Pharmacokinetic / pharmacodynamic relationships of liposomal amphotericin B and miltefosine in experimental visceral leishmaniasis.

BACKGROUND: There is a continued need to develop effective and safe treatments for visceral leishmaniasis (VL). Preclinical studies on pharmacokinetics and pharmacodynamics of anti-infective agents, such as anti-bacterials and anti-fungals, have provided valuable information in the development and dosing of these agents. The aim of this study was to characterise the pharmacokinetic and pharmacodynamic properties of the anti-leishmanial drugs AmBisome and miltefosine in a preclinical disease model of VL. METHODOLOGY / PRINCIPAL FINDINGS: BALB/c mice were infected with L. donovani (MHOM/ET/67/HU3) amastigotes. Groups of mice were treated with miltefosine (orally, multi-dose regimen) or AmBisome (intravenously, single dose regimen) or left untreated as control groups. At set time points groups of mice were killed and plasma, livers and spleens harvested. For pharmacodynamics the hepatic parasite burden was determined microscopically from tissue impression smears. For pharmacokinetics drug concentrations were measured in plasma and whole tissue homogenates by LC-MS. Unbound drug concentrations were determined by rapid equilibrium dialysis. Doses exerting maximum anti-leishmanial effects were 40 mg/kg for AmBisome and 150 mg/kg (cumulatively) for miltefosine. AmBisome displayed a wider therapeutic range than miltefosine. Dose fractionation at a total dose of 2.5 mg/kg pointed towards concentration-dependent anti-leishmanial activity of AmBisome, favouring the administration of large doses infrequently. Protein binding was >99% for miltefosine and amphotericin B in plasma and tissue homogenates. CONCLUSION / SIGNIFICANCE: Using a PK/PD approach we propose optimal dosing strategies for AmBisome. Additionally, we describe pharmacokinetic and pharmacodynamic properties of miltefosine and compare our findings in a preclinical disease model to available knowledge from studies in humans. This approach also presents a strategy for improved use of animal models in the drug development process for VL.

Effects of coadministration of corn oil and ponazuril on serum and cerebrospinal fluid concentrations of ponazuril in horses.

BACKGROUND: Ponazuril is used for the treatment of equine protozoal myeloencephalitis (EPM). Coadministration of ponazuril with oil could result in higher serum and cerebrospinal fluid (CSF) concentrations of ponazuril. HYPOTHESIS: Coadministration of corn oil will result in higher serum and CSF concentrations of ponazuril than when ponazuril is administered alone. ANIMALS: Ten resident university-owned adult horses of either sex and >2 years of age. METHODS: Cohort study. Ponazuril oral paste (5 mg/kg BW; ponazuril treatment group (PON); n = 5), or ponazuril oral paste (5 mg/kg BW; ponazuril and oil treatment group (PONOIL; n = 5) coadministered with 2 oz of corn oil q24h for 21 days. Horses were treated once daily, for 21 days. Blood was collected on days 0, 7, 14, and 21 before dosing. In addition, CSF was collected on days 1, 7, 14, and 21. The concentration of ponazuril was determined in serum and CSF and results compared using repeated measures ANOVA. RESULTS: Coadministration of ponazuril with 2 oz of corn oil resulted in higher concentrations of ponazuril in serum (at steady state) than that found in horses given ponazuril alone (6.2 ± 0.9 mg/L versus 4.5 ± 1.0 mg/L; P = .004) (mean ± 1 SD). Cerebrospinal fluid concentrations of ponazuril were also greater in horses that received ponazuril and oil (0.213 mg/L ± 0.04 versus 0.162 ± 0.04 mg/L) (P = .03). CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that coadministration of corn oil with ponazuril might enhance the effectiveness of treatment with ponazuril.

Antiplasmodial activity of Vernonia adoensis aqueous, methanol and chloroform leaf extracts against chloroquine sensitive strain of Plasmodium berghei in vivo in mice.

OBJECTIVE: The aim of this study was to investigate the antiplasmodial effects of the crude aqueous, methanol and chloroform extracts of the leaves of Vernonia adoensis in Plasmodium berghei infected Swiss albino mice using Peters' 4-day suppressive test. RESULTS: The number of mice used for the toxicity test was 20 (5/group) and for each extract and control groups 5 mice per group was used. The aqueous, methanol and chloroform extracts of V. adoensis leaves indicated statistically significant (P < 0.05) suppression of parasitaemia in the treated mice. The highest inhibition was that of the methanol extract treated mice (83.36%) followed by aqueous (72.26%) and chloroform (54.34%) at an oral dose of 600 mg/kg b.wt. Each extract prevented body weight loss and packed cell volume (PCV) reduction as compared to the negative control groups. The survival time of the mice treated with chloroform based on Kaplan-Meir analysis was 12.53 ± 0.37 at 600 mg/kg b.wt, while the negative control was 7.93 ± 0.37 days. The LD50 of the extracts was greater than 3000 mg/kg body weight. In conclusion, the crude leaves extract of V. adoensis have demonstrated antiplasmodial effect in vivo. P. berghei infection is suppressed in a dose-dependent manner showing relevance of the traditional use of the plant.

Fabrication of lecithin-gum tragacanth muco-adhesive hybrid nano-carrier system for in-vivo performance of Amphotericin B.

Nano-carriers are excellent systems for improving bioavailability of poor aqueous soluble drugs. This study focuses fabrication of lecithin-gum tragacanth muco-adhesive hybrid NPs for enhancing Amphotericin B (AmpB) oral bioavailability. AmpB loaded lecithin NPs were synthesized through solvent diffusion method. Green synthesis of stable muco-adhesive gum tragacanth (GT) gold NPs was confirmed through UV-vis spectrophotometer and FT-IR. AmpB loaded lecithin NPs hybrid with GT gold NPs were characterized for shape, size, polydispersity index (PDI), zeta potential, drug entrapment efficiency and drug-excepients interactions using atomic force microscope (AFM), zetasizer, UV-vis spectrophotometer and FT-IR respectively. In-vivo bioavailability of AmpB loaded in NPs was investigated in rabbits. AmpB loaded muco-adhesive NPs were found polydispersed with 358.3 ±â€¯1.78 nm mean size and -19.9 ±â€¯0.51 mV zeta potential. They entrapped 78.91 ±â€¯2.44% AmpB and enhanced its oral bioavailability in animals. Results reveal the hybrid NPs as efficient carriers for enhancing AmpB oral bioavailability in controlled manner.

Nigella sativa oil entrapped polycaprolactone nanoparticles for leishmaniasis treatment.

This study is the first to investigate the antileishmanial activities of Nigella sativa oil (NSO) entrapped poly-ɛ-caprolactone (PCL) nanoparticles on Leishmania infantum promastigotes and amastigotes in vitro. NSO molecules with variable initial doses of 50, 100, 150, and 200 mg were successfully encapsulated into PCL nanoparticles identified as formulations NSO1, NSO2, NSO3, and NSO4, respectively. This process was characterised by scanning electron microscope, dynamic light scattering, Fourier transform infrared, encapsulation efficiency measurements, and release profile evaluations. The resulting synthetised nanoparticles had sizes ranging between 200 and 390 nm. PCL nanoparticles encapsulated 98% to 80% of initial doses of NSO and after incubation released approximately 85% of entrapped oil molecules after 288 h. All investigated formulations demonstrated strong antileishmanial effects on L. infantum promastigotes by inhibiting up to 90% of parasites after 192 h. The tested formulations decreased infection indexes of macrophages in a range between 2.4- and 4.1-fold in contrast to control, thus indicating the strong anti-amastigote activities of NSO encapsulated PCL nanoparticles. Furthermore, NSO-loaded PCL nanoparticles showed immunomodulatory effects by increasing produced nitric oxide amounts within macrophages by 2-3.5-fold in contrast to use of free oil. The obtained data showed significant antileishmanial effects of NSO encapsulated PCL nanoparticles on L. infantum promastigotes and amastigotes.

Antileishmanial Efficacy and Pharmacokinetics of DB766-Azole Combinations.

Given the limitations of current antileishmanial drugs and the utility of oral combination therapy for other infections, developing an oral combination against visceral leishmaniasis should be a high priority. In vitro combination studies with DB766 and antifungal azoles against intracellular Leishmania donovani showed that posaconazole and ketoconazole, but not fluconazole, enhanced DB766 potency. Pharmacokinetic analysis of DB766-azole combinations in uninfected Swiss Webster mice revealed that DB766 exposure was increased by higher posaconazole and ketoconazole doses, while DB766 decreased ketoconazole exposure. In L. donovani-infected BALB/c mice, DB766-posaconazole combinations given orally for 5 days were more effective than DB766 or posaconazole alone. For example, 81% ± 1% (means ± standard errors) inhibition of liver parasite burden was observed for 37.5 mg/kg of body weight DB766 plus 15 mg/kg posaconazole, while 37.5 mg/kg DB766 and 15 mg/kg posaconazole administered as monotherapy gave 40% ± 5% and 21% ± 3% inhibition, respectively. Combination index (CI) analysis indicated that synergy or moderate synergy was observed in six of nine combined dose groups, while the other three were nearly additive. Liver concentrations of DB766 and posaconazole increased in almost all combination groups compared to monotherapy groups, although many increases were not statistically significant. For DB766-ketoconazole combinations evaluated in this model, two were antagonistic, one displayed synergy, and one was nearly additive. These data indicate that the efficacy of DB766-posaconazole and DB766-ketoconazole combinations in vivo is influenced in part by the pharmacokinetics of the combination, and that the former combination deserves further consideration in developing new treatment strategies against visceral leishmaniasis.

Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening.

Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 µM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug.

Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent.

Antimicrobial peptides (AMPs) are promising drugs to kill resistant pathogens. In contrast to bacteria, protozoan parasites, such as Leishmania, were little studied. Therefore, the antiparasitic mechanism of AMPs is still unclear. In this study, we sought to get further insight into this mechanism by focusing our attention on temporin-SHa (SHa), a small broad-spectrum AMP previously shown to be active against Leishmania infantum. To improve activity, we designed analogs of SHa and compared the antibacterial and antiparasitic mechanisms. [K3]SHa emerged as a highly potent compound active against a wide range of bacteria, yeasts/fungi, and trypanosomatids (Leishmania and Trypanosoma), with leishmanicidal intramacrophagic activity and efficiency toward antibiotic-resistant strains of S. aureus and antimony-resistant L. infantum. Multipassage resistance selection demonstrated that temporins-SH, particularly [K3]SHa, are not prone to induce resistance in Escherichia coli. Analysis of the mode of action revealed that bacterial and parasite killing occur through a similar membranolytic mechanism involving rapid membrane permeabilization and depolarization. This was confirmed by high-resolution imaging (atomic force microscopy and field emission gun-scanning electron microscopy). Multiple combined techniques (nuclear magnetic resonance, surface plasmon resonance, differential scanning calorimetry) allowed us to detail peptide-membrane interactions. [K3]SHa was shown to interact selectively with anionic model membranes with a 4-fold higher affinity (KD = 3 x 10-8 M) than SHa. The amphipathic α-helical peptide inserts in-plane in the hydrophobic lipid bilayer and disrupts the acyl chain packing via a detergent-like effect. Interestingly, cellular events, such as mitochondrial membrane depolarization or DNA fragmentation, were observed in L. infantum promastigotes after exposure to SHa and [K3]SHa at concentrations above IC50. Our results indicate that these temporins exert leishmanicidal activity via a primary membranolytic mechanism but can also trigger apoptotis-like death. The many assets demonstrated for [K3]SHa make this small analog an attractive template to develop new antibacterial/antiparasitic drugs.

Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study.

Miltefosine (MFS) is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD). This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%), good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs, allowing targeting via the oral route. From a clinical point of view, data suggest MFS-LNCs as a potential single dose oral nanomedicine for enhanced therapy of schistosomiasis mansoni and possibly other diseases.

In vitro metabolism of grandisin, a lignan with anti-chagasic activity.

Tetrahydrofuran lignans represent a well-known group of phenolic compounds capable of acting as antiparasitic agents. In the search for new medicines for the treatment of Chagas disease, one promising compound is grandisin which has shown significant activity on trypomastigote forms of Trypanosoma cruzi. In this work, the in vitro metabolism of grandisin was studied in the pig cecum model and by biomimetic phase I reactions, aiming at an ensuing a preclinical pharmacokinetic investigation. Although grandisin exhibited no metabolization by the pig microbiota, one putative metabolite was formed in a biomimetic model using Jacobsen catalyst. The putative metabolite was tested against T. cruzi revealing loss of activity in comparison to grandisin.

Investigations into an alternate approach to target mannose receptors on macrophages using 4-sulfated N-acetyl galactosamine more efficiently in comparison with mannose-decorated liposomes: an application in drug delivery.

In this study the potential of 2 different ligands, i.e., palmitoyl mannose (Man-Lip) and 4-SO(4)GalNAc (Sulf-Lip) to target resident macrophages was investigated after surface decoration of Amphotericin B (AmB) loaded liposomes. In the case of Sulf-Lip, the 4-SO(4)GalNAc was adsorbed through electrostatic interaction on cationic liposomes, which was confirmed by change in zeta potential from +48.2 ± 3.7 mV for Lip to +12.2 ± 1.3 mV for Sulf-Lip. The mean particle size of Sulf-Lip and Man-Lip was found to be 139.4 ± 7.4 nm and 147.4 ± 8.6 nm, respectively. Flow cytometric data reveal enhanced uptake of Sulf-Lip in both J774 and RAW cell lines in comparison with the uptake of Man-Lip. Intracellular localization studies indicate that the fluorescence intensity of Sulf-Lip was much higher in comparison with that of Man-Lip and Lip formulations. Sulf-Lip and Man-Lip showed significantly higher localization of AmB at all time points in comparison with Lip (P < 0.05) after intravenous (IV) administration. The studies provide evidence that 4-SO(4)GalNAc possesses a promising feature for targeting resident macrophages and its application in the conditions of leishmaniasis is in the offing. FROM THE CLINICAL EDITOR: This in vivo study compares two different ligands to deliver Amphotericin B l(AmB) loaded liposomes to resident macrophages. Targeted approaches showed significantly higher localization of AmB at all time points in comparison to non-targeted liposomes, and future applications in leishmaniasis are already under preparation.

Benzoxaboroles: a new class of potential drugs for human African trypanosomiasis.

Human African trypanosomiasis, caused by the kinetoplastid parasite Trypanosoma brucei, affects thousands of people across sub-Saharan Africa, and is fatal if left untreated. Treatment options for this disease, particularly stage 2 disease, which occurs after parasites have infected brain tissue, are limited due to inadequate efficacy, toxicity and the complexity of treatment regimens. We have discovered and optimized a series of benzoxaborole-6-carboxamides to provide trypanocidal compounds that are orally active in murine models of human African trypanosomiasis. A key feature of this series is the presence of a boron atom in the heterocyclic core structure, which is essential to the observed trypanocidal activity. We also report the in vivo pharmacokinetic properties of lead compounds from the series and selection of SCYX-7158 as a preclinical candidate.

Tropically stable novel oral lipid formulation of amphotericin B (iCo-010): biodistribution and toxicity in a mouse model.

BACKGROUND: The purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB) following multiple oral administrations of a novel tropically stable lipid-based formulation (iCo-010). METHODS: BALB/c mice were allocated into six groups: oral iCo-010 twice daily for 5 days in the dose of 20, 10, 5 and 2.5 mg/kg; vehicle control; and intravenous boluses of Fungizone 2 mg/kg once daily for 5 days. The animals were sacrificed 12 h following the last administration and blood and tissues were collected. RESULTS: The plasma concentrations of AmB were similar to previously reported after administration of iCo-009. Somewhat lower concentrations of AmB were detected in reticulo-endothelial system in the case of iCo-010 when compared with iCo-009. The concentration in kidney was higher with iCo-010 than with iCo-009. The creatinine levels in all oral treatment groups were in a normal range as in the case of iCo-009. Administration of Fungizone resulted in elevated plasma creatinine levels. Histopathology analysis detected no GI, liver or kidney toxicity following multiple dose oral administration of iCo-010. Fungizone treatment induced necrotic changes in hepatic and kidney tissues. CONCLUSIONS: Given the tropical stability of iCo-010, near identical activity against visceral leishmaniasis and significant concentrations in target organs this formulation has a potential to become a treatment of choice in tropical developing countries.

Chemical validation of trypanothione synthetase: a potential drug target for human trypanosomiasis.

In the search for new therapeutics for the treatment of human African trypanosomiasis, many potential drug targets in Trypanosoma brucei have been validated by genetic means, but very few have been chemically validated. Trypanothione synthetase (TryS; EC 6.3.1.9; spermidine/glutathionylspermidine:glutathione ligase (ADP-forming)) is one such target. To identify novel inhibitors of T. brucei TryS, we developed an in vitro enzyme assay, which was amenable to high throughput screening. The subsequent screen of a diverse compound library resulted in the identification of three novel series of TryS inhibitors. Further chemical exploration resulted in leads with nanomolar potency, which displayed mixed, uncompetitive, and allosteric-type inhibition with respect to spermidine, ATP, and glutathione, respectively. Representatives of all three series inhibited growth of bloodstream T. brucei in vitro. Exposure to one of our lead compounds (DDD86243; 2 x EC(50) for 72 h) decreased intracellular trypanothione levels to <10% of wild type. In addition, there was a corresponding 5-fold increase in the precursor metabolite, glutathione, providing strong evidence that DDD86243 was acting on target to inhibit TryS. This was confirmed with wild-type, TryS single knock-out, and TryS-overexpressing cell lines showing expected changes in potency to DDD86243. Taken together, these data provide initial chemical validation of TryS as a drug target in T. brucei.

Metronidazole loaded pectin microspheres for colon targeting.

A multiparticulate system having pH-sensitive property and specific enzyme biodegradability for colon-targeted delivery of metronidazole was developed. Pectin microspheres were prepared using emulsion-dehydration technique. These microspheres were coated with Eudragit(R) S-100 using oil-in-oil solvent evaporation method. The SEM was used to characterize the surface of these microspheres and a distinct coating over microspheres could be seen. The in vitro drug release studies exhibited no drug release at gastric pH, however continuous release of drug was observed from the formulation at colonic pH. Further, the release of drug from formulation was found to be higher in the presence of rat caecal contents, indicating the effect of colonic enzymes on the pectin microspheres. The in vivo studies were also performed by assessing the drug concentration in various parts of the GIT at different time intervals which exhibited the potentiality of formulation for colon targeting. Hence, it can be concluded that Eudragit coated pectin microspheres can be used for the colon specific delivery of drug.

Synthesis and evaluation of N-nicotinoyl-2-{2-(2-methyl-5-nitroimidazol-1-yl)ethyloxy}-D,L-glycine as a colon-specific prodrug of metronidazole.

Metronidazole (MTZ) is a drug of choice for protozoal infections such as luminal amoebiasis. We designed and synthesized N-nicotinoyl-2-{2-(2-methyl-5-nitroimidazol-1-yl)ethyloxy}-D,L-glycine (NMG) as a colon-specific prodrug of MTZ. The synthetic yield of NMG was about 34%. The apparent partition coefficient of MTZ was greatly reduced by the chemical modification. While (bio)chemically stable in the contents of the upper intestine, NMG was rapidly cleaved to liberate MTZ on incubation with the cecal contents of rats. MTZ metabolized quickly in the cecal contents at least partly by a microbial nitroreductase, suggesting that the metabolism of MTZ is relevant to its bioactivation leading to amoebicidal action. The systemic absorption, analyzed by the blood concentration and urinary recovery of NMG, was very low after oral administration of NMG. In parallel with this, whereas MTZ disappeared mostly during the transit of the proximal small intestine, a substantial amount of NMG remained in the small intestine moving down to the large intestine where it metabolized rapidly. Moreover, comparing systemic absorption of MTZ after oral administration of NMG or MTZ, NMG markedly reduced the systemic absorption. These results suggest that NMG is a potential colon-specific prodrug of MTZ which improves therapeutic and toxicological properties.

Antiparasitic activity of two Lavandula essential oils against Giardia duodenalis, Trichomonas vaginalis and Hexamita inflata.

Two essential oils derived from Lavandula angustifolia and Lavandula x intermedia were investigated for any antiparasitic activity against the human protozoal pathogens Giardia duodenalis and Trichomonas vaginalis and the fish pathogen Hexamita inflata: all of which have significant infection and economic impacts. The study has demonstrated that low (< or = 1%) concentrations of L. angustifolia and L. x intermedia oil can completely eliminate T. vaginalis, G. duodenalis and H. inflata in vitro. At 0.1% concentration, L. angustifolia oil was found to be slightly more effective than L x intermedia oil against G. duodenalis and H. inflata. The potential applications are discussed.

Polyoxyethylenated methyl esters of rape oil fatty acids as non-ionic surfactants in a model drug form with albendazole.

Systematic research has been conducted on the applying of Rofams (oxyethylathed rape oil methyl esters) as solubilizing agents of albendazole. Homologous series of Rofams containing average amount of oxyethylene units (nTE) ranging between 20 to 60 was used for investigation. An attempt has been made to apply investigated surface active agents as an auxiliary in production of model tablets with albendazole. Basic morphological parameters of granulates (bulk density, tapped density, Carr index, angle of repose) were determined. The dissolution testing procedure, friability and standard deviation from an average tablet mass were conducted to evaluate properties of produced tablets. The solubility of albendazole increases in the presence of Rofams in the aqueous solutions. The highest amount of albendazole was solubilized in the aqueous solution of Rofam containing 20 oxyethylene units. The increase in the content of oxyethylene units in a molecule of surfactant leads to a subsequent decrease in the amount of solubilized albendazole. Studied compounds can be applied in suggested quantities in the formulation of solid dosage forms. Tablets obtained with their content obeyed standards of Polish Pharmacopoeia. Rofams are increasing the amount of albendazole liberated from the tablets what can result in increasing it's bioavailability.

Chemotherapy of leishmaniasis.

Leishmaniasis, in its variety of visceral (VL), cutaneous (CL) and mucocutaneous (MCL) forms, directly affects about 2 million people per annum, with approximately 350 million individuals at risk worldwide. During the last 10 years there have been extensive epidemics of the visceral form of the disease, which is also emerging as an important opportunistic infection in immunocompromised patients, especially those co-infected with HIV. The control of leishmaniasis remains a problem principally a zoonotic infection, except in epidemics where it is anthroponotic, interruption of transmission is difficult, though not impossible. No vaccines exist for either VL, CL or MCL and chemotherapy is inadequate and expensive. Current regimes use pentavalent antimony as primary therapy, which must be administered parenterally. Should this fail, a number of other drugs may be employed, depending upon the species of Leishmania concerned and the resources available to the health professionals involved. Recommended secondary treatment employs a variety of drugs, again depending on the nature of the infection. The most widely used of these is amphotericin B, which is highly active but has extensive toxicity complications. The newer formulations of this drug are too expensive to use for the majority of endemic countries. Pentamidine and paromomycin are used in some instances, and a new anti-leishmanial, miltefosine, may be used in the future. In short, there remains a pressing need for new anti-leishmanials and this chapter reviews the current status of chemotherapy, the various avenues being investigated by researchers and their potential application in the future.

Pharmacokinetics of antimony during treatment of visceral leishmaniasis with sodium stibogluconate or meglumine antimoniate.

5 patients with visceral leishmaniasis were treated with sodium stibogluconate (2 patients) or meglumine antimoniate (3 patients) given intramuscularly at a dose of 10 mg antimony (Sb) per kg body weight daily for 30 d. Blood samples were obtained at intervals during treatment and blood Sb concentrations measured by anodic stripping voltametry. The pharmacokinetics of both drugs were remarkably similar, with peak concentrations of approximately 10 mg/litre occurring 2 h after the initial dose. Most of the Sb was eliminated rapidly, but nadir Sb concentrations increased gradually during treatment from 0.04-0.08 mg/litre 24 h after the first dose to 0.19-0.33 mg/litre 24 h after the 30th dose. For both drugs, the data were best described by a two compartment, three term pharmacokinetic model representing an initial absorption phase with a mean half-life of 0.85 h, a rapid elimination phase with a mean half-life of 2.02 h, and a slow elimination phase with a mean half-life of 76 h. The slow terminal elimination phase may be related to in vivo conversion of pentavalent Sb to trivalent Sb, which could contribute to the toxicity associated with long-term high dose therapy.