tone of the anal sphincter. Not surprisingly, many of these patients may respond to laxative therapy after the fecal impaction is removed, since this prevents the recurrence of the fecal impaction with overflow incontinence. Some patients can aggravate longstanding constipation with regular laxative abuse, and some theoretical concerns remain that this practice may indeed damage the normal innervation of the colon, rendering it atonic and nonfunctional. The physical findings are often minimal in the majority of patients with constipation, but specific secondary causes must be looked for. Signs of hypothyroidism may be present; signs of dehydration should be sought, as this may be an early indicator of hypercalcemia. Thorough cardiopulmonary and neurologic examinations are necessary to pick out associated diseases that may be treated, thereby improving the patients overall health, and thus improving bowel function and the quality of their lives. On abdominal examination, inspection for evidence of distention, hyperperistalsis or masses may point t the source of the impaired stool passage. Localized tenderness of the abdomen must be noted, along with any evidence of liver, spleen or renal enlargement. A complete digital rectal examination and proctosigmoidoscopy is required in any patient with constipation so that the presence or absence of a fecal impaction, dilation or enlargement of the rectum or the presence of proctitis can be determined. Pelvic Floor Dyssynergia The majority of patients with constipation have a form of irritable bowel Syndrome. But, there is a small subgroup of patients who may have a specific disorder in colonic and/or anorectal function that produces constipation. These patients can present major therapeutic dilemmas, and warrant further investigation in specialized coloproctology units. The Anal Canal The anal canal begins where the terminal portion of the large bowel passes through the pelvic floor muscles, and it ends at the anal verge. This is felt posteriorly and laterally as the anorectal ring on digital examination. In approximately the mid-anus there is a rolling line of demarcation called the dentate line. Above the line is columnar epithelium; below it is squamous epithelium without appendages (the anoderm). As the rectum narrows into the anal canal, the mucosa develops 6 to 14 longitudinal folds, Morgagnis columns. Blood is supplied to the anus via the inferior rectal artery, a branch of the internal pudendal artery. The superior rectal vein drains the upper part of the anal canal via the inferior mesenteric vein to the portal vein. The middle and inferior rectal veins drain the upper and lower anal canal into the systemic circulation via the internal iliac and internal pudendal veins, respectively. Lymphatic drainage above the dentate line is via the superior rectal lymphatics (accompanying the superior rectal vessels) to the inferior mesenteric nodes, and laterally along the middle and inferior rectal vessels to the internal iliac nodes. Lymphatic drainage from the anal canal below the dentate line may be in a cephalad or lateral direction, but is primarily to the inguinal nodes. Sympathetic innervation is from the first three lumbar segments via the preaortic plexus. Fibers from the preaortic plexus ultimately join the nervi erigentes to form the pelvic plexuses. Above the level of the inferior rectal nerve sensory distribution, there are only dull perceptions, mediated by parasympathetic fibers. Anorectal Spaces Around the anorectum there are a number of potential spaces filled with fat or connective tissue. The perianal space is at the anal verge, and is continuous with the intersphincteric space. The inferior boundary is the skin of the perineum, and the apex is the origin of the levator ani from the obturator fascia. Posteriorly is the gluteus maximus muscle, and anteriorly the transverse perinei muscles.