By C. Dolok. State University of New York College at Oneonta. 2019.

Te polypill consisted of a combina- and mortality associated with these conditions purchase generic priligy on line, tion of low doses of a thiazide diuretic purchase priligy 60 mg with amex, atenolol order discount priligy online, in large groups of human subjects over much ramipril, simvastatin and aspirin, and this was longer periods of time (46). Operational ques- compared with single agents or combinations of tions pose a challenge to the translation of exist- single agents. Te efect of the medication was ing evidence into policy. Tese questions need to measured on risk factors, including high blood be answered by clinical and observational stud- pressure, elevated cholesterol concentrations ies which include: (i) the safety profle and what and elevated heart rate. Polypill intake was also to do if one component of the polypill is con- assessed for feasibility and tolerability. Te appropriate diets, behaviour change and exer- Indian Polycap study reduced systolic blood cise. Research is needed to measure both the pressure by 7. Tese reductions were better or similar Main conclusions to those of single drugs or combinations of single ■ Early research shows that the Polycap for- drugs and tolerability was similar to that of other mulation, a single pill that combines several treatments. Efects of the polypill at the wider drugs, might be a simple and practical way population level might be afected by adherence. Comorbidity ofers the potential to evaluate more precisely the efcacy of for targeted treatment, if and when a polypill is the polypill, and for operational research used for primary prevention. Te drug is thus of reducing the risk of cardiovascular difcult to administer and constitutes a burden disease, such as dietary changes, the pre- both for the patient and for the health system. The efficacy of an alternative drug, paro- momycin sulfate (PM), has been demonstrated Case-study 7 in India (49). There is, however, limited infor- mation on the efficacy of PM for VL in the Combination treatment with African setting where response to treatment sodium stibogluconate (SSG) may be different. A large observational study of 4263 VL patients in South Sudan showed and paromomycin compared to that a combination of SSG and PM for a shorter SSG monotherapy for visceral period of time (17 days) yielded better results leishmaniasis: a randomized than SSG alone (50). For registration of PM and evaluation of the efficacy of combination treat- controlled trial in Ethiopia, ment with SSG and PM in East Africa, efficacy Kenya, Sudan and Uganda and safety data were required from a phase III randomized controlled trial. The need for research Human visceral leishmaniasis (VL), also known Study design as kala-azar, is a life-threatening parasitic dis- A multicentre randomized controlled trial ease caused by Leishmania donovani and trans- was conducted in four East African countries mitted by phlebotomine sandfies (Fig. Te VL is the second largest parasitic killer in the trial had three arms: (i) SSG monotherapy (a world afer malaria, with an annual worldwide dose of 20 mg/kg/day for 30 days) used as the incidence of approximately 500 000 cases (47). In East Africa, the SSG and PM given for a shorter period (SSG 20 incidence rate is 30 000 cases with 4000 deaths mg/kg/day; PM 15 mg/kg/day for 17 days). Te Leishmania parasite migrates aim was to compare the efcacy and safety of to internal organs such as the liver, spleen and PM monotherapy and the combination of SSG bone marrow (hence the term “visceral”) and, if and PM to the reference arm of SSG alone. Efective primary efcacy end point was defnitive cure measures to eradicate the sandfy are lacking, defned as parasite clearance from splenic, bone death rates are high, and there are few afordable marrow or lymph node aspirates six months and efective treatment options. In the comparison between PM monotherapy Treatment for VL in East Africa is primarily and SSG alone, 205 patients were enrolled in each limited to the antimonial sodium stibogluco- arm with primary efcacy data available for 198 nate (SSG), which is efcacious but requires four and 200 patients respectively. In the comparison weeks of hospitalization and daily intramuscular between the SSG/PM combination and the SSG 73 Research for universal health coverage Fig. Clinical examination of a 4-year-old girl with visceral leishmaniasis (kala-azar), in Sudan reference, 381 and 386 patients were enrolled in lowered the associated costs. Te cost of the each arm respectively with efcacy data available drugs also favoured the combination treatment for 359 patients per arm. Te efcacy of PM monotherapy was sig- Te potential risk of parasite resistance to SSG nifcantly lower than the efcacy observed in was also limited by combination therapy. Te efcacy SSG/PM combination therapy for treatment of of the SSG/PM combination given for a shorter VL in East Africa. A WHO Expert Committee duration of 17 days was similar to the efcacy of recommended its use as a frst-line treatment for SSG given alone for 30 days (91. Tere were no apparent diferences in the safety profle of Main conclusions the three treatment regimens. An observational multicountry study was con- ■ Te fndings supported the introduction of ducted in primary government health facilities SSG and PM combination therapy as a frst- in Bangladesh, Brazil, Uganda and the United line treatment for VL in East Africa. Te clinical perfor- mance of health workers with a longer duration of pre-service training (such as doctors and clin- Case-study 8 ical ofcers) was compared with those having a shorter duration of training (all other health Task shifting in the scale-up workers such as nurses, midwives and nurse of interventions to improve assistants providing clinical care). Te quality of care was evaluated using standardized indica- child survival: an observational tors and according to whether the assessment, multicountry study in Bangladesh, classifcation and management of sick children Brazil, Uganda and the United by IMCI guidelines had been fully carried out. Every child was assessed twice, frst by the IMCI- Republic of Tanzania trained health worker who was being assessed and second by a supervisor who was blinded to The need for research the original diagnosis and treatment made by WHO estimates that the global health workforce the health worker. Although this research has has a defcit of more than four million persons been classifed as a study of the management of (51). Countries with high child mortality rates diseases and conditions, it is also health policy also tend to have a lack of qualifed health work- and systems research. Te Integrated Management of Childhood Illness (IMCI) is a global strategy that has been Summary of fndings adopted by more than 100 countries with a view Te study included a total of 1262 children to reducing child mortality. IMCI clinical guide- from 265 government health facilities: 272 chil- lines describe how to assess, classify and manage dren from Bangladesh, 147 from Brazil, 231 children younger than fve years of age who have from the United Republic of Tanzania, and 612 common illnesses (52). In Brazil, 58% of health workers expanding IMCI coverage is the lack of qualifed with training of long duration provided cor- health workers. Task shifing, which is the term rect management, compared with 84% of those used to describe the process whereby specifc tasks with shorter duration of training. In Uganda are moved, where appropriate, to health workers the fgures were 23% and 33% respectively with fewer qualifcations and a shorter duration of (Table 3. Similarly, in Bangladesh and the pre-service training is seen as an option to address United Republic of Tanzania, the proportions of shortages of personnel (53). Assessment, classifcation and management of children by IMCI-trained health workers, classifed by length of pre-service training Longer duration of training Shorter duration of training Index of assessment of childrena Bangladesh 0. Adapted, by permission of the publisher,from Huicho et al. It should also be noted that these assessments pre-service training. Although all cadres of were made at the primary care level where fewer health workers apparently need additional children have serious illnesses (the proportion of training in some settings, task shifting has hospital referrals ranged from 1% in Brazil to 13% the potential to expand the capacity of IMCI in Uganda). Furthermore, health workers with a and other child survival interventions in shorter duration of training may be more willing underserved areas faced with staff shortages to comply with standard clinical guidelines (and (54–56). Randomized trials have also shown therefore be judged to have managed children that task shifting from doctors to other less correctly) whereas those with longer training qualified health workers is possible and can may use a wider variety of diferent procedures be beneficial where health service staff are in and yet obtain equally good outcomes. All nine peripheral health centre maternity units in the Case-study 9 district were linked to a central EMOC facility and an ambulance service via cell phones or high Improving access to emergency frequency radios. On receiving a woman with an obstetric care: an operational obstetric complication, health centre staf con- tacted the EMOC facility and an ambulance was research study in rural Burundi dispatched (accompanied by a trained midwife) to transfer the woman to the EMOC facility. Te The need for research distance from health centres to the EMOC facil- MDG 5 sets the target of reducing the maternal ity ranged from 1 km to 70 km. The MMR is an important measure by estimating how many deaths were averted of maternal health at the population level and is among women with a severe acute maternal defined as the number of maternal deaths in a morbidity (SAMM) who were transferred to and given time period per 100 000 live births during treated at the EMOC facility. Although maternal comparing the number of deaths among women mortality decreased in low- and middle-income with SAMM who were benefciaries of the EMOC countries from 440 deaths per 100 000 live intervention with the expected number of deaths births in 1990 to 290 per 100 000 in 2008, this among the same group of women assuming that 34% reduction is well short of the 75% target the EMOC intervention had not existed (63).

This study showed that mCPP-induced activation in dominantly in frontal brain regions including cingulate thalamus cheap 90mg priligy with visa, orbitofrontal cortex purchase priligy 60 mg with mastercard, caudate discount priligy 60 mg mastercard, and middle frontal gyrus and orbitofrontal cortex (64,65), but also in cerebel- gyrus was significantly blunted in patients with alcoholism lum (66). The reductions in benzodiazepine receptors in when compared with controls (74). This finding was inter- patients with alcoholism reported by these imaging studies preted as reflecting a hyporesponsive striatothalamoorbito- are consistent with postmortem studies and may indicate frontal circuit in patients with alcoholism. The abnormal either a toxic effect of alcoholism on benzodiazepine recep- response to mCPP suggests an involvement of the serotonin tors or a vulnerability factor for developing alcoholism. The system in the abnormalities seen in this circuit in patients reductions in benzodiazepine receptors in the orbitofrontal with alcoholism. This study showed a significant reduction in the availability of brainstem serotonin transporters in patients with alcoholism Dopamine System that was significantly correlated with lifetime alcohol con- DA D2 receptors were evaluated in patients with alcoholism sumption and with ratings of depression and anxiety during with PET and [11C]raclopride and showed significant re- withdrawal (75). As for the prior study, this finding provides ductions in DA D2 receptor availability when compared evidence of a role for serotonin in alcoholism and in its with controls (67,68). No significant correlations were involvement with depressive symptoms during withdrawal. One of these studies also Opioid System measured DATs in a subgroup of the alcoholics in whom reductions in DA D2 receptors were detected and reported The effects of an oral naltrexone challenge on CBF in pa- no changes in DAT availability (68). This finding was inter- tients with alcoholism during detoxification was studied preted as evidence of GABAergic involvement in patients with SPECT and HMPAO. At baseline, patients with alco- with alcoholism because DA D2 receptors in striatum are holism showed lower CBF in left orbitofrontal cortex and mainly localized in GABA cells. After naltrexone, a signifi- DAT availability in patients with alcoholism has been cant regional CBF decrease was found in basal ganglia and measured by various PET and SPECT studies. The results the left mesial temporal region, which are structures rich in have not been consistent. These results were interpreted as support- reported that a group of violent patients with alcoholism ing the involvement of the opioid system in alcohol depen- had increases (8%) and nonviolent patients with alcoholism dence (76). SPECT studies in nonviolent patients with late-onset Spectroscopic Studies alcoholism have also reported a reduction in DATs (70). However, a PET study done with [11C]D-threo-MP and a Patients with alcoholism had a significant reduction of the SPECT study done with [123I] -CIT showed no changes cerebellar N-acetylaspartate–to-creatine ratio, which was in- in DATs in patients with alcoholism (71,68). These discrep- terpreted as reflecting neuronal loss and a reduction of the ancies are likely to reflect in differences in the time since choline-to-creatine ratio, which was interpreted as reflecting detoxification. One SPECT study showed that whereas cell membrane modification or myelin alterations (77). DAT levels were significantly reduced in patients with alco- holism within the first few days of last alcohol use, the levels Subjects at Risk of Alcoholism returned to normal 4 weeks after detoxification (72). PET studies with 6-[18F]-FDOPA (a marker for the DA synthesis The regional brain metabolic response to lorazepam was in the DA terminal) in patients late-onset (type 1) alcohol- evaluated in subjects with a positive family history of alco- ism showed higher striatal 6-[18F]-FDOPA uptake in the holism (FHP) and was compared with that of subjects with- patients with alcoholism than in the controls, a finding that out a family history of alcoholism (FHN) (78). At baseline, was interpreted as a compensatory mechanism to low post- FHP subjects showed lower cerebellar metabolism than synaptic DA function (73). FHN, and when challenged with lorazepam, they also showed a blunted response in cerebellum and in anterior cingulate gyrus. Lorazepam-induced changes in cerebellar Serotonin System metabolism were significantly correlated with motor impair- The effects of m-chlorophenylpiperazine (mCPP), a mixed ment. The blunted cerebellar sensitivity to benzodiazepines serotonin agonist-antagonist drug, on brain glucose metab- in FHP could account for the decreased sensitivity to the olism was compared in patients with alcoholism and in con- motor effects of alcohol and benzodiazepines in FHP sub- 1484 Neuropsychopharmacology: The Fifth Generation of Progress jects. The decreased cerebellar baseline metabolism in FHP in cerebral high-energy phosphates and in phospholipid me- subjects as well as the blunted cerebellar response to lora- tabolites. Marijuana Opiates Marijuana is the most widely used illicit drug of abuse in the United States. Despite its widespread use, the mecha- The effects of morphine on brain glucose metabolism were 9 nisms by which -tetrahydrocannabinol (THC) (the main evaluated in polydrug abusers (79). This study showed that psychoactive substance of marijuana) exerts its psychoactive morphine reduced glucose metabolism by 10% in whole effects are still not known. Relatively few imaging studies brain and by about 5% to 15% in telencephalic areas and have been done to assess the effects of acute and chronic the cerebellar cortex. Morphine-induced metabolic decre- marijuana use in the human brain. The effects of acute fentanyl, a synthetic opiate, on CBF were measured with PET and [15O]water. Fentanyl Brain Metabolism and Cerebral Blood Flow administration was associated with significant increases in regional CBF in cingulate, orbitofrontal, and medial pre- SPECT studies assessed the effect of THC intoxication on frontal cortices, as well as caudate nuclei, areas known to CBF in chronic marijuana users (84,85). Acute marijuana be involved in reward and addiction (80). In a more continuation and then retested 2 weeks later (81). The recent study, these investigators extended these findings to initial scans demonstrated significant CBF defects in the a larger groups of subjects and documented increases in frontal, parietal, and temporal cortices. Two weeks later, CBF in anterior cingulate gyrus and in the insula in mari- the SPECT scans showed improvement. Interpretation of the effects of THC on this study provide evidence that long-term use of opiates CBF is confounded by the vasoactive properties of THC results in perfusion abnormalities that are partially reversible (87). Thus, it is difficult to separate the effects of THC that with short-term abstinence. This problem is obviated when using deoxyglucose to measure brain glucose metabo- Dopamine System lism because this agent is insensitive to fluctuations in CBF Using PET and [11C]raclopride, opioid-dependent subjects (88). Naloxone-induced withdrawal in opioid-depen- lism have been evaluated in nonabusing controls (89) as well dent subjects did not change [11C]raclopride binding, a as in marijuana abusers (90). The whole-brain metabolic finding indicating that withdrawal does not alter synaptic response to the effects of THC was variable among individu- DA in the striatum as measured by this method (82). Despite these variable responses in whole-brain metabolism, there was a very consistent pat- Opioid System tern of metabolic activation by THC. That is, under THC To date, there have been no published studies of opioid intoxication, most of the subjects showed activation of the abusers using these opiate receptor radioligands to study cerebellum. The cerebellar activation by THC was signifi- heroin abusers (see earlier). In marijuana abusers, THC also increased metabolism in the anterior cingulate gyrus and in the orbitofrontal cortex. A Spectroscopic Studies more recent study assessing the effects of marijuana on CBF Phosphorus magnetic resonance spectroscopy (31P MRS) at also reported an increase in cerebellar flow during intoxica- 1. The highly localized concentration of canna- caine and heroin dependence) (83). The phosphorus metab- binoid receptors in the cerebellum (92) supports involve- olite signal expressed as a percentage of total phosphorus ment of the cannabinoid receptors in the metabolic and signal was 15% higher for phosphomonoesters, 10% lower CBF response during THC intoxication. Activation of the for nucleotide triphosphates ( -NTP), and 7% lower for cerebellum by THC could explain the disruption in motor total nucleotide phosphates in polydrug abusers compared coordination and proprioception during THC intoxication. These findings were interpreted as suggesting Cannabinoid receptors are also localized in other discrete that long-term drug abuse or withdrawal results in changes areas, namely, hippocampus, substantia nigra, pars reticu- Chapter 103: Application of Imaging Technologies in Drug Addiction 1485 lata, and globus pallidus. Inhibition of MAO by cigarette smoke could with the spatial resolution of the PET instrument used.

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However purchase priligy 90 mg on-line, it is not always this clear discount priligy 30 mg line, and lated cheap priligy generic, awkward, and odd behaviors of a child with schizo- there is a high rate of misdiagnosis in both directions (72, phrenia. An identifiable traumatic event, abuse, or neglect 73). This is particu- Organic Psychoses larly so if the child has a positive family history of bipolar disorder, psychomotor retardation, rapid onset of symp- Neurologic Conditions toms, mood-congruent psychotic symptoms, or pharmaco- Seizure Disorder logically induced mania or hypomania. The characteristics Children with seizure disorders can experience hallucinations of the delusions and hallucinations are often mood con- as part of the seizure activity. Complex partial seizures, espe- gruent (expansiveness, grandiosity, and euphoria). There- cially those with a temporal focus, may be associated with fore, a child experiencing mania may have delusions of being interictal psychotic symptoms of delusions, hallucinations, 'superman' with special powers, of being able to fly and and unusual preoccupations. Conversely, the child may believe scribed a formal thought disorder in children with partial that he or she has special skills playing baseball, even though complex seizures (78,79), although their way of defining the child perhaps may have problems with gross motor skills thought disorder makes it intertwine closely with language and is clumsy and uncoordinated. However, they did emphasize that hear voices, the content of which are mood congruent, with these epileptic children usually do not display negative the altered state in mood (i. Hallucina- that the voice is saying that he or she is superior and can tions in children with epilepsy typically are brief. Caplan and co-workers also described rus–related syndromes, which can result in delirious states. They postulated that these chronic liver and kidney disease may cause delirious states symptoms may either reflect the underlying neuropathology associated with psychotic symptoms in children, manifested that produces the seizures or result from the 'kindling phe- by states of confusion, distortions in perceptions, and frank nomenon' as a secondary effect of the seizure activity. The best example of medication-induced psychosis is Deteriorative Neurologic Disorders that resulting from high doses of stimulants (the most com- Psychotic symptoms have been described in children who monly prescribed group of medications in this age group). Other disorders such as over-the-counter antihistamines and decongestants, include Wilson disease, lipid storage disorders, and Hun- can induce similar symptoms. These are usually differentiated from child- tions that can have a similar result are steroids, which can hood-onset schizophrenia by the presence of neurologic cause not only a disturbance in mood (depression and manic findings on physical examination of the child, further cor- symptoms), but also delirium. Children prescribed anticho- roborated by abnormal findings on laboratory testing. Chil- linergic drugs are also vulnerable to developing delirium, dren suffering from such neurologic deterioration often presenting with psychotic symptoms. Most children who develop These conditions include brain tumors, congenital malfor- drug-induced psychosis recover once the drugs are out of mations, and head trauma. The psychotic symptoms sometimes experienced by pa- tients after anesthesia should be included in the category of Metabolic and Hormonal Disturbances toxic psychoses. Although usually short-lived, this phenom- Various metabolic and hormonal conditions can be responsi- enon is reported by patients to be a very frightening experi- ble for psychotic symptoms in children. Support, reassurance, and ensuring safety at the time may include disorders of the adrenal, thyroid, or parathyroid are usually sufficient in the management of patients after glands. Exogenous metabolic disturbances leading to psy- anesthesia. MANAGEMENT AND TREATMENT Toxic Psychoses Assessment Toxic psychosis or delirium usually occurs secondary to bacte- rial or viral infections, high fevers, and exogenous toxins Effective treatment requires knowledge of the psychotic dis- including medications, illicit drugs, alcohol, and poison- orders, diagnostic criteria, symptoms, and longitudinal ings. Auditory hallucinations can also also addressing any comorbid disorders or biopsychosocial occur, but their content is qualitatively different from those stressors. The physician must prioritize symptoms and diag- experienced in childhood schizophrenia or mood disorders. Children and adolescents often question about delusions and hallucinations and whether describe the experience as 'losing their mind'—a frighten- the child endorses the psychotic symptoms only to please the ing concept, and they can become disoriented, unable to interviewer or to get attention. In addition, it is important to orient to person or place, or comprehend why they are be- determine whether the child acts on the basis of the delu- having in an unusual manner. They may also experience sional or hallucinatory perceptions—associated with an af- fluctuating levels of alertness. In children, infections (bacterial or viral) can cause en- The assessment of the child with psychotic symptoms cephalitis, meningitis, and human immunodeficiency vi- should include a careful, comprehensive, and thoughtful 620 Neuropsychopharmacology: The Fifth Generation of Progress evaluation. The assessment when the clinical picture is dominated by frank delusions should include a detailed evaluation of the symptom presen- and hallucinations and other positive symptoms such as a tation, course of illness, and phenomenology. A develop- formal thought disorder or strange and idiosyncratic behav- mental history of the child and a detailed family psychiatric iors. A positive family history, especially for an affec- to remit and dissipate. However, often there may still be tive disorder or schizophrenia because these disorders tend the presence of some psychotic symptoms, although they to run in families, often helps the clinician with the differen- are less disturbing to the child. In this phase, the child may tial diagnosis in the child. This will, in large part, determine tinue to subside, but the child continues to experience apa- the management and treatment of the child presenting with thy, lack of motivation, withdrawal, and restricted or flat psychosis. A thorough physical examination is essential, and affect. These may include imaging studies, an electroen- chronically impaired, despite what would be considered ad- cephalogram, toxicology screens, and renal and liver func- equate treatment. Usually, such impairment is characterized tion tests. Some children may require consultation with by persistent symptoms, which occur especially if the psy- other pediatric specialists. However, they can be helpful for intellectual assess- both the parents and the child. Interventions targeted at ment and to determine developmental delays, because these improving family functioning, problem solving, communi- deficits may influence the presentation or interpretation of cation skills, and relapse prevention have been shown to symptoms. Routine use of adaptive function measures is decrease relapse rates in adults (82). Children may benefit important for understanding actual function in social, daily from social skills training and may require specialized educa- living, and communication domains. These can be quite tional programs, academic adjustments, and support at helpful in planning and maintaining developmentally rele- school. Ongoing illness teaching and medication education, vant treatment goals. Similarly, speech and language evalua- are important to promote compliance with treatment and tions are often helpful, especially with a child who appears to help in coping with the daily and sometimes long-term to have linguistic impairments on examination. Every effort should be made for the child to be maintained in the least restrictive setting, such as home. However, in some cases, the severity Treatment and chronicity of the underlying illness may warrant long- If it is deemed that the cause is organic, then the first step term placement in a hospital or residential facility. This may include treating a partial complex sei- underlying cause of the psychosis, or for symptom control, zure disorder, managing a metabolic imbalance, or treating in those children who have psychotic symptoms secondary an underlying infection or reducing a fever. Informed consent from the parents or it is determined that there is no medical cause for the psy- guardian should be obtained before treatment with psycho- chotic symptoms, then the next step is to ascertain whether pharmacologic agents is instituted. If so, is it secondary to severe It is not in the purview of this chapter to discuss each depression or acute mania with psychotic symptoms or sec- medication in detail.

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In addition proven 30mg priligy, one of the 206 studies also assessed recurrence of AF at 1 month following conversion priligy 30 mg on line. Restoration of Sinus Rhythm Results for comparisons between antiarrhythmic drugs are shown in Table 12 discount priligy 60mg line. No statistically significant differences among the drugs were seen except between amiodarone versus ibutilide in one study and between ibutilide plus propafenone versus ibutilide alone in one study. Few adverse events were reported in any of the studies. Comparisons of antiarrhythmic drugs for restoration of sinus rhythm Study Sample Time Frame Restoration of SR pre-DCC P Value Restoration of SR Post-DCC P value Size (N) for (or Without DCC) Assessment Thomas, 140 12 hours Amiodarone: 27/52 (52%) NS Amiodarone: 22/25 (88%) NR 149 2004 Sotalol: 20/45 (44%) Sotalol: 23/25 (92%) Digoxin: 21/42 (50%) Digoxin: 20/21 (95%) Vijaya- 94 6 weeks Amiodarone: 7/27 (26%) 0. These studies represented 736 patients and estimated an OR of 1. Forest plot for restoration of sinus rhythm for amiodarone versus sotalol Study name Odds ratio and 95% CI Odds Lower Upper ratio limit limit Joseph, 2000 0. Two of these included a second antiarrhythmic drug arm. Three studies reported a statistically significantly greater restoration in sinus rhythm with amiodarone versus a rate- controlling drug, three studies showed no statistically significant difference between amiodarone and the rate-controlling drug, and one did not report a statistical analysis comparing amiodarone with a rate-controlling drug. One study showed that sotalol was better than digoxin at restoring sinus rhythm (88% vs. Three studies evaluated differences between an antiarrhythmic drug and rate-controlling drug in rates of conversion after an electrical cardioversion. In 1 study amiodarone had a greater rate of conversion than diltiazem or digoxin (91% for amiodarone, 76% for diltiazem, and 67% for digoxin) which was statistically significant, but the other 2 studies either found no statistically significant difference or did not report a statistical analysis. Studies including comparisons of an antiarrhythmic drug with a rate-controlling drug Study Sample Time Frame Restoration of SR pre- P Value Restoration of SR Post- P Value Size (N) for DCC (or Without DCC) DCC Assessment Thomas, 140 12 hours Amiodarone: 27/52 (52%) NS Amiodarone: 22/25 (88%) NR 149 2004 Sotalol: 20/45 (44%) Sotalol: 23/25 (92%) Digoxin: 21/42 (50%) Digoxin: 20/21 (95%) Joseph, 115 48 hours Amiodarone: 30/39 (77%) <0. This finding is unsurprising given that rate-controlling agents would not be expected to terminate sinus rhythm. Forest plot for restoration of sinus rhythm for amiodarone versus rate-control drugs Study name Odds ratio and 95% CI Odds Lower Upper ratio l i mi t l i mi t Capucci, 2000 10. In three of the studies, a comparison between drugs was 145,147,206 also made after an external electrical cardioversion procedure. Three of the studies 145,147,206 compared verapamil to digoxin for 2–4 weeks, and one compared IV esmolol to 189 digoxin during the infusion period. In three of the studies no difference was found between the 145,189,206 drugs in the proportion of patients converting to sinus rhythm. In 1 study, 14 percent of patients receiving verapamil converted to sinus rhythm compared with 0 percent receiving 147 digoxin, a difference that was statistically significant (p<0. In the three studies that also assessed outcomes after electrical cardioversion, only one found a statistically significant difference between the treatment arms; this favored digoxin over verapamil (65% of patients 147 receiving verapamil vs. Recurrece of Atrial Fibrillation Recurrence of AF within 24 hours of drug initiation was reported in 1 study that compared 191 antiarrhythmic drugs (amiodarone vs. Strength of Evidence Our review identified 42 studies exploring the use of antiarrhythmic drugs and electrical cardioversion for conversion to sinus rhythm. These studies demonstrated that a single biphasic waveform is more effective than monophasic waveform in patients with persistent AF. Conversely, the included studies did not identify a significant difference in restoration of sinus rhythm with use of an anterolateral versus anteroposterior positioning of cardioversion electrodes. Although the strength of this evidence was rated as low, this finding is potentially clinically helpful, as health care providers often debate the superiority of one positioning of cardioversion electrodes over another. Studies demonstrated a benefit of drug pretreatment for restoration and maintenance of sinus rhythm, although data were inconclusive as to whether specific drugs were more beneficial as compared to other pharmacological alternatives. This finding challenges the assumption that one antiarrhythmic medication is clearly superior to others and underscores the need for more studies comparing the effectiveness and safety of different antiarrhythmic medications in enhancing restoration of sinus rhythm. Table 14 summarizes the strength of evidence for the outcomes of interest comparing antiarrhythmic drugs and electrical cardioversion methods. For those comparisons where the number of studies was sufficient to estimate a summary effect we were able to have greater confidence in our findings. Strength of evidence domains for antiarrhythmic drugs versus electrical cardioversion Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Comparison of Various Methods for External Electrical Cardioversion (Biphasic vs. Monophasic Waveforms) Restoration of 4 (411) RCT/Low Consistent Direct Precise SOE=High Sinus Rhythm OR 4. Anteroposterior Cardioversions) Restoration of 4 (393) RCT/Low Inconsistent Direct Imprecise SOE=Low Sinus Rhythm OR 0. Strength of evidence domains for antiarrhythmic drugs versus electrical cardioversion (continued) Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Comparison of Various Methods for External Electrical Cardioversion (Energy Protocols) Restoration of 3 (432) RCT/Low Consistent Direct Precise SOE=High Sinus Rhythm OR 0. No Drug Enhancement) Restoration of 2 (218) RCT/Low Consistent Direct Imprecise SOE=Moderate Sinus Rhythm No significant benefit for patients given ibutilide or metoprolol pretreatment (p values NR) Maintenance of 2 (195) RCT/Low Consistent Direct Imprecise SOE=Moderate Sinus Rhytm Significant benefit for patients given verapamil or metoprolol pretreatment (p values of 0. Sotalol) Restoration of 4 (736) RCT/Low Inconsistent Direct Imprecise SOE=Low Sinus Rhythm OR 1. Rate-Control Drugs) Restoration of 7 (613) RCT/Low Consistent Direct Precise SOE=High Sinus Rhythm OR 2. Rhythm-Control Procedures and Drugs for Maintenance of Sinus Rhythm KQ 5: What are the comparative safety and effectiveness of newer procedural rhythm-control therapies, other nonpharmacological rhythm- control therapies, and pharmacological agents (either separately or in combination with each other) for maintenance of sinus rhythm in atrial fibrillation patients? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest? Key Points Procedural therapies: • Transcatheter pulmonary vein isolation (PVI) versus antiarrhythmic drugs o Based on 8 RCTs (5 good, 3 fair quality) involving 921 patients, transcatheter PVI is superior to antiarrhythmic drugs for maintenance of sinus rhythm over 12 months of followup in patients with paroxysmal AF (high strength of evidence). This evidence is strongest in younger patients with little to no structural heart disease, and with no or mild enlargement of the left atrium. Overall Description of Included Studies A total of 83 studies met our inclusion criteria and assessed the comparative safety and effectiveness of new procedural rhythm-control therapies, other nonpharmacological rhythm- control therapies, and pharmacological agents for the maintenance of sinus rhythm in patients with AF (Appendix Table F-5). Studies began enrollment from 1994 to 2007 and enrolled between 22 and 665 patients per study, resulting in a total of 11,014 patients. All were RCTs, 178,180,181,207-239 144,145,240-280 with 36 rated as being of good quality, 43 fair quality, and 4 poor 205,281-283 quality. A majority of studies (54 [65%] included 144,145,178,181,205,207-215,219-228,232-237,242,244,245,247,249-251,253-256,258-261,265,269,270,273-275,280- sites in Europe, 282 180,215-218,220,223-225,228-230,236,241,253,256,266,267,271,276,277,279 22 included sites in North America, 10 224,231,238,246,257,262-264,278,283 224,240,243,248,268 included sites in Asia, 5 included sites in South America, 224,252 239,272 2 included sites in Australia; and 2 studies did not report a location. A majority of 144,181,205,207,208,210,211,213- studies (51 [61%]), did not report their source of funding. Three of these six studies were multicenter trials; the other three were single-center trials. Linked/secondary papers used in the analyses below were: 284 285 286 180 • Atwood, 2007; Batcher, 2007; and Singh, 2009 – all linked to Singh, 2005 (SAFE-T) 59 287 288 289 230 • Dorian, 2003; Dorian, 2002; and Lumer, 2002 – all linked to Roy, 2000 (Canadian Trial of Atrial Fibrillation) 290 214 • Khargi, 2001 – linked to Deneke, 2002 291 229 • Leong-Sit, 2011 – linked to Roux, 2009 (5A) 292 226 • Pappone, 2011 – linked to Pappone, 2006 (APAF) 293 228 • Reynolds, 2010 – linked to Wilber, 2010 (ThermoCool AF)] Below we provide an overview and then detailed syntheses stratified by the comparisons evaluated in the 83 studies. Procedural Therapies for Rhythm Control Description of Studies We identified 65 studies of procedural therapies for rhythm control. They enrolled 6,739 patients across 5 continents, with the 207- majority (36 studies) including sites in Europe. Thirty-one studies were rated as good quality, 223,225-229,231-239 240,242-244,246-248,250-255,257,262-268,270-280 282,283 32 as fair quality, and 2 as poor quality. The majority of studies (39 [59%]) did 207,208,210,211,213-216,220,222,223,226,229,231,234,238-240,242,244,248,250- not report their funding source.

The top panel shows that increasing the glucose concen- 0 tration in the tubular fluid accelerates the transport rate of the 0 200 400 600 glucose transporters until a m axim al rate is achieved buy priligy. The term 400 threshold applies to the point that glucose first appears in the urine buy 90 mg priligy with mastercard. The m axim al overall rate of glucose transport by the proxi- Normal m al tubule SGLT1 and SGLT2 is term ed the Tm ax order on line priligy. Glucose is detected in urine either when the filtered load is increased (as in Type B renal glucosuria diabetes m ellitus) or, as shown in the bottom panel, when a defect occurs in tubular reabsorption (as in renal glucosuria). Kinetic 200 studies have dem onstrated two types of glucosuria caused by either reduced m axim al transport velocity (type A) or reduced affinity of Type A renal glucosuria the transporter for glucose (type B). M utations in the gene encoding SGLT1 cause glucose-galactose m alabsorption syndrom e, a severe autosom al recessive intestinal disorder associated with 0 m ild renal glucosuria (type B). Defects in SGLT2 result in a com - 0 200 400 600 paratively m ore severe renal glucosuria (type A). H owever, this dis- Filtered glucose load, mg/min 1. Am ong m em bers of the basolateral glu- cose transporter (GLUT) fam ily, only GLUT1 and GLUT2 are rele- vant to renal physiology. Clinical disorders associated with m utations in the genes encoding these transporters have yet to be described. FIGURE 12-3 O ver 95% of the filtered am ino acid load is norm ally reabsorbed in Cystine actually is a neutral am ino acid that shares a com m on the proxim al tubule. The term am inoaciduria is applied when m ore carrier with the dibasic am ino acids lysine, arginine, and ornithine. Am inoaciduria The transport of all four am ino acids is disrupted in cystinuria. The can occur in the context of m etabolic defects, which elevate plasm a rarer disorder, lysinuric protein intolerance, results from defects in am ino acid concentrations and thus increase the glom erular filtered the basolateral transport of dibasic am ino acids but not cystine. In addition, am inoaciduria can arise from genetic defects in consequent hyperam m onem ia. Three distinct groups of inherited am inoacidurias are distin- H artnup disease, blue diaper syndrom e, m ethioninuria, im inogly- guished based on the net charge of the target am ino acids at neutral cinuria, and glycinuria. Several neutral am ino acid transporters pH : acidic (negative charge), basic (positive charge), and neutral have been cloned and characterized. H artnup disease involves a neutral am ino acid transport system Acidic am inoaciduria involves the transport of glutam ate and in both the kidney and intestine, whereas blue diaper syndrom e aspartate and results from a defect in the high-affinity sodium - involves a kidney-specific tryptophan transporter. M ethioninuria potassium –dependent glutam ate transporter. It is a clinically appears to involve a separate m ethionine transport system in the benign disorder. Case reports describe seizures, m ental retardation, Four syndrom es caused by defects in the transport of basic and episodic hyperventilation in affected patients. The patho- am ino acids or cystine have been described: cystinuria, lysinuric physiologic basis for this phenotype is unclear. Im inoglycinuria protein intolerance, isolated cystinuria, and isolated lysinuria. Differences in the urinary Category Phenotype Intestinal transport defect excretion of cystine in obligate heterozygotes and intestinal amino acid transport studies in I hom ozygotes have provided the basis for Heterozygote No abnormality defining three distinct phenotypes of cystin- Homozygote Cystinuria, basic aminoaciduria, cystine stones Cystinine, basic amino acids uria. Genetic studies have identified II m utations in the gene (SCL3A1) encoding a Heterozygote Excess excretion of cystine and basic amino acids Homozygote Cystinuria, basic aminoaciduria, cystine stones Basic amino acids only high-affinity transporter for cystine and the III dibasic am ino acids in patients with type I Heterozygote Excess excretion of cystine and basic amino acids cystinuria [10,11]. In patients with type III Homozygote Cystinuria, basic aminoaciduria, cystine stones None cystinuria, SCL3A1 was excluded as the disease-causing gene. A second cystin- uria-susceptibility gene recently has been From Morris and Ives; with permission. Excessive urinary excretion of cystine (250 to 1000 mg/d of cystine/g of creatinine) coupled with its poor solubility in urine causes cystine precipitation with the formation of characteris- tic urinary crystals and urinary tract calculi. Stone formation often causes urinary tract obstruction and the associated problems of renal colic, infection, and even renal failure. The treatment objective is to reduce urinary cystine concentration or to increase its solubility. High fluid intake (to keep the urinary cystine concentration below the solubility threshold of 250 mg/L) and urinary alkalization are the mainstays of therapy. For those patients refractory to conservative management, treatment with sulfhydryl-containing drugs, such as D-penicillamine, mercaptopropionylglycine, and even captopril can be efficacious [14,15]. These disorders include X-linked hypo- osteomalacia in adults. These disorders can be distinguished on phosphatemic rickets (HYP), hereditary hypophosphatemic rickets the basis of the renal hormonal response to hypophosphatemia, the with hypercalciuria (HHRH), hypophosphatemic bone disease (HBD), biochemical profile, and responsiveness to therapy. In addition, the autosomal dominant hypophosphatemic rickets (ADHR), autosomal rare disorder XLRH is associated with nephrolithiasis. The clinical recessive hypophosphatemic rickets (ARHR), and X-linked recessive features of the two most common disorders HYP and HHRH are hypophosphatemic rickets (XLRH). W hereas both disorders have defects in renal Pi two com m on features: persistent hypophosphatem ia caused by reabsorption, the renal hormonal response to hypophosphatemia is decreased renal tubular phosphate (Pi) reabsorption (expressed as im paired in H YP but not in H H RH. Indeed, in children with decreased ratio of plasma concentration at which maximal phosphate HHRH, phosphate supplementation alone can improve growth rates, reabsorption occurs [Tm P] to glom erular filtration rate [GFR], resolve the radiologic evidence of rickets, and correct all biochemical [TmP/GFR], a normogram derivative of the fractional excretion of abnormalities except the reduced TmP GFR. Cell culture, parabiosis, and transplantation experiments have demonstrated that Phosphatonin Degradation the defect in HYP is not intrinsic to the kidney but involves a circulat- ing humoral factor other than parathyroid hormone [16,17]. Phosphate is transported across the lum inal m em brane of the proximal tubule by a sodium-phosphate cotransporter (NaPi). This ATP transporter is regulated by multiple hormones. Among these is a puta- + 3Na+ tive phosphaturic factor that has been designated phosphatonin. Na It is postulated that phosphatonin inhibits Pi reabsorption by way of Pi 2K+ the sodium-coupled phosphate cotransporter, and it depresses serum 1α-hydroxylase ADP 1,25-dihydroxy-vitamin D3 production by inhibiting 1- -hydroxlase activity and stimulating 24-hydroxylase activity. Positional cloning studies in families with HYP have identified a gene, designated PEX 25-Vitamin D 1,25-Vitamin D (phosphate-regulating gene with homologies to endopeptidases on the X chromosome), that is mutated in patients with X-linked hypophos- phatemia. PEX, a neutral endopeptidase, presumably inactivates Lumen Interstitium phosphatonin. Defective PEX activity would lead to decreased phosphatonin degradation, with excessive phosphaturia and deranged vitamin D metabolism. A similar scenario associated with increased FIGURE 12-7 phosphatonin production has been proposed as the basis for Proposed pathogenesis of X-linked hypophosphatemic rickets (HYP). The disorder is character- Na+— sodium ion; K+— potassium ion. Bergeron and coworkers have proposed a patho- ATP (2) physiologic model that involves the intracellular gradients of sodium, (1) + + adenosine triphosphate (ATP), and adenosine diphosphate (ADP).