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The Cochrane Database of Systematic... Jun 2013Human African trypanosomiasis, or sleeping sickness, is a painful and protracted disease affecting people in the poorest parts of Africa and is fatal without treatment.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Human African trypanosomiasis, or sleeping sickness, is a painful and protracted disease affecting people in the poorest parts of Africa and is fatal without treatment. Few drugs are currently available for second-stage sleeping sickness, with considerable adverse events and variable efficacy.
OBJECTIVES
To evaluate the effectiveness and safety of drugs for treating second-stage human African trypanosomiasis.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group Specialized Register (January 2013), CENTRAL (The Cochrane Library Issue 12 2012) , MEDLINE (1966 to January 2013), EMBASE (1974 to January 2013), LILACS (1982 to January 2013 ), BIOSIS (1926-January 2013), mRCT (January 2013) and reference lists. We contacted researchers working in the field and organizations.
SELECTION CRITERIA
Randomized and quasi-randomized controlled trials including adults and children with second-stage HAT, treated with anti-trypanosomal drugs.
DATA COLLECTION AND ANALYSIS
Two authors (VL and AK) extracted data and assessed methodological quality; a third author (JS) acted as an arbitrator. Included trials only reported dichotomous outcomes, and we present these as risk ratio (RR) with 95% confidence intervals (CI).
MAIN RESULTS
Nine trials with 2577 participants, all with Trypansoma brucei gambiense HAT, were included. Seven trials tested currently available drugs: melarsoprol, eflornithine, nifurtimox, alone or in combination; one trial tested pentamidine, and one trial assessed the addition of prednisolone to melarsoprol. The frequency of death and number of adverse events were similar between patients treated with fixed 10-day regimens of melarsoprol or 26-days regimens. Melarsoprol monotherapy gave fewer relapses than pentamidine or nifurtimox, but resulted in more adverse events.Later trials evaluate nifurtimox combined with eflornithine (NECT), showing this gives few relapses and is well tolerated. It also has practical advantages in reducing the frequency and number of eflornithine slow infusions to twice a day, thus easing the burden on health personnel and patients.
AUTHORS' CONCLUSIONS
Choice of therapy for second stage Gambiense HAT will continue to be determined by what is locally available, but eflornithine and NECT are likely to replace melarsoprol, with careful parasite resistance monitoring. We need research on reducing adverse effects of currently used drugs, testing different regimens, and experimental and clinical studies of new compounds, effective for both stages of the disease.
Topics: Animals; Antiprotozoal Agents; Drug Therapy, Combination; Eflornithine; Humans; Melarsoprol; Nifurtimox; Pentamidine; Prednisolone; Randomized Controlled Trials as Topic; Recurrence; Trypanosoma brucei gambiense; Trypanosomiasis, African
PubMed: 23807762
DOI: 10.1002/14651858.CD006201.pub3 -
PloS One 2013Leishmaniasis is an important public health problem in the Americas. A Cochrane review published in 2009 analyzed 38 randomized controlled trials (RCT). We conducted a... (Review)
Review
INTRODUCTION
Leishmaniasis is an important public health problem in the Americas. A Cochrane review published in 2009 analyzed 38 randomized controlled trials (RCT). We conducted a systematic review to evaluate the effects of therapeutic interventions for American cutaneous and mucocutaneous leishmaniasis.
METHODS
All studies were extracted from PubMed, Embase, Lilacs (2009 to July, 2012 respectively), the Cochrane Central Register of Controlled Trials (6-2012) and references of identified publications. RCTs' risk of bias was assessed.
RESULTS
We identified 1865 references of interest; we finally included 10 new RCTs. The risk of bias scored low or unclear for most domains. Miltefosine was not significantly different from meglumine antimoniate in the complete cure rate at 6 months (4 RCT; 584 participants; ITT; RR: 1.12; 95%CI: 0.85 to 1.47; I2 78%). However a significant difference in the rate of complete cure favoring miltefosine at 6 months was found in L. panamensis and L. guyanensis (2 RCTs, 206 participants; ITT; RR: 1.22; 95%CI: 1.02 to 1.46; I2 0%). One RCT found that meglumine antimoniate was superior to pentamidine in the rate of complete cure for L. braziliensis (80 participants, ITT; RR: 2.21; 95%CI: 1.41 to 3.49), while another RCT assessing L. guyanensis did not find any significant difference. Although meta-analysis of three studies found a significant difference in the rate of complete cure at 3 months favoring imiquimod versus placebo (134 participants; ITT; RR: 1.45; 95%CI: 1.12 to 1.88; I2 0%), no significant differences were found at 6 and 12 months. Thermotherapy and nitric oxide were not superior to meglumine antimoniate.
CONCLUSION
Therapeutic interventions for American cutaneous and mucocutaneous leishmaniasis are varied and should be decided according to the context. Since mucosal disease is the more neglected form of leishmaniasis a multicentric trial should be urgently considered.
Topics: Humans; Hyperthermia, Induced; Leishmaniasis, Cutaneous; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 23637917
DOI: 10.1371/journal.pone.0061843 -
Parasitology Jul 2013Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease,... (Review)
Review
Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.
Topics: Amidines; Animals; Antiprotozoal Agents; Humans; Intracellular Space; Microscopy, Electron, Transmission; Parasites; Pentamidine; Protozoan Infections; Ultrasonography
PubMed: 23561006
DOI: 10.1017/S0031182013000292 -
Acta Tropica May 2011Pentavalent antimonials are first-line drugs for the treatment of the cutaneous form of American tegumentary leishmaniasis. Second-line drugs include amphotericin B and... (Review)
Review
Pentavalent antimonials are first-line drugs for the treatment of the cutaneous form of American tegumentary leishmaniasis. Second-line drugs include amphotericin B and pentamidine. Although these drugs have been used for decades, there are no systematic reviews about their safety. The objective of this review was to identify and classify the main adverse effects associated with these drugs and to estimate the frequency of these effects, whenever possible. Intervention studies, case series and case reports containing information regarding clinical, laboratory or electrocardiographic adverse effects of drugs used for the treatment of cutaneous leishmaniasis were systematically retrieved from 10 databases searched between August 13, 2008 and March 31, 2009. The 65 studies included in this review had treated a total of 4359 patients from 12 countries infected with eight different Leishmania species. Despite the small number of drugs used in these studies, a wide variability in the therapeutic regimens was observed. As a consequence, the adverse effects of pentavalent antimonials and pentamidine needed to be classified jointly according to system, irrespective of formulation, daily dose, duration of treatment, and route of administration. The frequencies of adverse effects were calculated based on the data of 32 articles involving 1866 patients. The most frequently reported clinical adverse effects of pentavalent antimonials and pentamidine were musculoskeletal pain, gastrointestinal disturbances, and mild to moderate headache. Electrocardiographic QTc interval prolongation and a mild to moderate increase in liver and pancreatic enzymes were additional adverse effects of pentavalent antimonials. Patients treated with liposomal amphotericin B had mild dyspnea and erythema. The adverse effects associated with miltefosine were vomiting, nausea, kinetosis, headache, diarrhea, and a mild to moderate increase in aminotransferases and creatinine. Although closer surveillance is needed for the treatment of cutaneous leishmaniasis, antileishmanial drugs are basically safe and severe side effects requiring the discontinuation of treatment are relatively uncommon.
Topics: Amphotericin B; Antimony; Antiprotozoal Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Leishmaniasis, Cutaneous; Pentamidine
PubMed: 21420925
DOI: 10.1016/j.actatropica.2011.02.007 -
The Cochrane Database of Systematic... Aug 2010Human African trypanosomiasis, or sleeping sickness, is a painful and protracted disease affecting people in the poorest parts of Africa and is fatal without treatment.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Human African trypanosomiasis, or sleeping sickness, is a painful and protracted disease affecting people in the poorest parts of Africa and is fatal without treatment. Few drugs are currently available for second-stage sleeping sickness, with considerable adverse events and variable efficacy.
OBJECTIVES
To evaluate the effectiveness and safety of drugs for treating second-stage human African trypanosomiasis.
SEARCH STRATEGY
We searched the Cochrane Infectious Diseases Group Specialized Register (May 2010), CENTRAL (The Cochrane Library Issue 3 2010) , MEDLINE (1966 to May 2010), EMBASE (1974 to May 2010), LILACS (1982 to May 2010 ), BIOSIS (1926-May 2010), mRCT (May 2010) and reference lists. We contacted researchers working in the field and organizations.
SELECTION CRITERIA
Randomized and quasi-randomized controlled trials.
DATA COLLECTION AND ANALYSIS
Two authors (VL and AK) extracted data and assessed methodological quality; a third author (JS) acted as an arbitrator. Included trials only reported dichotomous outcomes, and we present these as risk ratio (RR) with 95% confidence intervals (CI).
MAIN RESULTS
Nine trials with 2577 participants, all with Trypansoma brucei gambiense HAT, were included. Seven trials tested currently available drugs: melarsoprol, eflornithine, nifurtimox, alone or in combination; one trial tested pentamidine, and one trial assessed the addition of prednisolone to melarsoprol. Fixed 10-day regimens of melarsoprol were found to be as effective as those of 26 days, with similar numbers of adverse events. Melarsoprol monotherapy gave fewer relapses than pentamidine or nifurtimox, but resulted in more adverse events.Later trials evaluate nifurtimox combined with eflornithine (NECT), showing this gives few relapses and is well tolerated. It also has practical advantages in reducing the burden on health personnel and patients, when compared to eflornithine monotherapy.
AUTHORS' CONCLUSIONS
Choice of therapy for second stage Gambiense HAT will continue to be determined by what is locally available, but eflornithine and NECT are likely to replace melarsoprol, with careful parasite resistance monitoring. We need research on reducing adverse effects of currently used drugs, testing different regimens, and experimental and clinical studies of new compounds, effective for both stages of the disease.
Topics: Animals; Antiprotozoal Agents; Drug Therapy, Combination; Eflornithine; Humans; Melarsoprol; Nifurtimox; Pentamidine; Prednisolone; Randomized Controlled Trials as Topic; Recurrence; Trypanosoma brucei gambiense; Trypanosomiasis, African
PubMed: 20687080
DOI: 10.1002/14651858.CD006201.pub2 -
Journal of the American Academy of... Aug 2010Cutaneous leishmaniasis (CL) has traditionally been underrecognized and underreported. Improved awareness is warranted as the number of cases has increased as a result... (Review)
Review
BACKGROUND
Cutaneous leishmaniasis (CL) has traditionally been underrecognized and underreported. Improved awareness is warranted as the number of cases has increased as a result of increased travel to endemic countries, the HIV/AIDS pandemic, and the larger number of military and contract workers deployed overseas.
OBJECTIVE
We sought to present a systematic review of evidence from a gamut of research trials on the treatment efficacy of different regimens and aggregate this knowledge for use as a guide for clinical practice decisions.
METHODS
We performed a comprehensive search of print and electronic sources to identify the accumulated research information on New World CL.
RESULTS
Topical treatment of New World CL lesions is generally not recommended. Findings support the systemic administration of pentavalent antimonials as first-line treatment. Exception to this is infection with L guyanensis in French Guiana where systemic pentamidine is suggested as first-line treatment.
LIMITATIONS
The reliability of the findings of this review of research evidence is dependent on the individual quality and potential bias in its component principal trials. There was a conscious attempt to only include evidence derived from randomized controlled studies, with adequate randomization, adequate patient numbers, and complete follow-up information. However, because of the relatively small number of such studies on New World CL, evidence from nonrandomized studies and case series studies was also considered.
CONCLUSIONS
The pentavalent antimony compounds remain the first-line treatment choice for the treatment of New World CL. Concerns with cost, availability, poor compliance, and systemic toxicity, however, may compel clinicians to opt for alternative treatment modalities. Some advances in the development of an antileishmanial vaccine have been made but none is yet available for clinic use. The increase, over recent years, in the incidence of CL warrants an enhanced effort to increase awareness of the disease, assure timely diagnosis, and implement effective management and treatment strategies.
Topics: Amebicides; Antifungal Agents; Antiprotozoal Agents; Humans; Leishmaniasis Vaccines; Leishmaniasis, Cutaneous
PubMed: 20303613
DOI: 10.1016/j.jaad.2009.06.088 -
The Cochrane Database of Systematic... Apr 2009Pentavalent antimonial drugs are the most prescribed treatment for American cutaneous and mucocutaneous leishmaniasis. Other drugs have been used with varying success. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pentavalent antimonial drugs are the most prescribed treatment for American cutaneous and mucocutaneous leishmaniasis. Other drugs have been used with varying success.
OBJECTIVES
To assess the effects of therapeutic interventions for American cutaneous and mucocutaneous leishmaniasis.
SEARCH STRATEGY
We searched the Cochrane Skin Group Specialised Register (January 2009), the Register of Controlled Clinical Trials in The Cochrane Library (Issue 1,2009), MEDLINE (2003 to January 2009), EMBASE (2005 to January 2009), LILACS (from inception to January 2009), CINAHL (1982-May 2007) and other databases.
SELECTION CRITERIA
Randomised controlled trials (RCTs) assessing treatments for American cutaneous and mucocutaneous leishmaniasis.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trial quality and extracted data.
MAIN RESULTS
We included 38 trials involving 2728 participants. Results are based on individual studies or limited pooled analyses. There was good evidence in:Leishmania braziliensis and L. panamensis infections:Intramuscular (IM) meglumine antimoniate (MA) was better than oral allopurinol for 28 days (1RCT n=127, RR 0.39; 95% CI 0.26, 0.58). Intravenous (IV)MA for 20-days was better than 3-day and 7-day IVMA plus 15% paromomycin plus 12% methylbenzethonium chloride (PR-MBCL) or 7-day IVMA (1RCT n= 150, RR 0.24; 95% CI 0.11, 0.50; RR 0.69; 95% CI 0.53, 0.90; RR 0.64; 95% CI 0.44, 0.92 respectively). Oral allopurinol plus antimonials was better than IV antimonials (2RCT n= 168, RR 1.90; 95% CI 1.40, 2.59; I(2)=0%).L. braziliensis infections:Oral pentoxifylline plus IV sodium stibogluconate (SSG) was better than IVSSG (1RCT n= 23, RR 1.66; 95% CI 1.03, 2.69); IVMA was better than IM aminosidine sulphate (1RCT n= 38, RR 0.05; 95% CI 0.00, 0.78) and better than IV pentamidine isethionate (1RCT n= 80, RR 0.45; 95% CI 0.29, 0.71). Intramuscular MA was better than Bacillus Calmette-Guérin (1RCT n= 93, RR 0.46; 95% CI 0.32, 0.65).L .panamensis infections:Oral allopurinol was better than IVMA (1RCT n= 58, RR 2.20; 95% CI 1.34, 3.60). Aminosidine sulphate at doses of 12 mg/kg/day and 18 mg/kg/day for 14 days were better than aminosidine sulphate 12 mg/kg/day for 7 days (1RCT n= 60, RR 0.23; 95% CI 0.07, 0.73; RR 0.23; 95% CI 0.07, 0.73 respectively). Oral ketoconazole for 28 days, oral miltefosine and topical PR-MBCL were better than placebo.
AUTHORS' CONCLUSIONS
Most trials have been designed and reported so poorly that they are inconclusive. There is a need for large well conducted studies that evaluate long-term effects of current therapies to improve quality and standardization of methods.
Topics: Administration, Oral; Antiprotozoal Agents; BCG Vaccine; Humans; Hyperthermia, Induced; Injections, Intramuscular; Injections, Intravenous; Interferon-gamma; Leishmaniasis Vaccines; Leishmaniasis, Cutaneous; Leishmaniasis, Mucocutaneous; Randomized Controlled Trials as Topic
PubMed: 19370612
DOI: 10.1002/14651858.CD004834.pub2 -
The Journal of Clinical Endocrinology... Mar 2009Drug-induced hypoglycemia is a significant adverse effect that may cause important morbidity. (Review)
Review
CONTEXT
Drug-induced hypoglycemia is a significant adverse effect that may cause important morbidity.
OBJECTIVE
The aim of the study was to systematically review the literature for drugs reported to cause hypoglycemia and assess the quality of evidence and strength of association supporting this causal link.
DATA SOURCES
We searched electronic databases (MEDLINE, EMBASE, Web of Science, and SCOPUS) and the drug information system Micromedex through November 2007 and sought additional references from experts.
STUDY SELECTION
Studies were eligible if they reported hypoglycemia as a side effect of a drug not used to treat hyperglycemia, regardless of their design, language, size, or follow-up duration. We excluded hypoglycemia caused by industrial exposures, nonpharmacological chemical exposures, alcohol, herbs, nutritional supplements, and in vitro and animal studies.
DATA EXTRACTION
Reviewers extracted study characteristics and methodological quality and, when possible, data to estimate the odds of developing hypoglycemia when exposed to the offending agent.
DATA SYNTHESIS
We found 448 eligible studies that described 2696 cases of hypoglycemia associated with 164 different drugs. The quality of evidence supporting associations between drugs and hypoglycemia was mostly very low due to methodological limitations and imprecision. The most commonly reported offending drugs were quinolones, pentamidine, quinine, beta blockers, angiotensin-converting enzyme agents, and IGF.
CONCLUSIONS
Very low quality evidence substantiates the association between hypoglycemia and the use of numerous nondiabetic drugs.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypoglycemia; Infant; Infant, Newborn; Male; Middle Aged
PubMed: 19088166
DOI: 10.1210/jc.2008-1416 -
Journal of Acquired Immune Deficiency... May 2008Limited clinical data exist to guide the choice of second-line salvage treatment for AIDS-associated Pneumocystis jirovecii pneumonia (PCP). (Review)
Review
BACKGROUND
Limited clinical data exist to guide the choice of second-line salvage treatment for AIDS-associated Pneumocystis jirovecii pneumonia (PCP).
METHODS
We did a systematic search of MEDLINE for all randomized and observational studies of PCP treatment published up to August 2007 and included individual treatment data of AIDS-associated PCP from a tricenter study. We calculated pooled estimates of reported outcome of second-line treatment using averaged odds ratios (ORs).
RESULTS
Twenty-nine studies with sufficient detail of second-line treatment and outcome, including data from 82 individual cases from the tricenter study, yielded a total of 468 PCP second-line treatment episodes. Response rates to second-line treatment were comparable for trimethoprim-sulfamethoxazole (TMP-SMX; 68%) and clindamycin-primaquine (73%) (OR for response = 2.1 [95% confidence interval (CI): 1.1 to 3.2] and 2.7 [95% CI: 1.3 to 4.0], respectively) but were considerably lower for intravenous pentamidine (44%; OR = 0.8 [95% CI: 0.6 to 1.0]).
CONCLUSIONS
Clindamycin-primaquine is an alternative to intravenous pentamidine as second-line treatment for PCP in patients who fail treatment with TMP-SMX. TMP-SMX should be used as a second-line treatment for those failing first-line treatments with regimens other than TMP-SMX.
Topics: AIDS-Related Opportunistic Infections; Clindamycin; Cohort Studies; Humans; Pentamidine; Pneumocystis carinii; Pneumonia, Pneumocystis; Primaquine; Salvage Therapy; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 18360286
DOI: 10.1097/QAI.0b013e31816de84d -
International Journal of Dermatology Feb 2008New World leishmaniasis is an important endemic disease and public health problem in developing countries. The increase in ecologic tourism has extended this problem to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
New World leishmaniasis is an important endemic disease and public health problem in developing countries. The increase in ecologic tourism has extended this problem to developed countries. Few drugs have emerged over the past 50 years, and drug resistance has increased, such that the cure rate is no better than 80% in large studies. Despite these data, there has been no systematic review with a meta-analysis of the therapy used in this important tropical disease. The aim of this study was to determine the best drug management in the treatment of cutaneous leishmaniasis (CL) in Latin America based on the best studies published in the medical literature.
METHODS
MEDLINE, LILACS, EMBASE, Web of Science, and Cochrane Library databases were searched to identify articles related to CL and therapy. Articles with adequate data on cure and treatment failure, internal and external validity information, and more than four patients in each treatment arm were included.
RESULTS
Fifty-four articles met our inclusion criteria and 12 were included in the meta-analysis. Pentavalent antimonials were the most studied drugs, with a total of 1150 patients, achieving a cure rate of 76.5%. The cure rate of pentamidine was similar to that of pentavalent antimonials. Other drugs showed variable results, and all demonstrated an inferior response.
CONCLUSION
Although pentavalent antimonials are the drugs of choice in the treatment of CL, pentamidine showed similar results. Nevertheless, several aspects, such as cost, adverse effects, local experience, and availability of drugs to treat CL, must be considered when determining the best management of this disease, especially in developing countries where resources are scarce.
Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Developing Countries; Endemic Diseases; Humans; Leishmaniasis, Cutaneous; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Paromomycin; Pentamidine
PubMed: 18211479
DOI: 10.1111/j.1365-4632.2008.03417.x