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.

Aim: This study aimed to investigate the effects of topical liposomal clarithromycin in combination with meglumine antimoniate (Glucantime®) on cutaneous leishmaniasis (CL) lesions. Methods: This pilot, randomized, double-blinded clinical trial was conducted on patients with CL lesions. Patients were randomly assigned to two groups: the first group received liposomal clarithromycin in combination with Glucantime for 28 days, while the second group received Glucantime and a placebo. Afterward, patients were followed up at 1.5, 3, and 6 months after treatment initiation and were evaluated for recovery time, induration, and size of the lesions. Results: Sixty patients with CL lesions were divided into two separate groups with 30 members each and were examined. Within-group analysis revealed that recovery time in the clarithromycin group was 26.65 ± 5.12 days, while in the placebo group, it was 32.84 ± 24.43, which was statistically insignificant (p = 0.18). Lesion size comparison in the first and last follow-ups reduced in both groups: 7.73 ± 4.31 to 0.48 ± 0.50 in the clarithromycin group (p = 0.006) and 5.47 ± 5.83 to 0.76 ± 0.88 in the placebo group (p = 0.03). Moreover, the size of lesions in the intervention group was significantly reduced compared to that in the placebo group (p = 0.02). Recognizable induration reduction was observed in the clarithromycin group (2.60 ± 0.77 to 1.0 ± 0.00). No adverse effects attributable to clarithromycin were reported. Conclusion: The administration of liposomal clarithromycin in combination with systemic Glucantime had a significant beneficial effect on reducing lesion size in leishmaniasis. Further studies on larger populations are recommended. Systematic Review Registration: https://www.irct.ir/trial/46611.

Cutaneous leishmaniasis can present in many different clinical forms. Diagnosis of atypical forms is often delayed. It is useful to keep in mind the diagnosis of cutaneous leishmaniasis, a mimicking disease, to reduce unnecessary treatment and patient morbidity. Erysipeloid leishmaniasis should be considered when presented as long-term erysipelas-like lesions that do not respond to antibiotics. We want to present our five patients with erysipeloid leishmaniasis, one of the atypical clinical forms.

BACKGROUND: Cutaneous leishmaniasis (CL) is a serious health problem in some parts of the world, such as Iran. Since the use of pentavalent antimonial compounds such as meglumine antimoniate (Glucantime, MA) for the treatment of CL has side effects, naloxone as a new treatment in the footpad of Leishmania major (L. major)-infected BALB/c mice was investigated by evaluating the lesion size and the parasite burden.
METHODS: The animals were infected with L. major (MRHO/IR/75/ER). 40 BALB/c mice were divided into 4 groups (10/group), and were treated as follows 39 days after L. major infection: Group 1 treated with intraperitoneal injections of MA (100 mg/kg, positive control group) daily for six weeks; Group 2 received a 100 μl injection of PBS (negative control group); Group 3 received subcutaneous (SC) injections of naloxone (10 mg/kg) daily for six weeks (Naloxone1), and Group 4 was SC injected with naloxone (10 mg/kg) weekly for six weeks (Naloxone2). The lesion size was measured using a digital caliper.
RESULTS: After the end of treatment, the lesion parasite burden was evaluated. As compared to the negative control group, the groups that received MA and naloxone (groups 1, 3, and 4) showed fewer parasites. Also, the naloxone-treated mice showed significantly smaller lesion sizes than the negative control group (p˂0.05), but they did not differ significantly from the MA-treated mice.
CONCLUSIONS: Taken together, the results suggest that naloxone might be a promising and alternative treatment for CL.

UNASSIGNED: The present study aimed at investigating the topical effect of the combination of Plantago ovata and vinegar on the improvement of rural cutaneous leishmaniasis lesions.
UNASSIGNED: The present randomized double-blind controlled clinical trial was performed on 42 patients with rural skin leishmaniasis. In the case group, in addition to injecting glucantime into the lesion according to the latest national instructions, a combination of P. ovata and vinegar was applied topically twice a day for 8 weeks. In the control group, only glucantime injection into the lesion was performed for 8 weeks according to the latest national guidelines. At the end of the 1st, 2nd, 3rd, 4th, 8th, and 12th weeks after the intervention, the lesion area and improvement were evaluated and recorded.
UNASSIGNED: The results of the present study indicated the lesion area in the case group with the mean of 0.35 ± 0.39 cm and 0.18 ± 0.27 cm in the 8th and 12th weeks, respectively was significantly less than that of the control group with the mean of 0.64 ± 0.78 cm and 0.56 ± 0.44, respectively (P < 0.05). Twelve weeks after the intervention, 84.1% of the lesions in the case group and 65.9% of the lesions in the control group were completely improved (P < 0.05).
UNASSIGNED: According to the results of the present study, the improvement of leishmaniasis lesion with the topical application of the combination of P. ovata and vinegar was significantly more than that of the control group in the 8th and 12th weeks after the intervention.

BACKGROUND: Treatment of cutaneous leishmaniasis (CL) remains a major challenge for the public health and medical community. It has been claimed that natural compounds derived from fly larvae have anti-leishmania properties against some species of Leishmania. The present study aimed at assessing the in vitro effects of larval products of Lucilia sericata against the promastigote and intracellular amastigote forms of Leishmania major. Also, the therapeutic effect of larval products on lesions induced by L. major infection was evaluated in BALB/c mice models.
METHODS: Parasite specimens and macrophage cells were exposed to varying concentrations of larval products for 24-120 h. Lesion progression and parasite load were investigated in the models to assess the therapeutic effects of the products.
RESULTS: The larval products displayed more potent cytotoxicity against L. major promastigotes. The IC50 values for larval saliva and hemolymph were 100.6 and 37.96 ug/ml, respectively. The IC50 of glucantime was 9.480 ug/ml. Also, the saliva and hemolymph of L. sericata exhibited higher cytotoxicity against the promastigotes of L. major but were less toxic to the macrophage cells. Treatment with leishmanicidal agents derived from larvae of L. sericata decreased the infection rate and the number of amastigotes per infected host cell at all concentrations. Lesion size was significantly (F (7, 38) = 8.54, P < 0.0001) smaller in the treated mice compared with the untreated control group. The average parasite burden in the treated mice groups (1.81 ± 0.74, 1.03 ± 0.45 and 3.37 ± 0.41) was similar to the group treated with a daily injection of glucantime (1.77 ± 0.99) and significantly lower (F (7, 16) = 66.39, P < 0.0001) than in the untreated control group (6.72 ± 2.37).
CONCLUSIONS: The results suggest that the larval products of L. sericata were effective against L. major parasites both in vivo and in vitro. However, more clinical trial studies are recommended to evaluate the effects of these larval products on human subjects.

UNASSIGNED: Topical nanoliposomes containing 0.4% amphotericin B (Lip-AmB 0.4%) have shown promising safety results in preclinical and phase 1 clinical trials in healthy volunteers.
UNASSIGNED: To evaluate safety and efficacy of Lip-AmB 0.4% in cutaneous leishmaniasis patients.
UNASSIGNED: Fourteen patients with a total of 84 lesions received national standard treatment of weekly intralesional meglumine antimoniate with biweekly cryotherapy, or daily intramuscular meglumine antimoniate (20 mg/kg/day for 14 days), and topical Lip-AmB 0.4% twice daily for 28 days. Twenty-two patients with a total of 46 lesions (7 at most) were treated with topical Lip-AmB 0.4% alone twice daily for 28 days. Thirty patients with a total of 68 lesions received national standard treatment of weekly intralesional meglumine antimoniate (to blanch around the lesion) and biweekly cryotherapy.
UNASSIGNED: Sixty-six patients with cutaneous leishmaniasis lesions completed the study. In the safety evaluation, 2 of the 36 patients evaluated reported a tolerable burning sensation and they preferred to continue treatment. Twelve (92%) of 14 patients with 84 lesions who received national standard treatment combined with Lip-AmB 0.4% completed the study with complete cure. In 1 of the patients with 4 lesions, 1 lesion showed complete cure and 3 showed partial cure. Among 22 patients with 46 lesions who received only topical LipAmB 0.4%, 19 completed the study and 18 showed complete cure (95% efficacy). In the 30 patients who received national standard treatment alone, 33 lesions in 15 patients showed complete cure (48.5%) on day 42 follow-up.
UNASSIGNED: Lip-AmB 0.4% alone or in combination with national standard treatment is safe with high-efficacy rate and warrants further investigation during phase 3 clinical trials.
دراسة ارتيادية لسلامة وفاعلية الاستخدام الموضعي لليبوسومال الأمفوتريسين B لعلاج داء الليشمانيات الجلدي الناجم عن الليشمانية الكبيرة في إيران.
علي خامسی پور، اکرم محمدي، محمود جعفري، سید إسكندري، مينو تسبيحي، أمير جوادی، فرزانه أفشاري، حسين مرتضوی، علي رضا فيروز.
UNASSIGNED: أظهر الاستخدام الموضعي لنانو ليبوسومال الذي يحتوي على الأمفوتريسين B بتركيز 0.4 ٪ (Lip-AmB 0.4٪) نتائج سلامة واعدة في التجارب السريرية في المرحلة قبل السريرية والمرحلة الأولى على المتطوعين الأصحاء.
UNASSIGNED: هدفت هذه الدراسة الى تقييم سلامة وفاعلية نانو ليبوسومال الذي يحتوي على الأمفوتريسين B بتركيز 0.4 ٪ (Lip-AmB 0.4٪) عند استخدامه مع مرضى داء الليشمانيات الجلدي.
UNASSIGNED: تلقى أربعة عشر مريضًا يعانون إجمالًًا من 84 آفةً العلاجَ الوطني المعياري، الذي يتمثل في إعطاء ميجلومين أنتيمونيات في الآفة أسبوعيًّا مع العلاج بالتبريد مرتين أسبوعيًّا، أو علاجًا يوميًّا بالحقن بميجلومين أنتيمونيات في العضل (20 ملجم/ كجم/يوميًّا لمدة 14 يومًا)، وعلاج موضعي باستخدام نانو ليبوسومال الذي يحتوي على الأمفوتريسين B بتركيز 0.4٪ مرتين يوميًّا لمدة 28 يومًا. وتلقى اثنان وعشرون مريضًا يعانون إجمالًًا من 46 آفة (7 على الأكثر) دواء نانو ليبوسومال الذي يحتوي على الأمفوتريسين B بتركيز 0.4٪ (Lip-AmB 0.4٪) الموضعي وحده مرتين يوميًّا لمدة 28 يومًا. وتلقى ثلاثون مريضًا يعانون إجمالًًا من 68 آفةً العلاجَ الوطني المعياري، وهو العلاج بميجلومين أنتيمونيات داخل الآفة أسبوعيًّا (لتبييض الجلد حول الآفة) والعلاج بالتبريد مرتين أسبوعيًّا.
UNASSIGNED: أتم المشاركة في الدراسة ستة وستون مريضًا مصابًا بداء الليشمانيات الجلدي. وفي تقييم السلامة، أبلغ مريضان من بين 36 مريضًا خضعوا للتقييم عن شعور بحرقة يمكن تحملها، وفضَّلا مواصلة العلاج. وأتم الدراسةَ اثنا عشر (92٪) مريضًا، من بين 14 مريضًا يعانون من 84 تقرُّحًا، وحصلوا على العلاج الوطني القياسي، بالإضافة إلى نانو ليبوسومال الذي يحتوي على الأمفوتريسين B بتركيز 0.4٪، وقد تحقق لهم الشفاء تمامًا. وأحد المرضى، الذين كانوا يعانون من 4 آفات، تحقق له الشفاء التام من آفة واحدة والشفاء الجزئي من ثلاث آفات. ومن بين 22 مريضًا يعانون من 46 آفة وتلقوا فقط نانو ليبوسومال الذي يحتوي على الأمفوتريسين B بتركيز 0.4٪ موضعيًّا، أكمل 19 مريضًا الدراسة، وشُفي 18 منهم تمامًا (بفاعلية تبلغ 95٪). أما المرضى الذين تلقوا العلاج الوطني القياسي فقط وعددهم 30، فقد شُفيت 33 آفة لدى 15 مريضًا منهم شفاء تامًّا (48.5٪) عند المتابعة في اليوم 42.
UNASSIGNED: استخدام نانو ليبوسومال الذي يحتوي على الأمفوتريسين B بتركيز 0.4٪ (Lip-AmB 0.4٪) وحدة، أو مع العلاج القياسي الوطني آمِن ويتميز بفاعلية عالية، ويستحق إجراء مزيد من الاستقصاء عليه في تجارب سريرية من المرحلة الثالثة.
Étude pilote sur l\'innocuité et l\'efficacité de l\'amphotéricine B liposomale topique pour le traitement de la leishmaniose cutanée causée par Leishmania major en République islamique d\'Iran.
UNASSIGNED: Les nanoliposomes topiques contenant 0,4 % d\'amphotéricine B ont montré des résultats prometteurs en termes d\'innocuité lors d\'essais précliniques et cliniques de phase 1 chez des volontaires en bonne santé.
UNASSIGNED: Évaluer l\'innocuité et l\'efficacité de l\'amphotéricine B à 0,4 % chez les patients atteints de leishmaniose cutanée.
UNASSIGNED: Quatorze patients présentant un total de 84 lésions se sont vu administrer le traitement standard national constitué d\'injections intralésionnelles d\'antimoniate de méglumine hebdomadaire avec cryothérapie bihebdomadaire, ou d\'antimoniate de méglumine intramusculaire de manière quotidienne (20 mg/kg/jour pendant 14 jours), et d\'amphotéricine B topique à 0,4 % deux fois par jour pendant 28 jours. Vingt-deux patients présentant un total de 46 lésions (sept au maximum) ont été traités seulement par amphotéricine B topique à 0,4 % deux fois par jour pendant 28 jours. Trente patients présentant au total 68 lésions ont reçu le traitement standard national d\'antimoniate de méglumine intralésionnel chaque semaine (pour blanchir le pourtour de la lésion) et de cryothérapie bihebdomadaire.
UNASSIGNED: Soixante-six patients présentant des lésions de leishmaniose cutanée ont terminé l\'étude. Dans l\'évaluation de l\'innocuité, deux des 36 patients évalués ont signalé une sensation de brûlure tolérable et ont préféré poursuivre le traitement. Douze (92 %) des 14 patients présentant 84 lésions qui ont reçu le traitement standard national associé à l\'amphotéricine B à 0,4 % ont terminé l\'étude avec une guérison complète. Chez l\'un des patients présentant quatre lésions, on a observé une guérison complète pour une lésion et une guérison partielle pour trois lésions. Parmi les 22 patients présentant 46 lésions qui ont reçu uniquement de l\'amphotéricine B topique à 0,4 %, 19 ont terminé l\'étude et 18 ont montré une guérison complète (efficacité à 95 %). Chez les 30 patients ayant reçu le traitement standard national seul, 33 lésions chez 15 patients ont présenté une guérison complète (48,5 %) au 42ème jour de suivi.
UNASSIGNED: L\'amphotéricine B à 0,4 % seule ou en association avec le traitement standard national est sans risque et présente un taux d\'efficacité élevé. Elle mérite donc d\'être étudiée de manière plus approfondie lors des essais cliniques de phase 3.

Two new eudesmane-type sesquiterpene lactones, 1β,3α,8α-trihydroxy-11β,13-dihydroeudesma-4(15)-en-12,6α-olide (1) and 1β,4α,8α-trihydroxy-11β,13-dihydroeudesma-12,6α-olide (2), and an unprecedented elemane-type sesquiterpene lactone, 1β,2β,8α-trihydroxy-11β,13-dihydroelema-12,6α-olide (3) along with a known eudesmanolide artapshin (4) were isolated from Seriphidium khorassanicum. Structures were elucidated by NMR, HR-ESI-MS, and ECD spectral data analysis. The anti-protozoal activity was evaluated against Leishmania major promastigotes and amastigote-infected macrophages. They showed dose- and time-dependent activity against L. major amastigotes with IC50 values in the range of 4.9 to 25.3 μM being favourably far below their toxicity against normal murine macrophages with CC50 values ranging from 432.5 to 620.7 μM after 48 h of treatment. Compound 3 exhibited the strongest activity and the highest selectivity index (SI) with IC50 of 4.9 ± 0.6 μM and SI of 88.2 comparable with the standard drug, meglumine antimoniate (Glucantime), with IC50 and SI values of 15.5 ± 2.1 μM and 40.0, respectively.

Leishmaniasis is a human and animal disease endemic in tropical and subtropical areas treated by means of pentavalent antimony as first-line approach. Unfortunately, the formulations available on the market are characterized by significant side effects and a total remission of the disease is difficult to be obtained. The aim of this investigation is to describe the development and characterization of aqueous-core poly-l-lactide (PLA) nanocapsules containing glucantime (meglumine antimoniate, MA) with the aim of increasing the pharmacological efficacy of the active compound. The polymeric systems characterized by a mean diameter of ≈300 nm exert a great interaction with murine macrophages. MA-loaded PLA nanocapsules show a great antileishmanial activity on mice infected with Leishmania infantum with respect to the free drug, favoring a decrease of the administration times. The biodistribution profiles demonstrate a lower renal accumulation of MA after its nanoencapsulation and a significant increase of its plasmatic half-life. The parasite load evaluated by immunohistochemistry shows a significant decrease in liver, spleen, and kidneys when mice are treated with MA-loaded PLA nanocapsules especially after 45 days. The obtained results demonstrate the potential application of MA-loaded PLA nanocapsules as novel nanomedicine for the treatment of leishmaniasis.

BACKGROUND: In the present study, we examined the effects of Fe3O4@bio-MOF nanoparticle (Nano-FO) plus artemisinin (Art) and glucantime (Glu) or shark cartilage extract (ShCE) on Leishmania major in vitro and in vivo.
METHODS: This experimental study was conducted at the laboratory of Department of Parasitology, Tarbiat Modares University, Tehran, Iran during 2016-2017. The promastigote and amastigote assays were performed were conducted at the presence of 3.12-400 μg/mL of the drug combinations. According to in vitro IC50 results, the combinations of 12.5μg/mL Nano-FO with 25 μg/mL Art as well as 200 μg/mL Glu and 0.5 mL of 20 mg/kg of ShCE were used to treat BALB/c mice. During and at the end of the treatment, the lesion sizes were measured. Parasite loads, cytokine levels were evaluated at the end of the treatment.
RESULTS: The IC50 of Fe3O4@bio-MOF-Artemisinin (Nano-FO/Art), Fe3O4@bio-MOF-Glucantime (Nano-FO/Glu), and Fe3O4@bio-MOF-Shark cartilage extract (Nano-FO/ShCE) on promasitigotes were 12.58±0.12, 235±0.17, and 18.54±0.15, respectively. These results on amastigotes were 10.32±0.01, 187±0.03, and 338±0.07 μg/mL, respectively. The apoptosis percentage of these combinations were 32.54%, 20.59%, and 15.68% in promastigotes and 15.68%, 12.84%, and 3.51% in infected macrophages, respectively with no toxicity on uninfected macrophages. In vivo results showed that the size of lesions significantly decreased against all drugs combinations, but Nano-FO/Art combination with Selectivity Index of 23.62 value was safe, and more effective on healing of lesions than other drugs combinations (P=0.003).
CONCLUSIONS: This study suggested that Nano-FO/Art combination can be considered as an anti-leishmania combination therapy in CL induced by L. major.