Papers by Lucila Hinrichsen
Journal of Endocrinological Investigation, Oct 1, 1985
The effects of the administration of pharmacological doses of estradiol were studied in two genet... more The effects of the administration of pharmacological doses of estradiol were studied in two genetically different lines of inbred rats, at two stages of development, to gain a new insight into the genetic and physiological organization of the response of bone and Ca metabolism to exogenous estrogens. The comparative analysis of the effects on bone tissue revealed that the pattern of cellular activities at bone surfaces, the increased trabecular bone volume and the increased calcium accretion are separate responses. Likewise, the closure of the epiphyseal plate may not be associated with the curtailment of body weight increase. In addition, only one of the lines increased its intestinal calcium absorption. It appears evident that the response to exogenous estradiol relies upon the action of more than one locus. The simultaneous occurence of partial responses (successful treatment) depends upon as yet undefined genetic and environmental (endocrine, nutritional, etc.) conditions. Extension of these conclusions to the human being implicates the recognition that a fraction of the patients undergoing estrogenic treatment may be insensitive to therapy.
BAG. Journal of basic and applied genetics, Jul 1, 2010
ABSTRACT El ratón de laboratorio (Mus musculus) es una especie ampliamente utilizada como organis... more ABSTRACT El ratón de laboratorio (Mus musculus) es una especie ampliamente utilizada como organismo modelo en diversos campos de la Biología. Esta especie está considerada como un modelo animal prácticamente perfecto no sólo por su corto intervalo generacional, fácil mantenimiento y alto potencial biótico, sino también por otras características que, sumadas, lo hacen una opción casi única para la genética experimental. El Instituto de Genética Experimental de la Facultad de Ciencias Médicas de la Universidad Nacional de Rosario cuenta con líneas de ratones obtenidas en experimentos de selección divergente por conformación corporal que han fijado distintas combinaciones alélicas, debido a los efectos conjuntos de la cría selectiva por más de 100 generaciones, la respuesta correlacionada a la selección, los efectos no direccionales de la endocría y la deriva génica, y la aparición de nuevas mutaciones. Este carácter de genotipo singular atribuido a cada línea fue corroborado por estudios morfométricos de la hemi-mandíbula y el fémur. Por ello, las líneas de esta colonia constituyeron un modelo murino atractivo para el estudio de rasgos genéticos complejos tales como crecimiento, desarrollo y composición corporal, propiedades contráctiles del músculo, resistencia a las parasitosis, susceptibilidad a la carcinogénesis espontánea de mama así como la influencia del hospedero en el crecimiento de un adenocarcinoma de mama transplantable. Los resultados obtenidos ponen en evidencia que estas líneas son una fuente de variancia genética significativa en todos los caracteres analizados.
PubMed, Dec 1, 1990
In individual altered hepatic foci (AHF), aneuploidy occurs before malignant changes can be diagn... more In individual altered hepatic foci (AHF), aneuploidy occurs before malignant changes can be diagnosed histologically (O. Sudilovsky and T. K. Hei. Fed. Proc., 42:2225, 1983). In the current experiments Sprague-Dawley rats of both sexes were given i.p. injections of diethylnitrosamine (50 mg/kg body weight) 18 h after partial hepatectomy and were given a choline-sufficient diet (CS) for 1 wk. Four treatment groups were then formed and fed CS, CS containing 0.05% phenobarbital (PHB), choline-deficient diet (CD), and CD with 0.05% PHB. An extra female group received infusions of saline after the hepatectomy and fared CD. Control animals were partially hepatectomized, inoculated i.p. with saline, and placed on CS. The rats were sacrificed 16 wk later, liver sections were stained with a combined Feulgen-gamma-glutamyl transpeptidase stain, and the DNA content of gamma-glutamyl transpeptidase-positive foci was measured cytospectrophotometrically. There were no AHF in the control animals. Hepatocytes from control livers and cells adjacent to foci in treated livers had peaks corresponding to the 2C, 4C, and 8C range. In AHF the ploidy, however, was predominantly diploid, tetraploid, or heterogeneous. The ratio of diploid to tetraploid cells in foci of rats provided with CS + PHB was 5.5 and in those supplied with CD + PHB was 0.09. This suggested that dietary manipulations change the nuclear DNA distribution of AHF. Aneuploidy was also present, as expected, in 4 of 33 AHF in the animals placed on CD + PHB. It was observed as well in 2 of 26 AHF of rats given CD but in none of the 20 AHF fed CS + PHB. These data indicate that CD (which acts as both initiator and promoter) may be responsible for the appearance of aneuploidy. A general model, based on these results and the clonality of each individual focus, is proposed for the development of cells through the preneoplastic stage.
Carcinogenesis, 1990
The mechanism(s) by which a diet devoid of choline (CD) induces hepatocellular carcinomas in rats... more The mechanism(s) by which a diet devoid of choline (CD) induces hepatocellular carcinomas in rats remains unknown. Although animals fed this diet develop nuclear lipid peroxidation, suggesting oxidative DNA damage, there is no direct evidence that this occurs. In this study, 8-hydroxydeoxyguanosine (8-OHdG), a DNA adduct generated by reactive oxygen species, was analyzed in the liver of rats fed a CD diet and in controls receiving a choline-sufficient (CS) diet. After partial hepatectomy, the animals were injected with diethylnitrosamine (DEN, 50 mg/kg body wt) or with saline and fed a CD or CS diet for 24 weeks. While liver DNA from rats injected either with DEN or saline and fed a CS diet did not show detectable amounts of the nucleotide, those who were fed DEN/CD and saline/CD demonstrated similar, easily measurable levels of 8-OHdG. These results indicate that there is a positive association between the continuous administration of a CD diet and the production of 8-OHdG in liver DNA, and support the idea that oxidative DNA damage is involved in carcinogenesis by a CD diet.
Drug Delivery and Translational Research, Sep 28, 2018
This work aimed to synthesize a novel β-cyclodextrin derivative, itaconyl-β-cyclodextrin to evalu... more This work aimed to synthesize a novel β-cyclodextrin derivative, itaconyl-β-cyclodextrin to evaluate whether albendazole inclusion complexes with the new β-cyclodextrin derivative-improved albendazole dissolution efficiency and its anthelminthic activity. The new derivative was thoroughly evaluated and characterized, and an average degree of substitution of 1.4 per cyclodextrin molecule was observed. Albendazole:itaconyl-β-cyclodextrin complexes were prepared by spray drying procedures and investigated using phase solubility diagrams, dissolution efficiency, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared, scanning electronic microscopy, mass spectrometry, and nuclear magnetic resonance spectroscopy. Phase solubility diagrams and mass spectrometry studies showed that the inclusion complex was formed in an equimolar ratio. Stability constant values were 602 M −1 in water, and 149 M −1 in HCl 0.1 N. Nuclear magnetic resonance experiments of the inclusion complex showed correlation signals between the aromatic and propyl protons of albendazole and the itaconyl-βcyclodextrin inner protons. The studies indicated solid structure changes of albendazole included in itaconyl-β-cyclodextrin. The maximum drug release was reached at 15 min, and the inclusion complex solubility was 88-fold higher than that of the pure drug. The in vitro anthelmintic activity assay showed that the complex was significantly more effective than pure albendazole.
Aaps Pharmscitech, Nov 23, 2016
The oral route has notable advantages to administering dosage forms. One of the most important qu... more The oral route has notable advantages to administering dosage forms. One of the most important questions to solve is the poor solubility of most drugs which produces low bioavailability and delivery problems, a major challenge for the pharmaceutical industry. Albendazole is a benzimidazole carbamate extensively used in oral chemotherapy against intestinal parasites, due to its extended spectrum activity and low cost. Nevertheless, the main disadvantage is the poor bioavailability due to its very low solubility in water. The main objective of this study was to prepare microcrystal formulations by the bottom-up technology to increase albendazole dissolution rate, in order to enhance its antiparasitic activity. Thus, 20 novel microstructures based on chitosan, cellulose derivatives, and poloxamer as a surfactant were produced and characterized by their physicochemical properties and in vitro biological activity. To determine the significance of type and concentration of polymer, and presence or absence of surfactant in the crystals, the variables area under the curve, albendazole microcrystal solubility, and drug released (%) at 30 min were analyzed with a three-way ANOVA. This analysis indicated that the microcrystals made with hydroxyethylcellulose or chitosan appear to be the best options to optimize oral absorption of the active pharmaceutical ingredient. The in vitro evaluation of anthelmintic activity on adult forms of Trichinella spiralis identified system S10A as the most effective, of choice for testing therapeutic efficacy in vivo.
Open Journal of Veterinary Medicine, 2015
Trichinella spiralis (T. spiralis), which is a cosmopolitan nematode that infects humans among ot... more Trichinella spiralis (T. spiralis), which is a cosmopolitan nematode that infects humans among other species, presents a complex host-parasite relationship that hinders the development of tools to eradicate the parasitosis. The aim of this research was to analyze the host response during a primary infection with T. spiralis in five genetically different mouse lines of the CBi-IGE stock. Adult males from the CBi+, CBi−, CBi, CBi/L and CBi/C lines were infected with 1, 2 or 4 L1 larvae per g of body weight. In the chronic stage, the number of parasites per g of tissue (relative larval load, rLL) showed a significant host genotype-dose interaction, since it did not increase in the same way in the five genotypes. At the lowest dose, both CBi− and CBi/L mice were resistant while CBi+, CBi/C, and CBi were susceptible. At the highest dose, only CBi/L remained resistant, and CBi+ was the most susceptible. The reproductive capacity index of adult worms (RCI = rLL/infective dose) evinced only a genotype effect, allowing rating each line as resistant or susceptible regardless of dose. Animals receiving 2 L1 larvae were also sacrificed in the intestinal phase (6 and 13 days p-i) to determine the number of adult parasites (nAP) recovered in a small intestine segment, and female fecundity (Ff). No differences in nAP were observed among genotypes on day 6 p-i. nAP decreased between days 6 and 13 p-i, this reduction being different among genotypes and significant only in CBi/L and CBi/C. Ff decreased in CBi/L and CBi/C on day 13 p-i. At the time of infection, serum cytokine baseline values showed a Th1 orientation for genotype CBi/L (high IFN-γ and IL-2) * Corresponding author. and a Th2 for CBi+ (high IL-4 and IL-10).The variability in the response observed in this murine model suggests its potential usefulness to gain insight into the mechanisms that regulate hostparasite relationship.
1. Basic Life Sci. 1991;57:263-77. Genetic instability occurs sooner than expected: promotion, pr... more 1. Basic Life Sci. 1991;57:263-77. Genetic instability occurs sooner than expected: promotion, progression and clonality during hepatocarcinogenesis in the rat. Sudilovsky O, Hinrichsen LI, Hei TK, Whitacre CM, Wang JH, Kasturi S, Jiang SH, Cechner R, Miron S, Abdul-Karim F ...
Archiv für Tierzucht, Oct 10, 1999
The effect of disruptive selection for body conformation on body weight and length, tail length, ... more The effect of disruptive selection for body conformation on body weight and length, tail length, and femur weight and length at different stages of development (21, 42, 63, and 120 days of age) was analysed in four mouse lines of the CBi stock selected for (CBi+, CBi-) and against (CBi/L, CBi/C) the phenotypic correlation between body weight and tail length, and die unselected control line CBi. As expected, body weight and tail length distributed according to the selection criteria; rrunk length (whole body length minus tail length) behaved as body we lg ht at all ages. CBi/L had the highest femoral length (p<0.01), and CBi/C attained the highest femoral weight (p<0.01). CBi+ and CBi-, harmonically large or small, differed between them and from the control line in both variables (p<0.001). These findings further corroborate the proposal that bone mass is markedly affected by the skeleton function as support of soft tissues. The allometric analysis ofthe regression of femur weight on femur length suggests that, in this model, a) the demand posed by the selective pressure forced each genotype to find a unique Solution, b) this response is sex-dependent, and c) genetic determination ofthe parameters involved in this allometric relationship is, at least, partially independent.
Parasitology, Jul 7, 2021
Albendazole (ABZ) is an anthelmintic pharmaceutical commonly used in the treatment of nematode in... more Albendazole (ABZ) is an anthelmintic pharmaceutical commonly used in the treatment of nematode infections. It is a Class II drug poorly water-soluble, with very low bioavailability, a feature particularly limiting to treat the trichinellosis chronic phase. Microcrystals obtained by controlled precipitation using hydroxyethyl cellulose and chitosan have previously been shown to improve ABZ biopharmaceutical properties. This investigation aimed to test the systems' in vivo efficacy in the CBi-IGE murine model of Trichinella spiralis infection in the infection's different phases and parasite’ stages. Treatment in the enteral phase led to a 90% decrease in the larval muscle load, probably due to its effect on T. spiralis female fecundity. Both microcrystal systems given in the migratory phase halved muscle load in males, a response not observed in females. The chitosan-based microcrystals proved to be the best when administered in the chronic phase of the infection – an increased proportion of L1 dead larvae was found compared to controls, except in CBi+-treated females. Males and females from the highly susceptible CBi+ line presented a significantly different treatment response in this phase. In vivo efficacy depended on the host genotype and sex and was related to the parasite cycle stage in which the formulations were administered.
Parasitology, 2021
Albendazole (ABZ) is an anthelmintic pharmaceutical commonly used in the treatment of nematode in... more Albendazole (ABZ) is an anthelmintic pharmaceutical commonly used in the treatment of nematode infections. It is a Class II drug poorly water-soluble, with very low bioavailability, a feature particularly limiting to treat the trichinellosis chronic phase. Microcrystals obtained by controlled precipitation using hydroxyethyl cellulose and chitosan have previously been shown to improve ABZ biopharmaceutical properties. This investigation aimed to test the systems' in vivo efficacy in the CBi-IGE murine model of Trichinella spiralis infection in the infection's different phases and parasite’ stages. Treatment in the enteral phase led to a 90% decrease in the larval muscle load, probably due to its effect on T. spiralis female fecundity. Both microcrystal systems given in the migratory phase halved muscle load in males, a response not observed in females. The chitosan-based microcrystals proved to be the best when administered in the chronic phase of the infection – an increase...
AAPS PharmSciTech, 2020
Albendazole (ABZ), an anthelmintic compound widely used in the treatment of systemic nematode inf... more Albendazole (ABZ), an anthelmintic compound widely used in the treatment of systemic nematode infections, is included in the list of class II drugs based on the Biopharmaceutical Classification System. ABZ has limited effectiveness due to its poor water solubility and consequent low bioavailability. Bioavailability of novel ABZ microcrystals based on hydroxyethylcellulose (S4A) or chitosan (S10A) was studied in male and female mice of two inbred lines, from the murine CBi-IGE model of trichinellosis, differing in susceptibility to this parasitosis (line CBi/L, resistant; line CBi+, susceptible). ABZ microcrystals were administered orally, and albendazole sulfoxide (ABZSO) was quantified in plasma by high-performance liquid chromatography. Mice given the microcrystals showed a significant increase in maximum plasmatic concentration ( C max ) compared with those receiving pure ABZ ( P < 0.01). In both genotypes, males and females given S4A had higher C max than those receiving S10A ( P < 0.05). CBi/L showed a greater C max than CBi+ (significantly different only in females treated with S4A ( P = 0.001)). CBi/L females attained a higher C max than males ( P < 0.05). No sex effect was observed for this variable in CBi+ ( P > 0.05). The results of the pharmacokinetic analysis indicate that the microcrystalline formulations optimize ABZ bioavailability, both in males and females, S4A being the best system in CBi/L mice and S10A in CBi+. In summary, the microcrystals increased ABZ bioavailability, and under the conditions of this investigation, both host genotype and sex influenced the pharmacokinetic parameters measured.
Archives Animal Breeding, 1999
The effect of disruptive selection for body conformation on body weight and length, tail length, ... more The effect of disruptive selection for body conformation on body weight and length, tail length, and femur weight and length at different stages of development (21, 42, 63, and 120 days of age) was analysed in four mouse lines of the CBi stock selected for (CBi+, CBi-) and against (CBi/L, CBi/C) the phenotypic correlation between body weight and tail length, and die unselected control line CBi. As expected, body weight and tail length distributed according to the selection criteria; rrunk length (whole body length minus tail length) behaved as body we lg ht at all ages. CBi/L had the highest femoral length (p<0.01), and CBi/C attained the highest femoral weight (p<0.01). CBi+ and CBi-, harmonically large or small, differed between them and from the control line in both variables (p<0.001). These findings further corroborate the proposal that bone mass is markedly affected by the skeleton function as support of soft tissues. The allometric analysis ofthe regression of femur weight on femur length suggests that, in this model, a) the demand posed by the selective pressure forced each genotype to find a unique Solution, b) this response is sex-dependent, and c) genetic determination ofthe parameters involved in this allometric relationship is, at least, partially independent.
Drug delivery and translational research, Jan 28, 2018
This work aimed to synthesize a novel β-cyclodextrin derivative, itaconyl-β-cyclodextrin to evalu... more This work aimed to synthesize a novel β-cyclodextrin derivative, itaconyl-β-cyclodextrin to evaluate whether albendazole inclusion complexes with the new β-cyclodextrin derivative-improved albendazole dissolution efficiency and its anthelminthic activity. The new derivative was thoroughly evaluated and characterized, and an average degree of substitution of 1.4 per cyclodextrin molecule was observed. Albendazole:itaconyl-β-cyclodextrin complexes were prepared by spray drying procedures and investigated using phase solubility diagrams, dissolution efficiency, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared, scanning electronic microscopy, mass spectrometry, and nuclear magnetic resonance spectroscopy. Phase solubility diagrams and mass spectrometry studies showed that the inclusion complex was formed in an equimolar ratio. Stability constant values were 602 M in water, and 149 M in HCl 0.1 N. Nuclear magnetic resonance experiments of the inclusion com...
Open Journal of Veterinary Medicine, 2015
Trichinella spiralis (T. spiralis), which is a cosmopolitan nematode that infects humans among ot... more Trichinella spiralis (T. spiralis), which is a cosmopolitan nematode that infects humans among other species, presents a complex host-parasite relationship that hinders the development of tools to eradicate the parasitosis. The aim of this research was to analyze the host response during a primary infection with T. spiralis in five genetically different mouse lines of the CBi-IGE stock. Adult males from the CBi+, CBi−, CBi, CBi/L and CBi/C lines were infected with 1, 2 or 4 L1 larvae per g of body weight. In the chronic stage, the number of parasites per g of tissue (relative larval load, rLL) showed a significant host genotype-dose interaction, since it did not increase in the same way in the five genotypes. At the lowest dose, both CBi− and CBi/L mice were resistant while CBi+, CBi/C, and CBi were susceptible. At the highest dose, only CBi/L remained resistant, and CBi+ was the most susceptible. The reproductive capacity index of adult worms (RCI = rLL/infective dose) evinced only a genotype effect, allowing rating each line as resistant or susceptible regardless of dose. Animals receiving 2 L1 larvae were also sacrificed in the intestinal phase (6 and 13 days p-i) to determine the number of adult parasites (nAP) recovered in a small intestine segment, and female fecundity (Ff). No differences in nAP were observed among genotypes on day 6 p-i. nAP decreased between days 6 and 13 p-i, this reduction being different among genotypes and significant only in CBi/L and CBi/C. Ff decreased in CBi/L and CBi/C on day 13 p-i. At the time of infection, serum cytokine baseline values showed a Th1 orientation for genotype CBi/L (high IFN-γ and IL-2) * Corresponding author. and a Th2 for CBi+ (high IL-4 and IL-10).The variability in the response observed in this murine model suggests its potential usefulness to gain insight into the mechanisms that regulate hostparasite relationship.
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Papers by Lucila Hinrichsen