Nanoemulsions containing amphotericin b and paromomycin for the treatment of cutaneous leishmaniasis.

Cutaneous leishmaniasis (CL) is a vector-borne disease characterized by skin lesions that can evolve into high-magnitude ulcerated lesions. Thus, this study aimed to develop an innovative nanoemulsion (NE) with clove oil, Poloxamer® 407, and multiple drugs, such as amphotericin B (AmB) and paromomycin (PM), for use in the topical treatment of CL. METHODS: Droplet size, morphology, drug content, stability, in vitro release profile, in vitro cytotoxicity on RAW 264.7 macrophages, and antileishmanial activity using axenic amastigotes of Leishmania amazonensis were assessed for NEs. RESULTS: After optimizing the formulation parameters, such as the concentration of clove oil and drugs, using an experimental design, it was possible to obtain a NE with an average droplet size of 40 nm and a polydispersion index of 0.3, and these parameters were maintained throughout the 365 days. Furthermore, the NE showed stability of AmB and PM content for 180 days under refrigeration (4 °C), presented a pH compatible with the skin, and released modified AmB and PM. NE showed the same toxicity as free AmB and higher toxicity than free PM against RAW 264.7 macrophages. The same activity as free AmB, and higher activity than free PM against amastigotes L. amazonensis. CONCLUSION: It is possible to develop a NE for the treatment of CL; however, complementary studies regarding the antileishmanial activity of NE should be carried out.

Antileishmanial efficacy and tolerability of combined treatment with non-ionic surfactant vesicle formulations of sodium stibogluconate and paromomycin in dogs.

Infection with Leishmania infantum causes the disease visceral leishmaniasis (VL), which is a serious clinical and veterinary problem. The drugs used to treat canine leishmaniasis (CanL) do not cause complete parasite clearance; they can be toxic, and emerging drug resistance in parasite populations limits their clinical utility. Therefore, in this study we have evaluated the toxicity and efficacy of joint treatment with a 1:1 mixture of sodium stibogluconate-NIV (SSG-NIV, 10 mg Sbv/day) and paromomycin-NIV (PMM-NIV, 10 mg PMM/kg/day), given intravenously daily for seven days from day 270 post-infection, to nine-month-old female beagle dogs (n = 6) experimentally infected with Leishmania infantum. Treatment significantly improved the clinical symptoms of VL infection in all the treated dogs, reduced parasite burdens in lymph nodes and bone marrow, and all symptomatic treated dogs, were asymptomatic at 90 days post-treatment. Treatment was associated with a progressive and significant decrease in specific IgG anti-Leishmania antibodies using parasite soluble antigen (p < 0.01) or rK39 (p < 0.01) as the target antigen. In addition, all dogs were classified as parasite negative based on Leishmania nested PCR and quantitative real time PCR tests and as well as an inability to culture of promastigote parasites from lymph nodes and bone marrow tissue samples taken at day 90 post-treatment. However, treatment did not cure the dogs as parasites were detected at 10 months post-treatment, indicating that a different dosing regimen is required to cause long term cure or prevent relapse.

Highly sensitive UPLC-MS/MS method for the quantification of paromomycin in human plasma.

A highly sensitive method was developed to quantitate the antileishmanial agent paromomycin in human plasma, with a lower limit of quantification of 5 ng/mL. Separation was achieved using an isocratic ion-pair ultra-high performance liquid chromatographic (UPLC) method with a minimal concentration of heptafluorobutyric acid, which was coupled through an electrospray ionization interface to a triple quadrupole - linear ion trap mass spectrometer for detection. The method was validated over a linear calibration range of 5 to 1000 ng/mL (r2≥0.997) with inter-assay accuracies and precisions within the internationally accepted criteria. Volumes of 50 µL of human K2EDTA plasma were processed by using a simple protein precipitation method with 40 µL 20 % trichloroacetic acid. A good performance was shown in terms of recovery (100 %), matrix effect (C.V. ≤ 12.0 %) and carry-over (≤17.5 % of the lower limit of quantitation). Paromomycin spiked to human plasma samples was stable for at least 24 h at room temperature, 6 h at 35 °C, and 104 days at -20 °C. Paromomycin adsorbs to glass containers at low concentrations, and therefore acidic conditions were used throughout the assay, in combination with polypropylene tubes and autosampler vials. The assay was successfully applied in a pharmacokinetic study in visceral leishmaniasis patients from Eastern Africa.

Evaluation of nephrotoxicity and ototoxicity of aminosidine (paromomycin)-allopurinol combination in dogs with leishmaniosis due to Leishmania infantum: A randomized, blinded, controlled study.

Canine leishmaniosis due to Leishmania infantum is a widespread zoonotic disease. Although aminosidine can be an effective treatment, current therapeutic recommendations do not advocate its use, mainly due to concerns regarding the potential nephrotoxicity and ototoxicity of this drug. The aim of this randomized, blinded, controlled study was to evaluate the nephrotoxicity and ototoxicity of aminosidine-allopurinol combination and compare it with that of meglumine antimonate-allopurinol combination in non-azotemic dogs with leishmaniosis. Forty dogs with leishmaniosis were randomly assigned to be treated with either aminosidine at 15 mg/kg, subcutaneously, once daily for 28 days (group A) or with meglumine antimonate at 100 mg/kg, subcutaneously, once daily for 28 days (group B). In addition to either drug, dogs in both groups were administered allopurinol at 10 mg/kg per os twice daily for 2 months. Kidney function was evaluated through measurement of serum creatinine, urea nitrogen, inorganic phosphorus, and cystatin-c concentrations and complete urinalysis, including protein-to-creatinine ratio, at baseline and after 14, 28, and 60 days from the beginning of the treatment. At the same time points, vestibular and auditory functions were evaluated through neurological examination and brainstem auditory evoked response (BAER) recordings of wave I, wave V, inter-wave I-V latencies, and minimum hearing thresholds. None of the dogs developed clinicopathological evidence of kidney disease during the study. Serum creatinine concentration increased >0.3 mg/dl over baseline in 2 dogs in group A and in 5 dogs in group B. Parameters of kidney function were not significantly different or were improved compared to baseline and the only difference between the two groups was the lower concentration of serum creatinine in group A. None of the dogs developed peripheral vestibular syndrome or hearing impairment. At the end of the study, parameters of auditory function were not significantly different or were improved compared to baseline and there were no differences between the two groups. The results of this study show that the nephrotoxicity and ototoxicity of aminosidine, when administered to non-azotemic dogs with leishmaniosis at 15 mg/kg subcutaneously once daily for 28 days along with allopurinol, is minimal and does not differ from that of meglumine antimonate.

Interventions for Old World cutaneous leishmaniasis.

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.

[Leg ulcer revealing cutaneous leishmaniasis]. / Ulcère de jambe révélant la leishmaniose cutanée.

Leishmaniases are parasitic diseases occurring in endemic tropical and subtropical areas and caused by protozoa of the genus leishmania, transmitted by a diptera (sand fly). We here report a case of topical cutaneous leishmaniasis discovered in a 15-year old boy with painless ulcer on his left leg, who had been staying in South Africa. Clinical examination showed painless non-itchy ulcer, occurred 1 month before, on the antero-internal part of his left leg with crusts and scars caused by insect bites, all evolving in a context of patient's general health status, without mucosal or visceral lesions. Skin biopsy allowed specific parasitologic diagnosis revealing topical zoonotic cutaneous leishmaniasis caused by L. major. The patient underwent topical treatment based on paramomycin and oral fluconazole resulting in ulcer healing at the end of 2 months.

Occult Amebic Liver Abscess as Cause of Extensive Inferior Vena Cava and Hepatic Vein Thrombosis.

The most common extraintestinal complication of Entamoeba histolytica is amebic liver abscess (ALA). Hepatic vein and inferior vena cava (IVC) thrombosis are rare but well-documented complications of ALA, typically attributed to mechanical compression and inflammation associated with a large abscess. We present a case of a previously healthy 43-year-old Canadian man presenting with constitutional symptoms and right upper quadrant abdominal pain. He was found to have thrombophlebitis of the IVC, accessory right hepatic vein, and bilateral iliac veins. Extensive investigations for thrombophilia were negative. Magnetic resonance imaging of the liver demonstrated a 3.2-cm focal area of parenchymal abnormality that was reported as presumptive hepatocellular carcinoma, and a 1.9-cm lesion in the caudate lobe with diffusion restriction and peripheral rim enhancement. Despite multiple biopsy attempts, a histopathological diagnosis was not achieved. Abdominal pain and fever 4 months later prompted repeat ultrasound demonstrating a 10.4- × 12.0-cm rim-enhancing fluid attenuation lesion felt to represent a liver abscess. Thick dark "chocolate brown" drainage from the lesion and positive serology for E. histolytica confirmed the diagnosis of ALA acquired from a previous trip to Cuba. The patient was started on treatment with metronidazole and paromomycin and repeat abdominal ultrasound demonstrated resolution of the abscess. This case is the first to demonstrate extensive IVC thrombosis secondary to a relatively small occult ALA and emphasizes the thrombogenic potential of ALA. Amebic infection should be considered as a rare cause of IVC thrombosis in the correct clinical context.

Drug Targeting to Macrophages With Solid Lipid Nanoparticles Harboring Paromomycin: an In Vitro Evaluation Against L. major and L. tropica.

Leishmaniasis is a worldwide disease that leads to high mortality and morbidity in human populations. Today, leishmaniasis is managed via drug therapy. The drugs that are already in clinical use are limited to a number of toxic chemical compounds and their parasite drug resistance is increasing. It is therefore essential, in order to circumvent the current difficulties, to design a new anti-leishmanial drug treatment strategy. Besides producing new, active anti-leishmanial entities, another promising strategy could be developing novel delivery systems and formulations of the existing pharmaceutical ingredients to improve drug efficacy. In the present study, paromomycin sulfate (PM), as one of the promising anti-leishmanial drugs, was formulated in solid lipid nanoparticles (SLN), and its in vitro efficacy was investigated against different strains of Leishmania using a MTT test, Parasite-Rescue-Transformation-Assay, SYTO Green staining, and fluorescent microscope imaging. The results show that PM-loaded SLN is significantly more effective than PM in inhibiting parasite propagation (P < 0.05) and that cytotoxicity of PM-SLN formulations is size dependent. According to our results, delivery of the drugs to the macrophages via nanoparticle utilization seems to be an accessible and practical approach.

Dynamic changes of the luminal and mucosa-associated gut microbiota during and after antibiotic therapy with paromomycin.

Gut microbiota play a key role in the host's health system. Broad antibiotic therapy is known to disrupt the microbial balance affecting pathogenic as well as host-associated microbes. The aim of the present study was to investigate the influence of antibiotic paromomycin on the luminal and mucosa-associated microbiota at the DNA (abundance) and RNA (potential activity) level as well as to identify possible differences. The influence of antibiotic treatment on intestinal microbiota was investigated in 5 healthy individuals (age range: 20-22 years). All participants received the antibiotic paromomycin for 3 d. Fecal samples as well as sigmoidal biopsies were collected before and immediately after cessation of antibiotic treatment as well as after a recovery phase of 42 d. Compartment- and treatment status-specific indicator operational taxonomic units (OTUs) as well as abundance- and activity-specific patterns were identified by 16S rRNA and 16S rRNA gene amplicon libraries and high-throughput pyrosequencing. Microbial composition of lumen and mucosa were significantly different at the DNA compared to the RNA level. Antibiotic treatment resulted in changes of the microbiota, affecting the luminal and mucosal bacteria in a similar way. Several OTUs were identified as compartment- and/or treatment status-specific. Abundance and activity patterns of some indicator OTUs differed considerably. The study shows fundamental changes in composition of gut microbiota under antibiotic therapy at both the potential activity and the abundance level at different treatment status. It may help to understand the complex processes of gut microbiota changes involved in resilience mechanisms and on development of antibiotic-associated clinical diseases.

Efficacy and safety of paromomycin for treating amebiasis in Japan.

The clinical management of amebiasis is a growing concern, particularly among human immunodeficiency virus (HIV)-infected individuals who are predisposed to severe illness. Treatment with a luminal amebicide is strongly recommended following acute-stage treatment with a nitroimidazole. In 2004, the Japanese Research Group on Chemotherapy of Tropical Diseases introduced paromomycin, which was not nationally licensed, and offered it to a number of patients. From 2004 to 2011, 143 case records of amebiasis (123 with amebic colitis, 16 with amebic liver abscess, and 4 with both) in which patients were treated with paromomycin, mainly 1,500 mg/day for 9 or 10 days following metronidazole treatment, were submitted. Among 123 evaluable cases, 23 (18.7%) experienced possible adverse effects, the most common being diarrhea (17/123, 13.8%) and other gastrointestinal problems that were resolved after the completion or discontinuation of treatment. In addition, single cases of bloody stools associated with Clostridium difficile colitis, skin rash, and the elevation of liver enzymes were also reported, although the causal relationship was not clear. HIV infection did not appear to increase the incidence of adverse drug effects. Each of the 11 asymptomatic or mildly symptomatic amebic colitis cases became negative for stool cysts after paromomycin treatment. Paromomycin was shown to be safe and well tolerated, as well as effective in a special subset of amebic colitis cases.

Paromomycin-loaded albumin microspheres: efficacy and stability studies.

In the present work, paromomycin-loaded albumin microspheres (PM-MS) have been formulated for passive targeting of paromomycin (PM) to macrophages, for the treatment of visceral leishmaniasis (VL). PM-MS were prepared by spray-drying method with a mean particle size of ≈ 3 µm. Thermal and chemical cross-linking methods were used for controlling drug release from the prepared microspheres (MS). PM-MS were then tested for efficacy and stability studies. In efficacy study, in vitro promastigote assay was carried out to assess the susceptibility of promastigote to PM in the concentration range of 5.0-150 µg/ml; cytotoxicity assay was performed to determine possible toxicity of PM for the host cells (peritoneal macrophages) and intracellular amastigote assay was carried out to determine the efficacy of free PM (PM solution) and encapsulated PM (PM-MS). Results obtained indicated a significant increase in efficacy of PM-MS in comparison to PM solution at equivalent concentration. Subsequently, stability studies of prepared formulation was carried out at various temperature and humidity conditions, these studies provided stability of formulation at all tested conditions including accelerated conditions. Thus, it can be concluded that present work provides an optimized formulation with stability and enhanced efficacy.

Treatment of canine leishmaniosis with aminosidine at an optimized dosage regimen: a pilot open clinical trial.

Leishmaniosis due to Leishmania infantum (Syn: L. chagasi) is one of the most common diseases of dogs in Mediterranean countries and also has zoonotic potential. The aim of this study was to evaluate the efficacy of an optimized dosage regimen of aminosidine for the treatment of canine leishmaniosis (CanL) in terms of clinical remission, restoration of clinicopathological abnormalities, evolution of antibody titer, lymph node and bone marrow parasitic density and of PCR-based parasitological cure. Twelve non-uremic dogs without proteinuria, presenting clinical signs of CanL were included in the study. The diagnosis was confirmed by serology, microscopy and PCR of lymph node and bone marrow samples. Aminosidine was administered subcutaneously at the dose of 15 mg/kg body weight, once daily, for 21 consecutive days. A partial remission of the clinical signs, amelioration of clinicopathological abnormalities such as anemia, lymphopenia, hyperproteinemia, hyperglobulinemia, and reduced albumin/globulin ratio and reduced lymph node and bone marrow parasitic density were witnessed, although parasitological cure was not achieved. Since data are not supportive enough for the use of aminosidine as an alternative treatment, a large-scale controlled clinical trial using this optimized dosage regimen of aminosidine is warranted to compare efficacy against currently used drugs.

Leishmaniasis chemotherapy--challenges and opportunities.

Although there have been significant advances in the treatment of visceral leishmaniasis (VL), there remain challenges to ensure that treatments effective in India are also effective in other regions of the world and to identify treatment for post kala-azar dermal leishmaniasis as well as the opportunity to develop a safe oral short-course treatment. At the same time, there have been few advances for the treatment of simple or complex forms of cutaneous leishmaniasis (CL), other than topical paromomycin formulations. The main challenge for CL is to ensure that this disease is on the research and development agenda, so that new drugs are evaluated or compounds are screened in appropriate models, and that the standardization of quality of clinical trials is guaranteed. Problems also remain in the treatment of HIV/leishmaniasis co-infected patients. We are some way from having the ideal treatments for VL and CL and drug research and development for these diseases must remain focused.

Paromomycin for the treatment of visceral leishmaniasis in Sudan: a randomized, open-label, dose-finding study.

BACKGROUND: A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days. METHODS: This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg. FINDINGS: 42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively). CONCLUSION: Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.

Efeito de uma formulação hidrofílica de paromomicina tópica na leishmaniose cutânea em pacientes com contra-indicações de tratamento com antimonial pentavalente / Effect of a hydrophilic formulation of topical paromomycin on cutaneous leishmaniasis among patients with contraindications for treatment with pentavalent antimonials

Descrevem-se o efeito terapêutico e os eventos adversos associados com o uso tópico de paromomicina 10 por cento em gel na leishmaniose cutânea. Quinze pacientes com leishmaniose cutânea cumpriram os critérios de inclusão descritos a seguir: contra-indicação para o uso de antimoniato de meglumina, intradermorreação de Montenegro positiva e até quatro lesões ulceradas. A fórmula foi prescrita duas vezes ao dia por 20 dias. Quatorze pacientes estiveram disponíveis para a avaliação do desfecho terapêutico e a proporção de cura foi de 21,4 por cento (3/14), 50 por cento melhoraram até a epitelização completa e a proporção de falha foi de 28,6 por cento. Nove pacientes que não apresentaram cura inicialmente foram re-tratados. Oito receberam uma nova série de paromomicina tópica e um foi tratado com antimoniato de meglumina. Dois pacientes não receberam novo tratamento e tiveram melhora lenta e contínua. Cinco de oito pacientes retratados com paromomicina tópica alcançaram a cura clínica, e três apresentaram falha, incluindo um paciente que tinha apresentado melhora com o primeiro tratamento. Os eventos adversos foram leves e locais em 53,3 por cento dos pacientes e nunca levaram à suspensão do tratamento.

The therapeutic effect of and adverse events associated with topical use of 10 percent paromomycin gel on cutaneous leishmaniasis are described. Fifteen patients with cutaneous leishmaniasis fulfilled the following inclusion criteria: contraindication for the use of meglumine antimoniate, positive Montenegro skin test and up to four ulcerated lesions. The formula was prescribed twice a day for 20 days. Fourteen patients were available for the therapeutic outcome evaluation. The cure rate was 21.4 percent (3/14); 50 percent improved as far as complete epithelialization; and the failure rate was 28.6 percent. Nine patients who did not initially present cure were retreated. Eight received a new series of topical paromomycin and one was treated with meglumine antimoniate. Two patients did not receive any new treatment and had continuous slow improvement. Five out of the eight patients retreated with topical paromomycin achieved clinical cure, and three presented failure, including one patient who had shown any improvement with the first treatment. For 53.3 percent of the patients, the adverse events were mild and local and never led to treatment suspension.

Cryptosporidium infection in patients with primary immunodeficiencies.

BACKGROUND: Cryptosporidium species infection is usually self-limited in immunocompetent populations, but can be severe and life-threatening among immunocompromised individuals, particularly in patients with AIDS and in these patients with primary immunodeficiencies (PIDs). PATIENTS AND METHODS: A group of 5 patients with genetically confirmed hyper-IgM syndrome type 1 (XHIM) and one patient with primary CD4 lymphopenia were enrolled in the study. At least 2 stool samples and a bile sample in one patient were examined for Cryptosporidium oocysts by a modified Ziehl-Neelsen technique, by immunofluorescence assay using a commercial kit, as well as by molecular analysis followed by genotyping. Immunological status at the time of PID diagnosis and the complex picture of disease are presented. RESULTS: Chronic cryptosporidiosis was confirmed in 3 patients with XHIM and in one patient with primary CD4 lymphopenia. Molecular diagnosis showed the presence of C parvum, C hominis, and C meleagridis in analyzed specimens. CONCLUSIONS: Cryptosporidium infection with serious clinical symptoms observed in patients with hyper-IgM syndrome calls for regular, repeated screening in this group of patients.

[Topical treatment of persistent cutaneous leishmaniasis with paromomycin]. / Topische Therapie einer persistierenden kutanen Leishmaniase mit Paromomycin.

Cutaneous leishmaniasis is an infectious disease with increasing prevalence in Germany. Diagnosis and therapy may be difficult due to the variability of the clinical and histomorphological picture and resistance to therapy. In this case study we report on a female patient with a persistent cutaneous leishmaniasis successfully treated with topical administration of paromomycin.

The efficacy of an oral treatment with paromomycin against an experimental infection with Giardia in calves.

A controlled and blinded study was conducted to evaluate the efficacy and safety of a treatment with paromomycin sulphate against an experimental Giardia infection in calves. Animals were infected with 10(5)Giardia cysts of cattle origin and were either treated 11 days later with 25, 50 or 75 mg paromomycin/(kg body weight per day) during 5 consecutive days or not treated (control group). Efficacy was evaluated based on reduction in cyst excretion. Furthermore weight gain and diarrhea scores were monitored. In the group treated with 75 mg/kg per day there was a 100% reduction in cyst excretion until 9 days after the start of the treatment (D9) and a very high reduction (> or =98%) until D13. There was a high reduction (> or =93%) until D9 and D13 in the groups treated with 25 and 50 mg/kg, respectively. The cumulative cyst excretion on D13 was significantly (P<0.05) lower in the groups treated with 75 and 50 mg/kg compared to the control group. Although there was a trend towards higher weight gain and less diarrhea in the treated groups, differences between groups were not significant. No adverse reactions to the paromomycin treatment were recorded. Furthermore, the need for reliable parameters for evaluation of treatments against protozoal infections is emphasised.

Tratamento tópico da leishmaniose cutânea experimental: avaliação de diferentes formulações contendo sulfato de paromomicina e da associação com imunoterapia / Topical therapy of experimental cutaneous leishmaniasis: assessment of different formulations containing paromomycin sulfate and the combination with immunotherapy

A leishmaniose é uma doença causada por protozoários do gênero Leishmania e nas Américas eles se agrupam em duas categorias: Leishmaniose Visceral Americana (LVA) e Leishmaniose Tegumentar Americana (LTA). A profilaxia da LTA baseia-se no combate aos transmissores, na redução das fontes de infecção e no tratamento de pacientes com agentes quimioterápicos, os quais são muito limitados, tóxicos e requerem um longo período de tratamento. Em virtude dos problemas associados ao tratamento convencional com antimoniais, uma grande diversidade de tratamentos alternativos, de uso tópico ou sistêmico, vem sendo estudados para essa doença. Dentre eles destaca-se a paromomicina que tem mostrado resultados surpreendentes no tratamento das várias formas da doença. Utilizamos a paromomicina em formulações de uso tópico para o tratamento de lesões ulceradas causadas por Leishmania major em camundongos BALB/c. Nossos resultados mostraram que das formulações utilizadas (emulsão e pomada), administradas duas vezes ao dia por doze dias, a emulsão foi mais eficaz que a pomada e que o tratamento conduzido com a remoção das crostas mostrou que essa formação funciona como uma barreira fisica interferindo na eficácia do tratamento. A associação com a uréia, como agente promotor da absorção cutânea, não aumentou a eficácia da pomada. O aumento da concentração de paromomicina nas formulações foi capaz de aumentar a eficiência do tratamento sendo insuficiente para a cura completa dos animais. A utilização da interleucina 12 como adjuvante ao tratamento foi fundamental para a modulação da resposta imunológica e para a cura clínica dos animais. Dessa forma, concluímos que o tratamento com a emulsão a 5 por cento de paromomicina associado a IL-12 durante e após o tratamento é eficaz para a cura clínica da doença neste modelo experimental.