Casearia sylvestris

Casearia sylvestris: A Comprehensive Reference

1. Identity, Taxonomy, and Botanical Description

Nomenclature and Classification

Casearia sylvestris Swartz (family Salicaceae) is a medicinal plant whose leaf extracts have exhibited important pharmacological activities. The species was historically classified within the family Flacourtiaceae, but molecular phylogenetic revisions now place it in Salicaceae sensu lato. Phytochemical screenings of Casearia plants have demonstrated that they mainly contain clerodane diterpenoids, sesquiterpenoids, phenylpropanoids and other constituents; species have been used as folk medicines in South American and Asian countries since ancient times.

Recorded synonyms include Samyda parviflora, Casearia parviflora, and Anavinga samyda. Common vernacular names encompass guacatonga, guassatonga, wild coffee, burro-kaa, café-bravo, cafeiillo, café silvestre, congonhas-de-bugre, corta-lengua, crack-open, dondequiera, erva-de-bugre, erva de pontada, guayabillo, mahajo, papelite, pau de lagarto, piraquina, raton, sarnilla, and ucho caspi. Parts used include bark and leaves.

Botanical Varieties

The species presents morphological, chemical, and genetic variation. Two varieties are recognized based on external morphological differences: C. sylvestris var. sylvestris and var. lingua, though there are difficulties in defining these varieties. Chromatographic analyses confirm that the diterpene profile differs between varieties, with predominance of these metabolites in var. sylvestris. The chemical profile of leaf extracts of var. sylvestris (from Atlantic Forest) presents a rich phytochemical composition with abundant diterpenes, considered taxonomic markers for this genus, while phenolic compounds (flavonoids) predominate in var. lingua.

Geographic Distribution and Habitat

Casearia sylvestris subsp. sylvestris is a shrub or tree with a very wide distribution spanning throughout the near entirety of Latin America. It grows in the seasonally dry tropical biome at altitudes ranging from 700–1,000 m. It is indigenous to Latin American nations including Brazil, Bolivia, and Peru, and may be found in a variety of environments, including the Amazon rainforest, Pampa, Cerrado, Atlantic Forest, and Pantanal.

Common Names

Casearia sylvestris var. lingua is referred to as "guaçatonga," "erva-de-lagarto," "cha-de-bugre," "café silvestre," or "cafezinho do mato" in Brazil. It is also commonly known as laurel espada, palo de queresas, and sarna de perro in Spanish-speaking regions.

Regulatory Status in Brazil

The plant is under surveillance by the National Health Agency Surveillance (ANVISA) and is included in the National List of Medicinal Plants of Interest to the Unified Health System (RENISUS). The Brazilian Pharmacopoeia suggests making a tea (infusion or decoction) from the dried leaves of the C. sylvestris plant.

2. Traditional and Historical Use

Indigenous and Folk Use in Brazil and Latin America

The Casearia sylvestris SW is utilized in folk medicine in Brazil and throughout Latin America to treat several pathological processes including inflammation, cancer, microbial infection, and snake bites. Brazilian Karajá Indian tribes and natives from the Shipibo-Conibo tribe of Peru have historical habits of preparing leaf extracts to treat snake bites, wounds, diarrhea, flu, and chest colds, probably due to their antifungal and antibacterial activity.

In different communities in Brazil, C. sylvestris is observed to treat dermal wound healing and gastric ulcers. Ethnomedicinal use is commonly associated with treatment against injuries produced by snake bites in human beings or animals, and topical application is very common as bandages prepared with macerated leaves of the plant.

Uses Across Latin America

C. sylvestris var. lingua holds a prominent place in traditional medicine across various cultures. Historically, indigenous communities have utilized different parts of the plant, including leaves, bark, and roots, to address a wide array of health conditions. Traditional uses encompass the treatment of gastrointestinal disorders, respiratory infections, wound healing, inflammation, and stomach ulcers.

Traditionally, a decoction of leaves has been administered internally to treat inflammatory diseases and malignant fevers. In traditional medicine, Casearia sylvestris is used to treat inflammation, skin lesions, and microbial infections. Steeped in water, the leaves and bark are also regarded as useful as a laxative and to help with rheumatic disorders.

Traditional Preparations

Traditional preparations described in the ethnobotanical literature include: aqueous decoctions and infusions of leaves and bark; ethanolic macerations of leaves; topical applications of macerated or crushed leaves as poultices; and aqueous extracts for internal use. It has been used in Brazilian folk medicine as a diuretic, appetite suppressant, weight loss product, and snakebite agent.

3. Key Constituents and Active Compounds

Clerodane Diterpenes: Casearins and Casearvestrins

New antitumor clerodane diterpenes, named casearins A–F, were isolated from the leaves of Casearia sylvestris Sw. (Flacourtiaceae), and their structures were completely elucidated by two-dimensional nuclear magnetic resonance, circular dichroism spectroscopy, X-ray analysis, and chemical evidence. Casearins G–R, additional cytotoxic clerodane diterpenes, were subsequently isolated from the leaves, and their structure-activity relationships were discussed.

Bioguided-assay fractionations led to the identification of secondary metabolites, especially the clerodane diterpenes casearins (A–X) and casearvestrins (A–C), compounds with remarkable cytotoxic and antitumor action. A significant portion of the ethanol extract of "guaçatonga" leaves consists of casearins, clerodane diterpenes responsible for most of the pharmacological properties of this species. There is a direct relationship between concentration of casearins and pharmacological potentiality.

Two highly oxygenated clerodane diterpenes—casearins U (1) and V (2)—and two ent-kaurane diterpene glucosides, sylvestrisides A (3) and B (4), were isolated from the leaves of Casearia sylvestris, together with 13 known compounds.

Sesquiterpenes in the Essential Oil

The major essential oil chemical components were (E)-caryophyllene, α-humulene, germacrene D, bicyclogermacrene, spathulenol, caryophyllene oxide, and humulene epoxide II. The essential oil composition obtained from the leaves of Casearia sylvestris has been investigated by GC and GC/MS; 37 compounds were identified, with the major constituents being β-caryophyllene (27.5%) and bicyclogermacrene (24.2%). The main essential oil components associated with reported bioactivities are α-zingiberene, (E)-caryophyllene, germacrene D, bicyclogermacrene, spathulenol, α-humulene, β-acoradiene, and δ-cadinene.

Phenolic Compounds: Flavonoids, Ellagic Acid Derivatives, and Gallic Acids

HPLC–PDA–ESI+/MS and GC/MS analysis of hydroethanolic fluid extract identified the flavonoids rutin, quercetin, and luteolin, as well as chlorogenic acid. The total phenolic content in the infusion of leaves from C. sylvestris var. lingua was 101.57 mg GAE g⁻¹, flavonoids 50.37 mg RE g⁻¹, and tannins 1.12 mg TAE g⁻¹. Quercetin, ferulic acid, gallic acid, ellagic acid, caffeic acid, β-sitosterol, lupeol, lupeol acetate, stigmasterol, and campesterol were identified and quantified.

Among the isolated phenolic compounds were ellagic acid, 3′-O-methyl ellagic acid, 3,3′-di-O-methyl ellagic acid, and 3-O-methyl-3′,4′-methylenedioxy ellagic acid. Fourteen glycosylated flavonoids and one catechin were isolated and identified from var. lingua extracts, including (+)-catechin, rutin (quercetin-3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside), and isorhamnetin derivatives (isorhamnetin-3-O-neo-hesperidoside; narcissin).

The plant is rich in bioactive compounds such as monoterpenes, sesquiterpenes, diterpenes, ellagic acid derivatives, and flavonoids.

Inter-Variety Chemical Differences

The two varieties exhibit distinct chemical profiles: var. sylvestris, predominant in dense and humid forests and ecotones, is characterized by clerodane diterpenes, while var. lingua, mainly found in xeric and open savannah areas, contains phenolic compounds.

4. Established Mechanisms of Action

Phospholipase A₂ (PLA₂) Inhibition

Leaf water extracts show phospholipase A₂ inhibitory activity that prevents damage effects on muscular tissue after toxin inoculation. This antiphospholipasic action is probably related to the use as an anti-inflammatory, proposing a pharmacological blockage similar to that obtained with non-steroidal anti-inflammatory drugs on arachidonic acid and cyclooxygenase pathways.

The crude aqueous extract from the leaves of Casearia sylvestris was demonstrated to inhibit phospholipase A₂ (PLA₂) activity and biological activities of bee and several snake venoms, as well as isolated PLA₂ enzymes. The extract induced partial inhibition of the PLA₂ activity of venoms containing class I, II, and III PLA₂s. Against purified toxins, it showed the highest efficacy against class II PLA₂s from viperid venoms. Additionally, the extract significantly inhibited the myotoxic activity of four Bothrops crude venoms and nine purified myotoxic PLA₂s, including Lys-49 and Asp-49 variants.

Aqueous extract of the plant has also inhibited the activity of inflammatory enzymes such as phospholipase A₂ and metalloproteases present in the venom of snakes and bees.

Cytotoxic and Apoptotic Mechanisms

Cytotoxicity against cancer cell lines is one of the most important biological activities of clerodane diterpenes from Casearia; it has been demonstrated that they induce DNA fragmentation, phosphatidylserine externalization, cell cycle arrest, and reduction of ERK phosphorylation and cyclin D1 expression.

The clerodane diterpene casearin J induces apoptosis of T-ALL cells through SERCA inhibition, oxidative stress, and interference with Notch1 signaling. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy; over 50% of human T-ALLs possess activating mutations of Notch1. Casearin J is a natural product that inhibits the sarcoendoplasmic reticulum calcium ATPase (SERCA) pump and induces cell death in leukemia cells.

Cytotoxicity of casearin L, O, and X isolated from Casearia sylvestris leaves was determined; casearin X was the most active compound, showing cytotoxic effects against CEM and HL-60 leukemia cell lines (IC₅₀ of 0.4 μM) and human peripheral blood mononuclear cells (PBMC, IC₅₀ of 1.2 μM).

Antiulcer / Gastroprotective Mechanisms

Ethanolic extracts and essential oil of leaves have antiulcerogenic activity and reduce gastric volume without altering the stomach pH, which corroborates their consumption for gastrointestinal disorders. Both its essential oil and ethanolic extract have anti-Helicobacter pylori properties both in vivo and in vitro.

Antioxidant Mechanisms

The plant's anti-inflammatory action was assessed by its capability in inhibiting cell migration, enzymatic activity of myeloperoxidase (MPO), and production of nitrite/nitrate or edema; in vitro antioxidant activity against lipid peroxidation and damage to proteins was also assessed as possible pathways contributing to anti-inflammatory mechanisms.

Effects on Enzymes and Ion Transporters

Casearia sylvestris has been shown to contain constituents that alter Na⁺/K⁺-ATPase and acetylcholinesterase activities, damage DNA, and inhibit phospholipase A₂ activity.

5. Scientific Evidence by Area of Use

5.1 Gastrointestinal and Antiulcer Activity

Preclinical evidence (animal models): An ethanol extract of the leaves of Brazilian Casearia sylvestris, given orally, inhibited gastric secretion in pylorus-ligated rats. At a prophylactic dose of 57.5 mg/kg, the extract showed a reduction of gastric juice more effective than misoprostol (500 μg/kg). Stress-induced lesions produced by restraint and water immersion were significantly prevented by the extract for all levels of severity compared with controls. The extract appeared more effective than misoprostol in suppressing light lesions, was equivalent to cimetidine and misoprostol for moderate lesions, and less effective than cimetidine and misoprostol for severe lesions.

To investigate the antiulcer and anti-inflammatory activities of the essential oil from Casearia sylvestris leaves (EOCS), tests included: rat paw edema, granulomatous tissue test, vascular permeability, writhing test, gastric ulcer stress-induced, and evaluation of gastric secretion (pylorus ligation test). The EOCS orally administered to rats at 125 mg/kg resulted in 36% inhibition in carrageenan-induced edema in the rat paw assay (p < 0.05, Student's t-test).

Research by Oliveira et al. (2022) supports the aqueous extract's potential application in treating gastrointestinal diseases by confirming its gastroprotective and ulcer-healing properties in animal models.

Evidence for ulcerative colitis (preclinical): A 2024 study evaluated the aqueous extract of C. sylvestris var. lingua in rats with TNBS-induced inflammatory bowel disease. The results imply that intestinal mucogenic, anti-inflammatory, and antioxidant properties of the C. sylvestris var. lingua leaf extract may be involved in its therapeutic actions for ulcerative colitis. In silico results indicate the possibility of quercetin and ellagic acid interacting with P38 and TLR8, respectively.

Evidence strength: This area has the most extensive preclinical support of any indication for C. sylvestris. All published data are from animal or in vitro models; no human clinical trials have been published as of available literature.

5.2 Anti-inflammatory and Analgesic Activity

Preclinical evidence: The anti-inflammatory and antioxidant properties of the hydroalcoholic crude extract of Casearia sylvestris were investigated; the effect of the extract (3–300 mg/kg) on reduction of inflammatory response to carrageenan was examined in pleurisy in rats or paw edema in mice. Carrageenan-induced hind paw edema (739.3±11.9 μm) was reduced by the extract at 30 mg/kg (to 462.8±28.38 μm) to similar extents as dexamethasone (365.1±16.7 μm).

This traditional use agrees with scientific demonstrations of antibothropic and anti-inflammatory actions. Finding that aqueous extract of the plant can inhibit phospholipase A₂ activity, a pivotal enzyme in the cascade of inflammatory mediator generation, is also of particular interest since this family of enzymes is also involved with skin homeostasis.

The major role of phospholipase A₂ in inflammation, allied to popular reports that Casearia sylvestris displays analgesic properties, led researchers to investigate whether this species might be useful in treating pain, especially that associated with inflammatory conditions.

Evidence strength: Multiple preclinical studies in rodents confirm anti-inflammatory activity, with a plausible mechanism (PLA₂ inhibition). No controlled human clinical trials exist.

5.3 Antitumor / Anticancer Activity

In vitro and in vivo preclinical evidence: A fraction with casearins extracted from C. sylvestris leaves and Casearin X were efficient in vivo antitumor substances against murine cells and human glioblastoma and colon carcinoma neoplasms by both intraperitoneal and oral routes, and caused reversible morphological changes in the liver, kidneys, and spleens. Ex vivo studies indicated apoptosis as the main way by which cell death is triggered.

A fraction from C. sylvestris leaves showed tumor inhibition rates ranging from 33% to 67% for human carcinomas and glioblastomas and from 35% to 90% for Sarcoma 180 murine cells.

C. sylvestris leaves contain casearins, casearvestrins, and unique clerodane diterpenes that have been shown to be cytotoxic to tumor cells, including HeLa, A-549, and HT-29.

Two gallic acid-derived compounds isolated from C. sylvestris leaves—isobutyl gallate-3,5-dimethyl ether (IGDE) and methyl gallate-3,5-dimethyl ether (MGDE)—showed significant chemotherapeutic potential against Ehrlich and Lewis lung cancer ascite tumor cells and increased animals' survival by approximately 90%, with IGDE possessing slightly superior activity compared to MGDE.

Although there is evidence that casearins have cytotoxic activity on cancer cells, the molecular mechanism involved in this process still remains poorly understood. In addition, there has been limited exploration in relation to the antiproliferative activity of the casearins.

Evidence strength: Antitumor activity is well-documented at the in vitro and in vivo animal model level; cytotoxic and apoptotic mechanisms have been partially elucidated. No human clinical trials on antitumor efficacy have been published. All evidence is preclinical and should not be interpreted as evidence of clinical efficacy in cancer treatment.

5.4 Anti-Ophidian (Antivenom) Activity

Preclinical evidence: Studies showed that C. sylvestris aqueous extract can inhibit many toxic effects caused by snake venoms from different species, mainly of the Bothrops genus. Inhibition of enzymatic and myotoxic activities, decrease of edema formation, and increase of the survival rate of rats injected with lethal doses of bothropic venoms are among the toxic effects inhibited by C. sylvestris.

The crude extract and pure substances from this plant induced partial inhibition of PLA₂ activity of snake venoms and some purified toxins. The extract efficiently neutralized the hemorrhagic and myotoxic activities caused by crude venoms and toxins.

Evidence strength: Preclinical animal model data are robust for the anti-ophidian indication. No clinical data in human envenomation exist. This use is grounded in both strong ethnobotanical tradition and multiple in vitro/in vivo studies.

5.5 Antimicrobial Activity

In vitro evidence: An ethanolic extract of leaves of Casearia sylvestris was tested for in vitro activity against oral pathogenic bacteria and fungi; results showed susceptibility of all microorganisms tested. All three casearvestrin compounds isolated displayed promising bioactivity in cytotoxicity assays against a panel of tumor cell lines and in antifungal assays via growth inhibition of Aspergillus niger.

Extracts of C. sylvestris were more active against S. mutans compared to effects against C. albicans, both in antimicrobial and antibiofilm analyses.

Studies employing in vitro or in vivo assays demonstrated antiviral activity (Simões et al., 1999) and antibacterial properties (Alves et al., 2000).

Bioactivities of the essential oils from leaves and their components include antimicrobial, antifungal, and antiviral activities. The main components associated with these activities include α-zingiberene, (E)-caryophyllene, germacrene D, bicyclogermacrene, spathulenol, α-humulene, β-acoradiene, and δ-cadinene.

Evidence strength: Antimicrobial evidence is limited to in vitro studies. No clinical trials in human infections have been conducted.

5.6 Antiparasitic Activity

Different parts of C. sylvestris exhibit activity against Leishmania donovani promastigotes, Trypanosoma cruzi amastigotes, Plasmodium falciparum strains resistant to chloroquine, and Aedes aegypti larvae.

Evidence strength: Entirely preclinical (in vitro), with no clinical human data available.

5.7 Cardiovascular and Lipid-Lowering Activity

A study demonstrated that methanolic extract of C. sylvestris (MECS) reduces serum lipids and oxidative stress when orally administered to Swiss and LDLr-null mice. It was also able to prevent arterial thickening induced by high-fat diet and inhibit platelet aggregation in vitro.

Extracts, essential oils, and molecules from C. sylvestris have shown hypolipidemic and cardiovascular protective actions in preclinical research.

Evidence strength: Cardiovascular effects have been studied only in animal models and in vitro. No human clinical data exist.

5.8 Antioxidant Activity

Additional pharmacological properties of Casearia sylvestris include antioxidant activity. During molecular docking analysis, quercetin, gallic acid, ferulic acid, caffeic acid, and ellagic acid demonstrated consistent binding affinities, forming stable interactions with relevant biological targets.

Evidence strength: Antioxidant activity is well-supported in vitro; the relevance of in vitro antioxidant testing to human clinical outcomes is an acknowledged limitation in phytochemical research generally.

6. Dosage Forms and Reported Dosages

The Brazilian Pharmacopoeia suggests making a tea (infusion or decoction) from the dried leaves of the C. sylvestris plant. In experimental pharmacological studies, the following dosages have been reported:

• Ethanol extract of leaves given orally to pylorus-ligated rats; a prophylactic dose of 57.5 mg/kg showed a reduction of gastric juice more effective than misoprostol (500 μg/kg).
• In acute toxicity testing, female Wistar rats were treated with a single dose of hydroethanolic fluid extract (FE) of 2,000 mg/kg administered by oral gavage and observed for 14 days; in subchronic toxicity, animals received 60, 120, and 240 mg/kg of FE by daily gavage for 28 and 90 days.
• In a short-term carcinogenesis evaluation, Wistar rats were orally treated for 12 weeks with 50, 250, or 500 mg/kg of crude extract or vehicle.
• In a maternal-fetal safety study, pregnant rats were daily treated orally with 0, 175, 350, or 700 mg/kg/body weight of aqueous extract from gestational day 6 to 15.
• In antitumor studies, FC was administered at 10 and 25 mg/kg/day intraperitoneally and 50 mg/kg/day orally; Casearin X at 25 mg/kg/day intraperitoneally.
• In anti-inflammatory paw edema studies, hydroalcoholic crude extract was used at doses of 3–300 mg/kg.

Note: The above dosages are exclusively from preclinical (animal) pharmacological and toxicological studies. No human clinical dosage regimen has been established in published peer-reviewed research.

7. Safety Considerations

Acute and Subchronic Toxicity in Animals

Casearia sylvestris is catalogued by the Brazilian Unified Health System as a plant of interest for the Brazilian population for treating inflammatory disorders, pain, and gastrointestinal disorders; however, no toxicological studies concerning the safety of extract fluid of this plant had been reported prior to 2015. Results of acute study indicated that the LD₅₀ is higher than 2,000 mg/kg; at 28- and 90-day oral toxicity, no toxic effects were detected in any of the parameters evaluated: body weight and relative organ weight, general behavioral changes, hematological and biochemical parameters, and histopathological examination.

A parallel acute and subacute toxicity study used dosages of 1,842 mg/kg and 57.5–143.9 mg/kg over 30 days, respectively, and found no negative effects. Based on these studies, the hydroethanolic fluid extract of C. sylvestris could be safe even when used over a long period for the therapeutic uses proposed by the Brazilian Unified Health System.

Essential Oil Toxicity

The total yield of the essential oil from C. sylvestris leaves was 2.5%, with an LD₅₀ of 1,100 mg/kg in mice. Data on the toxicity of essential oils from Casearia species are scarce in the literature.

Genotoxicity and Clastogenicity

The clastogenic and anticlastogenic effect of the oil was tested by chromosome aberration in cells of tissue hepatoma of Rattus norvegicus. Three different concentrations of C. sylvestris oil showed clastogenic effects; however, in tests of anticlastogenicity, the same concentrations showed protective activity when associated with ethyl methanesulfonate (EMS).

Casearin Fraction Toxicological Findings

The casearin-enriched fraction (FC) was cytotoxic against lung and fibroblast cells and caused DNA breaks, loss of integrity, and mitochondrial depolarization on ex vivo human leukocytes. Araújo et al. (2015) verified that FC-treated animals exhibited some alterations indicative of neurotoxicity, and recommend precaution regarding the consumption of medicinal formulations based on C. sylvestris.

Embryotoxicity and Developmental Safety

A 2023 study evaluated the maternal, embryotoxic, and teratogenic effects of the aqueous extract of Casearia sylvestris (AECS), a species listed in the Unique Health System of Brazil, and widely used for treating diarrhea, wounds, pain, and ulcers. Pregnant rats were daily treated orally with 0, 175, 350, or 700 mg/kg/body weight of AECS from gestational day 6 to 15. No clinical signs of toxicity were observed in the dams during the treatment. In the embryo-fetal development study, a significant increase in the basal zone height of the placenta was observed in the intermediate dose group. Furthermore, there was a significant increase in the relative anogenital distance measurement of female fetuses in the lowest and intermediate dose groups. These findings indicate potential embryotoxic effects at certain doses in animal models.

Short-Term Carcinogenesis Evaluation

C. sylvestris is an important medicinal plant widely used in Brazil for the treatment of various cardiovascular disorders; the species was included as of interest by Brazilian Unified Health System. Although preclinical studies described cardiovascular protective effects and apparent absence of toxicity, no studies had previously evaluated its carcinogenic potential. A short-term carcinogenesis evaluation of C. sylvestris in Wistar rats was proposed to check the safety of this species as proposed by Brazilian Unified Health System.

Summary of Safety Landscape

C. sylvestris folk data and toxicological studies did not indicate unsafe clinical evidence for humans. However, the cytotoxic and genotoxic properties of isolated casearin fractions and the signals of neurotoxicity at higher doses in animal models warrant caution, particularly with concentrated or purified preparations. The embryotoxic signals observed in rats at intermediate doses indicate that use during pregnancy is an area requiring further investigation. Data on the toxicity of essential oils from Casearia species are scarce in the literature, and no systematic human safety data are available. All safety conclusions must currently be extrapolated from animal studies.

8. Associated Body Systems and Areas of Health

• Gastrointestinal system: antiulcer, gastroprotective, anti-Helicobacter pylori, anti-inflammatory bowel activity, antidiarrheal.
• Immune / Inflammatory system: anti-inflammatory (PLA₂ inhibition, myeloperoxidase inhibition, nitric oxide modulation), analgesic/antinociceptive.
• Oncology (preclinical): cytotoxic and antiproliferative against multiple tumor cell lines; apoptosis induction.
• Toxicology / Envenomation: anti-ophidian, inhibition of snake venom PLA₂s and metalloproteases.
• Microbiology: antibacterial, antifungal, antiviral, antiparasitic (Leishmania, Trypanosoma cruzi, Plasmodium falciparum).
• Cardiovascular / Metabolic: hypolipidemic, anti-atherogenic, anti-platelet aggregation (preclinical).
• Skin / Wound healing: topical anti-inflammatory, wound healing (traditional).
• Neurological: anxiolytic effects reported in preclinical research; neurotoxicity signals observed with casearin-enriched fractions at higher doses.

References

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