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Molecular Pharmaceutics Feb 2022Nanoconfinement is a recent strategy to enhance solubility and dissolution of active pharmaceutical ingredients (APIs) with poor biopharmaceutical properties. In this...
Nanoconfinement is a recent strategy to enhance solubility and dissolution of active pharmaceutical ingredients (APIs) with poor biopharmaceutical properties. In this work, we combine the advantage of cocrystals of racemic praziquantel (PZQ) containing a water-soluble coformer (i.e., increased solubility and supersaturation) and its confinement in a mesoporous silica material (i.e., increased dissolution rate). Among various potential cocrystalline phases of PZQ with dicarboxylic acid coformers, the cocrystal with glutaric acid (PZQ-GLU) was selected and successfully loaded by the melting method into nanopores of SBA-15 (experimental pore size of 5.6 nm) as suggested by physical and spectroscopic characterization using various complementary techniques like N adsorption, powder X-ray diffraction (PXRD), infrared spectroscopy (IR), solid-state NMR (ss-NMR), differential scanning calorimetry (DSC), and field emission-scanning electron microscopy (FE-SEM) analysis. The PZQ-GLU phase confined in SBA-15 presents more mobility according to ss-NMR studies but still retains its cocrystal-like features in the IR spectra, and it also shows depression of the melting transition temperature in DSC. On the contrary, pristine PZQ loaded into SBA-15 was found only in the amorphous state, according to the aforementioned studies. This dissimilar behavior of the composites was attributed to the larger crystal lattice of PZQ over the PZQ-GLU cocrystal (3320.1 vs 1167.9 Å) and to stronger intermolecular interactions between PZQ and GLU, facilitating the confinement of a more mobile solid-like phase in the constrained channels. Powder dissolution studies under extremely nonsink conditions (SI = 0.014) of the confined PZQ-GLU and amorphous PZQ phases embedded in mesoporous silica showed transient supersaturation behavior when dissolving in simulated gastric fluid (HCl pH 1.2 at 37 ± 0.5 °C) in a similar fashion to the bare cocrystal PZQ-GLU. A comparison of the area under the curve (AUC) of the dissolution profiles afforded a dissolution advantage of 2-fold ( < 0.05) of the new solid phases over pristine racemic PZQ after 90 min; under these conditions, the solubilized API reprecipitated as the recently discovered PZQ hemihydrate (PZQ-HH). In the presence of a cellulosic polymer, sustained solubilization of PZQ from composites SBA-15/PZQ or SBA-15/PZQ-GLU was observed, increasing AUC up to 5.1-fold in comparison to pristine PZQ. The combination of a confined solid phase in mesoporous silica and a methylcellulose polymer in the dissolution medium effectively maintained the drug solubilized during times significant to promote absorption. Finally, powder dissolution studies under intermediate nonsink conditions (SI = 1.99) showed a fast release profile from the nanoconfined PZQ-GLU phase in SBA-15, which reached rapid saturation (95% drug dissolved at 30 min); the amorphous PZQ composite and bare PZQ-GLU also displayed an immediate release of the API but at a lower rate (69% drug dissolved at 30 min). In all of these cases, a large dissolution advantage was observed from any of the novel solid phases over PZQ.
Topics: Calorimetry, Differential Scanning; Pharmaceutical Preparations; Praziquantel; Silicon Dioxide; Solubility; X-Ray Diffraction
PubMed: 34967632
DOI: 10.1021/acs.molpharmaceut.1c00606 -
Journal of Fish Diseases Dec 2023
Topics: Animals; Sea Bream; Praziquantel; Gills; Fish Diseases; Trematoda
PubMed: 37650418
DOI: 10.1111/jfd.13854 -
Bioorganic & Medicinal Chemistry Letters Apr 2010Six amide and four urea derivatives of praziquantel were synthesized and tested for antischistosomal activity against juvenile and adults stages of Schistosoma mansoni...
Six amide and four urea derivatives of praziquantel were synthesized and tested for antischistosomal activity against juvenile and adults stages of Schistosoma mansoni in infected mice. Only one of these had significant activity against adult worms, but, unlike praziquantel, six of these had low to modest activity against juvenile worms. A praziquantel ketone derivative had the best combination of activity against juveniles and adults, but it had no effect on the motility of adult S. mansoni in ex vivo culture. Cytochrome P450 metabolic stability data support the hypothesis that the major trans-cyclohexanol metabolite of praziquantel plays an important role in the antischistosomal activity of this drug.
Topics: Animals; Anthelmintics; Mice; Praziquantel; Schistosoma mansoni
PubMed: 20303754
DOI: 10.1016/j.bmcl.2010.03.001 -
Zhongguo Ji Sheng Chong Xue Yu Ji Sheng... Dec 2007Praziquantel is the only effective drug of choice against five human species of schistosomes. Main advantages of praziquantel include convenient oral administration,... (Review)
Review
Praziquantel is the only effective drug of choice against five human species of schistosomes. Main advantages of praziquantel include convenient oral administration, high safety and efficacy as well as short treatment course. To better understand the mode of action of praziquantel against schistosomes would be helpful for further development of new broad-spectrum anthelminthics. This paper summarizes the 30 years' research progress on the mode of action of the drug against schistosomes proceeded by domestic and abroad laboratories.
Topics: Animals; Humans; Mice; Praziquantel; Schistosoma; Schistosomiasis; Schistosomicides
PubMed: 18441900
DOI: No ID Found -
European Journal of Pharmaceutical... Nov 2019The goal of this study was to enhance the oral bioavailability of praziquantel through its conjugation with human serum albumin (HSA). Praziquantel-HSA particles were...
The goal of this study was to enhance the oral bioavailability of praziquantel through its conjugation with human serum albumin (HSA). Praziquantel-HSA particles were produced by spray drying an emulsion of an aqueous solution of HSA and a solution of praziquantel in oil. The particles were agglomerates of multiple smooth corrugated particles containing amorphous praziquantel nearly equivalent to the theoretical doses. The solubility of praziquantel in an aqueous medium was enhanced in both the produced particles and the physical mixture. In addition, the dissolution rate in an aqueous medium was enhanced in the case of particles, but not in a physical mixture. Thus, the inclusion of HSA by emulsification followed by spray drying appeared to contribute to the enhanced dissolution rate. In a pharmacokinetic study, the maximum plasma concentration (C) and the area under the concentration-time curve (AUC) for the produced particles (HSA/praziquantel = 1/1 w/w) were approximately two times higher than the corresponding values for raw praziquantel. This increased oral bioavailability of the particles was considered to be due to the enhanced dissolution rate. This process for producing praziquantel-HSA particles could be useful in terms of improving the oral bioavailability of the other hydrophobic drugs.
Topics: Administration, Oral; Animals; Anthelmintics; Biological Availability; Desiccation; Drug Liberation; Emulsions; Male; Praziquantel; Rats, Wistar; Serum Albumin, Human; Solubility
PubMed: 31491499
DOI: 10.1016/j.ejps.2019.105064 -
Molecular Pharmaceutics Jul 2019Praziquantel (PZQ) is one of the most widespread anthelmintic drugs. However, the frequent insufficient application of PZQ after oral administration is associated with...
Praziquantel (PZQ) is one of the most widespread anthelmintic drugs. However, the frequent insufficient application of PZQ after oral administration is associated with its low solubility, penetration rate, and bioavailability. In the present study, the permeation of PZQ through a 1,2-dioleoyl- sn-glycero-3-phosphocholine (DOPC) membrane was investigated to probe glycyrrhizin-assisted transport. Glycyrrhizin (or glycyrrhizic acid, GA), a natural saponin, shows the ability to enhance the therapeutic activity of various drugs when it is used as a drug delivery system. However, the molecular mechanism of this effect is still under debate. In the present study, the transport rate was measured experimentally by a parallel artificial membrane permeation assay (PAMPA) and molecular dynamics (MD) simulation with DOPC lipid bilayers. The formation of the noncovalent supramolecular complex of PZQ with disodium salt of GA (Na2GA) in an aqueous solution was proved by the NMR relaxation technique. PAMPA experiments show a strong increase in the amount of the penetrating praziquantel molecules in comparison with a saturated aqueous solution of pure drug used as a control. MD simulation of PZQ penetration through the bilayer demonstrates an increase in permeability into the membrane in the presence of a glycyrrhizin molecule. A decrease in the free energy barrier in the middle of the lipid bilayer was obtained, associated with the hydrogen bond between PZQ and GA. Also, GA reduces the local bilayer surface resistance to penetration of PZQ by rearranging the surface lipid headgroups. This study clarifies the mechanism of increasing the drug's bioavailability in the presence of glycyrrhizin.
Topics: Administration, Oral; Anthelmintics; Biological Availability; Cell Membrane Permeability; Drug Delivery Systems; Glycyrrhizic Acid; Hydrogen Bonding; Lipid Bilayers; Magnetic Resonance Spectroscopy; Molecular Dynamics Simulation; Phosphatidylcholines; Praziquantel; Solubility
PubMed: 31198045
DOI: 10.1021/acs.molpharmaceut.9b00390 -
The Journal of Infectious Diseases Jun 1985To discern whether stage-specific resistance of Schistosoma mansoni to praziquantel occurs in vitro, we determined minimal effective concentrations (MECs) of drug needed...
To discern whether stage-specific resistance of Schistosoma mansoni to praziquantel occurs in vitro, we determined minimal effective concentrations (MECs) of drug needed to increase motor activity, produce contraction and/or paralysis, and cause tegumental vesiculation of developmental stages from day 0 to day 42 of S. mansoni. Recovery of these stages from exposure to praziquantel in vitro was also evaluated. MECs of praziquantel inducing increased motor activity and muscular contraction or paralysis or both were 0.005-0.01 micrograms/ml, irrespective of the stage examined. However, day-3 lung forms were more resistant than other stages when either drug-induced tegumental vesiculation (MEC, 1 microgram/ml) or recovery from drug exposure was tested. Three-day infections with S. mansoni in CF1 mice were also less responsive to praziquantel treatment than were infections of shorter or longer duration. The concentrations of praziquantel and periods of drug exposure causing gross tegumental damage to S. mansoni in vitro correlated with the peak serum levels and time course of unchanged praziquantel associated with reduction of worm burden in vivo. Thus, stage-specific resistance of S. mansoni to praziquantel does occur in vitro and correlates better with the tegumental than the muscular action of the drug.
Topics: Animals; Biotransformation; Dose-Response Relationship, Drug; Female; Isoquinolines; Metabolic Clearance Rate; Mice; Motor Activity; Praziquantel; Schistosoma mansoni; Schistosomiasis; Time Factors
PubMed: 3998507
DOI: 10.1093/infdis/151.6.1130 -
Arzneimittel-Forschung Oct 1990The metabolism of the non-labelled and 14C-labelled anthelmintic drug, praziquantel (PZQ; CAS 55268-74-1) was investigated by means of microsomal oxidation with rat...
The metabolism of the non-labelled and 14C-labelled anthelmintic drug, praziquantel (PZQ; CAS 55268-74-1) was investigated by means of microsomal oxidation with rat liver homogenates. The metabolites formed were determined with linear thin-layer chromatography (TLC) radioactivity scanner after TLC separation, separated with TLC and analysed with high-pressure liquid chromatography and mass spectrometry method. The amounts and properties of the formed metabolites were described. It was stated that after microsomal oxidation monohydroxylated PZQ derivatives were obtained in greatest amount; the main fraction formed (35%) contained 4-OH-PZQ derivate which consisted of 80% cis-4-OH-PZQ and 20% of trans-4-OH-PZQ.
Topics: Animals; Chromatography; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; In Vitro Techniques; Male; Mass Spectrometry; Microsomes, Liver; Molecular Conformation; Oxidation-Reduction; Praziquantel; Rats; Rats, Inbred Strains
PubMed: 2291756
DOI: No ID Found -
Molecules (Basel, Switzerland) Jul 2023Malaria and schistosomiasis are two of the neglected tropical diseases that persistently wreak havoc worldwide. Although many antimalarial drugs such as chloroquine are...
Malaria and schistosomiasis are two of the neglected tropical diseases that persistently wreak havoc worldwide. Although many antimalarial drugs such as chloroquine are readily available, the emergence of drug resistance necessitates the development of new therapies to combat this disease. Conversely, Praziquantel (PZQ) remains the sole effective drug against schistosomiasis, but its extensive use raises concerns about the potential for drug resistance to develop. In this project, the concept of molecular hybridization was used as a strategy to design the synthesis of new molecular hybrids with potential antimalarial and antischistosomal activity. A total of seventeen molecular hybrids and two PZQ analogues were prepared by coupling 6-alkylpraziquanamines with cinnamic acids and cyclohexane carboxylic acid, respectively. The synthesised compounds were evaluated for their antimalarial and antischistosomal activity; while all of the above compounds were inactive against (IC > 6 µM), many were active against schistosomiasis with four particular compounds exhibiting up to 100% activity against newly transformed schistosomula and adult worms at 50 µM. Compared to PZQ, the reference drug, the activity of which is 91.7% at 1 µM, one particular molecular hybrid, compound , which bears a para-isopropyl group on the cinnamic acid moiety, exhibited a notable activity at 10 µM (78.2% activity). This compound has emerged as the front runner candidate that might, after further optimization, hold promise as a potential lead compound in the fight against schistosomiasis.
Topics: Animals; Praziquantel; Antimalarials; Schistosoma mansoni; Schistosomicides; Schistosomiasis
PubMed: 37446846
DOI: 10.3390/molecules28135184 -
Parasitology Nov 2010Praziquantel is widely used for the treatment of human schistosomiasis. However, in recent years, there has been increasing concern about the resistance of Schistosoma...
Praziquantel is widely used for the treatment of human schistosomiasis. However, in recent years, there has been increasing concern about the resistance of Schistosoma species to praziquantel. The study described here was designed to evaluate the current susceptibility to praziquantel in S. japonicum in China. During the non-transmission period of schistosomiasis, a random sample of 4760 subjects from the main endemic foci of China were examined using parasitological stool examination. In total, 584 subjects were identified as being infected with S. japonicum, with a prevalence rate of 12.27%. Among them, 565 stool-egg-positive subjects were treated with praziquantel in a single oral dose of 40 mg/kg. Six weeks post-treatment, among the 505 villagers re-examined, 480 (95.05%) had no detectable S. japonicum eggs. Twenty-one subjects still excreting eggs after the first treatment were treated with praziquantel for the second time. All stool samples, including those from those participants with second treatment were re-examined 6 weeks after the second treatment, and no stool-egg-positives were found. The results indicate that the current efficacy of praziquantel against S. japonicum is still high and has not changed after more than 2 decades of repeated, expanded chemotherapy in the main endemic areas of China. It is suggested that no evidence of tolerance or resistance to praziquantel in S. japonicum was detected in China.
Topics: Adolescent; Adult; Aged; Animals; Anthelmintics; Child; China; Drug Resistance; Feces; Female; Humans; Male; Middle Aged; Praziquantel; Schistosoma japonicum; Schistosomiasis japonica; Young Adult
PubMed: 20810006
DOI: 10.1017/S0031182010001204