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The information will enable which occur at higher rates among people who treatment providers to compare the benefits inject drugs than in the general population generic cialis extra dosage 100mg erectile dysfunction drug samples. It details the histo- considerations in determining individual ry of the use of opioids in the United States; the dosages buy cialis extra dosage mastercard erectile dysfunction from smoking. Chapter 3 purchase cialis extra dosage 50 mg otc impotence cures natural, Pharmacology of Medications Chapter 6 discount cialis extra dosage 40 mg overnight delivery thyroid causes erectile dysfunction, PatientñTreatment Matching: Types Used To Treat Opioid Addiction, reviews the of Services and Levels of Care, describes a pharmacology and clinical applications of the multidimensional, clinically driven strategy medications used for treating opioid addiction. Patientñtreatment Most patients need more frequent, intensive matching involves individualizing the choice services in the acute phase, careful monitoring and application of treatment resources to each and diversified services during rehabilitative patientís needs, abilities, and preferences. The and supportive-care phases, and less frequent chapter describes alternative types of treat- services in subsequent phases. It explains how a comprehensive treat- elements of a treatment plan and the planning ment program improves patient retention in process, including the roles of counselor and treatment and the likelihood of positive treat- patient, the importance of cultural and linguistic ment outcomes. Patients who receive regular, competence, motivation for treatment, and the frequent, integrated psychosocial and medical need for a multidisciplinary team. Counseling phases are conceptualized as parts of a dynam- services are integral to comprehensive mainte- ic continuum of patient progress toward nance treatment and can be behavioral, intended treatment outcomes. After an orientation to introduce should be part of any comprehensive treatment patients to the program, successive treatment program. The chapter describes ways to phases include (1) the acute phase, during increase patient retention and avoid adminis- which patients attempt to eliminate illicit-opioid trative discharge. Administrative discharge use and lessen the intensity of other problems usually results in rapid relapse and may lead to associated with their addiction, (2) the rehabili- incarceration or death. Clear communication tative phase, during which patients continue to and awareness on the part of both patients address addiction while gaining control of other and staff members help avoid administrative major life domains, (3) the supportive-care discharge. Several drug- gradually reduce and eliminate opioid treat- testing methodologies are available or in devel- ment medication, and (6) the continuing-care opment, including tests of urine, oral fluid, phase, in which patients who have tapered blood, sweat, and hair. The chapter describes from treatment medication continue regular the benefits and limitations of these tests. The chapter focuses on methadone, acute and chronic medical problems and to which has been accepted for treating opioid perform periodic reassessments. To alcohol and certain sedatives, have a poten- develop and retain a stable team of treatment tially lethal effect when combined with an personnel, program administrators must opioid agonist or partial agonist medication. Implementing disulfiram, contingency management, dose community relations and community education adjustments, and counseling. Finally, the Disorders, addresses issues for patients who chapter provides a framework for gathering have substance use and co-occurring mental and analyzing program performance data. These patients often exhibit Program evaluation contributes to improved behaviors or experience emotions that inter- treatment services by enabling administrators fere with treatment and require special to base changes in services on evidence of what interventions. Evaluation also serves as a way to prevalence of co-occurring disorders, educate and influence policymakers and public screening and diagnosis of these disorders, and private payers. Types of tions among selected terms and phrases are treatment can include medical maintenance, discussed below. Abstinence does not refer to experience its positive effects or to avoid to withdrawal from legally prescribed mainte- negative effects associated with withdrawal nance medications for addiction treatment (for from that substance. At present, the most that research on opioid addiction and treatment is can be said is that there seems to be a clarifying what works to improve treatment specific neurological basis for the com- outcomes, with an emphasis on accelerating the pulsive use of heroin by addicts and incorporation of evidence-based methods into that methadone taken in optimal doses treatment. They found that genet- of Treatm ent ic, personal-choice, and environmental factors played comparable roles in the etiology and Opioid addiction as a m edical course for these disorders and that rates of relapse and adherence to medication were simi- disorder lar, although substance addiction often was Discussions about whether addiction is a medi- treated as an acute, not chronic, illness. Their cal disorder or a moral problem have a long review of outcome literature showed that, as history. For decades, studies have supported with the other disorders, substance addiction the view that opioid addiction is a medical dis- has no reliable cure but that patients who com- order that can be treated effectively with medi- ply with treatment regimens have more favor- cations administered under conditions consis- able outcomes. Fewer than 30 percent of tent with their pharmacological efficacy, when patients with asthma, hypertension, or diabetes treatment includes comprehensive services, adhered to their medication regimens, pre- such as psychosocial counseling, treatment for scribed diets, or other changes to increase their co-occurring disorders, medical services, voca- functional status and reduce their risk of symp- tional rehabilitation services, and case manage- tom recurrence. For ing neurological and endocrinologic example, patients who were older and processes in patients whose endogenous employed with stable families and marriages ligand-receptor function has been were found to be more likely to comply with deranged by long-term use of powerful treatment and have positive treatment results narcotic drugs. W hy some persons who than were younger, unemployed patients with are exposed to narcotics are more less stable family support. Treatment also was similar to such conditions as diabetes, hyper- associated with a significant reduction, but not tension, and asthma. For example, W oody and necessarily cessation, of drug use for many Cacciola (1994) found that the risk of relapse individuals. Similar findings on the positive for a person who was opioid addicted was high- health outcomes associated with maintenance est during the first 3 to 6 months after cessa- treatment of opioid addiction, regardless of tion of opioid use. This risk declined for the whether abstinence was attained, were seen in first 12 months after cessation and continued to studies finding that methadone maintenance decrease but at a much slower rate. The goal is always reducing or opioid addiction with maintenance medication, eliminating the use of illicit opioids and other along with other treatment services for related illicit drugs and the problematic use of pre- problems that affect patientsí motivation and scription drugs. Conversely, dis- The medical community recognizes that opioid continuation of maintenance medication often addiction is a chronic medical disorder that results in dropout from other services and a can be treated effectively with a combination of return to previous levels of opioid abuse, with medication and psychosocial services. After hearing from experts and C, and tuberculosis (see chapter 10) and to and the public and examining the literature, increase compliance with medical, psychiatric, the panel concluded that ì[opioid addiction] is and prenatal care (Chaulk et al. Recent data on ed with significant benefits for the patient and buprenorphine indicate that treatment with this societyî (National Institutes of Health 1997b, medication, like methadone, has similar positive p. It called for ìa commitment to Viewing opioid addiction as a medical disorder offer effective treatment for [opioid addiction] is consistent with the idea that treatment of to all who need itî (p. For through increased funding, less restrictive 4 Chapter 1 regulation, and efforts to make treatment avail- addiction. For example, many States Buprenorphine is have removed restrictions on the length of time used to treat individu- tion is a chronic that patients may remain in treatment. These medications are (Substance Abuse and Mental Health Services discussed in chapter 3. A designated medication unit tive treatment medications for chronic opioid Introduction 5 (e. Although important strides have been made, much remains to be done to improve and Based on the framework provided by the Drug expand treatment and to address the stigma Addiction Treatment Act of 2000 (21 United that affects patients and programs. From 1995 to 2002, the rate among chronically or occasionally use heroin in the youth ages 12 to 17 increased from 0. For people Abuse and Mental Health Services who abuse opioid medications normally Administration 2003c). Prom oting Evidence-Based Lack of funding for services remains a significant barrier to treatment. The Rikers Island jail facility in New York City has been providing inmates access to methadone treatment since Com bating Stigm a 1987 (National Drug Court Institute 2002). For almost a century, the predominant view of Rhode Island jail facilities offer a 30-day opioid addiction has been that it is a self- dose-tapering program. Use of methadone and other therapeutic medications has been viewed Prom oting Com prehensive traditionally as substitute therapyómerely Treatm ent replacing one addiction with another and the In its 1999 publication, Principles of Drug treatment of choice for those too weak to over- Addiction Treatment: A Research-Based Guide, come temptation. Fortunately, positive changes are munity institutions, affecting the attitudes of occurring in each area. It negative stereotypes discourages them from entering treatment and effective skills for and media stories. It cre- Managers and staff ates a barrier for those trying to access other working with the members should parts of the health care system.

Thus quality cialis extra dosage 200 mg male erectile dysfunction icd 9, the incidence of an X-linked reces- sive disease in the male portion of a population is a direct estimate of the gene frequency in the population order cialis extra dosage canada pump for erectile dysfunction. Therefore cheap 50 mg cialis extra dosage with mastercard erectile dysfunction pump uk, the chance that the two related half first cousins have the same disease gene purchase cialis extra dosage on line amex erectile dysfunction pills cape town, is 1/2 X 1/2 X 1/2 X 1/2, or (112)4. The chance that two heterozygous carriers of an auto- somal recessive trait will produce a homozygous affected child is one in 4, or ~. The total probability of these events happening together then is (112)4 X ~, or 1/64. In this example, the disease frequency, q2, is 1/100, and the allele frequency, q, is 1/10, or 0. Using the assumption that the normal allele frequency, p, is about 1 is not necessarily valid. With the application of the Hardy-Weinberg principle to this auto- somal recessive disease, if 1/100 individuals are affected in a population, then q2 = 1/100 and q = 1/10, or 0. These alterations may involve the presence of extra chromosomes or the loss of chromosomes. Chromosome abnormalities are seen in approximately 1 in 150 livd births and are the leading known cause of mental retardation. It is diploid, showing both copies of each autosome, the X and the Y chromo- some. Chromosomes are ordered according to size, with the sex chromosomes (X and Y) placed in the lower right portion of the karyotype. Metaphase chromosomes can be grouped according to size and to the position of the centromere, but accurate identification requires staining with one of a variety of dyes to reveal characteristic banding patterns. Chromosome banding To visualize chromosomes in a karyotype unambiguously, various stains are applied so that banding is evident. G-banding reveals a pattern of light and dark (G-bands) regions that allow chromosomes to be accurately identified in a karyotype. Cytoge~etics Chromosome abnormalities in some cases can be identified visually by looking at the banding pattern, but this technique reveals differences (for instance, larger deletions) only to a resolu- tion of about 4 Mb. Submetacentric chromosomes have the centromere displaced toward one end (for example, chromosome 4). In these chro- mosomes, the p arm contains little genetic information, most of it residing on the q arm. Only the acrocentric chromosomes are involved in Robertsonian translocations, which will be discussed in this chapter. Gametes (sperm and • Triploid (69 chromosomes): egg cells) are euploid cells that have 23 chromosomes (one member of each pair); they are said to be haploid. Most somatic cells are diploid, containing both members of each pair, or 46 rare lethal condition chromosomes. Two types of euploid cells with abnormal numbers of chromosomes are seen in • Tetraploid (92 humans: triploidy and tetraploidy. Triploidy refers to cells that contain three copies of each chromosome (69 total)! Triploidy, which usually occurs as a result of the fertilization of an ovum by two sperm cells, is common at conception, but the vast majority of these conceptions are lost prenatally. These babies have multiple defects of the heart and central nervous system, and they do not survive. Tetraploidy refers to cells that contain four copies of each chromosome (92 total): This lethal condition is much rarer than triploidy among live births: Only a few cases have been described. Aneuploidy - Aneuploidy, a deviation from the euploid number, represents the gain (+) or loss (-) of a spe- cific chromosome. Two major forms of aneuploidy are observed: • Monosomy (loss of a chromosome) • Trisomy (gain of a chromosome) Autosomal aneuploidy Two generalizations are helpful: • All autosomal monosomies are inconsistent with a live birth. Trisomy is the most common genetic cause of spontaneous At least one X chromosome is required for survival. If more than one X chromosome is present, all but one will become a Barr body in each cell. The two important sex chromosome aneuploidies are Turner syndrome and Klinefelter syn- drome. Mosaicism in Turner Edema of wrists and ankles in newborn syndrome is thought to arise Cystic hygroma in utero resulting in excess nuchal skin and "webbed" neck in early embryogenesis by Primary amenorrhea mechanisms that are not Coarctation of the aorta or other congenital heart defect in some cases completely understood. The original cell is diploid for all chromosomes, although only one homolo- gous pair is shown in the figure for simplicity. When fertilization occurs, the conception will be a trisomy 21 with Down syndrome. The other gametes with no copy of chromosome 21 will result in conceptions that are monosomy 21, a condition incompatible with a live birth. In this case, the sister chromatids of a chromosome (for example, chromosome 21) fail to segregate (disjoiri). When fertilization occurs, the conception will be a trisomy 21 with Down syndrome. One gamete has no copy of chromosome 21 and will result in a conception that is a monosomy 21. Clinical Correlate: Maternal Age, Risk of Down Syndrome, and Prenatal Diagnosis Surveys of babies with trisomy 21 show that approximately 90% to 95% of the time, the extra copy of the chromosome is contributed by the mother (similar figures are obtained for trisomies of the 18th I and 13th chromosomes). I The risk of bearing a child with Down syndrome is less than 1/1,006 for women younger than 30. The I risk increases to about 1/400 at age 35, 1/100 at age 40, and 3-4% or more after age 45. There is no corresponding increase in risk with advanced paternal age; sperm cells are generated continuously throughout the life of the male. The increased risk of trisomy with advanced maternal age motivates more than half of pregnant women in North America to undergo prenatal diagnosis (most commonly, amniocentesis or chorionic villus sampling, discussed in Chapter 6). Down syndrome can also be screened by assaying maternal serum levels of a-fetoprotein, chorionic gonadotropin, and unconjugated estriol. This so-called triple screen can detect approximately 70% of fetuses with Down syndrome. At During Metaphase 2, each the end of Meiosis 1, each chromosome aligns individually daughter cell has one homolog. In Anaphase 2, sister chromatids migrate to opposite poles and each daughter cell gets one chromatid Figure 11-3-2A. Some alterations may result in a loss or gain of genetic material and are called unbalanced alterations; balanced alterations do not result in a gain or loss of genetic material and usually have fewer clinical consequences. As with other types of mutations, structural alterations can occur either in the germ line or in somatic cells.

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Wolf M order cialis extra dosage 40 mg on-line erectile dysfunction causes diabetes, Alavi A buy cheap cialis extra dosage 60mg on line impotence what does it mean, Mosnaim A: Posttraumatic stress disorder in Vietnam posttraumatic stress disorder buy genuine cialis extra dosage on line impotence vitamins. Clark R generic cialis extra dosage 100 mg otc impotence young men, Canive J, Calais L, Qualls C, Tuason V: Divalproex in posttraumatic phenelzine and imipramine for posttraumatic stress disorder. J Nerv Divalproex in the treatment of posttraumatic stress disorder: a Ment Dis 1991, 179:366-370. Onder E, Tural U, Aker T: A comparative study of fluoxetine, clinical series of adjunctive therapy. Chung M, Min K, Jun Y, Kim S, Kim W, Jun E: Efficacy and tolerability of anxiety disorders: a case series. Taylor F: Tiagabine for posttraumatic stress disorder: a case series of 7 disorder: a randomized open label trial. 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The medical errors of one century constitute the Annals of Ireland (relating the effects of the Black Death in popular faith of the next cialis extra dosage 40 mg line erectile dysfunction protocol free. I would rather that any white rabbit on earth Attributed should have Asiatic cholera twice than that I Symptoms which cannot be readily marshalled should have it just once order 200 mg cialis extra dosage with amex xarelto erectile dysfunction. Bartholomew’s Hospital purchase cialis extra dosage master card erectile dysfunction 55 years old, London Forrester Cockburn – The young gastroenterologist of today is only Professor Child Health 200mg cialis extra dosage impotence cures, Glasgow, Scotland happy if he can learn another endoscopic The origins of physical and mental health and technique, the excitement of the ’s has been disease lie predominantly in the early development replaced by the decade of the Peeping Tom. Lancet :  () Preface to Children’s Medicine and Surgery () Sir Stanley Clayton ? British obstetrician Jean Baptiste Coffinhal-Dubail Until the end of the last century, and indeed, until ? Comment at trial of Antoine Lavoisier, Paris () Obstetrics by Ten Teachers (th edn, p. Henry, Lord Cohen of Birkenhead Attributed – Men are not going to embrace eugenics. They are British physician going to embrace the first likely, trim-figured girl with limpid eyes and flashing teeth who comes All diagnoses are provisional formulae for action. Annals of the Royal College of Surgeons of England : Attributed  ()  . Charles Caleb Colton – Miscellanies, Aesthetic and Literary English clergyman, sportsman, author, and suicide Oh sleep! The poorest man would not part with health for Table Talk  July () money, but the richest would gladly part with all their money for health. Alex Comfort – Epilogue to The Plague of the Spanish Lady (influenza English physician and sexologist epidemic October –January ) The idea of the human responsibility of the doctor has been present since medicine was John Churton Collins – indistinguishable from magic. Collins) Positivism To understand a science it is necessary to know its Mortimer Collins – history. British writer Positive Philosophy (–) A man is as old as he’s feeling, A woman as old as she looks. Arthur Conan Doyle – The Unknown Quantity British crime novelist The true way to render age vigorous is to prolong Education never ends, Watson. Thomas and George Underwood, London () Cyril Connolly – (Description of the first ligation of the aorta in  for left British journalist and writer femoral aneurysm) The one way to get thin is to re-establish a purpose Sir (Vincent) Zachary Cope in life. The Unquiet Grave Pt I – See Zeta Obesity is a mental state, a disease brought on by boredom and disappointment. A mistake which is commonly made about Attributed neurotics is to suppose that they are interesting. Alan Coren – British humorist and writer Psychoanalysis is spending forty dollars an hour to squeal on your mother. The Act of God designation on all insurance Bartlett’s Unfamiliar Quotations policies; which means, roughly, that you cannot be insured for the accidents that are most likely to Sir Edward Cook – happen to you. Editor of the Westminster Gazette The Lady from Stalingrad Mansions ‘A Short History of Insurance’ The doctors all say we eat too much. Sir Astley Paston Cooper – The Great Doctors—A Biographical History of Medicine p. Dover Publications, New York English surgeon, Guy’s Hospital, London and President of () (original W. Ltd ) the Royal College Surgeons (Eng) (1827 and 1836) The best surgeon, like the best general, is the one Bill Cosby who makes the fewest mistakes. They are pale, skinny people who look half I do not believe, that from the first dawn of dead. Penguin Books, London ()   ·    Nathaniel Cotton – Quentin Crisp – British physician and poet English-born writer Would you extend your narrow span, Life was a funny thing that occurred on the way And make the most of life you can; to the grave. Would you, when medicines cannot save, The Naked Civil Servant Descend with ease into the grave; Calmly retire, like the evening light, Colin Cromar –? Every day, in every way, I am getting better and A History of Colostomy () better. As a doctor you would be well advised to acquaint Abraham Cowley – yourself with your patients’ interests if not their English poet prejudices. Persons living very entirely on vegetables are seldom of a plump and succulent habit. A Short View of the Importance and Respectability of the Quoted on ‘neurosis’ in The Oxford English Dictionary Science of Medicine. An address to the Philadelphia Medical Society,  February () Bishop Richard Cumberland – Creole proverb Bishop of Peterborough, England Sickness comes riding upon a hare, but goes away It is better to wear out than to rust out. The Duty of Contending for the Faith, by Bishop George Horne Sir James Crichton-Brown Marie Curie – – Polish-born doctor and scientist British physician and psychiatrist In science we must be interested in things, not in There is no short-cut to longevity. Vincent Sheean) The Prevention of Senility Thomas Curling – President of the Royal College of Surgeons of England Francis H. Lancet : – () (first description of a colostomy in Letter to his son, Michael Crick,  March () English)    · . Daar English Conservative politician Contemporary medical anthropologist My message to businessmen of this country when Medicine cannot be practised without reference to they go abroad on business is that there is one thing social and cultural values, even in this post- above all they can take with them to stop them modern era. Current British Minister of State for Health as quoted in The Anthropology : – () Observer  February () The strongest possible piece of advice I would give J. Chalmers Da Costa – to any young woman is: Don’t screw around, and Surgeon and writer don’t smoke. They have The Observer ‘Sayings of the Week’,  April () one trait in common, that is, a most unfortunate tendency to longevity. Dubois) keen disappointments, the baffling perplexities, There is only one ultimate and effectual preventive the dread responsibilities, and the numerous self- for the maladies to which flesh is heir, and that is reproaches of one who spends his life as an death. The Medical Career and Other Papers ‘Medicine at the The Trials and Triumphs of the Surgeon Ch. A man who has a theory which he tries to fit to The Medical Career and Other Papers ‘Medicine at the facts is like a drunkard who tries his key Crossroads’ haphazard in door after door, hoping to find one I would like to see the day when somebody would it fits. Letter to Dr Henry Christian,  November () Scottish surgeon and discoverer of ulcerative colitis Nature saw fit to enclose the central nervous The affected bowel gives the consistence and system in a bony case lined by a tough, protecting smoothness of an eel in a state of rigor mortis and membrane, and within this case she concealed a the glands, though enlarged, are evidently not tiny organ which lies enveloped by an additional caseous. Crohn’s disease for the first time) Neurohypophysial Membrane From a Clinical StandpointYale University Press () Danish proverb Fresh air impoverishes the doctor. Darlington – The observer listens to Nature; the experimenter British geneticist questions and forces her to unveil herself. A large proportion of mankind, like pigeons and Attributed partridges, on reaching maturity, having passed through a period of playfulness or promiscuity, establish what they hope and Czech proverb expect will be a permanent and fertile mating Small children stamp on your lap, big ones on relationship. Life was originally from so simple a beginning Quoted by Marvin Corman in Classic articles in colonic and (that) endless forms most beautiful and most rectal surgery. Diseases of the Colon and Rectum : – wonderful have been and are being evolved. Self-destruction is the effect of cowardice in the Letter,  March () highest extreme.

New research suggests that their enhancing effect may also be partly due to the removal of fatty acids purchase cialis extra dosage cheap erectile dysfunction 5-htp, such as palmitic and oleic acids order cialis extra dosage on line amex erectile dysfunction pills for high blood pressure, which are minor membrane components order genuine cialis extra dosage online erectile dysfunction pills uk. Toxic effects A major disadvantage associated with the use of penetration enhancers is their potential deleterious effect on the epithelial tissue purchase 50mg cialis extra dosage free shipping what do erectile dysfunction pills look like. The damaging effects of various absorption enhancers have been investigated in vaginal absorption studies of gentamicin using ovariectomized rats. It was found that the penetration enhancers laureth-9 and lysophosphatidylcholine caused severe desquamation of the epithelium, whereas citric acid and palmitoylcarnitine were able to enhance absorption while causing only minor epithelial damage. The vaginal absorption of insulin was studied in ovariectomized rats and in the absence of any enhancer, no decrease in blood glucose was observed. Co-administration of various absorption enhancers was able to significantly increase the degree of hypoglycemia. The histological changes in the vaginal epithelium after treatment with the enhancer systems were variable and often severe: • palmitoylcarnitine chloride exhibited the greatest local toxicity including reduction of epithelial thickness and cell death. However, no conclusions can be drawn at this stage about the likely tolerability, safety and efficacy of the gel in the context of sexual intercourse. Antiviral vaginal devices Nonoxynol-9 is an approved spermicide with strong antiviral activity. The device, available as a diaphragm or a disk pessary, is fabricated from silicone elastomer matrix system. The drug release profile demonstrates square root time kinetics (M ∞ t / ) (see1 2 Section 4. While the spermicide-containing reusable diaphragms currently on the market are relatively effective when used in combination with a spermicidal formulation, they require careful fitting, insertion and maintenance. Moreover, adverse reactions, such as urinary tract infections, alterations in vaginal flora and occurrence of toxic shock syndrome, have been associated with their use. In contrast the silicone-based device described above has been reported to be stable, non-irritating and non-toxic. A vaginal sponge has also been recently developed comprising a soft poly(urethane) sponge impregnated with a gel containing 1% benzalkonium chloride, 0. The sponge therefore combines the actions of: • a physical barrier that blocks the cervix; • a material that absorbs the ejaculate; • a spermicide; • an antiviral agent. Antiviral liposomal preparations Intramuscular injection of α interferon was shown to be fairly efficacious in the treatment of genital warts; however, this route was associated with a number of side-effects including fever, myalgia, headache, nausea and fatigue. A liposomal preparation of α interferon for topical vaginal delivery has been developed, which offers the advantage of treating latent human papillomavirus infections as well as visible genital warts. The liposomal preparation can be self-administered intravaginally, without the need for multiple painful local, or im, injections. In the vagina, mucosal immune responses are initiated by the uptake of antigens from the vaginal surfaces (Figure 11. Whereas the gastrointestinal tract has identifiable aggregates of lymphoid tissue within the epithelium known as the Peyer’s patches (see Section 6. Antigen-specific effector lymphocytes (B cells and T cells) migrate through the lymphatics and exit via the thoracic duct into the bloodstream. The primed B and T cells home to various mucosal sites including the genital mucosa, where they undergo maturation and secretion. A vaginal vaccine has been developed for the treatment of recurrent urinary tract infections. The multi- strain vaccine, composed of 10 heat-killed bacterial uropathogenic strains, has been shown to be efficacious against cystitis in non-human primates when administered by the vaginal route. Bladder infections were significantly reduced and both systemic and local immune responses were generated. It was determined that vaginal immunization resulted in two different types of immune responses in mice: high and low. High responders to the immunizations had been immunized in the diestrous phase of the cycle. As explained above, the vaginal epithelium is thin and porous during this phase, which facilitates vaccine uptake. Similarly, rectal immunization induced high levels of specific IgA and IgG in rectal secretions, but not in female genital tract secretions. Thus, generation of optimal immune responses to sexually transmitted organisms in both the rectal and the genital mucosa of women may require local immunization at both of these sites. Association of an antigen with an appropriate microparticulate carrier may enhance antigen uptake by vaginal antigen-presenting cells. The effect was further enhanced when the penetration enhancer lysophosphatidylcholine was used. Hyaluronan ester microspheres Hyaluronan is a naturally occurring mucopolysaccharide, consisting of repeating disaccharide units of D- glucuronic acid and N-acetyl-D-glucosamine. By esterification of the carboxyl groups of the glucuronic acid residue with alcohols, modified biopolymers can be produced which are biocompatible, mucoadhesive and biodegradable. The degradation rate can be controlled by the degree of esterification and by the type of alcohol substituent. Experiments using radio-labeled microspheres have shown that after vaginal administration the microspheres are dispersed along the length of the vagina for prolonged periods, thereby demonstrating their potential as a long-acting intravaginal delivery system. Suppocire, a mixture of semi-synthetic polyethylene triglycerides, melts at 35–37 °C. After administration of the pessary, the formulation forms a fine emulsion on contact with the aqueous environment of the vagina, thus encouraging the dispersion of microspheres throughout the vaginal cavity. It has been proposed that the bioadhesive microspheres may induce transient widening of intercellular junctions when applied nasally, or added to Caco-2 cell monolayers. It is thought that drug microspheres take up water from the cells, causing the cells to dehydrate and “shrink”, thereby inducing the transient widening of the intercellular junctions and increased drug transport. Work in this field has concentrated on the use of poly(lactide-co-glycolide) microparticles, which have the advantages of being biocompatible, biodegradable and well tolerated in humans. Promising results have also been obtained with the use of biodegradable starch microspheres in conjunction with the absorption enhancer lysophosphatidylcholine. However, in general, only low levels of antibodies have been induced by intravaginal immunizations and the antibodies generated have been predominantly localized in the genital tract, even in the presence of potent antigen delivery systems. Such formulations are prone to leakage, which can result in: • low efficacy, due to limited contact time with the absorbing surface; • poor compliance. Bioadhesive polymers can be used to prolong the contact of a drug with a mucosal surface, without inducing adverse local effects on the epithelium. Other beneficial effects conferred by the use of bioadhesive polymers include: • increasing the local drug concentration at the site of adhesion/absorption; • protecting the drug from dilution and possible degradation by vaginal secretions; • prolonging the contact time of the dosage form near the absorbing surface. Thus such polymers have attracted considerable interest as a means of improving drug delivery at mucosal sites, including the vagina.

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