Pharmacokinetics of Nitazoxanide Dry Suspensions After Single Oral Doses in Healthy Subjects: Food Effects Evaluation and Bioequivalence Study.

Nitazoxanide (NTZ) is an effective antiparasitic drug with potent antiviral and antimicrobial activity. This randomized, open-label, 2-sequence, 2-period crossover trial was designed to evaluate the bioequivalence (BE) of the NTZ dry suspension in healthy subjects and investigated the effect of food intake on the pharmacokinetic (PK) properties of tizoxanide (an active metabolite of NTZ, TIZ). Sixty healthy Chinese subjects were enrolled and received a single dose of 500 mg/25 mL of preparations on days 1 and 4 under overnight fasting or fed conditions, respectively. The plasma concentration of TIZ was determined using high-performance liquid chromatography/tandem mass spectrometry. PK parameters were calculated using WinNonlin 8.2 and BE was evaluated using SAS 9.4. The 90% confidence intervals for the geometric mean ratio (test/reference) of maximum concentration (Cmax), the area under the curve from time 0 to the time of the last quantifiable concentration (AUC0-t), and the area under the curve from time 0 to extrapolation to infinity (AUC0-∞) were all within the equivalent interval of 80%-125%, compliant with BE requirements. In comparison with fasting, on taking the reference and test preparations of the NTZ dry suspension after a meal, the AUC0-t increased by 48.9% and 47.3%, respectively, the AUC0-∞ increased by 48.4% and 48.3%, respectively, and the post-meal Tmax was prolonged by 1.8-2 hours. Our results demonstrate that the test and reference preparations were bioequivalent. High-fat meals significantly improve the degree of drug absorption and delay the rate of drug absorption.

Is the antiparasitic drug ivermectin a suitable candidate for the treatment of epilepsy?

There are only a few drugs that can seriously lay claim to the title of "wonder drug," and ivermectin, the world's first endectocide and forerunner of a completely new class of antiparasitic agents, is among them. Ivermectin, a mixture of two macrolytic lactone derivatives (avermectin B1a and B1b in a ratio of 80:20), exerts its highly potent antiparasitic effect by activating the glutamate-gated chloride channel, which is absent in vertebrate species. However, in mammals, ivermectin activates several other Cys-loop receptors, including the inhibitory γ-aminobutyric acid type A and glycine receptors and the excitatory nicotinic acetylcholine receptor of brain neurons. Based on these effects on vertebrate receptors, ivermectin has recently been proposed to constitute a multifaceted wonder drug for various novel neurological indications, including alcohol use disorders, motor neuron diseases, and epilepsy. This review critically discusses the preclinical and clinical evidence of antiseizure effects of ivermectin and provides several arguments supporting that ivermectin is not a suitable candidate drug for the treatment of epilepsy. First, ivermectin penetrates the mammalian brain poorly, so it does not exert any pharmacological effects via mammalian ligand-gated ion channels in the brain unless it is used at high, potentially toxic doses or the blood-brain barrier is functionally impaired. Second, ivermectin is not selective but activates numerous inhibitory and excitatory receptors. Third, the preclinical evidence for antiseizure effects of ivermectin is equivocal, and at least in part, median effective doses in seizure models are in the range of the median lethal dose. Fourth, the only robust clinical evidence of antiseizure effects stems from the treatment of patients with onchocerciasis, in which the reduction of seizures is due to a reduction in microfilaria densities but not a direct antiseizure effect of ivermectin. We hope that this critical analysis of available data will avert the unjustified hype associated with the recent use of ivermectin to control COVID-19 from recurring in neurological diseases such as epilepsy.

High-resolution AP-SMALDI MSI as a tool for drug imaging in Schistosoma mansoni.

Schistosoma mansoni is a parasitic flatworm causing schistosomiasis, an infectious disease affecting several hundred million people worldwide. Schistosomes live dioeciously, and upon pairing with the male, the female starts massive egg production, which causes pathology. Praziquantel (PZQ) is the only drug used, but it has an inherent risk of resistance development. Therefore, alternatives are needed. In the context of drug repurposing, the cancer drug imatinib was tested, showing high efficacy against S. mansoni in vitro. Besides the gonads, imatinib mainly affected the integrity of the intestine in males and females. In this study, we investigated the potential uptake and distribution of imatinib in adult schistosomes including its distribution kinetics. To this end, we applied for the first time atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) for drug imaging in paired S. mansoni. Our results indicate that imatinib was present in the esophagus and intestine of the male as early as 20 min after in vitro exposure, suggesting an oral uptake route. After one hour, the drug was also found inside the paired female. The detection of the main metabolite, N-desmethyl imatinib, indicated metabolization of the drug. Additionally, a marker signal for the female ovary was successfully applied to facilitate further conclusions regarding organ tropism of imatinib. Our results demonstrate that AP-SMALDI MSI is a useful method to study the uptake, tissue distribution, and metabolization of imatinib in S. mansoni. The results suggest using AP-SMALDI MSI also for investigating other antiparasitic compounds and their metabolites in schistosomes and other parasites.

Encapsulation of curcumin into layered double hydroxides improve their anticancer and antiparasitic activity.

OBJECTIVES: Curcumin (CUR) has well-known activity against cancer cells and parasites; however, its applications are limited since this is an unstable molecule, which may suffer degradation by light and temperature, also, the low water solubility reduce its bioavailability. Layered double hydroxides (LDH) are well-known materials owing to the excellent anion exchange capacity, good biocompatibility and low toxicity. METHODS: Layered double hydroxides nanoparticles prepared with zinc and magnesium cations were used as a vehicle for CUR in Caco-2, Giardia lamblia and Entamoeba histolytica cultures. The physicochemical properties of Mg-LDH-CUR and Zn-LDH-CUR were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectrometry (FTIR) and X-ray powder diffraction (XRD). Additionally, the load efficiency, release profiles and photostability of CUR were quantified by high-performance liquid chromatography (HPLC) and UV-Vis spectrometry. Then, Mg-LDH-CUR and Zn-LDH-CUR were tested on Caco-2, G. lamblia and E. histolytica cultures. KEY FINDINGS: The experiments demonstrated that Zn-LDH-CUR protects better against photodegradation by UV light, while Mg-LDH-CUR showed increased toxicity against Caco-2 cell, G. lamblia and E. histolytica, in comparison with free CUR. CONCLUSIONS: Layered double hydroxides are good vehicles to improve stability, resistance to degradation of CUR, also they are useful to improve solubility, provide a controlled release and improve the cytotoxic activity. Additionally, it was shown that the composition of the M+2 cation of LDH affects its properties and structure and that this directly influences its biological activity. The findings are important to select the composition of the encapsulation vehicle for a specific activity.

Investigation of pharmacokinetic interaction between ivermectin and praziquantel after oral administration in healthy dogs.

The purpose of this study was to determine the pharmacokinetic interaction between ivermectin (0.4 mg/kg) and praziquantel (10 mg/kg) administered either alone or co-administered to dogs after oral treatment. Twelve healthy cross-bred dogs (weighing 18-21 kg, aged 1-3 years) were allocated randomly into two groups of six dogs (four females, two males) each. In first group, the tablet forms of praziquantel and ivermectin were administered using a crossover design with a 15-day washout period, respectively. Second group received tablet form of ivermectin plus praziquantel. The plasma concentrations of ivermectin and praziquantel were determined by high-performance liquid chromatography using a fluorescence and ultraviolet detector, respectively. The pharmacokinetic parameters of ivermectin following oral alone-administration were as follows: elimination half-life (t1/2λz ) 110 ± 11.06 hr, area under the plasma concentration-time curve (AUC0-∞ ) 7,805 ± 1,768 hr. ng/ml, maximum concentration (Cmax ) 137 ± 48.09 ng/ml, and time to reach Cmax (Tmax ) 14.0 ± 4.90 hr. The pharmacokinetic parameters of praziquantel following oral alone-administration were as follows: t1/2λz 7.39 ± 3.86 hr, AUC0-∞ 4,301 ± 1,253 hr. ng/ml, Cmax 897 ± 245 ng/ml, and Tmax 5.33 ± 0.82 hr. The pharmacokinetics of ivermectin and praziquantel were not changed, except Tmax of praziquantel in the combined group. In conclusion, the combined formulation of ivermectin and praziquantel can be preferred in the treatment and prevention of diseases caused by susceptible parasites in dogs because no pharmacokinetic interaction was determined between them.

Contributions of Hepatic and Intestinal Metabolism to the Disposition of Niclosamide, a Repurposed Drug with Poor Bioavailability.

Niclosamide, an antiparasitic, has been repositioned as a potential therapeutic drug for systemic diseases based on its antiviral, anticancer, and anti-infection properties. However, low bioavailability limits its in vivo efficacy. Our aim was to determine whether metabolic disposition by microsomal P450 enzymes in liver and intestine influences niclosamide's bioavailability in vivo, by comparing niclosamide metabolism in wild-type, liver-Cpr-null (LCN), and intestinal epithelium-Cpr-null (IECN) mice. In vitro stability of niclosamide in microsomal incubations was greater in the intestine than in liver in the presence of NADPH, but it was much greater in liver than in intestine in the presence of UDPGA. NADPH-dependent niclosamide metabolism and hydroxy-niclosamide formation were inhibited in hepatic microsomes of LCN mice, but not IECN mice, compared with wild-type mice. In intestinal microsomal reactions, hydroxy-niclosamide formation was not detected, but rates of niclosamide-glucuronide formation were ∼10-fold greater than in liver, in wild-type, LCN, and IECN mice. Apparent Km and V max values for microsomal niclosamide-glucuronide formation showed large differences between the two tissues, with the intestine having higher Km (0.47 µM) and higher V max (15.8) than the liver (0.09 µM and 0.75, respectively). In vivo studies in LCN mice confirmed the essential role of hepatic P450 in hydroxy-niclosamide formation; however, pharmacokinetic profiles of oral niclosamide were only minimally changed in LCN mice, compared with wild-type mice, and the changes seem to reflect the compensatory increase in hepatic UDP-glucuronosyltransferase activity. SIGNIFICANCE STATEMENT: These results suggest that efforts to increase the bioavailability of niclosamide by blocking its metabolism by P450 enzymes will unlikely be fruitful. In contrast, inhibition of niclosamide glucuronidation in both liver and intestine may prove effective for increasing niclosamide's bioavailability, thereby making it practical to repurpose this drug for treating systemic diseases.

Pharmacokinetics of ivermectin in sheep following pretreatment with Escherichia coli endotoxin.

The comparative pharmacokinetics of ivermectin (IVM), between healthy and in Escherichia coli lipopolysaccharides (LPS) injected sheep, was investigated after an intravenous (IV) administration of a single dose of 0.2 mg/kg. Ten Suffolk Down sheep, 55 ± 3.3 kg, were distributed in two experimental groups: Group 1 (LPS): treated with three doses of 1 µg LPS/kg bw at -24, -16, and -0.75 hr before IVM; group 2 (Control): treated with saline solution (SS). An IV dose of 0.2 mg IVM/kg was administered 45 min after the last injection of LPS or SS. Plasma concentrations of IVM were determined by liquid chromatography. Pharmacokinetic parameters were calculated based on non-compartmental modeling. In healthy sheep, the values of the pharmacokinetic parameters were as follows: elimination half-life (2.85 days), mean residence time (MRT) (2.27 days), area under the plasma concentration curve over time (AUC, 117.4 ng day-1 ml-1 ), volume of distribution (875.6 ml/kg), and clearance (187.1 ml/day). No statistically significant differences were observed when compared with the results obtained from the group of sheep treated with LPS. It is concluded that the acute inflammatory response (AIR) induced by the intravenous administration of E. coli LPS in adult sheep produced no changes in plasma concentrations or in the pharmacokinetic behavior of IVM, when it is administered intravenously at therapeutic doses.

Ivermectin 1% (CD5024) for the treatment of rosacea.

INTRODUCTION: Rosacea is a chronic and recurrent disease with a variety of cutaneous manifestations. The disorder is a centrofacial inflammatory dermatosis with significant financial, physical and psychological impacts. There are a number of topical, oral and systemic treatments available. Yet, treatment for rosacea remains difficult. The multifactorial nature of the disease combined with an incomplete understanding of the pathophysiology is challenging for providers and patients. Areas covered: This article provides an in-depth review of rosacea treatment and emerging use of ivermectin 1% cream for papulopustular rosacea based on multiple clinical trials. The PubMed database was searched using the combination of keywords "ivermectin, rosacea, and papulopustular." Expert opinion: Topical ivermectin 1% cream has emerged as a novel agent for treatment of papulopustular rosacea. The drug targets the Demodex mite which is increased in patients with rosacea. Though ivermectin 1% is a clinically efficacious medication, poor adherence continues to remain an issue due to topical application. Ultimately, the agent has the potential to be an effective drug when used as a single or combination agent. With the move to limit chronic antibiotic use, topical agents such as ivermectin 1% will continue to thrive as a specialized niche in the rosacea market.

Inclusion complex and nanoclusters of cyclodextrin to increase the solubility and efficacy of albendazole.

Albendazole (ABZ), a benzimidazole widely used to control gastrointestinal parasites, is poorly soluble in water, resulting in variable and incomplete bioavailability. This has favored the appearance ABZ-resistant nematodes and, consequently, an increase in its clinical ineffectiveness. Among the pharmaceutical techniques developed to increase drug efficacy, cyclodextrins (CDs) and other polymers have been extensively used with water-insoluble pharmaceutical drugs to increase their solubility and availability. Our objective was to prepare ABZ formulations, including ß-cyclodextrin (ßCD) or hydroxypropyl-ß-cyclodextrin (HPßCD), associated or not to the water-soluble polymer polyvinylpyrrolidone (PVP). These formulations had their solubility and anthelmintic effect both evaluated in vitro. Also, their anthelmintic efficacy was evaluated in lambs naturally infected with gastrointestinal nematodes (GIN) through the fecal egg count (FEC) reduction test. In vitro, the complex ABZ/HPßCD had higher solubility than ABZ/ßCD. The addition of PVP to the complexes increased solubility and dissolution rates more effectively for ABZ/HPßCD than for ABZ/ßCD. In vivo, 48 lambs naturally infected with GIN were divided into six experimental groups: control, ABZ, ABZ/ßCD, ABZ/ßCD-PVP, ABZ/HPßCD, and ABZ/HPßCD-PVP. Each treated animal received 10 mg/kg of body weight (based on the ABZ dose) for three consecutive days. After 10 days of the last administered dose, treatment efficacy was calculated. The efficacy values were as follows: ABZ (70.33%), ABZ/ßCD (85.33%), ABZ/ßCD-PVP (82.86%), ABZ/HPßCD (78.37%), and ABZ/HPßCD-PVP (43.79%). In vitro, ABZ/HPßCD and ABZ/HPßCD-PVP had high solubility and dissolution rates. In vivo, although the efficacies of ABZ/ßCD, ABZ/ßCD-PVP, and ABZ/HPßCD increased slightly when compared to pure ABZ, this increase was not significant (P > 0.05).

Methoxylated 2'-hydroxychalcones as antiparasitic hit compounds.

Chalcones display a broad spectrum of pharmacological activities. Herein, a series of 2'-hydroxy methoxylated chalcones was synthesized and evaluated towards Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum. Among the synthesized library, compounds 1, 3, 4, 7 and 8 were the most potent and selective anti-T. brucei compounds (EC50 = 1.3-4.2 µM, selectivity index >10-fold). Compound 4 showed the best early-tox and antiparasitic profile. The pharmacokinetic studies of compound 4 in BALB/c mice using hydroxypropil-ß-cyclodextrins formulation showed a 7.5 times increase in oral bioavailability.

Combined flubendazole-nitazoxanide treatment of cystic echinococcosis: Pharmacokinetic and efficacy assessment in mice.

The current chemotherapy of cystic echinococcosis (CE) is mainly based on the use of albendazole, and the results have been shown to be highly variable. Thus, new and more efficient treatment options are urgently needed. The goals of the current study were: a) to compare the ex vivo activity of flubendazole (FLBZ) and nitazoxanide (NTZ), given either separately or co-administered, against Echinococcus granulosus protoscoleces and cysts, b) to characterize the plasma disposition kinetics of FLBZ administered alone or combined with NTZ in mice; (c) to compare the in vivo activity of FLBZ and NTZ (either each alone or as a combined treatment) against secondary CE developed in mice. Ex vivo drug activity study: E. granulosus protoscoleces and cysts were incubated either with FLBZ, NTZ, or the FLBZ-NTZ combination. Protoscoleces and cyst viability was monitored by the methylene blue exclusion test and scanning electron microscopy (SEM). Pharmacokinetic study: Balb/C mice received FLBZ (5 mg/kg) orally either alone or co-administered with NTZ (100 mg/kg). Blood samples were collected up to 12 h post treatment and plasma analyzed for FLBZ/metabolites by HPLC. Clinical Efficacy study: following secondary infection, meaning i.p. injection of 1500 E. granulosus protoscoleces/animal (n=40), the both drugs were administered by intragastric inoculation on a daily basis for a period of 25 days. Balb/C mice received FLBZ (5 mg/kg, twice a day) alone, NTZ (100 mg/kg, once daily) alone or a combination of both molecules (FLBZ, 5mg/kg twice a day and NTZ, 100 mg/kg, once daily). Ten untreated animals were used as a control. All animals were killed and the weight of the cysts collected from each animal was recorded. The presence of NTZ did not markedly affect the FLBZ kinetic parameters in mice. FLBZ alone or combined with NTZ induced a reduction (P<0.05) of cyst weight in comparison to the untreated control and NTZ-treated treated mice. The data obtained here indicate that NTZ did not affect hydatid cyst development in mice. Conversely, FLBZ shows an excellent efficacy against CE.

Antigen presenting cells targeting and stimulation potential of lipoteichoic acid functionalized lipo-polymerosome: a chemo-immunotherapeutic approach against intracellular infectious disease.

Antigen presenting cells (APC) are well-recognized therapeutic targets for intracellular infectious diseases, including visceral leishmaniasis. These targets have raised concerns regarding their potential for drug delivery due to overexpression of a variety of receptors for pathogen associated molecular pathways after infection. Since, lipoteichoic acid (LTA), a surface glycolipid of Gram-positive bacteria responsible for recognition of bacteria by APC receptors that also regulate their activation for pro-inflammatory cytokine secretion, provides additive and significant protection against parasite. Here, we report the nanoarchitechture of APC focused LTA functionalized amphotericin B encapsulated lipo-polymerosome (LTA-AmB-L-Psome) delivery system mediated by self-assembly of synthesized glycol chitosan-stearic acid copolymer (GC-SA) and cholesterol lipid, which can activate and target the chemotherapeutic agents to Leishmania parasite resident APC. Greater J774A and RAW264.7 macrophage internalization of FITC tagged LTA-AmB-L-Psome compared to core AmB-L-Psome was observed by FACSCalibur cytometer assessment. This was further confirmed by higher accumulation in macrophage rich liver, lung and spleen during biodistribution study. The LTA-AmB-L-Psome overcame encapsulated drug toxicity and significantly increased parasite growth inhibition beyond commercial AmB treatment in both in vitro (macrophage-amastigote system; IC50, 0.082 ± 0.009 µg/mL) and in vivo (Leishmania donovani infected hamsters; 89.25 ± 6.44% parasite inhibition) models. Moreover, LTA-AmB-L-Psome stimulated the production of protective cytokines like interferon-γ (IFN-γ), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase and nitric oxide with down-regulation of disease susceptible cytokines, like transforming growth factor-ß (TGF-ß), IL-10, and IL-4. These data demonstrate the potential use of LTA-functionalized lipo-polymerosome as a biocompatible lucrative nanotherapeutic platform for overcoming toxicity and improving drug efficacy along with induction of robust APC immune responses for effective therapeutics of intracellular diseases.

Pharmacokinetics and metabolism of eprinomectin in cats when administered in a novel topical combination of fipronil, (S)-methoprene, eprinomectin and praziquantel.

Four studies were conducted to determine the pharmacokinetic characteristics and in vitro metabolism of eprinomectin, a semi-synthetic avermectin, in cats. Pharmacokinetic parameters including bioavailability of eprinomectin were determined in a parallel study design comprised of one group of eight cats which were treated once topically at 0.12 mL/kg bodyweight with BROADLINE(®), a novel combination product (fipronil 8.3% (w/v), (S)-methoprene 10% (w/v), eprinomectin 0.4% (w/v) and praziquantel 8.3% (w/v)), delivering a dose of 0.5mg eprinomectin per kg body weight, and a group of six cats which received 0.4% (w/v) eprinomectin at 0.4 mg/kg bodyweight once by intravenous injection. For cats treated by topical application, the average eprinomectin (B1a component) maximum plasma concentration (Cmax) was 20 ng/mL. The maximum concentrations were reached 24h after dosing in the majority of the animals (six of eight cats). The average terminal half-life was 114 h due to slow absorption ('flip-flop' kinetics). Following intravenous administration the average Cmax was 503 ng/mL at 5 min post-dose, and the mean elimination half-life was 23 h. Eprinomectin was widely distributed with a mean volume of distribution of 2,390 mL/kg, and the clearance rate was 81 mL/h/kg. Mean areas under the plasma concentration versus time curves extrapolated to infinity were 2,100 ngh/mL and 5,160 ngh/mL for the topical and intravenous doses, respectively. Topical eprinomectin was absorbed with an average absolute bioavailability of 31%. In a second parallel design study, the dose proportionality of eprinomectin after single topical administration of BROADLINE(®) was studied. Four groups of eight cats each were treated once topically with 0.5, 1, 2 or 5 times the minimum recommended dose of the combination, 0.12 mL/kg bodyweight. Based on comparison of areas under the plasma concentration versus time curves from the time of dosing to the last time point at which eprinomectin B1a was quantified, and Cmax, dose proportionality was established. In addition, the metabolic pathway of eprinomectin using cat liver microsomes, and plasma protein binding using cat, rat, and dog plasma were studied in vitro. Results of the analyses of eprinomectin B1a described here showed that it is metabolically stable and highly protein bound (>99%), and thus likely to be, as with other species, excreted mainly as unchanged parent drug in the feces of cats.

Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs.

Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1-0.2 µg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes.

Discovery of a new class of natural product-inspired quinazolinone hybrid as potent antileishmanial agents.

The high potential of quinazolinone containing natural products and their derivatives in medicinal chemistry led us to discover four novel series of 53 compounds of quinazolinone based on the concept of molecular hybridization. Most of the synthesized analogues exhibited potent leishmanicidal activity against intracellular amastigotes (IC50 from 0.65 ± 0.2 to 7.76 ± 2.1 µM) as compared to miltefosine (IC50 = 8.4 ± 2.1 µM) and nontoxic toward the J-774A.1 cell line and Vero cells. Moreover, activation of Th1 type and suppression of Th2 type immune responses and induction in nitric oxide generation proved that 8a and 8g induce murine macrophages to prevent survival of parasites. Compounds 8a and 8g exhibited significant in vivo inhibition of parasite 73.15 ± 12.69% and 80.93 ± 10.50% against Leishmania donovani /hamster model. Our results indicate that compounds 8a, 8g, and 9f represent a new structural lead for this serious and neglected disease.

Methotrexate: a detailed review on drug delivery and clinical aspects.

INTRODUCTION: Uses of methotrexate (MTX) are well established for the treatment of various types of malignancy, psoriasis, rheumatological diseases and the medical termination of pregnancy. Formulation and targeting approaches for MTX with controlled release carriers, multiparticulate systems, prodrug and drug conjugates have been found to improve bioavailability, reduce adverse effects and maximize clinical efficacy, compared with conventional methods. AREAS COVERED: This exhaustive literature survey on different electronic databases covers drug delivery and clinical trials on MTX. This review deals with the challenges and achievements of controlled release, multiparticulate, prodrug and drug conjugate systems of MTX. EXPERT OPINION: Therapeutic drug monitoring of MTX is crucial to attain a good efficacy. In spite of the advantages of multiparticulate, prodrug and drug conjugates, clinical applications of such formulations of MTX are still under infancy. These drug delivery systems require the special attention of medical experts for its wider clinical usage, and pharmaceutical experts for its scale-up. The combination of MTX with other antineoplastic and immunosuppressants should also be subjected to clinical trials, such as the combination of misoprostol with MTX in abortion.

Albendazole-praziquantel interaction in healthy volunteers: kinetic disposition, metabolism and enantioselectivity.

AIM: This study investigated the kinetic disposition, metabolism and enantioselectivity of albendazole (ABZ) and praziquantel (PZQ) administered alone and in combination to healthy volunteers. METHODS: A randomized crossover study was carried out in three phases (n= 9), in which some volunteers started in phase 1 (400 mg ABZ), others in phase 2 (1500 mg PZQ), and the remaining volunteers in phase 3 (400 mg ABZ + 1500 mg PZQ). Serial blood samples were collected from 0-48 h after drug administration. Pharmacokinetic parameters were calculated using a monocompartmental model with lag time and were analyzed using the Wilcoxon test; P ≤ 0.05. RESULTS: The administration of PZQ increased the plasma concentrations of (+)-ASOX (albendazole sulphoxide) by 264% (AUC 0.99 vs. 2.59 µg ml(-1) h), (-)-ASOX by 358% (0.14 vs. 0.50 µg ml(-1) h) and albendazole sulfone (ASON) by 187% (0.17 vs. 0.32 µg ml(-1) h). The administration of ABZ did not change the kinetic disposition of (+)-(S)-PZQ (-)-(R)-4-OHPZQ or (+)-(S)-4-OHPZQ, but increased the plasma concentration of (-)-(R)-PZQ by 64.77% (AUC 0.52 vs. 0.86 µg ml(-1) h). CONCLUSIONS: The pharmacokinetic interaction between ABZ and PZQ in healthy volunteers was demonstrated by the observation of increased plasma concentrations of ASON, both ASOX enantiomers and (-)-(R)-PZQ. Clinically, the combination of ABZ and PZQ may improve the therapeutic efficacy as a consequence of higher concentration of both active drugs. On the other hand, the magnitude of this elevation may represent an increased risk of side effects, requiring, certainly, reduction of the dosage. However, further studies are necessary to evaluate the efficacy and safety of this combination.

Ivermectina: sus múltiple usos, seguridad y toxicidad / Ivermectin: its multiple uses, safety and toxicity

La Ivermectina, con más de 30 años de uso en humanos, es una droga que aún sigue siendo estudiada en otras indicaciones. Su seguridad es alta; se han dado casi 2.000 millones de dosis en humanos con efectos colaterales mínimos. Se excreta por las heces, no es nefrotóxica ni hepatotóxica. Es el tratamiento de elección en pacientes con SIDA, recibiendo terapia HAART para estrongiloidiasis sistémica y sarna noruega. Es empleada en niños mayores de dos años de edad o con más de 15 kilos de peso. La dosis es de 200 microgramos/kg en forma oral, al 0,6 por ciento en gotas (1 gota/kg de peso) y de 400 microgramos/kg en forma tópica al 0,1 por ciento (0,4 cc/kg de peso). Logró erradicar la oncocercosis que produce la “ceguera del río” y fue considerada como el triunfo de la humanidad sobre la adversidad por la OMS en 2009.

Ivermectin has been used during more than 30 years and yet it is an old drug in search for additional indications. Ivermectin has high safety profile, and more than 2 billion doses have been administered with mild side effects. Ivermectin is metabolized in the liver, and the drug or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1percent of the oral dose excreted in the urine. The plasma half-life of ivermectin in humans is approximately 18 hours following oral administration. Ivermectin is primarily metabolized by CYP3A4, and does not provoke hepato /nephrotoxicicty. This molecule is the gold standard treatment for strongyloidiasis and crusted scabies in patients with AIDS during treatment with HAART therapy. Ivermectin is used in children older than 2 years or more than 15 kg weight. Oral ivermectin 0.6 percent dose is 200 micrograms/kg (1 drop per kg) and topical ivermectin 0.1 percent dose is 400 micrograms/kg (0.4 cc per kg). Ivermectin was able to eliminate human river blindness (onchocerciasis) and “represent one of the most triumphant public health campaigns ever waged in the developing world” by WHO in 2009.