Administration Of Amphotericin B Research Articles

Application and evaluation of topical amphotericin B for the treatment of respiratory fungal infections

BackgroundIn recent years, the prevalence of respiratory fungal diseases has increased. Polyene antifungal drugs play a pivotal role in the treatment of these conditions, with amphotericin B (AmB) being the most representative drug. This study aimed to evaluate the efficacy and safety of topical administration of AmB in the treatment of respiratory fungal infections.MethodsWe conducted a retrospective study on hospitalized patients treated with topical administered AmB for respiratory fungal infections from January 2014 to June 2023.ResultsData from 36 patients with invasive pulmonary fungal infections treated with topical administration of AmB were collected and analyzed. Nebulization was administered to 27 patients. After the treatment, 17 patients evidenced improved conditions, whereas 10 patients did not respond and died in the hospital. One patient experienced an irritating cough as an adverse reaction. Seven patients underwent tracheoscopic instillation, and two received intrapleural irrigation; they achieved good clinical therapeutic efficacy without adverse effects.ConclusionThe combined application of systemic antifungal treatment and topical administration of AmB yielded good therapeutic efficacy and was well-tolerated by the patients. Close monitoring of routine blood tests, liver and kidney function, and levels of electrolytes, troponin, and B-type natriuretic peptide supported this conclusion.

Local amphotericin B therapy for Cutaneous Leishmaniasis: A systematic review.

Cutaneous leishmaniasis (CL) is characterized by potentially disfiguring skin ulcers carrying significant social stigma. To mitigate systemic drug exposure and reduce the toxicity from available treatments, studies addressing new local therapeutic strategies using available medications are coming up. This review systematically compiles preclinical and clinical data on the efficacy of amphotericin B (AmB) administered locally for cutaneous leishmaniasis. Structured searches were conducted in major databases. Clinical studies reporting cure rates and preclinical studies presenting any efficacy outcome were included. Exclusion criteria comprised nonoriginal studies, in vitro investigations, studies with fewer than 10 treated patients, and those evaluating AmB in combination with other antileishmanial drug components. A total of 21 studies were identified, encompassing 16 preclinical and five clinical studies. Preclinical assessments generally involved the topical use of commercial AmB formulations, often in conjunction with carriers or controlled release systems. However, the variation in the treatment schedules hindered direct comparisons. In clinical studies, topical AmB achieved a pooled cure rate of 45.6% [CI: 27.5-64.8%; I2 = 79.7; p = 0.002), while intralesional (IL) administration resulted in a 69.8% cure rate [CI: 52.3-82.9%; I2 = 63.9; p = 0.06). In the direct comparison available, no significant difference was noted between AmB-IL and meglumine antimoniate-IL administration (OR:1.7; CI:0.34-9.15, I2 = 79.1; p = 0.00), however a very low certainty of evidence was verified. Different AmB formulations and administration routes have been explored in preclinical and clinical studies. Developing therapeutic technologies is evident. Current findings might be interpreted as a favorable proof of concept for the local AmB administration which makes this intervention eligible to be explored in future well-designed studies towards less toxic treatments for leishmaniasis.

Amphotericin B Pharmacokinetics: Inter-strain Differences in Rats Following Intravenous Administration of the Most Commonly Marketed Formulations of the Drug.

Amphotericin B (AmB) is the first-line drug to treat invasive fungal infections. However, its delivery to the body and clinical use faces many challenges because of its poor solubility, poor pharmacokinetics, and severe nephrotoxicity. Due to the necessity for designing safer and more effective nanocarriers for AmB and the importance of preclinical pharmacokinetic studies in evaluating these novel drug delivery systems, the present study was framed to explore the influence of rat strain on the pharmacokinetic profile of this drug. Twenty-four Wistar and Sprague-Dawley (SD) rats were intravenously injected with 1 mg/kg AmB as Fungizone or AmBisome, which are the two most commonly marketed formulations of the drug. Blood samples were collected before and at regular intervals up to 24 h after administration. Drug concentration was analyzed by a validated HPLC method, and pharmacokinetic parameters were determined by the non-compartmental method. Irrespective of the type of formulation, the AUC0-t and AUC0-∞ values were significantly higher (P < 0.001), and Cl as an important PK parameter was markedly lower (P < 0.001) in SD rats compared to the Wistar strain. For Fungizone, the mean Cl values in SD and Wistar rats were 206.90 and 462.95 mL/h/kg (P < 0.001), respectively. The apparent volume of distribution (Vss) was also lower in SD rats compared to Wistar; however, for AmBisome, the difference in Vss was not statistically significant. Our further investigation suggested that the higher amount of total protein in the SD strain may justify the higher plasma concentrations and lower Cl and Vss of amphotericin B in this strain compared to the Wistar strain. Overall, following intravenous administration of AmB, there were significant differences in the pharmacokinetic parameters of the drug between two rat strains for both formulations. The obtained data is important for correctly interpreting experimental data from different research groups.

Second wave of COVID-19 pandemic and the surge of mucormycosis: Lessons learnt and future preparedness: Indian Society of Anaesthesiologists (ISA National) Advisory and Position Statement.

Second wave of COVID-19 pandemic and the surge of mucormycosis: Lessons learnt and future preparedness: Indian Society of Anaesthesiologists (ISA National) Advisory and Position Statement.

Sustained intrathecal delivery of amphotericin B using an injectable and biodegradable thermogel

Cryptococcal meningitis is a fungal infectious disease with a poor prognosis and high mortality. Amphotericin B (AMB) is the first choice for the treatment of cryptococcal meninges. The blood-brain barrier (BBB) is the major barrier for the effective delivery of drugs to the brain. In this study, AMB was incorporated in a thermosensitive gel for intrathecal injection. We first synthesized AMB-loaded thermogel, investigated its in vitro cumulative release, and in vivo neurotoxicity, and therapeutic effect. The thermosensitive gel was comprised of 25 wt% poly (lactic acid-co-glycolic acid)-poly (ethylene glycol)-poly (lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock polymer aqueous solution. The AMB loaded in the thermosensitive gel (AMB in gel) had low viscosity at low temperature and resulted in the formation of a non-flowing gel at 37 °C (physiological temperature). AMB loading in gel sustained its release for 36 days and the in vitro cumulative release rate was satisfactory. Compared with the AMB solution, intrathecal administration of AMB in gel could reduce the neurovirulence of AMB and get a better treatment effect. The findings of the current study show that the injectable PLGA–PEG–PLGA thermogel is a biocompatible carrier for the delivery of drugs into the intrathecal.

Amphotericin B Loaded Nanostructured Lipid Carriers for Parenteral Delivery: Characterization, Antifungal and In vitro Toxicity Assessment.

Amphotericin B (AmB) is important for the treatment of systemic fungal infections. Nowadays, only intravenous administration (IV) of AmB has been available due to its low aqueous solubility. Two forms of AmB are available. The first is Fungizone®, a mixture of AmB and sodium deoxcycholate that produces severe nephrotoxicity. The second are lipid-based formulations that reduce nephrotoxicity, but they are costly and require higher dose than Fungizone®. Thus, a cheaper delivery system with reduced AmB toxicity is required. To develop and characterize AmB loaded-nanostructured lipid carriers (AmB-loaded NLCs) for IV administration to reduce AmB toxicity. AmB-loaded NLCs with different solid lipids were prepared by the high-pressure homogenization technique. Their physicochemical properties and the drug release profile were examined. The molecular structure of AmB, antifungal and hemolysis activities of developed AmB-loaded NLCs were also evaluated. AmB-loaded NLCs ~110 to ~140 nm in diameter were successfully produced with a zeta potential of ~-19 mV and entrapment efficiency of ~75%. In vitro release showed fast release characteristics. AmB-loaded NLCs could reduce the AmB molecular aggregation as evident from the absorbance ratio of the first to the fourth peak showing a partial aggregation of AmB. This result suggested that AmB-loaded NLCs could offer less nephrotoxicity compared to Fungizone®. In vitro antifungal activity of AmB-loaded NLCs showed a minimum inhibitory concentration of 0.25 µgmL-1. AmB-loaded NLCs present high potential carriers for effective IV treatment with prolonged circulation time and reduced toxicity.

Compressed nanofibrous oral tablets: An ingenious way for controlled release kinetics of Amphotericin-B loaded gelatin nanofibers

Amphotericin B (AmB) is one of the potent antimycotic drugs used to cure invasive fungal infections and Leishmaniasis. However, it’s appalling collateral toxicity restricts its applicability for only parenteral administration with frequent dosing. Further, AmB is amphipathic and exhibits negligible absorption during oral administration due to its poor solubility. Current research unfolds the possibility to deliver AmB in a controlled way through oral route. First, homogeneous solution of gelatin-AmB was successfully electrospun into the nanofibers followed by crosslinking and compression to form compressed nanofibrous oral tablet (CNOT) containing 20 mg AmB in a 500 mg tablet. In-vitro biodegradation and thermal stability were investigated followed by studying the drug release kinetics. Antifungal activity was also examined up to seven days. AmB loaded CNOT showed zero order release profile with prominent antifungal activity up to seven days against Candida albicans. This study paves the way for a safe, yet effective oral administration of AmB while still maintaining the therapeutic efficacy for treating life-threatening fungal infections.

Continuous intrathecal administration of liposomal amphotericin B for treatment of refractory Cryptococcus neoformans encephalitis: A case report.

The aim of the present study was to investigate the treatment of refractory Cryptococcus neoformans encephalitis with continuous administration of liposomal amphotericin B (AmB). Liposomal AmB was administered to a 28-year-old male by intravenous injection, with daily increasing dosages up to 150 mg per day and combined use of fluconazole (0.4 g per day) and oral flucytosine tablets (1.5 g per day). Following 5 months of treatment, C. neoformans could still be detected in the ink stain of cerebrospinal fluid, but the patient could not tolerate a further increase in the dosage of liposomal AmB. Instead, continuous intrathecal administration of AmB through tube drainage on the lumbar cistern was used. A total dosage of 28 mg liposomal AmB was administered to the patient over the course of 1 month. The effect of AmB administered by intravenous injection was not as great as expected and the patient's tolerance was not good. However, the patient recovered following treatment by continuous intrathecal administration of AmB through tube drainage on the lumbar cistern for 1 month. This case suggests that continuous intrathecal administration of liposomal AmB should be considered for clinical treatment of refractory cryptococcal encephalitis.

In vitro interactions between amphotericin B and hydrocortisone: potential implications for intrathecal therapy.

Fungal meningitis remains a severe and often lethal infection requiring aggressive antifungal therapy and in refractory cases the use of intrathecal amphotericin B (AmB). Administration of amphotericin B by this method may result in clinically apparent adverse reactions such as paresthesias, radiculitis, or myelopathy. Coadministration of hydrocortisone is therefore often given in an attempt to avoid these effects; however, the potential consequences of this approach on fungal growth or on drug synergy/antagonism had not previously been assessed. We used the checkerboard titration broth microdilution method to analyze interactions by fractional inhibitory concentration indices (FICIs). The combination of amphotericin B and hydrocortisone resulted in synergy or indifference against all isolates (Candida, Cryptococcus, and Coccidioides) during in vitro testing at low concentrations. Antagonism was observed using higher hydrocortisone concentrations (those not observed in vivo) suggesting possible steric hindrance or binding to AmB may occur at doses unlikely to be present during clinical care. Concurrent hydrocortisone and AmB administration should not be avoided due to in vitro antagonism concerns.

Efficacy of Amphotericin-B, Clinicopathologic Variables and Oxidative Stress Markers in three Staffordshire Bull Terrier Dogs with Visceral Leishmaniasis

This study was aimed at evaluating the effects of Leishmania infection and AMB (amphotericin-B) treatment on hematological, biochemical and oxidative stress parameters in three Staffordshire Bull Terrier dogs with visceral leishmaniasis (VL). These dogs were presented with weight loss, weakness, and cutaneous lesions. Canine kala-azar detect kit was positive in dogs with VL. AMB was administered to cases with VL at a dose of 0.6 to 1.5 mg/kg/week for four months. Leishmania agents caused the liver injury in cases 1 and 2 due to increase in ALT level, decrease in erythrocyte, hemoglobin, and hematocrit level and increase in MDA, and decrease in GSH-Px in case 3 and did not affect the kidney functions due to normal urea and creatinine level in the dogs with VL. A gradual response to the administration of AMB was observed. At the end of treatment course, cases with VL were cured clinically. It was concluded that 4-month of AMB administration may be effective to treat VL due to no clinical recurrence for six months follow-up.

Hearing Loss with Amphotericin B Therapy in Patients with Rhinocerebral Aspergillosis: Is it a Reality?

ABSTRACT Context Study carried out to investigate the relationship of amphotericin B (AmB) therapy with hearing loss developing in patients with rhinocerebral aspergillosis during prolonged AmB therapy. Aim To study the effect of prolonged AmB therapy on the hearing acuity of patients suffering from invasive fungal sinusitis. Setting and design: Nonrandomized prospective study carried in Department of Otolaryngology and Head and Neck Surgery from January, 2010 to June, 2013. Materials and methods High frequency pure tone audiometry (PTA) and cold caloric test (CCT) were done for all patients before starting of therapy with AmB. Both tests were repeated at 500 mg, 1 and 2 gm of AmB administration. Follow-up was done for all patients at 3 and 6 months after completion of therapy. Results Twenty-four patients of invasive fungal sinusitis included. On prolonged AmB therapy some patients had deterioration in hearing. But these changes were not statistically significant. The changes were mild and shift was one grade above or below. It was also seen that the hearing complaints were reported in the middle of the therapy although all these patients had baseline hearing loss. Conclusion Amphotericin B does cause some change in hearing pattern; although not statistically significant. A further study is required with more number of patients so as to say definitively that AmB causes a change in hearing. Though these patients have numerous factors which can affect hearing in many ways, a systematic study is required to go a long way in clearing the doubts attached to AmB therapy. Key message Amphotericin related hearing loss has not been reported in English literature till date. Our study focuses on the effect of AmB on hearing. Amphotericin B does cause some change in hearing pattern, although not statistically significant. All the patients complained of hearing deterioration while some showed improvement on audiogram (though not significant) showing a paradoxical feature. How to cite this article Mohindra S, Gupta B, Mohindra S, Gupta K, Singh D. Hearing Loss with Amphotericin B Therapy in Patients with Rhinocerebral Aspergillosis: Is it a Reality? J Postgrad Med Edu Res 2015;49(2):66-69.

Reversible dilated cardiomyopathy associated with amphotericin B therapy

Amphotericin B (AmB) is commonly used to treat a broad spectrum of fungal infections and leishmaniasis. Its use is limited by numerous adverse effects. Reversible dilated cardiomyopathy associated with AmB is a rare disorder with only four previously reported cases, and all of them referring to patients who presented with a predisposing factor for heart failure. A previously healthy 45-year-old man with visceral leishmaniasis treated with AmB developed acute dilated cardiomyopathy. Other causes of heart failure as well-known predisposing factors for this condition were ruled out. As with previously reported cases, the cardiac function of our patient returned to normal shortly after. We describe the first case of dilated cardiomyopathy associated with the administration of AmB in a patient without any known predisposing factor for developing cardiac dysfunction. Available evidence suggests that AmB may induce cardiotoxicity. Further investigations are needed to clarify this issue.

Management of cryptococcal meningitis in adults at Mthatha Hospital Complex, Eastern Cape, South Africa

Background. Cryptoccocal meningitis (CM) remains prevalent in HIV-infected individuals across South Africa (SA). Early diagnosis and management, aided by the existing Southern African HIV Clinicians Society (SAHIVSoc) 2007 guidelines on management of CM, could reduce the mortality associated with this condition. Objective. To review the management of adult patients with CM and adherence to the SAHIVSoc 2007 guidelines in a district hospital.Methods. A retrospective chart review of patients admitted with CM from December 2011 to May 2012 was performed. The following key recommendations of the guidelines were evaluated: measurement of cerebrospinal fluid (CSF) opening pressure at the first lumbar puncture (LP), prescription of amphotericin B (AMB)/fluconazole therapy, intravenous prehydration preceding administration of AMB, monitoring of renal function and performance of serial LPs to manage raised intracranial pressure (ICP).Results. A total of 57 patient charts were reviewed, of which 40 (70%) were of females. The mean age (range) of the cohort was 36 (21 - 60) years. Fifty-two (91%) patients presented with headache. Confusion was recorded in 30 (53%) and vomiting in 26 (46%). The major signs observed were fever (n=29 (51%)) and neck stiffness (n=34 (60%)). Fifty-five (96%) patients were HIV-infected at presentation, with a median (range) CD4+ count of 77 (13 - 90) cells/µl. None of the patients had a CSF opening pressure measured at first LP. AMB was used as an induction agent in 51 (89%) patients, of whom 47 (92%) completed 2 weeks of AMB. Of these 51, only 20 (40%) were prehydrated and 10 (18%) had two repeat LPs performed 1 week apart. Renal function was monitored in only 27 (53%) of the patients receiving AMB. This was done at baseline and twice weekly, and was consistent with the guidelines. No abnormality in renal function was recorded in these cases during the study. The mortality rate was 30% in the first 10 days of admission.Conclusion. This chart review showed inadequate adherence to the recommendations of the 2007 SAHIVSoc guidelines in the majority of cases except for the use of AMB as a first-line antifungal agent. Control of ICP and monitoring for drug toxicity were not done as per guidelines and may impact on clinical care and outcome. Despite this, the early 30% mortality is comparable with published reports from other regions in SA, but is higher than in developed health systems.

Management of cryptococcal meningitis in adults at Mthatha Hospital Complex, Eastern Cape, South Africa

Background. Cryptoccocal meningitis (CM) remains prevalent in HIV-infected individuals across South Africa (SA). Early diagnosis and management, aided by the existing Southern African HIV Clinicians Society (SAHIVSoc) 2007 guidelines on management of CM, could reduce the mortality associated with this condition. Objective. To review the management of adult patients with CM and adherence to the SAHIVSoc 2007 guidelines in a district hospital. Methods. A retrospective chart review of patients admitted with CM from December 2011 to May 2012 was performed. The following key recommendations of the guidelines were evaluated: measurement of cerebrospinal fluid (CSF) opening pressure at the first lumbar puncture (LP), prescription of amphotericin B (AMB)/fluconazole therapy, intravenous prehydration preceding administration of AMB, monitoring of renal function and performance of serial LPs to manage raised intracranial pressure (ICP). Results. A total of 57 patient charts were reviewed, of which 40 (70%) were of females. The mean age (range) of the cohort was 36 (21 - 60) years. Fifty-two (91%) patients presented with headache. Confusion was recorded in 30 (53%) and vomiting in 26 (46%). The major signs observed were fever ( n =29 (51%)) and neck stiffness ( n =34 (60%)). Fifty-five (96%) patients were HIV-infected at presentation, with a median (range) CD4 + count of 77 (13 - 90) cells/µl. None of the patients had a CSF opening pressure measured at first LP. AMB was used as an induction agent in 51 (89%) patients, of whom 47 (92%) completed 2 weeks of AMB. Of these 51, only 20 (40%) were prehydrated and 10 (18%) had two repeat LPs performed 1 week apart. Renal function was monitored in only 27 (53%) of the patients receiving AMB. This was done at baseline and twice weekly, and was consistent with the guidelines. No abnormality in renal function was recorded in these cases during the study. The mortality rate was 30% in the first 10 days of admission. Conclusion. This chart review showed inadequate adherence to the recommendations of the 2007 SAHIVSoc guidelines in the majority of cases except for the use of AMB as a first-line antifungal agent. Control of ICP and monitoring for drug toxicity were not done as per guidelines and may impact on clinical care and outcome. Despite this, the early 30% mortality is comparable with published reports from other regions in SA, but is higher than in developed health systems.

Amphotericin B Formulations – The Possibility of Generic Competition

From the 1950s, Amphotericin B (AmB) in the form of Fungizone® was considered the “gold standard” in anti- fungal therapy. This was due to its broad-spectrum of activity. In the 1990s, Fungizone® was relegated to a second line treatment option after the commercialization of lipid-based formulations (AmBisome®, Abelcet® and Amphocil®). These new medicines have similar efficacies but more favourable safety profiles. These formulations will be coming off patent over the coming months and so there is an opportunity for generics manufacturers to enter the arena. However, the lack of clear regulatory guidance on how to perform bioequivalence studies with liposomal drugs makes it difficult to ensure that generic parenteral formulations present quality, efficacy and safety profiles similar to the innovator product. To date, AmB therapy relies mostly on parenteral administration although infusion-related side effects and nephrotoxicity can lead to treatment being halted. Non-parenteral AmB administration would potentially lead to safer treatments and expand the benefits of antifungal and antileishmanial therapy with this drug worldwide. Despite real scientific advances in the area over the last ten years, very few delivery systems have progressed from proof-of-concept to clinical trials as oral, topical or pulmonary AmB medicines. Cyclodextrins and nanoparticle based formulations (self-emulsifying systems, cochleates and liposomes) are the most promising delivery systems to date.

Dual Physiologically Based Pharmacokinetic Model of Liposomal and Nonliposomal Amphotericin B Disposition

To investigate the biodistribution of amphotericin B (AmB) in mice and rats following administration of liposomal AmB (AmBisome®) using a physiologically-based pharmacokinetic (PBPK) modeling framework and to utilize this approach for predicting AmBisome® pharmacokinetics in human tissues. AmB plasma and tissue concentration-time data, following single and multiple intravenous administration of nonliposomal and liposomal AmB to mice and rats, were extracted from literature. The whole-body PBPK model was constructed and incorporated nonliposomal and liposomal subcompartments. Various structural models for individual organs were evaluated. Allometric relationships were incorporated into the model to scale parameters based on species body weight. A non-Michaelis-Menten mechanism was included into the structure of the liver and spleen liposomal compartments to describe saturable uptake of particles by the reticuloendothelial system. The model successfully described plasma and tissue pharmacokinetics of AmB after administration of AmBisome® to rats and mice. The dual PBPK model demonstrated good predictive performance by reasonably simulating AmB exposure in human tissues. This modeling framework can be potentially utilized for optimizing AmBisome® therapy in humans and for investigating pathophysiological factors controlling AmB pharmacokinetics and pharmacodynamics.

Fungal sinusitis with ocular involvement: Case report

Rhino-orbital-cerebral mucormycosis (ROCM) is an acute, often fatal, fungal infection caused by members of the class Zygomycetes and the order Mucorales. The genus Rhizopus accounts for most cases of ROCM. The disease is characterized by fungal hyphal invasion of blood vessels resulting in thrombosis and infarction of the nasal, paranasal sinus, orbital, and cerebral tissues. The most commonly associated condition is diabetes mellitus; other associated conditions include immunocompromised states, renal disease, deferoxamine use and acidotic states. The most frequent sites of infection are pulmonary, rhinocerebral, cutaneous and disseminated. Rhino-orbital and Rhino-cerebral are two forms of the disease. As such the condition is a medical emergency. Early recognition and treatment are essential because it may lead to death in a few days. CROP usually begins in the palate or paranasal sinuses and rapidly spreads to the orbital contents. Proptosis, loss of vision and ophthalmoplegia occur and death from cerebral involvement commonly ensues. The fungus tends to invade arteries and cause thrombosis and tissue infarction. Rhizopus is the most commonly isolated genus in CROP, accounting for almost all cases. The diagnosis can be strongly suspected by the characteristic clinical manifestations. Therapy includes the treatment of the underlying disease, surgical excision of the necrotic tissue containing fungal elements and the systemic administration of amphotericin-B. Here we report the clinical features of a 32-years-old man presented mucormycosis.

Pharmacokinetics comparison of amphotericin B using three administrating approach in a rabbit model

Background Intracameral or intracorneal administration of amphotericin B (AMB) can achieve significant therapeutic efficacy in the treatment of recalcitrant fungal keratitis in cases that do not respond to conventional antifungal therapy. However, the ocular pharmacokinetics of the two routes of administration is unclear.Objective The goal of this study was to investigate the level of amphotericin B in cornea and aqueous humor of rabbits after administration of AMB via three different routes. Methods Forty-five healthy domestic rabbits were randomly divided into three groups. 1% amphotericin B of 10 μg was intrastromally or intracamerally injected into 15 rabbits, respectively,in group A and group B. Topical 0. 25% amphotericin B was topically administered to the eyes with corneal epithelial debridement (group C). Experimental animals were sacrificed and the corneas and aqueous humor samples were obtained for the detection of levels of amphotericin B at 30 minutes,6 hours, 1 day,3 and 7 days by high-performance liquid chromatography (HPLC). Results Calibration curves were linear over the range of 0. 10-100. 00 mg/L. The concentration of 0. 10 mg/L was the lowest quantifiable limit. The recovery of amphotericin B ranged from 89. 1% -95.7% from aqueous humor samples and 81.4% -83.6% from the cornea samples. After a single injection,effective drug levels were achieved and maintained for 7 days in cornea in group A, exceeding the minimum inhibitory concentration at which 90% of isolates are inhibited (MIC90) for a wide spectrum of fungi and molds with significant differences in comparison with group B and group C ( P＜0. 05 ). Effective drug levels were achieved in the aqueous humor in group B at 30 minutes after a single injection, but drug levels decreased dramatically within 6 hours. The evident differences were found between group B and group A or group C (P＜ 0.05). A considerable amount of amphotericin B was detected in the cornea and aqueous humor in group C within 1 day.Conclusion Effective high drug levels can be reached in rabbit cornea and aqueous humor after intrastromal and intracameral injection, respectively. Penetration of topical amphotericin B was greatly elevated after epithelial debridement. Key words: Amphotericin B; Chromatography; High pressure liquid; Pharmacokinetics

Biodistribution and tissue toxicity of amphotericin B in mice following multiple dose administration of a novel oral lipid-based formulation (iCo-009)

The purpose of this study was to assess the biodistribution and toxicity of amphotericin B (AMB) following multiple dose administration of an oral lipid-based formulation (iCo-009). BALB/c female mice were used. ICo-009 was administered twice daily for 5 days at doses of 2.5-20 mg/kg. Untreated animals, oral vehicle or intravenous Fungizone® (1 or 2 mg/kg) served as control groups. The animals were sacrificed 12 h following the last administration of AMB, and blood and multiple tissues were harvested for drug analysis and histopathological evaluation. Plasma or tissue samples were analysed for concentrations of AMB or creatinine by means of HPLC-UV. A dose-dependent accumulation of AMB in liver, spleen, kidney and lung tissues was found. The concentration of the drug in all these organs exceeded the corresponding concentrations in plasma at the same dose. The concentrations of AMB in heart and brain were similar to the corresponding concentrations in plasma. Creatinine concentrations were elevated above normal concentrations in the 2 mg/kg Fungizone® group only. Histopathological analysis of kidney and liver tissues revealed a normal pattern in all treated groups, except the 2 mg/kg Fungizone® group. No gastrointestinal toxicity was found in this study. A multiple dose treatment regimen with iCo-009 in mice results in a gradual accumulation of AMB in tissues. Despite significant concentrations of AMB, no kidney or liver toxicity of orally administered AMB was detected in this study. Furthermore, multiple oral administration of iCo-009 or of vehicle control did not induce gastrointestinal toxicity.

Visceral leishmaniasis affects liver and spleen concentrations of amphotericin B following administration to mice

To assess the impact of visceral leishmaniasis (VL) on the concentration of amphotericin B (AmB) recovered in the liver and spleen following either intravenous (AmBisome) or oral (iCo-009) AmB administration to mice. Livers and spleens previously obtained from VL-infected BALB/c mice (following intravenous AmBisome or oral AmB treatments) were analysed for AmB concentrations. Then, non-infected BALB/c mice were divided into three treatment groups: a single dose of intravenous AmBisome (2 mg/kg, n = 5); and oral AmB every 12 h for 5 days (10 mg/kg, n = 6 and 20 mg/kg, n = 6). The animals were sacrificed 7 days after the initiation of the treatment and the livers and spleens were harvested for drug analysis by HPLC. The single intravenous injection of AmBisome resulted in a 77-fold lower concentration of AmB in infected compared with non-infected liver tissue, while the difference in AmB concentration in the spleen was only 5-fold. The multiple dose oral administration of AmB resulted in a 3-fold lower concentration of AmB in infected compared with non-infected livers for both oral doses, while the differences in AmB concentrations in the spleen were not statistically different for the oral treatment groups. VL significantly lowered the concentration of AmB in the liver and the spleen when compared with uninfected animals. This effect seems to correlate with the degree of infection of the tissue. In the case of the intravenous liposomal formulation (AmBisome), the differences between the infected and non-infected tissues are of a higher magnitude than in the case of orally administered AmB (iCo-009).