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International Journal of Molecular... Dec 2020The alterations in serum trace element levels are common phenomena observed in patients with different psychiatric conditions such as schizophrenia, autism spectrum... (Meta-Analysis)
Meta-Analysis
The alterations in serum trace element levels are common phenomena observed in patients with different psychiatric conditions such as schizophrenia, autism spectrum disorder, or major depressive disorder. The fluctuations in the trace element concentrations might act as potential diagnostic and prognostic biomarkers of many psychiatric and neurological disorders. This paper aimed to assess the alterations in serum trace element concentrations in patients with a diagnosed schizophrenia. The authors made a systematic review, extracting papers from the PubMed, Web of Science, and Scopus databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Among 5009 articles identified through database searching, 59 of them were assessed for eligibility. Ultimately, 33 articles were included in the qualitative synthesis. This review includes the analysis of serum levels of the following trace elements: iron, nickel, molybdenum, phosphorus, lead, chromium, antimony, uranium, magnesium, aluminum, zinc, copper, selenium, calcium, and manganese. Currently, there is no consistency regarding serum trace element levels in schizophrenic patients. Thus, it cannot be considered as a reliable prognostic or diagnostic marker of schizophrenia. However, it can be assumed that altered concentrations of those elements are crucial regarding the onset and exaggeration of either psychotic or negative symptoms or cognitive dysfunctions.
Topics: Biomarkers; Case-Control Studies; Female; Humans; Maternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Schizophrenia; Schizophrenic Psychology; Trace Elements
PubMed: 33334078
DOI: 10.3390/ijms21249566 -
The Cochrane Database of Systematic... Aug 2020On the American continent, cutaneous and mucocutaneous leishmaniasis (CL and MCL) are diseases associated with infection by several species of Leishmania parasites.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
On the American continent, cutaneous and mucocutaneous leishmaniasis (CL and MCL) are diseases associated with infection by several species of Leishmania parasites. Pentavalent antimonials remain the first-choice treatment. There are alternative interventions, but reviewing their effectiveness and safety is important as availability is limited. This is an update of a Cochrane Review first published in 2009.
OBJECTIVES
To assess the effects of interventions for all immuno-competent people who have American cutaneous and mucocutaneous leishmaniasis (ACML).
SEARCH METHODS
We updated our database searches of the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and CINAHL to August 2019. We searched five trials registers.
SELECTION CRITERIA
Randomised controlled trials (RCTs) assessing either single or combination treatments for ACML in immuno-competent people, diagnosed by clinical presentation and Leishmania infection confirmed by smear, culture, histology, or polymerase chain reaction on a biopsy specimen. The comparators were either no treatment, placebo only, or another active compound.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Our key outcomes were the percentage of participants 'cured' at least three months after the end of treatment, adverse effects, and recurrence. We used GRADE to assess evidence certainty for each outcome.
MAIN RESULTS
We included 75 studies (37 were new), totalling 6533 randomised participants with ATL. The studies were mainly conducted in Central and South America at regional hospitals, local healthcare clinics, and research centres. More male participants were included (mean age: roughly 28.9 years (SD: 7.0)). The most common confirmed species were L. braziliensis, L. panamensis, and L. mexicana. The most assessed interventions and comparators were non-antimonial systemics (particularly oral miltefosine) and antimonials (particularly meglumine antimoniate (MA), which was also a common intervention), respectively. Three studies included moderate-to-severe cases of mucosal leishmaniasis but none included cases with diffuse cutaneous or disseminated CL, considered the severe cutaneous form. Lesions were mainly ulcerative and located in the extremities and limbs. The follow-up (FU) period ranged from 28 days to 7 years. All studies had high or unclear risk of bias in at least one domain (especially performance bias). None of the studies reported the degree of functional or aesthetic impairment, scarring, or quality of life. Compared to placebo, at one-year FU, intramuscular (IM) MA given for 20 days to treat L. braziliensis and L. panamensis infections in ACML may increase the likelihood of complete cure (risk ratio (RR) 4.23, 95% confidence interval (CI) 0.84 to 21.38; 2 RCTs, 157 participants; moderate-certainty evidence), but may also make little to no difference, since the 95% CI includes the possibility of both increased and reduced healing (cure rates), and IMMA probably increases severe adverse effects such as myalgias and arthralgias (RR 1.51, 95% CI 1.17 to 1.96; 1 RCT, 134 participants; moderate-certainty evidence). IMMA may make little to no difference to the recurrence risk, but the 95% CI includes the possibility of both increased and reduced risk (RR 1.79, 95% CI 0.17 to 19.26; 1 RCT, 127 participants; low-certainty evidence). Compared to placebo, at six-month FU, oral miltefosine given for 28 days to treat L. mexicana, L. panamensis and L. braziliensis infections in American cutaneous leishmaniasis (ACL) probably improves the likelihood of complete cure (RR 2.25, 95% CI 1.42 to 3.38), and probably increases nausea rates (RR 3.96, 95% CI 1.49 to 10.48) and vomiting (RR 6.92, 95% CI 2.68 to 17.86) (moderate-certainty evidence). Oral miltefosine may make little to no difference to the recurrence risk (RR 2.97, 95% CI 0.37 to 23.89; low-certainty evidence), but the 95% CI includes the possibility of both increased and reduced risk (all based on 1 RCT, 133 participants). Compared to IMMA, at 6 to 12 months FU, oral miltefosine given for 28 days to treat L. braziliensis, L. panamensis, L. guyanensis and L. amazonensis infections in ACML may make little to no difference to the likelihood of complete cure (RR 1.05, 95% CI 0.90 to 1.23; 7 RCTs, 676 participants; low-certainty evidence). Based on moderate-certainty evidence (3 RCTs, 464 participants), miltefosine probably increases nausea rates (RR 2.45, 95% CI 1.72 to 3.49) and vomiting (RR 4.76, 95% CI 1.82 to 12.46) compared to IMMA. Recurrence risk was not reported. For the rest of the key comparisons, recurrence risk was not reported, and risk of adverse events could not be estimated. Compared to IMMA, at 6 to 12 months FU, oral azithromycin given for 20 to 28 days to treat L. braziliensis infections in ACML probably reduces the likelihood of complete cure (RR 0.51, 95% CI 0.34 to 0.76; 2 RCTs, 93 participants; moderate-certainty evidence). Compared to intravenous MA (IVMA) and placebo, at 12 month FU, adding topical imiquimod to IVMA, given for 20 days to treat L. braziliensis, L. guyanensis and L. peruviana infections in ACL probably makes little to no difference to the likelihood of complete cure (RR 1.30, 95% CI 0.95 to 1.80; 1 RCT, 80 participants; moderate-certainty evidence). Compared to MA, at 6 months FU, one session of local thermotherapy to treat L. panamensis and L. braziliensis infections in ACL reduces the likelihood of complete cure (RR 0.80, 95% CI 0.68 to 0.95; 1 RCT, 292 participants; high-certainty evidence). Compared to IMMA and placebo, at 26 weeks FU, adding oral pentoxifylline to IMMA to treat CL (species not stated) probably makes little to no difference to the likelihood of complete cure (RR 0.86, 95% CI 0.63 to 1.18; 1 RCT, 70 participants; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
Evidence certainty was mostly moderate or low, due to methodological shortcomings, which precluded conclusive results. Overall, both IMMA and oral miltefosine probably result in an increase in cure rates, and nausea and vomiting are probably more common with miltefosine than with IMMA. Future trials should investigate interventions for mucosal leishmaniasis and evaluate recurrence rates of cutaneous leishmaniasis and its progression to mucosal disease.
Topics: Administration, Oral; Adult; Antiprotozoal Agents; Azithromycin; BCG Vaccine; Female; Humans; Hyperthermia, Induced; Immunocompetence; Injections, Intramuscular; Injections, Intravenous; Interferon-gamma; Leishmaniasis Vaccines; Leishmaniasis, Cutaneous; Leishmaniasis, Mucocutaneous; Male; Meglumine Antimoniate; Pentoxifylline; Phosphorylcholine; Randomized Controlled Trials as Topic
PubMed: 32853410
DOI: 10.1002/14651858.CD004834.pub3 -
Environmental Health Perspectives Mar 2020Electronic cigarettes (e-cigarettes) have become popular, in part because they are perceived as a safer alternative to tobacco cigarettes. An increasing number of...
BACKGROUND
Electronic cigarettes (e-cigarettes) have become popular, in part because they are perceived as a safer alternative to tobacco cigarettes. An increasing number of studies, however, have found toxic metals/metalloids in e-cigarette emissions.
OBJECTIVE
We summarized the evidence on metal/metalloid levels in e-cigarette liquid (e-liquid), aerosols, and biosamples of e-cigarette users across e-cigarette device systems to evaluate metal/metalloid exposure levels for e-cigarette users and the potential implications on health outcomes.
METHODS
We searched PubMed/TOXLINE, Embase®, and Web of Science for studies on metals/metalloids in e-liquid, e-cigarette aerosols, and biosamples of e-cigarette users. For metal/metalloid levels in e-liquid and aerosol samples, we collected the mean and standard deviation (SD) if these values were reported, derived mean and SD by using automated software to infer them if data were reported in a figure, or calculated the overall mean (mean ± SD) if data were reported only for separate groups. Metal/metalloid levels in e-liquids and aerosols were converted and reported in micrograms per kilogram and nanograms per puff, respectively, for easy comparison.
RESULTS
We identified 24 studies on metals/metalloids in e-liquid, e-cigarette aerosols, and human biosamples of e-cigarette users. Metal/metalloid levels, including aluminum, antimony, arsenic, cadmium, cobalt, chromium, copper, iron, lead, manganese, nickel, selenium, tin, and zinc, were present in e-cigarette samples in the studies reviewed. Twelve studies reported metal/metalloid levels in e-liquids (bottles, cartridges, open wick, and tank), 12 studies reported metal/metalloid levels in e-cigarette aerosols (from cig-a-like and tank devices), and 4 studies reported metal/metalloid levels in human biosamples (urine, saliva, serum, and blood) of e-cigarette users. Metal/metalloid levels showed substantial heterogeneity depending on sample type, source of e-liquid, and device type. Metal/metalloid levels in e-liquid from cartridges or tank/open wicks were higher than those from bottles, possibly due to coil contact. Most metal/metalloid levels found in biosamples of e-cigarette users were similar or higher than levels found in biosamples of conventional cigarette users, and even higher than those found in biosamples of cigar users.
CONCLUSION
E-cigarettes are a potential source of exposure to metals/metalloids. Differences in collection methods and puffing regimes likely contribute to the variability in metal/metalloid levels across studies, making comparison across studies difficult. Standardized protocols for the quantification of metal/metalloid levels from e-cigarette samples are needed. https://doi.org/10.1289/EHP5686.
Topics: Aerosols; Electronic Nicotine Delivery Systems; Humans; Metalloids; Metals; Saliva
PubMed: 32186411
DOI: 10.1289/EHP5686 -
International Journal of Environmental... Nov 2019Antimony (Sb) trioxide and antimony trisulfide are "2B: Possibly carcinogenic to humans" and "3: Unclassifiable" according to the International Agency for Research on...
BACKGROUND
Antimony (Sb) trioxide and antimony trisulfide are "2B: Possibly carcinogenic to humans" and "3: Unclassifiable" according to the International Agency for Research on Cancer (IARC). The U.S. National Toxicology Program (NTP) concluded that antimony trioxide "is reasonably anticipated to be a human carcinogen based on studies in rats and mice". We investigated the cancer hazard of antimony compounds for workers, a population with high exposure to antimony substances.
METHODS
Using the "Guidelines for performing systematic reviews in the development of toxicity factors" (Texas Commission on Environmental Quality (TCEQ) 2017) as a guidance, we established a human and an animal toxicology data stream in Medline and ToxLine. Data from this review were applied in a human health risk assessment.
RESULTS
A final pool of 10 occupational and 13 animal toxicology articles resulted after application of TCEQ guidelines.
CONCLUSIONS
Antimony carcinogenicity evidence involving workers is inadequate, based on confounding, small sample sizes, incomparability across studies, and inadequate reference populations. An increased lung cancer risk cannot be excluded. Evidence for lung neoplasms caused by antimony trioxide inhalation in experimental animals is sufficient. Overall, carcinogenicity in workers is probable (International Agency for Research on Cancer (IARC) 2A). It remains unclear from what occupational exposure duration and dose this effect arises and whether exposure threshold values should be reconsidered.
Topics: Animals; Antimony; Carcinogens; Humans; Mice; Models, Animal; Neoplasms; Occupational Exposure; Rats; Risk Assessment; Texas
PubMed: 31739404
DOI: 10.3390/ijerph16224474 -
Epidemiology and Health 2019Cutaneous leishmaniasis (CL) is most common form of leishmaniasis and is characterized by ulcerative skin lesions. The objective of this study was to conduct a... (Meta-Analysis)
Meta-Analysis
Cutaneous leishmaniasis (CL) is most common form of leishmaniasis and is characterized by ulcerative skin lesions. The objective of this study was to conduct a systematic review and meta-analysis of clinical trials that compared the efficacy of miltefosine and glucantime for the treatment of CL. We searched the following databases: Cochrane, PubMed, Embase, Scopus, Web of Science, ProQuest, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform search portal of World Health Organization, Sid, Irandoc, Magiran, and clinicaltrials.gov. We used keywords including "miltefosine," "glucantime," and "Leishmania." The quality of studies was assessed using the Cochrane risk of bias tool. A random-effects model was employed for the analysis. We assessed heterogeneity by the chi-square test and the I2 index statistic. When heterogeneity was present, meta-regression analyses were performed. The Egger method was used to assess publication bias; when it was significant, the trim-and-fill method was used to test and adjust for publication bias. A total of 1,570 reports were identified, of which 10 studies were included in the meta-analysis. In the meta-analysis, there was no significant difference between the efficacy of miltefosine and glucantime; however, subgroup analysis showed that, regarding parasite species other than Leishmania braziliensis, miltefosine was significantly superior to glucantime (intention to treat; relative risk, 1.15; 95% confidence interval, 1.01 to 1.32). In the meta-regression, only the glucantime injection type was significant at the p=0.1 level. The Egger test found statistically significant publication bias; however, including the 3 missing studies in the trim-and-fill analysis did not change the results. This meta-analysis found that miltefosine seems to be more effective than glucantime, at least in species other than L. braziliensis, for treating CL.
Topics: Humans; Leishmaniasis, Cutaneous; Meglumine Antimoniate; Non-Randomized Controlled Trials as Topic; Phosphorylcholine; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 30999735
DOI: 10.4178/epih.e2019011 -
Dermatology Research and Practice 2018The first choice drugs for the treatment of cutaneous and mucocutaneous leishmaniasis are pentavalent antimonials, sodium stibogluconate, or meglumine antimoniate.... (Review)
Review
The first choice drugs for the treatment of cutaneous and mucocutaneous leishmaniasis are pentavalent antimonials, sodium stibogluconate, or meglumine antimoniate. However, the treatment with these drugs is expensive, can cause serious adverse effects, and is not always effective. The combination of two drugs by different routes or the combination of an alternative therapy with systemic therapy can increase the efficacy and decrease the collateral effects caused by the reference drugs. In this systematic review we investigated publications that described a combination of nonconventional treatment for cutaneous and mucocutaneous with pentavalent antimonials. A literature review was performed in the databases Web of Knowledge and PubMed in the period from 01 of December 2004 to 01 of June 2017, according to Prisma statement. Only clinical trials involving the treatment for cutaneous or mucocutaneous leishmaniasis, in English, and with available abstract were added. Other types of publications, such as reviews, case reports, comments to the editor, letters, interviews, guidelines, and errata, were excluded. Sixteen articles were selected and the pentavalent antimonials were administered in combination with pentoxifylline, granulocyte macrophage colony-stimulating factor, imiquimod, intralesional sodium stibogluconate, ketoconazole, silver-containing polyester dressing, lyophilized LEISH-F1 protein, cryotherapy, topical honey, and omeprazole. In general, the combined therapy resulted in high rates of clinical cure and when relapse or recurrence was reported, it was higher in the groups treated with pentavalent antimonials alone. The majority of the articles included in this review showed that cure rate ranged from 70 to 100% in patients treated with the combinations. Serious adverse effects were not observed in patients treated with drugs combination. The combination of other drugs or treatment modalities with pentavalent antimonials has proved to be effective for cutaneous and mucocutaneous leishmaniasis and for most seemed to be safe. However, new randomized, controlled, and multicentric clinical trials with more robust samples should be performed, especially the combination with immunomodulators.
PubMed: 30675152
DOI: 10.1155/2018/9014726 -
PLoS Neglected Tropical Diseases Dec 2018Case management in children with cutaneous leishmaniasis (CL) is mainly based on studies performed in adults. We aimed to determine the efficacy and harms of...
BACKGROUND
Case management in children with cutaneous leishmaniasis (CL) is mainly based on studies performed in adults. We aimed to determine the efficacy and harms of interventions to treat CL in children.
METHODS
We conducted a systematic review of clinical trials and cohort studies, assessing treatments of CL in children (≤12 years old). We performed structured searches in PubMed, CENTRAL, LILACS, SciELO, Scopus, the International Clinical Trials Registry Platform (ICTRP), clinicaltrials.gov and Google Scholar. No restrictions regarding ethnicity, country, sex or year of publication were applied. Languages were limited to English, Spanish and Portuguese. Two reviewers screened articles, completed the data extraction and assessment of risk of bias. A qualitative summary of the included studies was performed.
RESULTS
We identified 1092 records, and included 8 manuscripts (6 Randomized Clinical Trials [RCT] and 2 non-randomized studies). Most of the articles excluded in full-text review did not report outcomes separately for children. In American CL (ACL), 5 studies evaluated miltefosine and/or meglumine antimoniate (MA). Their efficacy varied from 68-83% and 17-69%, respectively. In Old-World CL (OWCL), two studies evaluated systemic therapies: rifampicin and MA; and one study assessed efficacy of cryotherapy (42%, Per Protocol [PP]) vs intralesional MA (72%, PP). Few studies (4) provided information on adverse events (AEs) for children, and no serious AEs were reported in participants. Risk of bias was generally low to unclear in ACL studies, and unclear to high in OWCL studies.
CONCLUSION
Information on efficacy of treatment for CL in children is scarce. There is an unmet need to develop specific formulations, surveillance of AEs, and guidelines both for the management of CL and clinical trials involving the pediatric population.
REGISTRATION
The protocol of this review was registered in the PROSPERO International register of systematic reviews, number CRD42017062164.
Topics: Antiprotozoal Agents; Clinical Trials as Topic; Humans; Leishmania; Leishmaniasis, Cutaneous; Meglumine Antimoniate; Phosphorylcholine; Rifampin
PubMed: 30550538
DOI: 10.1371/journal.pntd.0006986 -
Infectious Diseases of Poverty Oct 2018Ethiopia has the highest number of visceral leishmaniasis (VL) cases after Sudan in Sub-Saharan Africa. However, there was lack of comprehensive data on VL treatment... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Ethiopia has the highest number of visceral leishmaniasis (VL) cases after Sudan in Sub-Saharan Africa. However, there was lack of comprehensive data on VL treatment outcome despite the huge burden of the diseases in the country. Hence, we aimed to perform a systematic review and meta-analysis on this topic to obtain stronger evidence on treatment outcomes of VL from the existing literature in Ethiopia.
METHODS
The Cochrane guidelines to conduct meta-analysis following the Preferred Reporting Items for Systematic review and Meta-Analysis statement was used to conduct a computerized systematic search of the PubMed, Google Scholar, and ScienceDirect databases. Random effects model was used to combine studies showing heterogeneity of Cochrane Q P < 0.10 and I > 50. Treatment outcomes were assessed at end of treatment and at 6 months follow-up. Subgroup analyses were performed on treatment outcomes based on the different antileishmanial treatment options and patients' HIV status.
RESULTS
Fifteen studies were included in the final analyses. At end of treatment, an overall treatment success rate of 82.6% was noticed. At 6 months follow-up, the overall treatment success rate was 72.2%. For patients treated with sodium stibogluconate (SSG), the treatment success rates at the end of treatment and at six-month follow-up were 81.5% and 80.7%, respectively. Multiple doses of liposomal-amphotericin B (L-AMB) had treatment success rates of 96.7 and 71-100% at the end of treatment and at 6 months follow-up, respectively. The combination of SSG with paromomycin (PM) gave treatment success rates of up to 90.1% at the end of treatment. HIV-infected individuals were found to have a higher mortality (odds ratio = 4.77, 95% CI: 1.30-17.43, P = 0.009) rate at 6 months follow-up.
CONCLUSIONS
SSG alone has shown lower treatment efficacy in the management of VL when compared to combination of SSG with PM and multiple doses of L-AMB. The combination of SSG with PM gave good treatment success rates with shorter duration of treatment. Hence, the combination of SSG with PM should be used preferentially over SSG monotherapy. Multiple doses of L-AMB showed great efficacy especially among patients with complications, severe disease, HIV co-infection, and intolerance to the adverse effects of antimonials. HIV-infected individuals had a worse prognosis than their HIV-negative counterparts.
Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Coinfection; Female; HIV Infections; Humans; Leishmaniasis, Visceral; Male; Odds Ratio; Treatment Outcome
PubMed: 30340519
DOI: 10.1186/s40249-018-0491-7 -
The Cochrane Database of Systematic... Dec 2017Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low- and middle-income countries. Old World... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low- and middle-income countries. Old World cutaneous leishmaniasis (OWCL) is caused by species found in Africa, Asia, the Middle East, the Mediterranean, and India. The most commonly prescribed treatments are antimonials, but other drugs have been used with varying success. As OWCL tends to heal spontaneously, it is necessary to justify the use of systemic and topical treatments. This is an update of a Cochrane Review first published in 2008.
OBJECTIVES
To assess the effects of therapeutic interventions for the localised form of Old World cutaneous leishmaniasis.
SEARCH METHODS
We updated our searches of the following databases to November 2016: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We wrote to national programme managers, general co-ordinators, directors, clinicians, WHO-EMRO regional officers of endemic countries, pharmaceutical companies, tropical medicine centres, and authors of relevant papers for further information about relevant unpublished and ongoing trials. We undertook a separate search for adverse effects of interventions for Old World cutaneous leishmaniasis in September 2015 using MEDLINE.
SELECTION CRITERIA
Randomised controlled trials of either single or combination treatments in immunocompetent people with OWCL confirmed by smear, histology, culture, or polymerase chain reaction. The comparators were either no treatment, placebo/vehicle, and/or another active compound.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion and risk of bias and extracted data. We only synthesised data when we were able to identify at least two studies investigating similar treatments and reporting data amenable to pooling. We also recorded data about adverse effects from the corresponding search.
MAIN RESULTS
We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly.Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle.In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow-up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results.When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow-up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results.Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons.
AUTHORS' CONCLUSIONS
There was very low-certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome.We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well-designed international studies that evaluate long-term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, andL donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful.It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring.
Topics: Adult; Animals; Anti-Infective Agents; Antiprotozoal Agents; Complementary Therapies; Cryotherapy; Asia, Eastern; Female; Hot Temperature; Humans; Itraconazole; Laser Therapy; Leishmania major; Leishmania tropica; Leishmaniasis, Cutaneous; Male; Middle Aged; Middle East; Ointment Bases; Paromomycin; Photochemotherapy; Randomized Controlled Trials as Topic
PubMed: 29192424
DOI: 10.1002/14651858.CD005067.pub5 -
The Cochrane Database of Systematic... Nov 2017Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low- and middle-income countries. Old World... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low- and middle-income countries. Old World cutaneous leishmaniasis (OWCL) is caused by species found in Africa, Asia, the Middle East, the Mediterranean, and India. The most commonly prescribed treatments are antimonials, but other drugs have been used with varying success. As OWCL tends to heal spontaneously, it is necessary to justify the use of systemic and topical treatments. This is an update of a Cochrane Review first published in 2008.
OBJECTIVES
To assess the effects of therapeutic interventions for the localised form of Old World cutaneous leishmaniasis.
SEARCH METHODS
We updated our searches of the following databases to November 2016: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We wrote to national programme managers, general co-ordinators, directors, clinicians, WHO-EMRO regional officers of endemic countries, pharmaceutical companies, tropical medicine centres, and authors of relevant papers for further information about relevant unpublished and ongoing trials. We undertook a separate search for adverse effects of interventions for Old World cutaneous leishmaniasis in September 2015 using MEDLINE.
SELECTION CRITERIA
Randomised controlled trials of either single or combination treatments in immunocompetent people with OWCL confirmed by smear, histology, culture, or polymerase chain reaction. The comparators were either no treatment, placebo/vehicle, and/or another active compound.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion and risk of bias and extracted data. We only synthesised data when we were able to identify at least two studies investigating similar treatments and reporting data amenable to pooling. We also recorded data about adverse effects from the corresponding search.
MAIN RESULTS
We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly.Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle.In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow-up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results.When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow-up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results.Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons.
AUTHORS' CONCLUSIONS
There was very low-certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome.We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well-designed international studies that evaluate long-term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, andL donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful.It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring.
Topics: Animals; Anti-Infective Agents; Antiprotozoal Agents; Complementary Therapies; Cryotherapy; Hot Temperature; Humans; Itraconazole; Laser Therapy; Leishmania major; Leishmania tropica; Leishmaniasis, Cutaneous; Paromomycin; Photochemotherapy; Randomized Controlled Trials as Topic
PubMed: 29149474
DOI: 10.1002/14651858.CD005067.pub4