griseofulvin and Disease-Models--Animal

There are many chemicals that affect porphyrin metabolism. Certain of these can be used to induce experimental porphyria in animal. Human porphyrias are relatively uncommon, thus preventing their adequate examination in human patients. But using experimental animals, the pathogenesis, biochemical pathways and treatment of these diseases may be studied. In this paper, we conducted our own investigations on griseofulvin induced protoporphyria, and also reviewed experimental porphyrias induced by hexachlorobenzen and polychlorinated biphenyls.

Topics: Animals; Disease Models, Animal; Griseofulvin; Hexachlorobenzene; Humans; Mice; Polychlorinated Biphenyls; Porphyrias

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Erythropoietic protoporphyria (EPP) is a disease associated with ferrochelatase deficiency and characterized by the accumulation of protoporphyrin IX (PROTO IX) in erythrocytes, liver, and skin. In some cases, a severe hepatic failure and cholestasis were observed. Griseofulvin (Gris) develops an experimental EPP with hepatic manifestations in mice such as PROTO IX accumulation followed by cellular damage as wells as necrotic and inflammatory processes. The antioxidant defense system was also altered. The aim was to evaluate the possible protective effect of different antioxidant compounds: trolox (Tx), ascorbic acid (Asc), the combination Tx and Asc, melatonin (Mel), and the polyphenols: ellagic acid, quercetin, chlorogenic acid, caffeic acid, gallic acid, and ferulic acid on liver damage and oxidative stress markers in a mouse model of EPP. Coadministration of Gris with Tx, Asc, and its combination, or Mel mainly affected heme biosynthetic pathway, resulting in a decrease in ALA-S activity which was increased by Gris, while the tested polyphenols exerted a protective effect on oxidative stress, decreasing lipid peroxidation and the activity of some antioxidant enzymes. In conclusion, antioxidant compounds can only protect partially against the liver damage induced by Gris, reducing oxidative stress or acting on heme regulation.

Topics: Animals; Antifungal Agents; Antioxidants; Biomarkers; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Glutathione; Griseofulvin; Heme; Male; Mice; Superoxide Dismutase

It has been demonstrated that the function of mammalian clock gene transcripts is controlled by the binding of heme in vitro. To examine the effects of heme on biological rhythms in vivo, we measured locomotor activity (LA) and core body temperature (T(b)) in a mouse model of porphyria with impaired heme biosynthesis by feeding mice a griseofulvin (GF)-containing diet. Mice fed with a 2.0% GF-containing diet (GF2.0) transiently exhibited phase advance or phase advance-like phenomenon by 1-3 h in terms of the biological rhythms of T(b) or LA, respectively (both, P < 0.05) while mice were kept under conditions of a light/dark cycle (12 h:12 h). We also observed a transient, ~0.3 h shortening of the period of circadian T(b) rhythms in mice kept under conditions of constant darkness (P < 0.01). Interestingly, the observed duration of abnormal circadian rhythms in GF2.0 mice lasted between 1 and 3 wk after the onset of GF ingestion; this finding correlated well with the extent of impairment of heme biosynthesis. When we examined the effects of therapeutic agents for acute porphyria, heme, and hypertonic glucose on the pathological status of GF2.0 mice, it was found that the intraperitoneal administration of heme (10 mg·kg(-1)·day(-1)) or glucose (9 g·kg(-1)·day(-1)) for 7 days partially reversed (50%) increases in urinary δ-aminolevulinic acids levels associated with acute porphyria. Treatment with heme, but not with glucose, suppressed the phase advance (-like phenomenon) in the diurnal rhythms (P < 0.05) and restored the decrease of heme (P < 0.01) in GF2.0 mice. These results suggest that impairments of heme biosynthesis, in particular a decrease in heme, may affect phase and period of circadian rhythms in animals.

Topics: Animals; Body Temperature; Circadian Rhythm; Disease Models, Animal; Glucose; Griseofulvin; Heme; Locomotion; Male; Mice; Mice, Inbred ICR; Porphyrias

The present study is aimed at the encapsulation of griseofulvin in the deformable membrane vesicles (DMVs) for dermal delivery. Presently, griseofulvin is available only in conventional oral dosage forms that suffer from the issues of poor and highly variable bioavailability, numerous systemic side effects and long duration of treatment. Multi-lamellar drug-loaded DMVs of griseofulvin (Indian Patent Application 208/DEL/2009) were prepared by thin-film hydration method and were optimized for type and concentration of edge activator (EA). The optimized formulation was evaluated for vesicular shape, size, drug entrapment efficiency, drug content, pH, stability, spreadability, ex vivo skin permeation, dermatokinetics, skin sensitivity, in vitro antifungal assay and in vivo antifungal activity against Microsporum canis using guinea pig model for dermatophytosis. The optimized DMVs illustrated remarkably higher drug permeation and skin retention when compared with liposomes. A complete clinical and mycological cure was observed in animals treated with topical griseofulvin formulation in 10 days. The formulation was observed to be non-sensitizing, histopathologically safe, and stable at 5±3 °C, 25±2 °C and 40±2 °C for a period of six months. The results indicated that the topical formulation of DMVs of griseofulvin could be utilized as an alternative to reduce the encumbrance of conventional oral formulations.

Topics: Administration, Topical; Animals; Antifungal Agents; Disease Models, Animal; Drug Carriers; Drug Compounding; Drug Stability; Griseofulvin; Guinea Pigs; Hexoses; In Vitro Techniques; Male; Mice; Microsporum; Paraffin; Skin; Skin Absorption; Tinea; Treatment Outcome; Waxes

To evaluate the wound healing and antimicrobial activity of root extracts of Ixora coccinea (I. coccinea).. To investigate the wound healing efficacy of root extract of I. coccinea Linn, five groups of animals were divided each containing six animals. Two wound models including incision and excision wound models were used in this study. The parameters studied were tensile strength on incision wound model and in terms of wound contraction for excision wound model were compared with standard Nitrofurazone (NFZ) ointment (0.2% w/w). Six extracts (ethanol, aqueous, petroleum ether, benzene, chloroform and ethyl acetate) of I. coccinea were screened for in vitro growth inhibiting activity against different bacterial strains viz, Staphylococcus aureus, Bacillus pumilius, Enterococcus faecalis, Escherichia coli, Salmonella typhi and Pseudomonas aeruginosa and fungi Candida albicans and Aspergillus niger were compared with the standard drugs ciprofloxacin and chloramphenicol for antibacterial and griseofulvin for antifungal screening. The serial dilution and cup (or) well plate methods were used for the antimicrobial study and MIC was determined.. The ethanolic extract showed significant (P<0.001) wound healing activity when compared to standard drug NFZ with respect to normal control group. Amongst all, ethanolic extract showed highly significant antibacterial activity against all bacterial strains used in this study when compared to standard. The aqueous extract showed moderate significant inhibition against all bacterial strains when compared to standard. All the extracts were shown negligible activity against the fungal strains used in this study.. The ethanolic root extract of I. coccinea showed pronounced wound healing and antibacterial activity. The probable reason to heal the wound was that the external application of the extract prevented the microbes to invade through the wound thus the protection of wound occurs against the infection of the various organisms.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Bacterial Infections; Chloramphenicol; Ciprofloxacin; Disease Models, Animal; Griseofulvin; Mycoses; Phytotherapy; Plant Extracts; Plant Roots; Rats; Rats, Wistar; Rubiaceae; Tensile Strength; Wound Healing

The study aimed to predict effective human jejunal permeability (P(eff)) using a biophysical model based on parametrized paracellular, aqueous boundary layer, and transcellular permeabilities, and the villus-fold surface area expansion factor (k(VF)). Published human jejunal data (119 P(eff), 53 compounds) were analyzed by a regression procedure incorporating a dual-pore size paracellular model. Transcellular permeability, scaled by k(VF), was equated to that of Caco-2 at pH 6.5. The biophysical model predicted human jejunal permeability data within the experimental uncertainty. This investigation revealed several surprising predictions: (i) many molecules permeate predominantly (but not exclusively) by the paracellular route, (ii) the aqueous boundary layer thickness in the intestinal perfusion experiments is larger than expected, (iii) the mucosal surface area in awake humans is apparently nearly entirely accessible to drug absorption, and (iv) the relative "leakiness" of the human jejunum is not so different from that observed in a number of published Caco-2 studies.

Topics: Animals; Disease Models, Animal; Dogs; Humans; Jejunal Diseases; Kidney Diseases; Models, Biological; Permeability; Porosity; Regression Analysis

Erythropoietic Protoporphyria (EPP) is a disease associated with ferrochelatase deficiency, which produces accumulation of protoporphyrin IX (PROTO IX) in erythrocytes, liver and skin. In some cases, a severe hepatic failure and cholestasis was observed. Griseofulvin (Gris) develops an experimental EPP with hepatic manifestations in animals. The aim of this work was to further characterize this model studying its effect on different metabolisms in mice Gris feeding (0-2.5%, 7 and 14 days). PROTO IX accumulation in liver, blood and feces, induction of ALA-S activity, and a low rate of Holo/Apo tryptophan pyrrolase activity was produced, indicating a reduction of free heme pool. The progressive liver injury was reflected by the aspect and the enlargement of liver and the induction of hepatic damage. Liver redox balance was altered due to porphyrin high concentrations; as a consequence, the antioxidant defense system was disrupted. Heme oxygenase was also induced, however, at higher concentrations of antifungal, the free heme pool would be so depleted that this enzyme would not be necessary. In conclusion, our model of Protoporphyria produced liver alterations similar to those found in EPP patients.

Topics: Animals; Antifungal Agents; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP3A; Disease Models, Animal; Griseofulvin; Heme; Heme Oxygenase (Decyclizing); Immunohistochemistry; Liver; Male; Mice; Oxidative Stress; Protoporphyria, Erythropoietic; Protoporphyrins; Tryptophan Oxygenase

Most patients with hepatic porphyria exhibit neuropsychiatric symptoms, including abdominal pain, peripheral neuropathy, confusion, insomnia and mental disturbances such as anxiety and depression. Although heme deficiency and accumulation of heme precursors are thought to be responsible for neuropsychiatric manifestations in patients with acute porphyria, the pathogenetic mechanisms remain poorly understood. In the present study, we observed psychiatric behaviors in mice with hepatic porphyria induced by the ingestion of a griseofulvin (GF)-containing diet over a period of 12 weeks. GF ingestion by the mice caused an accumulation of porphyrins in the feces and a decrease in heme in the liver; these effects were observed throughout the entire duration of the experiment, with maximum levels observed after circa 1 week of ingestion of this diet. In addition, the mice developed enlargement of the liver, hepatocyte injury, and cholestasis. Mice with hepatic porphyria manifested an anxiety-like behavior by the long-term treatment (over 5 weeks) in a GF-dose and duration dependent manner. The hepatic porphyria mice also manifested depression-like behaviors by the short-term treatment (3 weeks) of GF2.0, which was reversed by administration of anti-depressant, imipramine. In conclusion, this study for the first time demonstrated psychiatric manifestations in GF-induced hepatic porphyria mice. The present results suggest that model animals could be useful for elucidating the mechanisms underlying psychiatric manifestations in syndromes such as hepatic porphyria and hepatic encephalopathy that are associated with the impairment of hepatic function.

Topics: Animals; Anxiety; Behavior, Animal; Cytochrome P-450 Enzyme System; Depression; Disease Models, Animal; Enzymes; Feces; Griseofulvin; Heme; Liver; Male; Mice; Mice, Inbred ICR; Muscle, Skeletal; Porphyrias, Hepatic; Swimming

BALB/c Fech(m1Pas) mice have a mutated ferrochelatase gene resulting in protoporphyria that models the hepatic injury occurring sporadically in human erythropoietic protoporphyria. We used this mouse model to study the development of the injury and to compare the dysfunction of heme synthesis with hepatic gene expression of liver metabolism, oxidative stress, and cellular injury/inflammation. From an early age expression of total cytochrome P450 and many of its isoforms was significantly lower than in wild-type mice. However, despite massive accumulation of protoporphyrin in the liver, expression of the main genes controlling heme synthesis and catabolism (Alas1 and Hmox1, respectively) were only modestly affected even in the presence of the cytochrome P450-inducing CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. In contrast, in BALB/c mice exhibiting griseofulvin-induced hepatic protoporphyria with induction and destruction of cytochrome P450, both Alas1 and Hmox1 genes were markedly up-regulated. Other expression profiles in BALB/c Fech(m1Pas) mice identified roles for oxidative mechanisms in liver injury while modulated gene expression of hepatocyte transport proteins and cholesterol and bile acid synthesis illustrated the development of cholestasis. Subsequent inflammation and cirrhosis were also shown by the up-regulation of cytokine, cell cycling, and procollagen genes. Thus, gene expression profiles studied in Fech(m1Pas) mice may provide candidates for human polymorphisms that explain the sporadic hepatic consequences of erythropoietic protoporphyria.

Topics: Aging; Animals; Antifungal Agents; Cholestasis; Disease Models, Animal; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Griseofulvin; Heme; Hemeproteins; Immunoblotting; Liver; Male; Mice; Protoporphyria, Erythropoietic; Protoporphyrins; Reverse Transcriptase Polymerase Chain Reaction

Although oxygen radicals are thought to play a key role in the skin injury that is caused by protoporphyria, there is no direct evidence of generation of these radicals in vivo. This study measured the generation of oxygen radicals caused by visible light non-invasively in the skin of griseofulvin-induced protoporphyria model mice, using an in vivo electron spin resonance spectrometer equipped with a surface-coil-type resonator that could detect radicals within about 0.5 mm of the skin surface. A durable nitroxyl radical was administered intravenously as a probe. Light irradiation enhanced the decay of the nitroxyl signal in griseofulvin-treated mice, whereas light irradiation did not enhance the signal decay in control mice. The enhanced signal decay was completely suppressed by intravenous administration of hydroxyl radical scavengers, superoxide dismutase or catalase, or the intraperitoneal administration of desferrioxamine. The enhanced signal decay with illumination was reversible, and quickly responded to turning the light on and off. These observations suggest that the hydroxyl radical is generated via an iron-catalyzed reaction in the skin. This paper demonstrates, for the first time, the specific generation of oxygen radicals in response to light irradiation of the skin of protoporphyria model mice.

Topics: Animals; Antifungal Agents; Catalase; Deferoxamine; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Griseofulvin; Hydroxyl Radical; Iron Chelating Agents; Light; Male; Mice; Porphyria, Hepatoerythropoietic; Reactive Oxygen Species; Skin; Superoxide Dismutase

Topics: Administration, Oral; Animals; Antifungal Agents; Dermatomycoses; Disease Models, Animal; Female; Fluconazole; Griseofulvin; Guinea Pigs; Tinea; Treatment Outcome

Reduced activity of ferrochelatase in erythropoietic protoporphyria (EPP) results in protoporphyrin (PP) accumulation in erythrocytes and liver. Liver disease may occur in patients with EPP, some of whom develop progressive liver failure that necessitates transplantation. We investigated the mechanisms underlying EPP-associated liver disease in a mouse model of EPP.. Liver histology, indicators of lipid peroxidation, plasma parameters of liver function, and bile composition were studied in mice homozygous (fch/fch) for a point mutation in the ferrochelatase gene and in heterozygous (fch/+) and wild-type (+/+) mice.. Microscopic examination showed bile duct proliferation and biliary fibrosis with portoportal bridging in fch/fch mice. PP content was 130-fold increased, and thiobarbituric acid-reactive substances (+30%) and conjugated dienes (+75%) were slightly higher in fch/fch than in fch/+ and +/+ livers. Levels of hepatic thiols (-12%) and iron (-52%) were reduced in fch/fch livers. Liver enzymes and plasma bilirubin were markedly increased in the homozygotes. Plasma bile salt levels were 80 times higher in fch/fch than in fch/+ and +/+ mice, probably related to the absence of the Na(+)-taurocholate cotransporting protein (Ntcp) in fch/fch liver. Paradoxically, bile flow was not impaired and biliary bile salt secretion was 4 times higher in fch/fch mice than in controls. Up-regulation of the intestinal Na(+)-dependent bile salt transport system in fch/fch mice may enhance efficiency of bile salt reabsorption. The bile salt/lipid ratio and PP content of fch/fch bile were increased 2-fold and 85-fold, respectively, compared with +/+, whereas biliary glutathione was reduced by 90%. Similar effects on bile formation were caused by griseofulvin-induced inhibition of ferrochelatase activity in control mice.. Bile formation is strongly affected in mice with impaired ferrochelatase activity. Rather than peroxidative processes, formation of cytotoxic bile with high concentrations of bile salts and PP may cause biliary fibrosis in fch/fch mice by damaging bile duct epithelium.

Topics: Animals; Bile; Bile Acids and Salts; Biliary Tract; Blotting, Northern; Blotting, Western; Disease Models, Animal; Female; Ferrochelatase; Fibrosis; Griseofulvin; Immunohistochemistry; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred BALB C; Porphyria, Hepatoerythropoietic; Protoporphyria, Erythropoietic

Chronic griseofulvin (GF) feeding induces preneoplastic foci followed by hepatocellular carcinoma in the mouse liver. Our previous study suggested that GF-induced hepatocellular proliferation had a different mechanism from that of peroxisome proliferator (PP)-induced direct hyperplasia. The GF-induced hepatocellular proliferation was mediated through activation of immediate early genes such as Fos, Jun, Myc, and NFKB. In contrast, PP-induced direct hyperplasia does not involve activation of any of these immediate early genes. It has been shown that nuclear hormone receptors including peroxisome proliferator activated receptors (PPARs) and retinoid x receptors (RXRs) play important roles in mediating the pleiotropic effects of PPs. To examine the possible roles of PPARs and RXRs during non-PP-induced hepatocellular proliferation and the interaction between PP and non-PP-induced proliferation, we have studied the expression of the PPAR and RXR genes in the GF model using northern blot hybridizations and gel retardation assays. The data showed that the expression of PPARalpha and RXRalpha genes was down-regulated in the livers containing preneoplastic nodules and in the liver tumors induced by GF. The mRNA down-regulation was accompanied by a decrease in the amount of nuclear protein-bound to peroxisome proliferator and retinoic acid responsive elements. Down-regulation was also associated with the suppressed expression of the PPARalpha/RXRalpha target genes (i.e., acyl-Co oxidase and cytochrome P450 4A1) and the catalase gene. The RXR-gamma gene was also down-regulated, but the RARalpha, beta, and gamma and PPARbeta and gamma genes were up-regulated. These results indicated that the hepatocarcinogenesis induced by GF is accompanied by suppression of the PPARalpha/RXRalpha-mediated direct hyperplasia pathway. The differential expression of these nuclear hormone receptors reveals a new aspect for understanding the individual roles and intercommunication of PPAR, RXR, and RAR isoforms in the liver.

Topics: Acyl-CoA Oxidase; Animals; Carcinoma, Hepatocellular; Catalase; Cell Nucleus; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Genes, fos; Griseofulvin; Hyperplasia; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C3H; Mixed Function Oxygenases; NF-kappa B; Oxidoreductases; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Retinoid X Receptors; Transcription Factor AP-1; Transcription Factors

Photosensitization of choriocapillary endothelium with blood-borne photosensitizers, such as protoporphyrin IX, has been proposed as a mechanism for the choriocapillary sclerosis and Bruch's membrane deposits seen in age-related macular degeneration. Utilizing a mouse model of protoporphyria with approximately a 10-fold increase in protoporphyrin IX level and exposure to blue light (14 microW/cm2; bandwidth, 390 to 430 nm), a time- and light-dependent increase in choriocapillary and sub-retinal pigment epithelium basal laminar-like deposits could be demonstrated at 7 months by transmission electron microscopy. Thickening of the choriocapillary endothelial basement membrane with a homogeneous electron-dense material was first noted in protoporphyric mice exposed to blue light for 13 weeks. At 28 weeks the experimental animals exhibited a thick band of homogeneous deposits at the level of the choriocapillary basement membrane and electron-dense fibrillogranular deposits of varying sizes along the inner aspect of Bruch's membrane, with fibrils measuring up to 16 nm, with a periodicity of 13 nm. These deposits contributed to an overall thickening of Bruch's membrane with narrowing of the choriocapillaris. The morphologic appearance and localization of these deposits within Bruch's membrane of this animal model are similar to previously described deposits noted in the aging Bruch's membrane prior to the development of age-related macular degeneration.

Topics: Animals; Bruch Membrane; Capillaries; Choroid; Disease Models, Animal; Extracellular Matrix; Griseofulvin; Light; Macular Degeneration; Mice; Mice, Inbred BALB C; Porphyria, Hepatoerythropoietic; Protoporphyrins

In nude mice grieofulvin given by intraperitoneal injections produces a severe porphyric state within 1 week. Compared with peroral administration of griseofulvin to produce experimental porphyria, this model is much more efficient and can be more easily controlled.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chromatography, Liquid; Disease Models, Animal; Erythropoiesis; Griseofulvin; Injections, Intraperitoneal; Male; Mice; Mice, Nude; Porphyrias; Porphyrins; Protoporphyrins; Skin Diseases

Acute cutaneous photosensitivity is a major manifestation of certain forms of human porphyria and also occurs in patients treated with hematoporphyrin derivative (HpD) photoradiation for the diagnosis and treatment of malignant tumors. In this study a quantitative animal model useful for in vivo studies of acute porphyrin photosensitization in cutaneous tissue was developed. C3H mice injected with HpD and irradiated 6 h later with 405 nm energy developed a 40-90% increase in ear thickness which was present immediately after irradiation and persisted for at least 24 h. No ear swelling occurred in animals receiving 405 nm radiation alone or HpD alone. Histologically, this photosensitivity reaction was manifest as edema, vascular dilatation, and mast cell degranulation immediately after irradiation followed by an influx of polymorphonuclear leukocytes and epidermal necrosis 24 h later. Tissue injury evoked by HpD and light was accompanied by extravasation of intravenously administered 125I-labeled albumin in the irradiated ears, indicating that photosensitization was accompanied by transudation of serum into the site of tissue injury. An in vivo correlation of this approach was verified by detection of measurable increase in ear thickness in irradiated mice rendered porphyric by the ingestion of a griseofulvin-containing diet. The mouse ear swelling model offers a useful system with which to study acute porphyrin photosensitization in the skin, and may lead to important new insights into the pathogenesis and prevention of this form of phototoxicity.

Topics: Animals; Diet; Disease Models, Animal; Ear; Female; Griseofulvin; Hematoporphyrins; Hypersensitivity, Immediate; Mice; Mice, Inbred C3H; Photosensitivity Disorders; Porphyrins; Skin

A Trichophyton mentagrophytes infection of guinea pigs induced by an occlusive procedure is described. The method of evaluation permits comparison of efficacy of antifungal agents which are not tested simultaneously. Activity was demonstrated following topical application of clotrimazole, miconazole, tolnaftate or griseofulvin and oral administration of griseofulvin. Oral ketoconazole had little effect in this dermatophyte model.

Topics: Animals; Antifungal Agents; Clotrimazole; Disease Models, Animal; Female; Griseofulvin; Guinea Pigs; Ketoconazole; Microbial Sensitivity Tests; Time Factors; Tinea

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Griseofulvin; Liver; Mice; Porphyrias; Porphyrins

Short-term effects of cholic acid ingestion on hepatic accumulation, fecal excretion, and blood levels of protoporphyrin were studied in vivo in griseofulvin-induced protoporphyric mice. Experimental mice that received feed with 2% griseofulvin and 0.5% cholic acid were compared with control mice that received feed with 2% griseofulvin for 4 wk. Five mice from each group were assessed each week for liver and blood porphyrin levels. Fecal protoporphyrin was compared weekly in the total pooled output of each population. Mean protoporphyrin levels were significantly lower for liver (P less than 0.0001), erythrocytes (P less than 0.05), and plasma (P less than 0.05), and higher for feces (P less than 0.001) for the mice that were fed cholic acid. Microscopic protoporphyrin deposits, inflammation, necrosis, and dysplasia were more severe in livers of control mice. A second experimental design compared four regimens in the feed given to all mice after 1-wk induction with 2% griseofulvin: (a) 0.5% cholic acid, (b) no adulterant, (c) 2% griseofulvin and 0.5% cholic acid, and (d) 2% griseofulvin. No difference in protoporphyrin removal from livers of mice in groups 1 and 2 was observed after 1 and 2 wk of these regimens. The apparent reduction in hepatic protoporphyrin content in mice of group 3 as compared with group 4 at weeks 2 and 3 was not significant at P less than 0.05. These data suggest that in selected circumstances, hepatic protoporphyrin secretion may be enhanced in protoporphyric disease states by bile salt supplementation.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cholic Acids; Disease Models, Animal; Feces; Female; Griseofulvin; Humans; Liver; Liver Diseases; Mice; Porphyrias; Porphyrins; Protoporphyrins

Topics: Animals; Chick Embryo; Crystallography; Culture Techniques; Cytoplasmic Granules; Disease Models, Animal; Glucose-6-Phosphatase; Griseofulvin; Liver; Mice; Porphyrias; Protoporphyrins

Albino mice were made protoporphyric with griseofulvin according to an established procedure. Photosensitivity flares were elicited once a week throughout a 10-month period, using black light as a source for 410 nm radiation and the flares were monitored by the intravenous injection of vascular tracers and by light and electron microscopy. Each irradiation led to a selective destruction of the endothelial cells of superficial capillaries which was followed by massive vascular leakage. The basal lamina remained largely intact, providing the scaffold for regenerating endothelial cells which deposited new basal lamina material at their periphery. Subsequent exposures to 410 nm radiation reproduced the endothelial damage and subsequent basal lamina formation; multiple irradiations thus resulted in excessive, concentric, tubelike basal lamina deposits around dermal vessels which light microscopically appeared as PAS-positive hyaline material and clinically gave the skin a thickened, waxy appearance. This model thus reproduced the skin of erythropoietic protoporphyria clinically, microscopically, and at the ultrastructural level.

Topics: Animals; Capillaries; Disease Models, Animal; Erythropoiesis; Female; Griseofulvin; Male; Mice; Photosensitivity Disorders; Porphyrias; Skin; Ultraviolet Rays

Experimental studies on the significance and origin of hepatocellular "alcoholic" hyalin (Mallory bodies) are hampered by the lack of a suitable animal model. In the present paper, the experimental production of hepatocellular hyalin identical with human alcoholic hyalin both light and electron microscopically in long term griseofulvin-treated mice is described. Moreover, the results conclusively disprove the specificity of Mallory alcoholic hyalin for alcohol-induced liver cell damage.

Topics: Alcoholism; Animals; Basement Membrane; Disease Models, Animal; Griseofulvin; Humans; Hyalin; Liver; Liver Cirrhosis, Experimental; Mice; Microscopy, Electron; Porphyrias; Time Factors

Outbred albino mice were rendered protoporphyric by a diet containing 2.5% (weight) of griseofulvin. There was a 5-fold increase in liver weight, hepatocellular degeneration and necrosis, cholestasis, ductular proliferation and cirrhosis. Liver protoporphyrin values were elevated and brown pigment granules were present in hepatocytes, Kupffer cells, and bile ducts. The granules showed red fluorescence, birefringence, and, at the ultrastructural level, consisted of aggregates of needle-like crystals. Crystals isolated from such livers showed solubility and absorption characteristics of protoporphyrin; in vitro recrystallization of protoporphyrin, extracted from protoporphyric mouse livers, yielded crystals identical with those observed in vivo, and commercial protoporphyrin exhibited similar morphologic features. The liver pathology and protoporphyrin crystals observed in these animals are identical to the liver pathology and crystals observed in the human disease, erythropoietic protoporphyria. In this mouse model, protoporphyrin crystals are intimately associated with hepatocellular injury and it appears that their accumulation within hepatocytes leads to hepatocellular destruction. A similar pathogenesis is postulated for the hepatic damage that occurs in some cases of erythropoietic protoporphyria.

Topics: Animals; Bile Ducts; Crystallization; Disease Models, Animal; Erythrocytes; Female; Griseofulvin; Humans; Kupffer Cells; Liver; Male; Mice; Microscopy, Electron; Organ Size; Porphyrias; Porphyrins; Protoporphyrins

Topics: Animals; Dermatomycoses; Disease Models, Animal; Griseofulvin; Rodent Diseases

Topics: Animals; Barbiturates; Disease Models, Animal; Griseofulvin; Mice; Porphyrias; Porphyrins

Topics: Animals; Antibody Formation; Antineoplastic Agents; Disease Models, Animal; Griseofulvin; Microsporum; Mycoses; Polysaccharides, Bacterial; Rabbits