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PubMed2003

Chemopreventive action of Boerhaavia diffusa on DMBA-induced skin carcinogenesis in mice.

Boerhaavia diffusa, Linn (Fam: Nyctagenaceae), is widely used for the treatment of Jaundice in various parts of India. In the present study, cancer chemopreventive property of B. diffusa was evaluated on 7,12-dimethyl benz(a)anthracene (DMBA) induced skin papillomagenesis in male Swiss albino mice (6-7 weeks old). A single topical application of 7,12-dimethyl benz(a)anthracene (50 microg/50 microl of acetone), followed 2 weeks later by repeated application of croton oil (1% in acetone three times a week) and continued till the end of the experiment exhibited 100% tumor incidence. In contrast, mice treated topically on the shaven backs with the Boerhaavia diffusa extract at either the peri-initiational phase (i.e. 7 days before and 7 days after the application of DMBA; Group II), post initiational phase (i.e. from the day of start of croton oil treatment and continued till the end of the experiment; Group III) or continuously at the peri- and post-initiational stages (i.e. 7 days prior to DMBA application and continued till the end of the experiment; Group IV), a significant reduction in the values of tumor incidence (Group II - 65%; Group III - 30%; Group IV - 25%), average number of tumors per tumor bearing mouse (Group II - 2.8; Group III - 0.75; Group IV - 0.35) and papillomas per papilloma bearing mouse (Group II - 3.1; Group III - 2.5; Group IV - 1.2) were observed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

N-ras mutation in ultraviolet radiation-induced murine skin cancers.

UV radiation is a potent DNA-damaging agent and a known inducer of skin cancer in experimental animals. To elucidate the role of oncogenes in UV carcinogenesis, we analyzed UV-induced murine skin tumors for mutations in codon 12, 13, or 61 of Ha-ras, Ki-ras, and N-ras oncogenes by amplification of genomic tumor DNAs by the polymerase chain reaction followed by dot-blot hybridization to synthetic oligonucleotide probes designed to detect single base-pair mutations. In addition to UV-induced C3H mouse skin tumors, we also analyzed skin tumors induced in the same strain of mice by other carcinogenic agents such as 8-methoxypsoralen + UVA, angelicin + UVA, dimethylbenz-[a]anthracene + UV + croton oil, and 4-nitroquinoline-1-oxide. We found that 4 of 20 UV-induced skin tumors contained either C----A or A----G base substitutions at N-ras codon 61. In addition, 2 of 5 melanomas possessed a G----A transition in N-ras codon 13 and an A----T transversion in N-ras codon 61, respectively. Interestingly, none of the 8-methoxypsoralen + UVA- or angelicin + UVA-induced tumors we analyzed contained mutations in any of the ras genes. However, 1 of 4 4-nitroquinoline-1-oxide-induced tumors exhibited a G----T transversion at Ki-ras codon 12, a potential site for formation of a 4-nitroquinoline-1-oxide adduct with a guanine residue. We also found that 2 nonmelanoma tumors induced by dimethylbenz[a]anthracene + UV + croton oil contained an A----T transversion at Ha-ras codon 61 position 2, which is characteristic of most dimethylbenz[a]anthracene-induced tumors. These results suggest that UV-induced C3H mouse tumors display mutations preferentially in the N-ras oncogene. Since most N-ras mutations in UV-induced tumors occurred opposite dipyrimidine sequences (T-T or C-C), one can infer that these sites are the targets for UV-induced mutation and transformation.

Animals↗
PubMed1991

[Anti-edema effects of some H1-receptor antagonists].

Experiments carried out with mice of CFLP strain have shown that antihistaminics (chloropyramine, cyproheptadine and dimethindene maleate) significantly inhibit the extents of ear oedema induced by croton oil, dithranol or capsaicin. In rats of Wistar strain, oedema was induced in the hind paw by the subplantar injection of carrageenin, and simultaneously by the application of croton oil to the inner surface on the ear. Preliminary antihistamine treatment inhibited the development of both types of oedema, to statistically significant extent.

Animals↗
PubMed1989

A novel class of local antiinflammatory steroids. 2nd communication: pharmacological studies of methyl 11 beta,17 alpha,21- trihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate and methyl 11 beta,21-dihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate.

Two novel 16-substituted steroidal carboxylate esters derived from prednisolone, methyl 11 beta,17 alpha,21- trihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate (P16CM) and methyl 11 beta,21-dihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha- carboxylate (DeoxyP16CM) were evaluated for in vivo antiinflammatory and glucocorticoid activities. Results indicate that incorporation of a methoxycarbonyl group at the 16 position of prednisolone, as in P16CM, resulted in 5.5 times more local activity in the cotton pellet granuloma assay and 14 times more topical activity in the croton oil induced ear edema bioassay as compared with the parent compound prednisolone (P). The 17 alpha-dehydroxy analogue of P16CM (DeoxyP16CM) retained one-half the local activity of P in the cotton pellet granuloma bioassay and topical activity equal to P in the croton oil induced ear edema bioassay. Favorable dissociation of local from systemic effects is seen for these steroidal 16-carboxylate esters since their systemic antiinflammatory activity was significantly less than that of P, and their suppression of plasma corticosterone and ACTH levels was minimal. While P16CM does exhibit some thymolytic activity, DeoxyP16CM is essentially devoid of thymus atrophogenic effects at equiactive doses. Thus, these compounds may represent safer topical therapeutic agents.

Administration, Topical↗
PubMed1977

Cholinesterase activity in rat liver and serum during experimentally induced inflammation.

Cholinesterase activity of albino rats with acute local oedematous inflammation induced by turpentine, croton oil or Freund's adjuvant was elevated in the liver homogenate but decreased in the serum. Aprotinin administration prevented the decrease of serum activity. In the oedema fluid of rats treated with croton oil an enzyme with cholinester splitting activity was detected and it was shown to be identical with serum cholinesterase (EC 3. 1. 1. 8.).

Animals↗
PubMed1984

Cocarcinogens of the tumour-promoter type as potential risk factors of cancer in man. A first complete experimental analysis of an etiological model situation and some of its consequences.

The black and Creole population of the Caribbean island of Curaçao (Netherlands Antilles) is burdened by an exceedingly high rate of oesophageal cancer. As a part of the local diet, the fresh green leaves of the aromatic bush Croton flavens L., known locally as 'welensali', are used to prepare a 'bush tea' drunk commonly as a beverage. Additional habitual uses of the leaves and of other parts of the plant are widespread. Investigations of soluble extracts of roots and leaves of welensali and of welensali tea revealed the presence of a multitude of irritant 'welensali factors', of which there are essentially two activity types, F and F'. F-types exhibit strong initiation (or tumour)-promoting activity on the back skin of the mouse, qualitatively and quantitatively comparable with that of the chemically related and well established promoter 12-O-tetradecanoyl-phorbol-13-acetate. F'-types are less active than the corresponding F-types, yet they are 'cryptic promoters' operationally. F- and F'-types are, respectively, diterpene di- and triesters, with polyfunctional tigliane structures, e.g., welensali factor F1. Together, they comprise a minimum content of 0.32 and 0.04% in roots and fresh green leaves, respectively. Welensali tea contains two mixtures of F- and of F'-types, each comprising three welensali factors, irritant and promoting in mouse skin. The estimated total minimum content of welensali factors per cup of tea is 1.6 micrograms/L. The estimated content of welensali factors type F in one cup of welensali tea, (the preparation of Croton flavens most frequently consumed on Curaçao) is equivalent to more than 10 times the irritant dose 50 of the typical welensali promoter F1 on the mouse ear. Welensali factors type F' contained in one cup are approximately equivalent to the irritant dose 50 of the typical 'cryptic' welensali promoter F1-20-decanoate. Therefore, the overall exposure of persons at risk on Curaçao exceeds that expected to maintain chronic irritation in the human oesophagus, which is considered an important element of initiation/promotion. After completion of chemical analyses, on the basis of epidemiological hints derived from the local situation, experimental evidence for the involvement in cancer associated with consumption of this plant also of putative initiators of the polycyclic aromatic hydrocarbon type is presented. Thus, for the first time in an epidemiologically established dietary cancer, chronic exposure to well-defined cocarcinogens of the promoter type is shown most likely to represent the principal carcinogenic risk involved ('cocarcinogen hypothesis').(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Lymphocyte reactivity in normal and malignant cell proliferation against a phylogenetically conserved antigen in fetal extracts.

Lymphocyte reactivity to 3-M KCl extracts from fetuses of different species of origin was shown by the macrophage electrophoretic mobility (MEMB) and/or the leukocyte migration inhibition tests in tumor-bearing mice and humans. In chemical carcinogenesis, reactivity was detectable before tumors developed. Six weeks after sc injection of 1,000 micrograms benzo[a]pyrene [(BP) CAS: 50-32-8] into XVII/Bln mice, the MEMB test became positive. The latent period was 15 weeks after 1.0 micrograms BP, indicating a dose-response relationship of the phenomenon. Painting of mouse skin with 7,12-dimethylbenz[a]anthracene [(DMBA) CAS: 57-97-6], croton oil (CAS: 8001-28-3), or benzene (CAS: 71-43-2) had the same sensitizing effect as BP. In contrast to the strong carcinogens BP and DMBA that caused lymphocyte reactivity to persist until tumors developed, benzene and the promoter croton oil induced only a transient effect. Termination of treatment abolished reactivity within 12 weeks. Lymphocyte reactivity to fetal extract in normal cell proliferation was evident from the fact that two-thirds-hepatectomized rats and BCG-treated mice became MEMB-positive. In hepatectomized rats the effect was reversible according to the completion of liver regeneration. Lymphocytes from tumor-bearing mice reacted with mouse and human fetal extract as well as with extracts from different developmental stages of frogs and fish. Fetal extracts were assumed to contain a phylogenetically conserved antigen.

Animals↗
PubMed1982

Isolation and characterization of C-reactive protein and serum amyloid P component in the rat.

C-reactive protein (RP) and serum amyloid P component (SAP) have been identified for the first time in rat serum and isolated by calcium-dependent affinity chromatography. Rat CRP closely resembled human CRP in its amino acid composition, in having five subunits per molecule and in its electron microscopic appearance as a pentameric annular disc. It differed, however, from all other mammalian CRP's characterised hitherto in being a glycoprotein bearing a single complex oligosaccharide on each polypeptide subunit. Furthermore one pair of tis subunits per molecule was linked by a interchain disulphide bridges whereas in other animals the subunits of both CRP and SAP are all non-covalently associated. The serum concentration of CRP in normal healthy laboratory rats and in specific pathogen-free rats was 300-600 micrograms/ml which is much greater than has been described in any other species and exceeds even maximal acute phase levels of CRP in man. Following injections of casein or croton oil, serum CRP levels rose to a maximum of about 900 micrograms/ml. Rat CRP bound to pneumococcal C-polysaccharide (CPS( but, in marked contrast to the behaviour of CRP from man, rabbit and marine teleost fish, it did not precipitate with CPS solutions, agglutinate CPS-coated sheep erythrocytes or initiate complement activation. Rat SAP, like SAP of other species, was a glycoprotein but unlike them it was composed only of a single pentameric disc not two such discs interacting face-to-face. The normal level of SAP in rat serum was 20-50 micrograms/ml, very similar to the levels seen in man, and it did not behave as an acute phase reactant in response to casein or croton-oil injections. In this respect it resembled human SAP but differed from murine SAP which is a major acute phase reactant.

Amino Acids↗
PubMed1980

[Anti-inflammatory activity of a topical glucocorticoid, fludroxycortide tape in experimental animals (author's transl)].

Fludroxycortide tape is a thin plastic tape which contains a synthetic glucocorticoid, fludroxycortide of 4 microgram/cm2. fludroxycortide tape with a topical application of 1 cm2 inhibited significantly contact hypersensitivities to oxazolone and picryl chloride in the ear skin of mice and PCA caused by IgE-like antibodies in the depilated abdominal skin of rats. Topical application of 1 to 4 cm2 of fludroxycortide tape produced a significant inhibition against histamine-induced vascular permeability, skin edema induced by intradermal injection of carrageenin into the depilated back and ear edema induced by topical application of croton oil in rats. Topical to oxazolone in dose-dependent manner, and had no thymolytic action, while in a dose of 100 microgram/ear, thymus atrophy occurred. Ear edema induced by croton oil was markedly inhibited by topical application of fludroxycortide (0.4 microgram/ear). Thus, fludorxycortide tape has topical anti-inflammatory activity against both allergic and non-allergic inflammation in mice and rats, and the topical anti-inflammatory activity of fludroxycortide appears to be favourably dissociated from its thymolytic action.

Administration, Topical↗
PubMed1994

[Effect of glycyrrhetinic acid on DNA damage and unscheduled DNA synthesis induced by benzo (a) pyrene].

Glycyrrhetinic acid (GA) is an active component of Glycyrrhiza uralensis Fisch. In this study, the effects of glycyrrhetinic acid on DNA damage and unscheduled DNA synthesis induced by benzo (alpha) pyrene were studied. Mouse ear edema was visible obviously at the 6th h after topical application of single dose croton oil. A topical application of croton oil on the back of ICR mice for 5 h, induced elevation of ornithine decarboxylase (ODC) activity in epidermal. The administration of glycyrrhetinic acid (50-200 mg.kg-1.d-1) to animals for 3 days exhibited 20%-80% inhibition of epidermal ornithine decarboxylase activity in a dose-dependent manner. Benzo (alpha) pyrene obviously caused DNA damage and unscheduled DNA synthesis mediated by S9 fraction in Chinese hamster lung cell line. Glycyrrhetinic acid was found to protect the rapid DNA damage induced by benzo (alpha) pyrene. At concentration of 5 micrograms.ml-1, glycyrrhetinic acid exhibited 70% protection. At 20 micrograms.ml-1, this action was more potent and approached to 80%. The addition of hydroxyurea 10 mmol.L-1 suppressed DNA replicative synthesis to 84.04% and benzo (alpha) pyrene stimulated the DNA repair synthesis (6-fold). Glycyrrhetinic acid (20 micrograms.ml-1 and 50 micrograms.ml-1 significantly decreased the stimulation of DNA repair synthesis induced by benzo (alpha) pyrene. This suggests that glycyrrhetinic acid has effective anti-initiating and anti-promoting activities and could be used for cancer chemopreventive purpose.

Animals↗
PubMed1993

Inhibitory effects of propionyl-L-carnitine on plasma extravasation induced by irritants in rodents.

The effects of propionyl-L-carnitine (PLC) in various models of inflammation were studied in rats and mice. PLC (50-200 mg/kg i.p.) dose-dependently inhibited the granuloma pouch induced by croton oil in rats, but failed to inhibit either cotton pellet granuloma or carrageenin-induced paw oedema and peritonitis. PLC (100 mg/kg i.p.) significantly reduced mouse ear oedema induced by croton oil, tetradecanoylphorbol acetate and arachidonic acid; in these models, PLC concomitantly reduced plasma extravasation, as evaluated by the leakage of Evans blue. In all the tested models, L-carnitine and acetyl-L-carnitine were ineffective, suggesting a specific protective role of PLC in the vascular component of the inflammatory process.

Acetylcarnitine↗
PubMed1993

[Anti-edematous effects of cinnarizine].

Experiments carried out with male mice (28-32 g) of CFLP strain have shown that cinnarizine significantly inhibits the extents of ear oedema induced by croton oil or capsaicin. In rats of Wistar strain, oedema was induced in the hind paw by subplantar injection of carrageenin, and simultaneously by the application of croton oil to the inner surface on the ear. Preliminary cinnarizine treatment inhibited the development of both types of oedema, to statistically significant extent.

Animals↗
PubMed1996

Neutralization of IL-12 in vivo prevents induction of contact hypersensitivity and induces hapten-specific tolerance.

IL-12 is a heterodimeric cytokine with a powerful positive regulatory influence on the development of Th1 cell-mediated immune responses. Th1 cells are critically involved in contact hypersensitivity (CHS), so we were interested in studying whether IL-12 is of relevance in the induction phase of CHS. BALB/c mice were sensitized by epicutaneous application of 0.5% 2,4-dinitrofluorobenzene (DNFB) on the abdomen, draining lymph nodes obtained at various time points thereafter. RNA was extracted, and PCR analysis was performed using primers specific for the IL-12 subunits p35 and p40. Although p35 was constitutively expressed and not affected by hapten application, p40 transcripts were found to be enhanced in lymph nodes obtained between 12 and 24 h after sensitization. To study whether IL-12 is functionally relevant for the induction of CHS, an mAb directed against recombinant murine IL-12 was injected i.p. 3 and 24 h before sensitization. Challenge was performed 5 days later by painting the left ear with 0.3% DNFB. Whereas mice injected with sodium chloride or an isotype control Ab responded with a normal ear swelling after challenge with DNFB, mice treated with anti-IL-12 Ab showed a significantly reduced ear swelling response. To study whether injection of the IL-12 Ab causes transient nonresponsiveness or tolerance, resensitization was performed after a resting period of 14 days. Groups of mice initially treated with the anti-IL-12 Ab plus DNFB showed only a minimal response to DNFB after resensitization, suggesting that these mice became tolerant. Tolerance appeared to be hapten-specific because these mice could be successfully sensitized with the nonrelated hapten 2,4,6-trinitrochlorobenzene. Furthermore, when the anti-IL-12 Ab was injected into already sensitized mice before challenge, ear swelling response was significantly suppressed, suggesting that IL-12 also is involved in the effector phase of CHS. To exclude the possibility that the inhibitory effect of the anti-IL-12 Ab is simply due to an anti-inflammatory activity of the Ab, the anti-IL-12 Ab was injected i.p. 3 and 24 h before epicutaneous application of the toxic compound croton oil. However, irritant dermatitis elicited by croton oil was not affected by the Ab. Thus, the present study demonstrates that in vivo application of an anti-IL-12 Ab inhibits sensitization and induces hapten-specific tolerance and thus suggests that IL-12 may play a dominant in vivo role in the induction of CHS.

Animals↗
PubMed1995

[Isolation and reassociation of acetogen and methanogen in a syntrophobic coculture degrading butyrate anaerobically].

Anaerobic coculture BF2 which degraded butyrate into acetate and produced methane was isolated from granular methanogenic sludge. The coculture is associated syntrophically the Syntrophomonas subsp. saponavida strain CF2 with Methanobacterium formicicum strain MF2 and appeared to degraded C4 approximately C18 fatty acids including isobutyrate. The optimal temperature and pH for growth was 37 degrees C and 7.7 respectively. The strain CF2 was obtained in pure culture with crotonate as substrate and produces acetate and butyrate. The doubling time of strain CF2 in crotonate media was about 20 hours. Strain CF2 is Gram negative, slightly curved 0.2 approximately 0.3 x 2.0 approximately 3.0 micron with round ends, motile by lateral flagellation at the concave side, non sporeforming. With a hydrogen scavenging organism, such as Methanospillum hungatei JF1, Methanobacterium formicicum 1535, Methanobrevibacterium bryantii 1125 and Desulfovibrio sp. B11, the strain CF2 paired up and the defined coculture degraded butyrate to acetate. When the strain CF2 associated with the original accompanist, Methanobacterium formicius strain MF2, the reassociated couculture degraded butyrate to acetate and produced methane again.

Butyrates↗
PubMed1962

The fine structure of the basement membrane in epidermal tumors.

Epidermal tumors were induced in Swiss female mice by a topical application of 9,10-dimethyl-1,2-benzanthracene solution followed by repeated applications of croton oil solutions. Fourteen benign and malignant tumors were sampled 25 weeks after the treatment had begun, fixed in osmium tetroxide or potassium permanganate, and embedded in Epon. Sections stained with lead hydroxide were examined. In three tumors defects of the epidermal basement membrane were seen. These defects accompanied local invasion of the tumors. The possible mechanisms of the development of this unusual anatomical situation are discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2006

Reversal of regioselectivity and enhancement of rates of nitrile oxide cycloadditions through transient attachment of dipolarophiles to cyclodextrins.

The reactions of nitrile oxides with monosubstituted dipolarophiles, such as propiolamide, typically afford proportionally 80 % or more of the 3,5-disubstituted cycloadducts. By contrast, the reactions of 6(A)-deoxy-6(A)-propynamido-beta-cyclodextrin with 4-tert-butylbenzonitrile oxide and 4-phenylbenzonitrile oxide afford >90 % and approximately 85 % of the corresponding 3,4-disubstituted isoxazoles, respectively. As well as reversing the regioselectivity, the cyclodextrin increases the rates of these cycloadditions. The extent of the acceleration is up to more than three orders of magnitude for the production of the cycloadduct preferred by the cyclodextrin, but even the rate of reaction to give the less favored regioisomer is increased. With 6(A)-deoxy-6(A)-propynamido-beta-cyclodextrin, the cycloadducts are not easily separated from the cyclodextrin, as the amide bond is not readily cleaved. In comparison, the regioselectivity of the cycloadditions of 4-tert-butylbenzonitrile oxide with acrylic acid, methacrylic acid, and crotonic acid is also altered by formation of the corresponding cyclodextrin esters, by factors of 500, >10, and >100, respectively. The rates of cycloaddition are also increased by up to 475 times, and in these cases the products of cycloaddition are readily released from the cyclodextrin through ester hydrolysis. Incorporating these processes into a reaction cycle, acylation of beta-cyclodextrin with p-nitrophenyl acrylate and subsequent treatment first with 4-tert-butylbenzonitrile oxide and then with base, the latter to catalyze ester hydrolysis and regenerate the beta-cyclodextrin, affords proportionally fivefold more of the 3,4-disubstituted isoxazoline than is produced directly from acrylic acid.

Acrylates↗
PubMed2006

CCL17 transgenic mice show an enhanced Th2-type response to both allergic and non-allergic stimuli.

CC chemokine ligand (CCL)17 is implicated in the pathogenesis of atopic dermatitis (AD). To study the effect of CCL17 produced by keratinocytes (KC) during inflammation, we created transgenic (Tg) mice in which CCL17 is overexpressed in KC. Th2-type contact hypersensitivity (CHS) was enhanced and Th1-type CHS was suppressed in these mice. Increased numbers of CC chemokine receptor (CCR)4(+) cells and mast cells infiltrated in Tg mice. Levels of IL-4 mRNA were higher and those of IFN-gamma mRNA were lower in both acute and chronic CHS. Higher levels of serum IgE were observed after CHS. Numbers of CCR4(+) cells among PBMC were increased in Tg mice challenged acutely on the trunk. Chronic irritation with croton oil induced dermatitis and an elevation of serum IgE levels. Tg mice showed enhanced ear swelling after tape stripping. CCL17 was thought to modify the inflammation caused by sensitizing reagents as well as irritant reagents by attracting CCR4(+) cells into the lesional skin and creating a Th2-dominant condition. AD-like conditions such as increased number of mast cells and elevated levels of serum IgE were observed. Thus, CCL17 may participate in the pathogenesis of skin diseases such as AD by regulating both allergic and irritant inflammation.

Acute Disease↗
PubMed1984

Biogenic silica fibre promotes carcinogenesis in mouse skin.

Silica fibres derived from plants are common contaminants of human diet in certain regions of the world where oesophageal cancer reaches extremely high incidences. We show here that one of these types of fibre (derived from Phalaris canariensis L) promotes the occurrence of tumours in the skin of mice initiated with a polycyclic carcinogen. Three experiments are described. In the first, the grain which bears these fibres was added to the diet. This did not result in any abnormality in any part of the gastrointestinal tract, but there was a significant induction of tumours in the skin around the mouth and nose; these were the areas of the body surface which most frequently came into contact with the grain. In the second experiment, the mice were separated from the grain by an intervening wire gauze barrier; a similar number of tumours appeared on initiated mice treated in this way. In this case, contact now occurred most frequently on the dorsal surface, which was rubbed against the gauze barrier, and it was on this surface that the tumours appeared. No tumours appeared if the grain was removed. In the third experiment, pure fibres were isolated from the surface of the grain and boiled in strong nitric acid so as to remove any organic material. When these acid-cleaned fibres were applied to the initiated skin with light pressure, they promoted carcinogenesis in the same way as croton oil. In each experiment the majority of tumours produced were benign neoplasms, together with at least one squamous carcinoma. It seems possible that the size and shape of these fibres are the critical properties determining their promoting activity. Their mean diameter is 15 microns, their modal length close to 200 microns, and they are sharply pointed with a tip diameter of 0.5 micron.

Administration, Oral↗