Natural resistance to meglumine antimoniate is associated with treatment failure in cutaneous leishmaniasis caused by Leishmania (Viannia) panamensis.

The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship between parasite susceptibility to meglumine antimoniate (SbV) and therapeutic outcome of cutaneous leishmaniasis, risk factors for treatment failure were considered in evaluating this relationship in ninety-one cutaneous leishmaniasis patients and corresponding clinical strains of Leishmania (Viannia) panamensis. Parasite susceptibility to 32 µg SbV/mL (plasma Cmax) was evaluated in primary human macrophages, PBMCs, and U937 macrophages. Early parasitological response to treatment was determined in lesions of a subgroup of patients, and pathogenicity of Sb-resistant and sensitive clinical strains was compared in BALB/c mice. Parasite survival in cell models and patient lesions was determined by qRT-PCR of Leishmania 7SLRNA transcript. Parasite loads in BALB/c mice were quantified by limiting dilution analysis. The disparate Sb-susceptibility of parasite subpopulations distinguished by isoenzyme profiles (zymodemes) was manifest in all cell models. Notably, Sb-resistance defined by parasite survival, was most effectively discerned in U937 macrophages compared with primary human host cells, significantly higher among strains from patients who failed treatment than cured and, significantly associated with treatment failure. Each unit increase in transformed survival rate corresponded to a 10.6-fold rise in the odds of treatment failure. Furthermore, treatment failure was significantly associated with naturally Sb-resistant zymodeme 2.3 strains, which also produced larger lesions and parasite burdens in BALB/c mice than Sb-sensitive zymodeme 2.2 strains. The confounding effect of host risk factors for treatment failure in discerning this association was evidenced in comparing strains from patients with and without the defined risk factors for treatment failure. These results establish the association of natural resistance to meglumine antimoniate with treatment failure, the importance of host risk factors in evaluating drug susceptibility and treatment outcome, and the clinical and epidemiological relevance of natural Sb-resistance in L. (V.) panamensis subpopulations.

Owners' experiences of administering meglumine antimoniate injections to dogs with leishmaniosis: An online questionnaire study.

BACKGROUND: This study examined the experiences of owners of dogs with leishmaniosis who treated their dogs with daily subcutaneous meglumine antimoniate injections. The owners' perceived ease of administering the injections, the occurrence of problems and the effects on the owners and on the dog‒owner bond were evaluated. METHODS: Dogs prescribed meglumine antimoniate as a treatment for leishmaniosis were identified using the database of the veterinary pharmacy of the Faculty of Veterinary Medicine, Utrecht University. An online questionnaire was sent to the owners of these dogs to evaluate the perceived ease of administering the injections, the occurrence of problems and the effects on the owner and the dog-owner bond. RESULTS: Responses were received from 64 dog owners. Most respondents (78%) reported that administering the injections was not difficult. Pain or the development of nodules at the injection site was reported in 50% and 40% of the dogs, respectively. Polyuria was reported in 44% of the dogs. Some owners reported that administering the injections had a negative impact on their psychological wellbeing (20%), and some would have liked more veterinary support (11%). LIMITATIONS: Some questions were answered by a limited number of people, and their responses may not be representative. CONCLUSION: Dog owners remain highly motivated to persevere with meglumine antimoniate treatment and are willing to administer the injections themselves. The availability of active support when needed during the therapy cycle may further improve their acceptance of and confidence in giving the injections.

Topical application of ozonated sunflower oil accelerates the healing of lesions of cutaneous leishmaniasis in mice under meglumine antimoniate treatment.

Besides being scarce, the drugs available for treating cutaneous leishmaniasis have many adverse effects. Ozone is an option to enhance the standard treatment due to the wound-healing activity reported in the literature. In this study, we evaluated the efficiency of ozonated sunflower oil as an adjuvant in treating cutaneous lesions caused by Leishmania amazonensis. BALB/c mice were infected with L. amazonensis, and after the lesions appeared, they were treated in four different schedules using the drug treatment with meglumine antimoniate (Glucantime®), with or without ozonated oil. After thirty days of treatment, the lesions' thickness and their parasitic burden, blood leukocytes, production of NO and cytokines from peritoneal macrophages and lymph node cells were analyzed. The group treated with ozonated oil plus meglumine antimoniate showed the best performance, improving the lesion significantly. The parasitic burden showed that ozonated oil enhanced the leishmanicidal activity of the treatment, eliminating the parasites in the lesion. Besides, a decrease in the TNF levels from peritoneal macrophages and blood leukocytes demonstrated an immunomodulatory action of ozone in the ozonated oil-treated animals compared to the untreated group. Thus, ozonated sunflower oil therapy has been shown as an adjuvant in treating Leishmania lesions since this treatment enhanced the leishmanicidal and wound healing effects of meglumine antimoniate.

Efficacy of the treatment using a microemulsion loaded with epoxy-α-lapachone in combination with meglumine antimoniate against murine infection by Leishmania (Leishmania) amazonensis.

Leishmaniasis is a disease caused by Leishmania spp., affecting millions of people around the world. For decades, its treatment has been based on pentavalent antimonials, which notoriously cause toxic side effects in patients. In this study, epoxy-α-lapachone incorporated into an oil-in-water-type microemulsion (ELAP-ME) and meglumine antimoniate (MA) were assayed in monotherapy and in combination (ELAP-ME/MA) in BALB/c mice infected with Leishmania (Leishmania) amazonensis. In general, there was a reduction in paw lesion size (up to 37% reduction) and decreases of parasite loads in the footpad (∼40%) and lymph nodes (∼31%) of animals treated with ELAP-ME/MA, when compared to the non-treated control groups. Analyses of serum biochemical parameters revealed that the ELAP-ME/MA showed lower renal and hepatic toxicity when compared to MA 2-doses/week monotherapy. These findings indicate that the ELAP-ME/MA combination may be a promising approach for the treatment of cutaneous leishmaniasis.

The efficacy and safety of diterpene ginkgolides meglumine injection for cerebral infarction: A meta-analysis of randomized controlled trials.

OBJECTIVE: To systemically evaluate the efficacy and safety of diterpene ginkgolides meglumine injection (DGMI) on cerebral infarction (CI). METHODS: Comprehensively collect randomized controlled trials of DGMI in the treatment of CI in 7 databases including Embase, PubMed, the Cochrane Library, the China National Knowledge Infrastructure Database, the WanFang Database, the China Science and Technology Journal Database, and the China Biology Medicinedisc as of January 2023. The studies were screened according to the inclusion and exclusion criteria and evaluated according to the criteria recommended by the Cochrane Handbook, then RevMan 5.3, Stata 12.0 software were used for Meta-analysis. RESULTS: A total of 22 randomized controlled trials with 2194 patients were included. Meta analysis showed that: the total effective rate of treatment (relative risk = 1.29, 95% confidence interval (1.21, 1.38), P < .001), National Institute of Health stroke scale score, Barthel index and Modified Rankin Scale were better in DGMI group than in Conventional Western Medicine Treatment group. The included studies reported 42 adverse events, 25 of which belonged to DGMI groups. CONCLUSION: Available evidence suggested that DGMI can significantly improve the clinical efficiency in the treatment of CI. DGMI is an ideal treatment for CI, which has high clinical application value.

THE WATER-SOLUBLE CONTRAST FOR ADHESIVE SMALL BOWEL OBSTRUCTION: ARE THERE ADVANTAGES?

BACKGROUND: Adhesive small bowel obstruction is one of the most common causes of surgical emergencies, representing about 15% of hospital admissions. Defining the need and timing of surgical intervention still remains a challenge. AIMS: To report the experience of using meglumine-based water-soluble contrast in a tertiary hospital in southern Brazil, comparing with the world literature. METHODS: Patients suspected of having adhesive small bowel obstruction, according to their clinical conditions, underwent an established protocol, consisting of the administration of water-soluble contrast, followed by plain abdominal radiograph within 12 hours and by a new clinical evaluation. The protocol was initiated after starting conservative management, including fasting and placement of a nasogastric tube, as well as intravenous fluid reposition. RESULTS: A total of 126 patients were submitted to the protocol. The water-soluble contrast test sensitivity and specificity after the first radiograph were 94.6 and 91.0%, respectively; after the second radiograph, these values were 92.3 and 100%. The general test values for sensitivity and specificity were 91.9 and 100%, respectively. CONCLUSIONS: The measure parameters evaluated in this study were similar to those found in the literature, contributing to endorse the importance of this test in the evaluation of patients with adhesive small bowel obstruction. The particular relevance of this study was the similar results that were found using a different type of meglumine-based contrast, which is available in Brazil.

Treatment of Cutaneous Leishmaniasis with Allopurinol Plus Itraconazole in Iran.

Cutaneous leishmaniasis (CL) is a serious tropical disease and a neglected health challenge in Iran. Although limited data are available regarding anthroponotic CL, cases resistant to meglumine antimoniate (Glucantime) are increasingly being reported. Via an open-label noncontrolled case series, allopurinol (10 mg/kg/day) plus itraconazole (3-4 mg/kg/day) were orally administered for 1 month to 27 patients (56 lesions) with anthroponotic CL, most of whom were resistant to Glucantime. A mean lesion size of 3.5 ± 1.9 cm at baseline was reduced to 0.6 ± 1.0 after 1 month of treatment. Excellent treatment response was observed in 85.7% of lesions after 1 month. Recurrence only occurred in one patient in the 3-month follow-up session. This study presents preliminary evidence that oral allopurinol plus itraconazole could be an effective treatment in patients with anthroponotic CL.

Efficacy of intralesional meglumine antimoniate in the treatment of canine tegumentary leishmaniasis: A Randomized controlled trial.

Dogs living in areas of Leishmania (Viannia) braziliensis transmission may present canine tegumentary leishmaniasis (CTL) characterized by cutaneous or muzzle ulcers as well as asymptomatic L. braziliensis infection. It is not clear if dogs participate in the transmission chain of L. braziliensis to humans. However, dogs may remain with chronic ulcers for a long time, and as there are no public policies about CTL, these animals die or are sacrificed. Here we compare the efficacy of intralesional meglumine antimoniate with intralesional 0.9% NaCl solution in CTL treatment. This randomized control study included 32 dogs with cutaneous or muzzle lesions who had L. braziliensis DNA detected by PCR in tissue biopsied. Group one received 5ml of intralesional Glucantime, and group two received 5ml 0.9% NaCl solution, both applied in the four cardinal points on days 0, 15, and 30. Cure was defined as complete healing of the ulcers in the absence of raised borders on day 90. There was no difference in animals' demographic and clinical features in the two groups (p >.05). While at the endpoint, the cure rate was 87.5% in the group test, and in those who received 0.9 NaCl the cure rate was only 12.5%. As important as the high cure rate, the healing time was faster in dogs treated with antimony than in those treated with saline (p < .001). Intralesional meglumine antimoniate is effective in the treatment of dogs with L. braziliensis infection and accelerates the healing time of CTL.

[Infusion therapy with reamberin in military conditions]. / Ispol'zovanie rastvora reamberina v voennykh usloviyakh.

The article is devoted to infusion therapy with Reamberin 1.5% (Meglumine sodium succinate) in patients with various traumatic injuries. The authors substantiate the relevance and significance of this issue. Specifics and purposes of therapy are considered. The authors reviewed national studies devoted to clinical aspects and determined the main directions of therapy in emergency patients with mechanical injuries, burns, traumatic brain injury and cognitive impairment caused by combat trauma. Moreover, experimental studies of protective properties of Reamberin under combined action of cold, vibration and immobilization, as well as acute massive blood loss are analyzed.

Comparison Of Oral Dapsone With Intramuscular Meglumine Antimoniate In Cutaneous Leishmaniasis.

BACKGROUND: Many drugs are effective are used as second line treatment for cutaneous leishmaniasis. Dapsone therapy is tolerated well and cost effective. The aim of present study is to determine the efficacy of oral dapsone in comparison with intramuscular meglumine antimoniate in patients with cutaneous leishmaniasis and thus find out an effective second line treatment agent. METHODS: This randomized controlled trial was carried out at dermatology department, of tertiary care centre Rawalpindi, Pakistan from November 2017 to June 2018. Hundred biopsy proven patients of cutaneous leishmaniasis completed the study with 50 patients in two group. Group A received intramuscular meglumine antimoniate (15 mg/kg/day). Group B received oral dapsone2.5 mg /kg/body weight /day (200 mg per day). Efficacy of therapeutic response was noted at the end of treatment. Data was analyzed with statistical analysis program (IBM-SPSS V22). Chi-square test was applied to compare efficacy, p value of ≤0.05 was significant. Stratification of data with respect to age, gender, duration of disease, number of lesions and weight was done to see their effect on treatment efficacy. Post stratification chi-square test for both groups was applied (p≤0.05 considered significant). RESULTS: A total of 100 participants took part in the study. Duration of treatment (p-value <0.001) and the efficacy of the drugs (p-value=0.020) were significant. Meglumine antimoniate therapy group displayed a comparatively fast-paced recovery in (21- 40 days) whereas Dapsone group showed better recovery in (41-60 days) in their lesions. CONCLUSIONS: Dapsone is an effective treatment for cutaneous Leishmaniasis.

Comparison Of Efficacy Of Miltefosine Versus Meglumine Antimonate In The Treatment Of Cutaneous Leishmaniasis.

BACKGROUND: Cutaneous Leishmaniasis is a morbid condition that generates stigmatization and disfiguring scars. Pakistan is among the ninety-eight countries where cutaneous Leishmaniasis is endemic. Purpose of study was to compare the efficacy of miltefosine and meglumine antimoniate in the treatment of cutaneous Leishmaniasis. METHODS: All patients with cutaneous Leishmaniasis (CL) who met the inclusion criteria were divided into two groups using the envelop method. Capsule Miltefosine 50 mg (2.5 mg/ kg) was given to group A, while intralesional Glucantime injection was given to group B. The treatment's efficacy was evaluated after four weeks and again after eight weeks. RESULTS: Out of 74 patients, 37 patients were included in each group. In group A (miltefosine group), 56.75% were males, and 43.25% were females. In group B (meglumine antimoniate group), 62% were males, while 38% were females (p=0.63). The mean age was 32.81 years±12.09 SD, the mean duration of the disease was 5.4 months±2.3 SD and the mean number of lesions was 2.56±1.33 SD. The efficacy of Miltefosine and meglumine antimoniate (I/L) was 91.9% and 56.75%, respectively (p<0.001). CONCLUSIONS: Miltefosine was more effective than intralesional meglumine antimoniate in the treatment of cutaneous Leishmaniasis (p<0.001).

Leishmania RNA virus 2 (LRV2) exacerbates dermal lesions caused by Leishmania major and comparatively unresponsive to meglumine antimoniate treatment.

PURPOSE: The present study investigated the possible role of Leishmania RNA virus 2 (LRV2) in the severity of dermal lesions and treatment failure due to Leishmania major. METHODS: The drug susceptibility of 14 clinical isolates of L.major, including resistant (n = 7) and sensitive (n = 7) isolates, was checked in the J774A.1 macrophage cell line. The presence of LRV2 among isolates was investigated by the RdRp gene and semi-nested PCR. Moreover, 1 × 106 sensitive L. major LRV2+ and LRV2- promastigotes were inoculated subcutaneously into the base tails of the 40 BALB/c mice divided into 4 groups (n = 10 in each group), including clinical LRV2+, clinical LRV2-, positive control LRV2+ and negative control LRV2-. The groups were infected with a unique isolate. The lesion size and parasite burden were evaluated. RESULTS: Sensitive and resistant isolates were determined by the drug susceptibility method. A higher presence of LRV2 was observed among MA-resistant isolates (6/7) compared with susceptible isolates (4/7), which was not statistically significant (P = 0.237). On the other hand, a comparison of the lesion sizes between the LRV2+ and LRV2- BALB/c mice groups revealed that the mean size of the lesion in the LRV2+ groups was significantly higher than the LRV2- (P = 0.034). In the same direction, there was an increased parasite burden in mice inoculated with LRV2+ groups compared with the LRV2- BALB/c mice groups (P = 0.002). CONCLUSIONS: Our findings showed that the presence of LRV2 could be one of the factors contributing to exacerbating CL. Although we found a higher presence of LRV2 in the resistant isolates, it seems that further investigations are recommended to determine the detailed association between lesions' aggravation and being comparatively unresponsive to treatment.

Efficacy of Diterpene Ginkgolides Meglumine injection in elderly patients with ischemic stroke: A post hoc analysis of a randomized controlled trial.

BACKGROUND: Elderly patients with ischemic stroke (IS) have worse functional outcomes and poorer quality of life after suffering a stroke than younger patients. The identification of effective agents is critical to optimizing the therapy of IS in elderly patients. PURPOSE: To examine the efficacy of diterpene ginkgolides meglumine injection (DGMI) vs. Ginaton in treating patients with IS, across different age subgroups. METHODS: Efficacy was determined through the post hoc analysis of a randomized controlled study, which had a cohort of 998 patients with IS. Participants were pooled and grouped by age (elderly [aged ≥ 65 yr] vs. non-elderly [aged < 65 yr]). The primary efficacy outcome was the proportion of patients with modified Rankin Scale (mRS) score ranging from 0 to 1 at 90 d. The secondary outcomes were neurological deficit (tested using the National Institutes of Health Stroke Scale [NIHSS] score) and quality of life (tested using the EuroQol-5 Dimension [EQ-5D] and EQ visual analog scale [EQ-VAS] questionnaires). RESULTS: There were 399 (40%) patients in the elderly group (average age = 69.8±3.3 yr) and 599 (60%) patients in the non-elderly group (average age = 55.8±6.8 yr). The randomized treatment groups had similar baseline characteristics. For the elderly group, 174 (94%) of the 185 participants in the DGMI group and 169 (79%) of the 214 participants in the Ginaton group achieved the main outcome of a mRS score of 0-1 after three months (odds ratio [OR] = 0.87 [95% confidence interval [CI] = 0.81-0.93], p<0.001). For the non-elderly group, 301 (96%) of the 314 participants in the DGMI group and 237 (83%) of the 214 participants in the Ginaton group achieved the main outcome of a mRS score of 0-1 after three months (OR = 0.88 [95% CI = 0.84-0.92], p<0.001). The overall mean EQ-5D index score and EQ-VAS of the DGMI group were higher than that of the Ginaton group for elderly patients. After controlling other covariates including treatments, gender, weight, height and medical history, the results of mRS score, NIHSS score, EQ-5D index score, and EQ-VAS based on generalized linear model were similar to those of the single covariate analysis. CONCLUSIONS: DGMI demonstrated a superior efficacy to Ginaton for patients with IS in both elderly and non-elderly ages.

A family cluster of cutaneous Leishmania major infection unresponsive to intralesional meglumine antimonial: Case reports.

We describe a family cluster of L. major that became infected by traveling to an endemic focus of CL, which did not respond to intralesional meglumine antimonial treatment whilst two were hospitalized due to the progressive disease that responded to 4 weeks of oral ketoconazole. Parasite genotyping of the internal transcribed spacer 1 gene revealed the same infecting parasite strain in all family members and was the same strain in GenBank that caused mucosal L. major in a tourist who visited several North African countries. We hypothesise a reduced host immune response in the two hospitalized patients.

Clinical Efficacy of Ulinastatin Combined with Meglumine Adenosine Cyclophosphate in the Treatment of Acute Myocardial Infarction.

Ulinastatin, a common adjuvant drug in the clinical treatment of acute circulatory failure, has a good effect on various inflammatory diseases. In this study, we aim to explore the clinical efficacy of ulinastatin combined with meglumine adenosine cyclophosphate in patients with acute myocardial infarction (AMI) and its effect on cardiac function and endothelial function of patients. 100 AMI patients treated in our hospital (February 2020-October 2020) were randomly chosen and divided into group J and group Q, with 50 cases in each group. Group Q was treated with meglumine adenosine cyclophosphate only, while group J was treated with ulinastatin combined with meglumine adenosine cyclophosphate to compare the treatment efficiency, cardiac structure indexes, cardiac systolic function, blood lipid levels, vascular endothelial function, QLI (quality of life) scores, BI indexes, and FMA (motor function) scores between the two groups. The treatment efficiency, QLI score, BI index, and FMA score in group J were notably higher compared with group Q (P < 0.05). The cardiac structure indexes, cardiac systolic function, blood lipid level, and vascular endothelial function in group J were notably better compared with group Q (P < 0.05). Ulinastatin combined with meglumine adenosine cyclophosphate can obviously enhance the therapeutic effect of AMI patients and improve the endothelial function and cardiac function of patients, which is very promising in this medical area.

A phase II multicenter randomized study to evaluate the safety and efficacy of combining thermotherapy and a short course of miltefosine for the treatment of uncomplicated cutaneous leishmaniasis in the New World.

BACKGROUND: Systemic pentavalent antimonials, mainly meglumine antimoniate, continue to be the first-choice drugs for treatment of cutaneous leishmaniasis (CL) despite their toxicity, difficulty of administration and high cost. In the search for therapeutic alternatives, combining two treatment interventions has emerged as a potential alternative to either reduce the use of antimonials with the associated toxicities, or to increase efficacy. Here, we report the results of a recently completed trial assessing the efficacy and safety of a combination of thermotherapy (TT) plus a short course of miltefosine (MLT) for the treatment of uncomplicated CL in Colombia and Peru. METHODS: A multicenter, randomized, evaluator-blinded, phase II, controled clinical trial was conducted. Adult volunteers with a parasitologically confirmed diagnosis of uncomplicated CL were randomly allocated to receive either a single session of TT or a combination of TT plus a short course of MLT (3 weeks). Therapeutic response outcomes and safety were assessed. RESULTS: 130 subjects were included in the study, of whom 64 were randomly assigned to the TT arm and 66 to the TT + MLT arm. Cure at 3 months' follow-up was achieved in 57.8% (n = 37) and 80.3% (n = 53) in the TT and TT + MLT groups, respectively, in the intention to treat analysis. The TT + MLT regimen was better that TT alone (p = 0.0055). The presence of vesicles at the site of heat application was the most common adverse event reported associated with the use of TT; while vomiting (31.8%) and elevation of liver enzymes (28.8%) were the most frequent adverse events reported associated with the use of MLT. CONCLUSION: The combination of TT plus a short course of MLT was shown to be significantly better than TT alone for the treatment of uncomplicated CL in the New World. TRIAL REGISTRATION: Registered in clinicaltrials.gov NCT02687971.

Antiproliferative properties of Turmerone on Leishmania major: Modes of action confirmed by antioxidative and immunomodulatory roles.

Treatment of leishmaniasis by conventional synthetic compounds has faced a serious challenge worldwide. This study was performed to evaluate the effect and modes of action of aromatic Turmerone on the Leishmania major intra-macrophage amastigotes, the causative agent of zoonotic cutaneous leishmaniasis in the Old World. In the findings, the mean numbers of L. major amastigotes in macrophages were significantly decreased in exposure to Turmerone plus meglumine antimoniate (Glucantime®; MA) than MA alone, especially at 50 µg/mL. In addition, Turmerone demonstrated no cytotoxicity as the selectivity index (SI) was 21.1; while it induced significant apoptosis in a dose-dependent manner on L. major promastigotes. In silico molecular docking analyses indicated an affinity of Turmerone to IL-12, with the MolDock score of - 96.8 kcal/mol; which may explain the increased levels of Th1 cytokines and decreased level of IL-10. The main mechanism of action is more likely associated with stimulating a powerful antioxidant and promoting the immunomodulatory roles in the killing of the target organism.