T. Akascha. Westfield State College.

For the sake of argument generic trihexyphenidyl 2mg on-line, if one were to clopidogrel generic trihexyphenidyl 2mg visa, it would be prudent to choose such a drug over PPIs assume a linear relationship between platelet inhibition and reduc- that are known CYP2C19 inhibitors cheap trihexyphenidyl 2 mg online. In contrast cheap 2 mg trihexyphenidyl with visa, for patients who are predominantly metabolism (CYP2C19, possibly PON1) of clopidogrel have been medically managed, the addition of clopidogrel to aspirin reduces investigated for potential association with clopidogrel response. Partial genetic blockade would then be CYP2C19 expected to result in a risk ratio of only 1. The CYP2C19 gene is polymorphic, with known loss-of-function and gain-of-function variants. Among the The enhanced function CYP2C19*17 variant has also been reported loss-of-function variants, such as the *2, *3, *4, *5, *6, *7, *8 to influence the response to clopidogrel. The CYP2C19*17 variant variants per the Karolinska Institute nomenclature, the *2 variant is involves a single base pair mutation of C 3 T at position 808. The the most common, with nearly 30% of a Caucasian population CYP2C19*17 variant has been associated with increased transcrip- carrying 1 or 2 copies. The *2 variant (rs4244285) involves a single tional activity of the CYP2C19 enzyme, more extensive clopidogrel base pair mutation of G 3 A at position 681, which creates an metabolism with enhanced production of active clopidogrel metabo- aberrant splice site, resulting in downstream synthesis of a truncated lites, and greater inhibition of ADP-induced platelet aggregation. Clinically, it has been associated with an increased risk of bleeding in a gene-dose-dependent fashion without significant impact on Several candidate gene studies and a genome-wide association stent thrombosis or the combined 30-day ischemic end point of study have identified loss-of-function CYP2C19 variants to be death, myocardial infarction, or urgent target vessel revasculariza- independently associated with diminished inhibition of ADP- tion. The C3435T polymorphism has been variably associ- stent thrombosis compared with noncarriers. The 3435TT genotype has been confirmed in a meta-analysis of 9 studies of close to 10 000 patients associated with decreased peak plasma concentrations of clopi- 22-28 dogrel and its active metabolites. For clopidogrel, esterases shunt the should be noted that the PON1 Q192R was not associated with majority of ingested clopidogrel to a dead-end inactive pathway, clopidogrel pharmacologic effect in the previously published ge- with the remaining prodrug requiring a 2-step CYP-dependent nome-wide association study of clopidogrel pharmacogenomics,24 oxidation process to produce active clopidogrel metabolites; for and that the very study that identified this novel PON1 Q192R prasugrel, esterases are part of the activation pathway and activation polymorphism was unable to reproduce the well-replicated effect of of prasugrel requires only a single CYP-dependent oxidative step. Subse- quent pharmacology studies have now questioned the supposition The other third-generation P2Y12 inhibitor is ticagrelor, which is an that paraoxonase-1 plays a role in the bioactivation of clopi- active compound and not a prodrug, so it does not require hepatic dogrel. In the PLATO trial, ticagrelor com- a role for the Q192R polymorphism affecting cardiovascular pared with clopidogrel reduced the composite of vascular death, outcomes in patients treated with clopidogrel. As would be expected, In March 2010, the FDA approved a new label for Plavix, with the CYP2C19 polymorphisms do not affect either the pharmacologic or addition of a boxed warning on pharmacogenetics, noting dimin- 55 clinical response to ticagrelor. A genetic analysis within the ished effectiveness of therapy in poor metabolizers (defined as PLATO trial found ticagrelor to be superior to clopidogrel in the having 2 loss-of-function CYP2C19 alleles). The boxed warning treatment of ACS irrespective of CYP2C19 polymorphism, but also further states that “tests are available to identify a patient’s found that the magnitude of benefit tended to be greater in carriers of CYP2C19 genotype and can be used as an aid in determining 35 loss-of-function alleles. One issue is defining what treatment Escalating doses of clopidogrel would be given in the control arm (assuming that in the arm with Potential therapeutic modifications for individuals found to carry a genotyping, loss-of-function carriers all would receive a third- loss-of-function CYP2C19 allele include escalation of clopidogrel generation P2Y12 inhibitor). If the control arm receives clopidogrel, dosage or switching to an alternate agent. The ELEVATE-TIMI 56 one must bear in mind that the pivotal trials that demonstrated the trial demonstrated that tripling the maintenance dose of clopidogrel benefit of the third-generation P2Y12 inhibitors over clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes would achieve required 15 000-20 000 patients each. If only 30% of the experi- on-treatment platelet reactivity comparable to that seen with the mental arm is getting a third-generation P2Y12 inhibitor, the sample standard 75 mg dose in wild-type individuals. Similar data exist from the CLOVIS-2 gave everyone in the control arm an (expensive) third-generation trial for increasing the loading dose. Therefore, the genetic substudies in the randomized controlled trials of prasugrel and ticagrelor are likely the best data Third-generation P2Y12 inhibitors we will have and, as noted above, both suggest greater benefit of Alternatively, one could use a third-generation P2Y12 inhibitor such using a third-generation P2Y12 inhibitor in patients who harbor a as prasugrel or ticagrelor. Prasugrel is also a thienopyridine that CYP2C19 loss-of-function allele. A genetic analysis within the TRITON-TIMI 38 trial ogy Foundation (ACCF)/American Heart Association (AHA) PCI found that loss-of-function polymorphisms in CYP2C19 did not guidelines do not mandate such testing, but rather simply note that Hematology 2014 345 “Genetic testing might be considered to identify whether a patient at nary Stenting and Antithrombotic Regimen: Choose Between 3 High high risk for poor clinical outcomes is predisposed to inadequate Oral Doses for Immediate Clopidogrel Effect) Trial. Impact of platelet reactivity on 12 favor their use. However, we recognize that clopidogrel continues to clinical outcomes after percutaneous coronary intervention: a collabora- tive meta-analysis of individual participant data. In patients with ACS undergoing PCI in which the 2011;58(19):1945-1954. Platelet reactivity and current literature supports the use of prasugrel or ticagrelor when clinical outcomes after coronary artery implantation of drug-eluting not contraindicated clinically in patients who carry a loss-of- stents (ADAPT-DES): a prospective multicentre registry study. Risk of adverse outcomes Disclosures associated with concomitant use of clopidogrel and proton pump Conflict-of-interest disclosures: M. Bristol Myers Squibb, Critical Diagnostics, Daiichi-Sankyo, Eisai, 15. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmaco- Genzyme, Intarcia, Merck, Roche Diagnsotics, Sanofi-Aventis, and kinetics of clopidogrel in healthy subjects: randomized, placebo- Takeda and has received honoraria from Amgen, AstraZeneca, controlled, crossover comparison studies. Pharmacodynamic Healthcare, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & effect and clinical efficacy of clopidogrel and prasugrel with or without Johnson, Sanofi-Aventis, Accumetrics, Nanosphere, and the Na- a proton-pump inhibitor: an analysis of two randomised trials. Clinical events as a function of proton drug use: Clopidogrel at doses beyond the approved dose. Sabatine, MD, MPH, TIMI Study Group, Division of 2011;123(5):474-482. Cardiovascular Medicine, Brigham and Women’s Hospital and Har- 18. Clopidogrel with or without omepra- vard Medical School, 75 Francis Street, Boston, MA 02115; Phone: zole in coronary heart disease. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors References and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 1. A randomized comparison expert consensus document on reducing the gastrointestinal risks of of antiplatelet and anticoagulant therapy after the placement of coronary- antiplatelet therapy and NSAID use. Cytochrome P450 2C19 loss-of- antithrombotic-drug regimens after coronary-artery stenting. N Engl function polymorphism is a major determinant of clopidogrel responsive- J Med. The Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic 21. Effects of clopidogrel in addition to aspirin in CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacody- patients with acute coronary syndromes without ST-segment elevation. Cytochrome P450 2C19 aspirin and fibrinolytic therapy for myocardial infarction with ST- 681G A polymorphism and high on-clopidogrel platelet reactivity segment elevation. Addition of clopidogrel to aspirin in ous coronary intervention with drug-eluting or bare-metal stents. JAm 45,852 patients with acute myocardial infarction: randomised placebo- Coll Cardiol. Impact of P-glycoprotein on phisms and Response to Clopidogrel. Association of cyto- major determinant of clopidogrel efficacy. Cuisset T, Morange PE, Quilici J, Bonnet JL, Gachet C, Alessi MC. Genetic determinants of Paraoxonase-1 and clopidogrel efficacy. Relation of cytochrome P450 CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and 2C19 loss-of-function polymorphism to occurrence of drug-eluting in vivo antiplatelet response. Cytochrome P450 2C19 loss-of- metabolization, and antiplatelet effects of 300-, 600-, and 900-mg function polymorphism and stent thrombosis following percutaneous loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoro- coronary intervention. Effects of CYP2C19 genotype on and the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Preven- outcomes of clopidogrel treatment. The relationship between polymorphisms on the effect of high- and standard-dose clopidogrel CYP2C19 polymorphisms and ischaemic and bleeding outcomes in after percutaneous coronary intervention: the GIFT (Genotype Informa- stable outpatients: the CHARISMA genetics study. Paraoxonase-1 is not a major genotype, clopidogrel metabolism, platelet function, and cardiovascular determinant of stent thrombosis in a Taiwanese population. CYP2C19 genotype and cardiovascu- variant and response to clopidogrel and prasugrel [abstract]. Plavix (clopidogrel bisulfate) tablets: prescribing infor- variant, platelet aggregation, bleeding events, and stent thrombosis in mation. Genetic variants in ABCB1 and based on CYP2C19 genotype and the effect on platelet reactivity in CYP2C19 and cardiovascular outcomes after treatment with clopidogrel patients with stable cardiovascular disease. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospec- 35. Effect of CYP2C19 and ABCB1 single tive, randomised, proof-of-concept trial. No association of paraoxonase-1 (Clopidogrel and Response Variability Investigation Study 2). JACC Q192R genotypes with platelet response to clopidogrel and risk of stent Cardiovasc Interv.

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Those hypotheses call attention to the sorts of experimental perturbations that should be in- formative quality trihexyphenidyl 2 mg. Their model focused on competition between immune cell lineages for stimulation by epitopes order 2mg trihexyphenidyl overnight delivery. Immune cells receive relatively stronger stimulation as their matching epitopes increase in numbers generic 2 mg trihexyphenidyl with mastercard. The strongest immune- epitope match leads to the largest buy trihexyphenidyl 2 mg low cost, immunodominant population of im- mune cells. That immunodominant lineage expands until its killing ef- fect reduces the parasite population within the host down to a point of balance. At that balance point, the parasite population stimulates division of the immunodominant population of immune cells just enough to match the tendency of the immune cell population to die off. In turn, the immu- nodominant immune cells reduce the parasites just enough to balance their births and deaths and hold the parasite population at a constant level. Other immune cell lineages receive weaker stimulation by the par- asites because of their weaker binding characteristics to epitopes. Those subdominant lineages decline because the dominant lineage pushes par- asite abundance down tothepoint where the weaker stimulation re- ceived by the subdominant lineages cannot overcome their tendency to decline. IMMUNODOMINANCE WITHIN HOSTS 91 The bottom line from thismathematicalanalysismatches the sim- plest, standard theory of predator-prey population dynamics: the most efficient predator reduces the prey down to a level where less efficient predators cannot survive. Can such idealized mathematical models capture the complex molec- ular and kinetic details of the immune response? On the one hand, immunodominance is shaped in part by competition between lineages of immune cells, and thus the population dynamics of competition contribute in some way to the pat- terns of immunodominance. On the other hand, the model abstracts away many aspects of regulatory control, such as the role of helper T cells, the distinction between equilibrium binding affinity and kinetic on-rates of binding in different phases of the immune response, and structural properties that governaffinityandcross-reactivity. The mathematical abstraction pays off as long as one understands the goal: to bring into sharp focus a hypothesis about how essential processes shape immunodominance. Some of the studies described in the text support this prediction. If one suspects that the distinction between equilibrium affinity and kinetic on-rates matters in an essential way for immunodominance, then an extended mathematical model would pro- vide testable predictions about that aspect of the system. Iemphasizetheseissues here because the dynamics of immune cells andparasite populations within each infected host provide one of the few subjects that has been developed mathematically (Nowak and May 2000). The simple principles from those models do seem to be impor- tant, if only because the rules of population dynamics must play a key role in shaping how populations of immune cells and parasites interact. One can, of course, make more specific mathematical models to pre- dict the dynamics ofparticularparasites or the role of particular mo- lecular mechanisms. Those specific models require empirical study of their specialized predictions. And that is exactly what we want: tests of clearly and logically formulated quantitative predictions. Helper T cells pro- vide an important stimulus in the development of an antibody response. As B cells bind antigen to their BCR, they often pull the antigen into the 92 CHAPTER 6 cell. The B cells process protein antigens into small peptides, bind those peptides to MHC class II molecules, and present the peptide-MHC com- plexes on their cell surfaces. Helper T cells with matching specificity in their TCRs bind the peptide-MHC complexes and stimulate the B cells. Thus, an antigen must have two epitopes to stimulate a robust B cell response with affinity maturation. One epitope binds the BCR, and a second must survive digestion and be presented on the B cell surface bound to a class II molecule for the TCR of a helper T cell. Several factors likely affect the degree to which helper T cell epitopes modulate the immunodominance of B cellepitopes. These factors in- clude the proximity of the two epitopes, the binding kinetics of the T cell epitope to the TCR, the nature of the helper T cell signal that pro- vides stimulation to the B cell, and the population dynamics of the helper Tcelllineages with different TCR specificities. In particular, ahelperTcellepitope near the hypervariable region of thehepatitis C virus envelope gene aids in generation of antibodies to the hypervariable region. Antibody attack favors antigenic variation in parasites’ surface molecules. By contrast, CTLs favor varia- tion in any parasite molecule that can be presented by the host’s MHC system. The balance of antibody versus CTL defense affects the popula- tion dynamics of the parasites within the host, the time before clearance, and the memory properties of host immunity against reinfection (Seder and Hill 2000). The factors that tip an immune response toward anti- body, CTL, or a mixture ofthetwoarenot fully understood (Constant and Bottomly 1997; Power 2000). Studies of model systems sometimes show a sharp dichotomy between CTL and antibody response controlled by a simple variable such as antigen dosage (Menon and Bretscher 1998). But the immune response to many viruses includes robust antibody and CTLattack (Knipe and Howley 2001). As more parasite genomes are sequenced, it may be useful to look at which potential antigenic sites do in fact show significant variation. Those highly variable sites can be studied to determine if they are CTL or antibody epitopes, providing clues about which type of immunity imposes the strongest selective pressure on the parasite. Parasite Escape within Hosts 7 Specific immunity favors parasites that change their epitopes and escape recognition. In this chapter, I summarize examples of parasite escape and the consequences for antigenic diversity within hosts. The first section presents HIV and hepatitis C virus (HCV) as two pathogens that evolve within hosts to escape specific immunity. HIV variants escape recognition by CTLs, whereas HCV variants escape rec- ognition by specific antibodies. HIV also diversifies its surface molecules in order to attack different cell types. Changing tissue tropisms over the course of an infection provide an additional force to drive the evolu- tion of parasite diversification within hosts. HIV and HCV are both RNA viruses, which mutate frequently and evolve rapidly. The importance of within-host immune escape by random mutations in DNA-encoded pathogens remains to be studied. The second section describes how parasites interfere with host immu- nity. For example, viruses may disrupt MHC presentation of antigens, send misleading signals to natural killer cells, block programmed cell death (apoptosis) of infected cells, orexpress cytokines that alter im- mune regulation. In some cases, parasite antigens may lack variation because the parasite repels immune attack by interfering with host im- munity rather than altering the specificity of its epitopes. The third sectionfocuseson parasites that escape host immunity by switching gene expression between variants stored within each genome. Asingleparasite expresses onlyoneofthevariants from the archival genomic library. Each parasite lineage changes expression from one stored gene to another at a low rate. As host immunity builds against acommon variant, one or more newly expressed variants can rise. The host must then build another specific immune response against the new variants. Parasites that switch variants in this way may gain by extending the total time of infection. Additionally, switching may help to avoid the immunological memory of a previously infected host. The fourth section introduces processes that enhance or retard the coexistence of antigenic variants within hosts. If antigenic variants com- pete for a common resource, such as host cells or a limiting nutrient, 94 CHAPTER 7 then one competitively dominant variant tends to drive the other vari- ants extinct. Resource specialization allows different variants to coexist, for example, when each variant attacks a different cell type.

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Many fistula patients are not able to find their way 8 purchase trihexyphenidyl with amex. Talk with political leaders about the problem order discount trihexyphenidyl online, to the hospital for repair of their fistulas buy 2 mg trihexyphenidyl overnight delivery. Several they might be able to facilitate in transport as reasons are given: well cheap trihexyphenidyl 2mg visa. They do not have the knowledge about the Most patients with vesico-vaginal fistulae do not disease and where they should go for repair. They do not have the funds for transport and for free using funds from NGOs who are involved to stay in the hospital for longer. They are not able to reach the hospital by if you can offer fistula surgery in order to let as public transport because they are sent off the many women profit as possible. They have to eat, and they lose income as International Society of Obstetric Fistula surgeons. It cannot be stressed enough that primary preven- Addis Ababa Fistula Hospital. Health personnel from hos- org pitals and remote healthcare facilities should receive International Federation of Gynaecologists (FIGO). Surgery Training Manual can be accessed under pub- In many regions of the world less than 50% of lications, miscellaneous, on this site. Traditional birth attendants must be aware of the causes, early signs Teaching Aids at Low Cost. Available from Teaching Aids at Low Cost (TALC), Box 49, St Albans Global Library of Women’s Medicine. Practical Obstetric Fistula Sur- this website there is a link to the complete contents gery. Global Competency Based Fistula Surgery Training Manual. First steps in Vesico-Vaginal Fistula Repair, and also a Published by the International Federation of Gynae- film of four operations performed at the Addis cology and Obstetrics. May be downloaded from the Ababa Fistula Hospital in 1999. Obstetric labour in- jury complex: obstetric fistula formation and the multi- faceted morbidity of maternal birth trauma in the developing world. The immediate management of fresh obstetric fistulas. Br J Obstet Gynaecol 2009;116:1265–7 272 Vesico-vaginal and Recto-vaginal Fistula APPENDIX 2: CLASSIFICATION Thus, there may be considerable interobserver variation; however, if a surgeon applies the same Goh’s classification criteria in all cases, this will enable a meaningful This is based on three variables: audit to be done. For example, this classification has been used to confirm the suspicion that the • The length of the urethra (types 1–4) worst fistulae occur in primiparous patients and • The size of the fistula (a–c) those having a vaginal delivery. This system of grading from type 1aI to type 4cIII does indicate an increasingly poor prognosis, Urethral length although it is not always an indication of difficulty Type 1: Distal edge of fistula >3. Type 1aI cases have the best prognosis ternal urethral orifice (EUO), i. An additional refinement is to Fistula size measure functional bladder capacity during dye testing. No or mild fibrosis around fistula/vagina, and/ Fistulae not involving the closing mechanism (5 cm or vaginal length >6cm or normal capacity. Moderate or severe fibrosis around fistula and/ or vagina, and/or reduced vaginal length and/ Type II or capacity. This is a popular system and used by many fistula b. It is based on the variables of involve- • There may be lack of agreement as to what con- ment of the closing mechanism, circumferential stitutes a circumferential fistula. It is used by the juxta-urethral fistulae may be slightly detached many surgeons whom he has trained, although from the bladder, although some surgeons re- others find it difficult to understand the cut-off serve the term ‘circumferential’ for cases where between A and B fistulas. In other countries similar headlights may often be found in resources for dental surgeons. Scope of the problem The prevalence of FGM is illustrated in Figure 11. Female circumcision or genital mutilation is still widely practiced in over 30 countries in the world. WHO estimates that over 120 million women have been circumcised and several thousand more are circumcised each day. Due to population move- Figure 1 Prevalence of female genital mutilation in ments women and girls living in western nations Africa. The practice has become an issue for most healthcare providers, particularly History and practice midwives and obstetricians who may, however, not be aware of the consequences. All health workers Female sexuality has been repressed in a variety of who are involved in caring for the mutilated ways in all parts of the world throughout history up patient have an important role to play: they to the present time. Female slaves in ancient Rome must recognize the sensitive nature and com- had one or more rings put through their labia to plexity of the issues related to FGM, and should prevent them from becoming pregnant. Chastity have knowledge on the possible complications in belts were brought to Europe by the crusaders dur- childbirth. Caregivers should avoid becoming ing the 12th century. In the 19th century the re- tion particularly the sexual problems and the moval of the clitoris was performed as a surgical possible serious gynecological and obstetric remedy against masturbation in Europe and in the complications. FGM may be viewed upon as one of the 275 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS extreme forms of female oppression seen across • Type III: excision of part or all of the external centuries. FGM is found across many African coun- genitalia and stitching/narrowing of the vaginal tries (Figure 1) and some countries in Asia and the opening, or infibulation (may be known as Middle East such as Malaysia, Indonesia and the pharaonic circumcision of infibulation). It is traditional in many • Type IV: pricking, piercing or incising of the different groups and faiths, including Christians and clitoris and/or labia; stretching of the clitoris Muslims. Although there is no clear obligatory and/or labia; cauterization by burning of the statement in the Qur’an for this practice, it is still clitoris and surrounding tissue; scraping of tissue carried out in the name of religion, although the surrounding the vaginal orifice (angurya cuts) or practice is not exclusive to Muslims. It varies from a few days’ old baby to cause bleeding, or for the purpose of tighten- (e. Mali, the Jewish Flashas in Ethiopia and the ing or narrowing it – and any other procedure Nomads of the Sudan) to about 7 years old (as in that falls under the definition given above. Egypt and many countries of Central Africa), or to adolescents (among the Ibo of Nigeria) where exci- Cultural issues sion takes place shortly before marriage or before the first child (as among the Ahols in mid-Western Several theories exist about its origin: Nigeria). Most experts agree, however, that the age • To control women’s sexuality or an attempt to of mutilation is becoming younger and has less and obtain control of women’s magic power. The excision Most frequently, FGM is performed by an of the clitoris would decrease sexual desire and old woman of the village (known as ‘Noumou pleasure of the women before marriage. Mousso’ in Mali, ‘Gadda’ in Somalia) or traditional • To ensure a secure future for a female child in a birth attendants (called Daya in Egypt and the society ‘that requires infibulated wives, and since Sudan). In northern Nigeria and in Egyptian a girl has no other choice in life but to marry, villages barbers carry out the task and on rare occa- she must undergo the operation’. Anesthetics • As a protection against rape for young girls who are never used and the child is usually held down take the animals out to pasture. Herb mix- • For hygienic and esthetic reasons because a tures, earth, cow dung or ashes are rubbed into woman’s genitalia were considered unclean and the wound to stop bleeding. Needles, thorns, catgut or thread are Mossi in Burkina Faso believe that contact used to stitch the wound. There is no attempt at between the clitoris and child’s head during asepsis. In FGM is practiced on thousands or hundreds of other cases it is believed that removal of the thousands of newborn and small girls worldwide. These girls have the most awful experiences and the degree of post-traumatic stress will never be fully assessed in most individuals. Continuation of the practice Forms of female genital mutilation3 Why does the practice continue when the personal, 4 psychological and heath complications are so Figure 2 illustrates the types of FGM : severe? A study in 1984 of 300 women in Sierra • Type I: excision of the prepuce (a retractable Leone found that of the 90% who were circum- piece of skin covering part of the clitoris), with cised the reasons cited were tradition (85. Leone woman who practices FGM in a village 276 Female Genital Mutilation (a) (c) (b) (d) Figure 2 Different types of female genital mutilation (FGM). ISBN: 2–913326–49–8 explains ‘If the women of our village stop this prac- Acute complications tice, life will be meaningless to us all. It is our cul- These may include the immediate ones such as ture, and nobody has the right to take it away from shock due to pain, infection or severe hemor- us’.

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HAM-D scores at endpoint showed no significant difference between treatment groups in depressive symptoms (P=0 discount trihexyphenidyl 2mg free shipping. More nefazodone-treated patients were abstinent during treatment; however order trihexyphenidyl canada, the difference did not reach statistical significance (P=0 order genuine trihexyphenidyl. Paroxetine compared with placebo A fair study randomized 42 subjects with social anxiety disorder and a co-occurring alcohol use 316 disorder to paroxetine (10-60 mg/d) or placebo for 16 weeks discount trihexyphenidyl 2mg on line. Decreases in total LSAS scores were significantly greater for paroxetine- compared to placebo-treated patients (53% compared with 32%, P=0. A higher percentage of paroxetine-treated patients were CGI responders (defined as improvement score of 1 or 2) compared to placebo-treated patients (55% compared with 27%). The mean reductions in Social Phobia Inventory (SPIN) results were greater in the paroxetine group but did not reach statistical significance (46% compared with 31%, P=0. Three specific adverse events occurred significantly more frequently in paroxetine-treated patients: tremor (45% compared with 14%, P=0. Second-generation antidepressants 97 of 190 Final Update 5 Report Drug Effectiveness Review Project Sertraline compared with placebo Three fair RCTs compared sertraline and placebo in the treatment of patients with depression and 317-319 co-occurring alcohol dependence. A 24-week study compared sertraline (50-150 mg/d) with placebo in recently detoxified 317 alcohol-dependent patients with current depressive symptoms. Response (> 50% decrease in MADRS score) was slightly higher in sertraline- than placebo-treated patients (44% compared with 39%). Both groups experienced significant improvements in HAM-D and MADRS scores during the study, but the two groups did not differ significantly. Relapse rates were higher in sertraline- than placebo-treated patients (31. Adverse event rates were similar for both treatment groups. The overall attrition rate was greater than 40 percent; however, there was not a significant difference in withdrawal between groups (sertraline, 45% compared with placebo, 44%). In this fair study, 82 currently depressed, actively drinking alcohol-dependent subjects were randomized to sertraline (50-200 mg/d) or placebo. There was no significant difference between groups in depression symptoms. However, in women, treatment with sertraline was associated with less depression at the end of treatment than those receiving placebo based on HAM-D scores (P=0. There was no difference between groups in time to first heavy drinking day (P=0. Sertraline-treated subjects had fewer drinks per drinking day compared to placebo-treated subjects; the difference was significant (P=0. Less drinking during the study was associated with improved depression outcomes. Serious adverse events occurred in four subjects: three treated with sertraline and one treated with placebo. Loss to follow-up was twice as high in the placebo group (33%) compared to the sertraline group (16%); however, details were not reported on withdrawals due to tolerability or lack of efficacy. This study randomized 328 patients with co-occurring MDD and alcohol dependence to sertraline (50-200 mg/d) or placebo for 10 weeks. After the run-in period, two groups of patients were randomized separately based on HAM-D scores: Group A scores were > 17 while Group B scores were < 16. Mean reduction in HAM-D scores did not differ significantly between all sertraline-treated (-10. There were significant differences in HAM- D response rates by group stratification. In Group A, sertraline led to significantly higher response rate than placebo (64% compared with 47%, P=0. However, in Group B, sertraline patients had a significantly lower response rate than placebo patients (58% compared with 77%, P=0. There were no significant differences between medication groups in the reduction in BDI score from baseline to endpoint nor within Group A or Group B. No significant differences were detected between medication groups in drinking measures. Overall, the incidence of adverse events was similar between medication groups; however, significantly more sertraline-treated patients discontinued due to adverse events than placebo-treated patients (P<0. Alzheimer’s disease/dementia Two randomized trials compared sertraline and placebo for patients with depression and 320, 321 comorbid Alzheimer’s disease. More patients treated with sertraline responded to treatment (full responders, 38%; partial responders, 46%) than did patients treated with placebo (full responders, 20%; partial responders, 15%) (P<0. A second fair 12-week trial which randomized 133 patients with mild-to-moderate Alzheimer’s disease and depression to either sertraline (100mg/d) or placebo did not replicate the above findings. Mood was assessed by the modified Alzheimer Disease Cooperative Study- Clinical Global Impression of Change index and the CSDD. At the end of week 12, CSDD scores and remission rates did not differ between sertraline and placebo (OR 2. Treatment with sertraline, however, was associated with more adverse events, specifically gastrointestinal adverse events than with placebo. Serious adverse events occurred in 321 20 percent of patients in the sertraline group compared with 11 percent in the placebo group. Arthritis Our searches yielded only one trial that evaluated the efficacy of an antidepressants in depressed 322 patients with comorbid arthritis. This study is a subgroup analysis of a larger placebo- 323 controlled trial in elderly patients randomized to duloxetine (60 mg/d) or placebo. The subgroup analysis analyzed 233 subjects with MDD and co-occurring arthritis, diabetes and/or vascular disease; 55 percent of patients had diabetes. There were no statistically significant treatment-by-comorbidity interactions for any comorbidity (P < 0. Results must be interpreted with caution as this was the only study addressing this topic. Cancer Fluoxetine compared with placebo 324 We detected only one trial that studied the efficacy of fluoxetine in cancer patients; however, this placebo-controlled trial failed to meet our inclusion criteria because the duration of the study was less than 6 weeks. We mention it here because it was the only trial on this topic. This 5- week trial studied the efficacy of fluoxetine in 91 cancer patients with depression or adjustment disorder. The majority of the patients were female; 13 percent in the fluoxetine group and 5 percent in the placebo group had metastatic disease. Efficacy according to the main, observer-rated outcome measures (HADS, MADRS, HAS) did not differ significantly between the active drug and placebo groups. Improvements were generally greater in the fluoxetine group but statistically significant only for the SCL90-R (33% compared with 15%; P=0. No statistically significant difference in quality of life was reported. However, study duration was short and a substantially greater percentage of patients in the fluoxetine group had a more advanced stage of cancer at baseline. Fluoxetine-treated patients had a significantly greater drop-out rate than placebo-treated patients (33% compared with 15%; P=0. Paroxetine compared with placebo A 6-week randomized trial compared paroxetine (20 mg/d) and placebo in depressed breast cancer patients who were receiving at least four cycles of chemotherapy to evaluate whether the 325 use of an antidepressant can alleviate symptoms of depression and reduce fatigue. Although Second-generation antidepressants 99 of 190 Final Update 5 Report Drug Effectiveness Review Project this study was rated poor because of lack of ITT analysis and inadequate description of study duration, we included it because it was the only study conducted in cancer patients that satisfied our inclusion criteria. Paroxetine was more effective in reducing depression during chemotherapy, as measured by the Center for Epidemiological Studies of Depression (CES-D) (P=0. No differences between treatment groups were apparent with respect to fatigue. Diabetes Our searches yielded two trials that evaluated the efficacy of an antidepressants in depressed 322, 326 patients with comorbid diabetes. One fair-rated study randomized 89 depressed, low- income Hispanics and African Americans with diabetes to sertraline (50-100 mg/day) or placebo 326 for 6 months.

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