Topical Paromomycin with or without Gentamicin for Cutaneous Leishmaniasis

The optimal treatment for cutaneous leishmaniasis (CL) is not known. Topical paromomycin is one of the many drugs that have been suggested for the treatment of CL caused by Leishmania major. Recently, topical photodynamic therapy (PDT) has been reported to be effective in the treatment of CL. To compare the parasitological and clinical efficacy of PDT vs. topical paromomycin in patients with Old World CL caused by L. major in Iran. In this trial, 60 patients with the clinical and parasitological diagnosis of CL were recruited and were randomly divided into three treatment groups of 20 subjects each. Group 1 was treated with weekly topical PDT, and groups 2 and 3 received twice-daily topical paromomycin and placebo, respectively. The duration of treatment was 4 weeks for all groups. These groups were followed for 2 months after the end of treatment. In total, 57 patients with 95 lesions completed the study. At the end of the study, complete improvement was seen in 29 of 31 (93.5%), 14 of 34 (41.2%) and 4 of 30 lesions (13.3%) in groups 1, 2 and 3, respectively (P<0.001). At the same time point, 100%, 64.7% and 20% of the lesions had parasitological cure in group 1, 2 and 3, respectively (P<0.001). Topical PDT can be used safely as a rapid and highly effective alternative treatment choice for Old World CL in selected patients.

Successful outcomes of clinical studies for acne vulgaris depend greatly on achieving statistically significant reduction in acne lesion count and improvement in Investigator's Global Assessment score of the investigational drug product against its vehicle control. To date, there has not been a validated preclinical acne model to evaluate investigational drug products in order to improve the probability of clinical success. An inflammatory acne-like lesion mouse model developed in-house has previously been used for clinical guidance in our drug development program. In this study, we aim to implement and assess the adequacy of swept-source optical coherence tomography (SS-OCT) in quantifying the dynamic changes in inflammatory acne-like lesions. Live Propionibacterium acnes bacteria were injected intradermally resulting in inflammatory acne-like lesions. Topical 1% and 2% minocycline gels were applied to the lesions in separate groups once daily for 2 weeks and compared with vehicle and untreated control groups. The growth of these lesions was monitored and measured with a ruler (height)/microcaliper (width)-an approach previously developed, and with SS-OCT. The reliability of the two methods were assessed. Acquired OCT images across the apex of these inflammatory lesions were statistically analyzed for lesion volume reduction from baseline as well as between the treatment groups and the control groups. The OCT technique allowed for reliable lesion volume analysis with varying conic profiles. After 14 days of topical minocycline treatments (1%, 2% minocycline), statistically significant reduction in lesion volume (P ≤ 0.05) based on OCT image analysis was observed compared with untreated and vehicle control groups as well as compared with baseline measurements. Under the right conditions, some morphological aspects of the P. acnes injection site were discernible within the skin in images captured with OCT. We demonstrated the first use of SS-OCT in evaluating in vivo inflammatory acne-like lesions in a murine model. Our findings support the use of OCT in assessing lesion size and evolution of P. acnes injection sites non-invasively in preclinical in vivo studies, which could potentially lead to more consistent and predictable outcomes in clinical development. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

To compare the liver protective activity of fresh/dried dandelion extracts against acetaminophen (APAP)-induced hepatotoxicity. Totally 90 Kunming mice were randomly divided into 10 groups according to body weight (9 mice for each group). The mice in the normal control and model (vehicle control) groups were administered sodium carboxymethyl cellulose (CMC-Na, 0.5%) only. Administration groups were pretreated with high and low-dose dry dandelion extract (1,000 or 500 g fresh herb dried and then decocted into 120 mL solution, DDE-H and DDE-L); low-, medium- and high-dose dandelion juice (250, 500, 1,000 g/120 mL, DJ-L, DJ-M, and DJ-H); fresh dandelions evaporation juice water (120 mL, DEJW); dry dandelion extract dissolved by pure water (1 kg/120 mL, DDED-PW); dry dandelion extract dissolved by DEJW (120 g/120 mL, DDED-DEJW) by oral gavage for 7 days at the dosage of 0.5 mL solution/10 g body weight; after that, except normal control group, all other groups were intraperitonealy injected with 350 mg/kg APAP to induce liver injury. Twenty hours after APAP administration, serum and liver tissue were collected and serum alanine aminotransferase (AST), aspartate transaminase (ALT), alkaline phosphatase (AKP), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD) activities were quantified by biochemical kits; tumor necrosis factor (TNF-α), interleukin (IL)-2, and IL-1 β contents in liver tissue were determined by enzyme linked immunosorbent assay kits. Histopathological changes in liver tissues were observed by hematoxylin and eosin staining; TUNEL Assay and Hoechst 33258 staining were applied for cell apoptosis evaluation. The expressions of heme oxygenase-1 (HO-1), nuclear factor erythroid-2-related factor 2 (Nrf-2), caspase-9, B-cell leukemia/lymphoma 2 (Bcl-2), Bax and p-JNK were determined by Western blot analysis. Pretreatment with fresh dandelion juice (FDJ, including DJ-L, DJ-M, DJ-H, DEJW and DDED-DEJW) significantly decreased the levels of serum ALT, AST, AKP, TNF-α and IL-1β compared with vehicle control group (P<0.05 or P<0.01). Additionally, compared with the vehicle control group, FDJ decreased the levels of hepatic MDA and restored GSH levels and SOD activity in livers (P<0.05 or P<0.01). FDJ inhibited the overexpression of pro-inflammatory factors including cyclooxygenase-2 and inducible nitric oxide synthase in the liver tissues (P<0.05 or P<0.01). Furthermore, Western blot analysis revealed that FDJ pretreatment inhibited activation of apoptotic signaling pathways via decreasing of Bax, and caspase-9 and JNK protein expression, and inhibited activation of JNK pathway (P<0.05 or P<0.01). Liver histopathological observation provided further evidence that FDJ pretreatment significantly inhibited APAP-induced hepatocyte necrosis, inflammatory cell infiltration and congestion. FDJ pretreatment protects against APAP-induced hepatic injury by activating the Nrf-2/HO-1 pathway and inhibition of the intrinsic apoptosis pathway, and the effect of fresh dandelion extracts was superior to dried dandelion extracts in APAP hepatotoxicity model mice.

A Multicenter, Randomized, Double-blind, Parallel Group Pilot Evaluation of the Efficacy and Safety of Intravesical Sodium Chondroitin Sulfate Versus Vehicle Control in Patients With Interstitial Cystitis/Painful Bladder Syndrome

Topical photodynamic therapy with chloroaluminum phthalocyanine liposomes is as effective as systemic pentavalent antimony in the treatment of experimental cutaneous leishmaniasis.

REALISE-ing the Net Health Benefit of EPIT for Peanut Allergy

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.

Long-term application of diethylstilbestrol upregulates expressions of µ - and m-calpains in pituitary intermediate lobe of female Wistar rats*

Introduction: Cutaneous leishmaniasis(CL) is an endemic disease with variable therapeutic agents. Microwave radiation has been used in many medical disciplines as therapeutic and diagnostic tools. Objective: To evaluate the efficacy of microwave radiofrequency in the treatment of cutaneous leishmaniasis. Patients and methods: This is a case, controlled, therapeutic, clinical trial. Thirty five patients completed the study, 18 (51.43%) females and 17 (48.57%) males, with female to male ratio 1.1:1, their ages ranged from 6–60 (26.98±15.22) years and the duration of lesions ranged between 1–6 (2.17±1.44) months. The size of lesions ranged from 1-6.5 (2.87±1.60) cm. Eleven (31.43%) patients had single lesion and 24 (68.57%) patients had multiple lesions. Classical cases of CL were studied and diagnosis was confirmed by histopathological examination. Lesions had been divided in 2 groups, Group A: lesions were exposed to a microwave radiation once every two weeks for a maximum of 8 weeks, while Group B lesions, received no treatment and left as a control group. Patients were seen every 2 weeks for 8 weeks to reassess the therapeutic effect and to record any side effects. Follow up after cure was carried out for 2-6 months to watch any sign of relapse. Results: The total number of lesions were 99;52 (52.53%) ulcerated lesions and 47 (47.47%) dry lesions. In Group A, 64 (85.33%) lesions out of 75 showed clinical cure with 1-4 (2.77±0.91) sessions while in Group B, 5 (20.83%) lesions out of 24 lesions showed slight healing during the treatment period. No side effects appear in all patients. Conclusion: Microwave thermotherapy is highly effective, new therapy for cutaneous leishmaniasis with no harmful side effects.

Importance of the field: Cutaneous leishmaniasis (CL) is a major tropical skin disease. Its incidence continues to increase, and disease control and management are challenging. Available therapies remain inadequate and are associated with low efficacy, toxicity, difficulties with administration, or are expensive.Areas covered in this review: This article describes progress in the therapeutics of CL since 2006. Clinical trials have provided further evidence for the use of alternative systemic agents to first-line antimonials, an enhanced topical paromomycin preparation, the efficacy of thermotherapy, photodynamic therapy as an emerging physical therapy, and the role of immunotherapy and immunomodulators as adjuncts to chemotherapy. In addition, in vitro studies have demonstrated the anti-leishmanial effects of several drugs, which might represent potential future therapeutic agents for CL.What the reader will gain: An overview of the magnitude and complexity of this heterogenous disease, and an update on recent advances in therapeutics and future directions for new drug development.Take home message: Drug therapy for CL must be tailored according to infective species, endemic region, and host responses; a range of different therapies and modalities is therefore required. The impetus for new drug development must continue, combination therapies need to be evaluated, and robust and comparative trials of existing agents are required to adequately assess their efficacy and tolerability.

This study aimed to evaluate the efficacy of binary combinations of suboptimal schedules of drugs with different administration routes (topical paromomycin, intramuscular meglumine antimoniate and oral miltefosine) to treat animals infected with Leishmania (Viannia) braziliensis. Hamsters were inoculated with L. (V.) braziliensis and after ulceration of lesions, divided into seven groups: untreated control, paromomycin, miltefosine, meglumine antimoniate, meglumine antimoniate + paromomycin, miltefosine + paromomycin and meglumine antimoniate + miltefosine. Meglumine antimoniate and miltefosine were administered at low doses and topical paromomycin at a single daily application regimen. The animals were treated for 20 consecutive days (meglumine antimoniate and/or paromomycin) and/or 10 alternate days (miltefosine). Lesion sizes were determined weekly. Upon completion of treatment, parasites were recovered from skin lesions and spleens and evaluated by limiting dilution assay. The combinations of a once daily application of paromomycin with low doses of miltefosine or meglumine antimoniate yielded higher efficacies in reducing the parasite load as well as lesion size when compared with any of these drugs administered as monotherapy regimens at the same suboptimal schedules. Considering the parameters evaluated, the combinations of a systemic therapy with topical treatment were more effective than monotherapy with each of these drugs. These combinations may represent an alternative combination strategy for the treatment of leishmaniasis caused by L. (V.) braziliensis.

Background: It is imperative to develop novel therapeutics to overcome chemoresistance, a major obstacle in the clinical management of prostate cancer (PCa) and other cancers. Drug repositioning is being pursued as an attractive approach due to its potentially lower overall development costs and shorter timelines. The purpose of this study is to investigate the preclinical efficacy and mechanism of action of nicardipine, an FDA-approved hypertension drug, as a new treatment against chemoresistant prostate cancer. Methods: A panel of FDA-approved non-oncology drugs was screened for their selectivity and potency to inhibit chemoresistant PCa cells using a two-tier phenotypic screening platform (Theranostics, 2021, 11(14): 6873-6890). The mechanism of action of potential candidate(s) was evaluated using in silico docking, cellular and molecular assays in ARCaPE-shEPLIN and C4-2B-TaxR, two independent chemoresistant PCa cell lines. The in vivo efficacy was evaluated in clinically-relevant xenograft models of PCa. Results: Nicardipine exhibited high selectivity and potency against chemoresistant PCa cells via effectively inducing apoptosis and cell cycle arrest. The IC50 of nicardipine was determined as 0.5 μM and 2.1 μM in ARCaPE-shEPLIN and C4-2B-TaxR cells, respectively. Mechanically, nicardipine targeted a novel non-canonical enhancer of zeste homolog 2 (EZH2) signal pathway in chemoresistant PCa cells. Specifically, nicardipine might bind embryonic ectoderm development (EED), interrupt the integrity and stability of the polycomb repressive complex 2 (PRC2), reduce the phosphorylation and expression of EZH2, and subsequently inhibit downstream effectors including signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B1 (ABCB1) and survivin. In animal models, as a monotherapy, nicardipine significantly suppressed the intratibial growth of chemoresistant C4-2B-TaxR xenografts, with an average PSA level of 43.47 ng/ml, 36.63 ng/ml, and 28.78 ng/ml for the vehicle control, docetaxel, and nicardipine groups at the endpoint, respectively (p &amp;lt; 0.05 between the nicardipine group and the vehicle control or docetaxel groups). As a combination regime, nicardipine synergistically enhanced the efficacy of docetaxel against the intratibial growth of C4-2 xenografts, with an average PSA level of 79.17 ng/ml, 49.04 ng/ml, 42.80 ng/ml, and 23.23 ng/ml for the vehicle control, docetaxel, nicardipine, and combination groups at the endpoint, respectively (p &amp;lt; 0.0001 or 0.01 between the combination group and the vehicle control or docetaxel groups, respectively). Conclusion: These results demonstrated that, for the first time, nicardipine could be a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes. Citation Format: Xin Li, Alira Danaher, Jason M. Wu, Yifei Wu, Zhong-Ru Xie, Nicholas Cook, Nathan Bowen, Daqing Wu. Repositioning nicardipine as a novel targeted therapy for chemoresistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5365.

The Gut Microbiome Regulates FVIII Immune Responses

Dear Editor, Literature data on the use of fluconazole in cutaneous leishmaniasis (CL) by Leishmania braziliensis are poor and conflicting.1-4 We present four patients with severe CL by L. braziliensis who were successfully treated with fluconazole (Supplementary Table 1). The patients were four Caucasians who acquired CL after trips to Brazil, Bolivia, and Colombia. All patients were previously, but unsuccessfully, treated with different drugs. All patients were subjected to general and dermatologic examination, laboratory tests, cytologic, and histopathologic examinations, culture in Novy-MacNeal-Nicolle medium and polymerase chain reaction (PCR). In all patients CL was characterized by ulcerative lesions (Figure 1A). Laboratory tests were within normal ranges. Cytologic and histopathologic examinations revealed the presence of Leishmania spp. Culture was positive for Leishmania spp. PCR was positive for L. braziliensis. Leishmanin Skin/Montenegro test was carried out in three patients, who resulted to be positive. Fluconazole was used at the dosage of 400 mg/day for 6–11 months. All patients were examined every month. Laboratory examinations were performed every 2 months. The first clinical improvement was observed 4–6 weeks after the beginning of the therapy. In all patients, complete remission was obtained (Figure 1A–F). Follow-up (≤7 years and 11 months) was negative in all patients. Side effects were local itching, weakness, arthralgia, myalgia and gastralgia (one patient), and local pain and weakness (one patient). In one patient mild increase in azotaemia was detected. In all patients it was unnecessary to stop the therapy. Azole and triazole drugs inhibit the growth of Leishmania spp. by inhibiting the cytochrome P-450–mediated 14α-demethylation of lanosterol, blocking ergosterol synthesis, and causing accumulation of 14α-methyl sterols.5 A recent study demonstrated that L. braziliensis is sensitive in vitro to fluconazole.6 The first report on the use of fluconazole in CL by L. braziliensis was published in 2007: no clinical results were observed in three Austrian soldiers who acquired the infection in Belize.1 Sousa et al.2 successfully used fluconazole in 28 patients. They started with a dosage of 5 mg−1kg−1day−1 and reached 8 mg−1kg−1day−1. The duration of the therapy was 4–12 weeks. With the low dosage, 75% patients recovered; with 8 mg−1kg−1day−1, the cure rate was 100%. The drug was well tolerated. A randomized, controlled study was carried out to compare the efficacy and safety of fluconazole (6.5–8 mg−1kg−1day−1 for 28 days) versus pentavalent antimony (20 mg−1kg−1day−1 for 20 days). A total of 53 patients were included: 27 patients were treated with fluconazole and 26 with antimony. Initial cure rates (two months after treatment) were of 22.2% (6/27 patients) in the fluconazole group and 53.8% (14/26 patients) in the antimony group. No relapses were observed. The frequency of adverse events in the antimony and fluconazole groups was similar: 34.6% versus 37%, respectively. In the group of patients treated with fluconazole, dizziness was observed in 22.2% of them, nausea in 11.1% and headache in 7.4%. One patient discontinued the treatment because of headache and dizziness. According to this study, fluconazole was not considered as an effective therapy.4 Our experience on the use of fluconazole in CL is based on approximately 30 patients: we successfully treated patients with CL by L. panamensis7 and L. infantum.8, 9 Fluconazole was also successfully used in pediatric patients with CL caused by L. major and L. tropica. Furthermore, no important side effects were observed.10, 11 It is possible that the duration of the therapy is important. As previously mentioned, we used fluconazole for 6–11 months: in the first 4–6 weeks of therapy clinical results were slow and partial. In the previously cited study,4 fluconazole was used for only 28 days. We also observed that a long therapy induced neither important side effects nor laboratory abnormalities. In spite of the small number of patients treated, we think that fluconazole can be taken into consideration in patients with CL by L. braziliensis in those countries where pentavalent antimony is no more marketed. The authors declare no potential conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Supplementary Table 1 Patients' characteristics. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Dear Sir: We read with interest the clinical trial reported by Sosa and others1 in which topical paromomycin/WR 279,369/gentamicin was compared with paromomycin alone for the treatment of New World cutaneous leishmaniasis (NWCL) caused by Leishmania panamensis. The authors concluded that the combination product may provide greater clinical benefit than paromomycin alone. The authors stated that paromomycin plus methylbenzethonium chloride (MBCL) ointment has not been evaluated alone against L. panamensis. However, Krause and others2 published a non-randomized study of patients in Ecuador with L. panamensis NWCL, with paromomycin sulphate plus MBCL ointment administrated twice a day for 10 days or once a day for 20 days, compared with untreated patients. Cure rates were 85%, 85%, and 9%, respectively. Moreover Armijos and others3 in 2004 performed a randomized controlled trial in Ecuador in patients with Leishmania guyanensis, Leishmania braziliensis, and Leishmania panamensis NWCL, in which topical paromomycin plus MBCL ointment was compared with topical paromomycin sulphate plus urea, both twice a day for 30 days, compared with meglumine antimoniate for 10 days. The cure rates at 3 months were 79%, 70%, 92%, respectively. The cure rates in these two studies were similar to those seen by Sosa and others1 with combination therapy (86%). Thus, good cure rates for L. panamensis NWCL can be obtained when paromomycin ointment is combined with other agents. However, this was not shown for Leishmania major old world cutaneous leishmaniasis, where no significant difference in efficacy between paromomycin with or without gentamicin was seen.4 Currently a phase 3, randomized, double-blind trial to determine if WR 279,396 is superior to paromomycin alone for L. panamensis NWCL in Panama is ongoing.5 Taking the previous data into account, probably a third therapeutic regimen based on paromomycin 15% plus MBCL 12% should have been included. Finally, we would like to mention that Sosa and others1 assert that their entry criteria of < 10 cutaneous lesions and no evidence of systemic dissemination conferred a very low risk for future mucosal infection. However, other authors consider local therapy for NWCL caused by L. braziliensis and L. panamensis unsuitable because of the potential risk of metastasis or secondary mucosal spread, and local therapy is recommended only for patients with ≤ 4–5 lesions.6,7 New clinical trials comparing local treatments for L. panamensis NWCL with long follow-up periods to determine the risk of mucosal dissemination are necessary.