Camphor--a fumigant during the Black Death and a coveted fragrant wood in ancient Egypt and Babylon--a review.

The fragrant camphor tree (Cinnamomum camphora) and its products, such as camphor oil, have been coveted since ancient times. Having a rich history of traditional use, it was particularly used as a fumigant during the era of the Black Death and considered as a valuable ingredient in both perfume and embalming fluid. Camphor has been widely used as a fragrance in cosmetics, as a food flavourant, as a common ingredient in household cleaners, as well as in topically applied analgesics and rubefacients for the treatment of minor muscle aches and pains. Camphor, traditionally obtained through the distillation of the wood of the camphor tree, is a major essential oil component of many aromatic plant species, as it is biosynthetically synthesised; it can also be chemically synthesised using mainly turpentine as a starting material. Camphor exhibits a number of biological properties such as insecticidal, antimicrobial, antiviral, anticoccidial, anti-nociceptive, anticancer and antitussive activities, in addition to its use as a skin penetration enhancer. However, camphor is a very toxic substance and numerous cases of camphor poisoning have been documented. This review briefly summarises the uses and synthesis of camphor and discusses the biological properties and toxicity of this valuable molecule.

Sunscreens: are they beneficial for health? An overview of endocrine disrupting properties of UV-filters.

Today, topical application of sunscreens, containing ultraviolet-filters (UV-filters), is preferred protection against adverse effects of ultraviolet radiation. Evidently, use of sunscreens is effective in prevention of sunburns in various models. However, evidence for their protective effects against melanoma skin cancer is less conclusive. Three important observations prompted us to review the animal data and human studies on possible side effects of selected chemical UV-filters in cosmetics. (1) the utilization of sunscreens with UV-filters is increasing worldwide; (2) the incidence of the malignant disorder for which sunscreens should protect, malignant melanoma, is rapidly increasing and (3) an increasing number of experimental studies indicating that several UV-filters might have endocrine disruptive effects. The selected UV-filters we review in this article are benzophenone-3 (BP-3), 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), Homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate (OD-PABA) and 4-aminobenzoic acid (PABA). The potential adverse effects induced by UV-filters in experimental animals include reproductive/developmental toxicity and disturbance of hypothalamic-pituitary-thyroid axis (HPT). Few human studies have investigated potential side effects of UV-filters, although human exposure is high as UV-filters in sunscreens are rapidly absorbed from the skin. One of the UV-filters, BP-3, has been found in 96% of urine samples in the US and several UV-filters in 85% of Swiss breast milk samples. It seems pertinent to evaluate whether exposure to UV-filters contribute to possible adverse effects on the developing organs of foetuses and children.

The common cold.

1) Most colds are due to viruses and resolve spontaneously after a few days. Available drugs do not modify the course of a viral cold; 2) Some drugs used to treat colds carry a risk of serious adverse effects. This includes nasal sprays, especially vasoconstrictors such as pseudo-ephedrine and, in young children, menthol, camphor, and terpene derivatives.

Safety Threshold Considerations for Sunscreen Systemic Exposure: A Simulation Study.

Sunscreens are regulated as over-the-counter drugs in the United States. Some sunscreen ingredients are absorbed into the systemic circulation, which raises concerns about the safety of these drugs. There is limited information on the systemic exposure for most sunscreen ingredients. This report estimates the systemic absorption of two sunscreen active ingredients, oxybenzone and enzacamene, by developing a pharmacokinetic model from published sunscreen absorption data and compares the results with safety thresholds proposed by the US Food and Drug Administration and in the literature. Our analysis indicates that systemic absorption can be substantial, and evaluation of the systemic exposure of sunscreen ingredients is warranted to better assess any long-term risks of use.

Region-specific growth effects in the developing rat prostate following fetal exposure to estrogenic ultraviolet filters.

BACKGROUND AND OBJECTIVES: Exposure to environmental endocrine disruptors is a potential risk factor for humans. Many of these chemicals have been shown to exhibit disruption of normal cellular and developmental processes in animal models. Ultraviolet (UV) filters used as sunscreens in cosmetics have previously been shown to exhibit estrogenic activity in in vitro and in vivo assays. We examined the effects of two UV filters, 4-methylbenzylidene camphor (4-MBC) and 3-benzylidene camphor (3-BC), in the developing prostate of the fetal rat. METHODS: Pregnant Long Evans rats were fed diets containing doses of 4-MBC and 3-BC that resulted in average daily intakes of these chemicals corresponding to the lowest observed adverse effects level (LOAEL) and the no observed adverse effects level (NOAEL) doses in prior developmental toxicity studies. Using digital photographs of serial sections from postnatal day 1 animals, we identified, contoured, and aligned the epithelial ducts from specific regions of the developing prostate, plus the accessory sex glands and calculated the total volume for each region from three-dimensional, surface-rendered models. RESULTS: Fetal exposure to 4-MBC (7.0 mg/kg body weight/day) resulted in a significant increase (p < 0.05) in tissue volume in the prostate and accessory sex glands. Treated males exhibited a 62% increase in the number of ducts in the caudal dorsal prostate. Increased distal branching morphogenesis appears to be a consequence of exposure in the ventral region, resulting in a 106% increase in ductal volume. CONCLUSIONS: 4-MBC exposure during development of the male reproductive accessory sex glands exhibited classical growth effects associated with estrogenic endocrine disruptors. The different regional responses suggest that the two developmental processes of ductal outgrowth and branching morphogenesis are affected independently by exposure to the environmental chemicals.

Ability of root canal antiseptics used in dental practice to induce chromosome aberrations in human dental pulp cells.

Root canal antiseptics are topically applied to root canals within the pulpless teeth to treat the root canal and periapical infections. Because the antiseptics that are applied to root canals can penetrate through dentin or leak out through an apical foramen into the periodontium and distribute by the systemic circulation, it is important to study the safety of these antiseptics. In the present study, we examined the ability to induce chromosome aberrations in human dental pulp cells of five root canal antiseptics, namely, carbol camphor (CC), camphorated p-monochlorophenol (CMCP), formocresol (FC), calcium hydroxide, and iodoform which are most commonly used in dental practice. Statistically significant increases in the levels of chromosome aberrations were induced by CC, FC, or iodoform in a concentration-dependent manner. Conversely, CMCP and calcium hydroxide failed to induce chromosome aberrations in the absence or presence of exogenous metabolic activation. The percentages of cells with polyploid or endoreduplication were enhanced by FC or iodoform. Our results indicate that the root canal antiseptics that exhibited a positive response are potentially genotoxic to human cells.

Camphor ingestion: an unusual cause of seizure.

Camphor is a pleasant smelling cyclic ketone with propensity of causing neurologic side-effects especially seizures. We report two patients who after inadvertent consumption of camphor experienced an episode of generalized tonic clonic seizure. These cases highlight the importance of enquiring any intake of material (medicinal or otherwise) in every patient presenting with seizure.

Staining potential of calcium hydroxide and monochlorophenol following removal of AH26 root canal sealer.

AIM: The focus of this study was to examine the staining potential of calcium hydroxide (Ca(OH)2) on tooth structure following the removal of AH26 root canal sealer. METHODS AND MATERIALS: Fifty maxillary anterior teeth were prepared and obturated with AH26 and gutta percha. The sealers were then removed 24 hours later and the teeth were randomly divided into two groups. Ca(OH)2 was then placed in the root canals of the first group of teeth as a medicament and camphorated monochlorophenol (CMCP) was placed in the second group of teeth after the filling material was removed. The color of the external tooth surfaces was determined before tooth preparation and two weeks after the placement of the medicaments. The Z test was used for statistical analysis. RESULTS: All experimental teeth showed varying degrees of coronal discoloration with the Ca(OH)2 group showing more discoloration than the CMCP group (p<0.05). CONCLUSION: Using Ca(OH)2 as a medicament after removing AH26 caused progressive discoloration of the teeth, whereas using CMCP caused only slight discoloration. CLINICAL SIGNIFICANCE: To avoid staining of the treated tooth, AH26 root canal sealer must be completely removed from the dentin walls before using a medicament.

UV-selective face cream (Acne RA-1,2) in acne patients: clinical study of its effects on epidermal barrier function, sebum production, tolerability and therapy adherence.

BACKGROUND: General skin care recommendations such as the use of moisturizers and products with adequate photoprotection are important components of management for acne patients to complement the medical regimen. This study aimed to evaluate the real-life clinical effects of a novel UV-selective face cream (Acne RA-1,2, Meda Pharma, Solna, Sweden) on acne, epidermal barrier function, sebum production, adherence and tolerability when used together with pharmacological acne treatment. METHODS: Forty patients receiving pharmacological acne treatment applied Acne RA-1,2 once-daily for three months. Investigator's Global Assessment of acne, trans-epidermal water loss, sebum production and tolerability were assessed at one and three months. RESULTS: After 3 months, there was a 38% significant clinical improvement in mean Investigator Global Assessment score (3.4 to 2.1), a 29% significant reduction in trans-epidermal water loss (13.2 to 9.4 g/h/m2), and a 17% significant decrease in sebum production vs. baseline (234.6 to 195.6 µg/cm2; all P<0.01). One hundred percent of patients reported complete adherence to pharmacological therapy over the summer of the study vs. 52.5% in the previous summer. About 87.5% of patients considered their acne improved over the summer of the study, vs. 55.0% in the previous summer. Pruritus, erythema, dryness and total tolerability symptom scores were significantly reduced after 3 months vs. baseline (P<0.05). CONCLUSIONS: Acne RA-1,2 is a useful daily adjunct to pharmacological therapy as it helps to mitigate the irritation these therapies cause, increasing adherence to therapy, and leading to a clinical improvement in acne and epidermal barrier function and a decrease in sebum production.

Acne RA-1,2, a novel UV-selective face cream for patients with acne: Efficacy and tolerability results of a randomized, placebo-controlled clinical study.

BACKGROUND: General skincare measures such as the use of moisturisers and products containing adequate photoprotection are important components of acne patients' management to complement the pharmacological regimen. Acne RA-1,2 is a novel dermato-cosmetic product which contains selective photofilters and active ingredients against the multifactorial pathophysiology of acne. OBJECTIVES: To evaluate the tolerability of Acne RA-1,2 and its effect on the clinical signs of acne. METHODS: This double-blind, placebo-controlled study randomized 40 adult patients with 10-25 comedones per half face to once-daily application of Acne RA-1,2 or placebo for 8 weeks. Evaluations after 4 and 8 weeks included the number of comedones, transepidermal water loss (TEWL), sebum production, and tolerability. RESULTS: In the Acne RA-1,2 group, there was a significant 35% decrease in the mean number of comedones from 26 at baseline to 17 at Week 8 (P<.001), a 7% significant reduction in TEWL (9.32 to 8.66 g/h/m2 ; P<.001), and a 24% significant reduction in sebum production (154.8 to 117.6 µg/cm2 ; P<.001). The reductions in TEWL and sebum production were significantly greater than those in the placebo group at Weeks 4 and 8 (P<0.05). There were no adverse events. CONCLUSIONS: Acne RA-1,2 was well tolerated and effective at reducing comedones and sebum production and improving epidermal barrier function. These results suggest that Acne RA-1,2 is useful against acne-prone facial skin, particularly as it targets sebum production, which topical pharmacological acne therapies do not address.

Camphor-related self-inflicted keratoconjunctivitis complicating delusions of parasitosis.

PURPOSE: To report a case of camphor-related self-inflicted keratoconjunctivitis secondary to delusions of parasitosis. METHODS: A 61-year-old man with delusions of parasitosis suffered from camphor-related self-inflicted ocular trauma that manifested with corneal epithelial defects and secondary anterior chamber reaction. Two episodes of exacerbation of the ocular conditions related to the use of camphor occurred. The left eye had secondary infection with Sternotrophomonas maltophilia and Staphylococcus aureus in the second episode of exacerbation. RESULTS: The right eye recovered well with the treatment of topical lubricants and corticosteroids and had best-corrected visual acuity (BCVA) of 20/25. The infection of the left eye led to corneal perforation, necessitating penetrating keratoplasty; BCVA was hand motions because of a mature cataract. Olanzapine therapy for 1 month to decrease the delusions of parasitosis and 24-hour watch to prevent the use of camphor led to the resolution of self-inflicted keratoconjunctivitis in the patient. CONCLUSIONS: Delusions of parasitosis may lead to vision-threatening self-inflicted ocular trauma. This may be the first case report of pure camphor-related self-inflicted toxic keratoconjunctivitis.

Transdermal permeation of drugs with differing lipophilicity: Effect of penetration enhancer camphor.

The aim of the present study was to investigate the potential application of (+)-camphor as a penetration enhancer for the transdermal delivery of drugs with differing lipophilicity. The skin irritation of camphor was evaluated by in vitro cytotoxicity assays and in vivo transdermal water loss (TEWL) measurements. A series of model drugs with a wide span of lipophilicity (logP value ranging from 3.80 to -0.95), namely indometacin, lidocaine, aspirin, antipyrine, tegafur and 5-fluorouracil, were tested using in vitro transdermal permeation experiments to assess the penetration-enhancing profile of camphor. Meanwhile, the in vivo skin microdialysis was carried out to further investigate the enhancing effect of camphor on the lipophilic and hydrophilic model drugs (i.e. lidocaine and tegafur). SC (stratum corneum)/vehicle partition coefficient and Fourier transform infrared spectroscopy (FTIR) were performed to probe the regulation action of camphor in the skin permeability barrier. It was found that camphor produced a relatively low skin irritation, compared with the frequently-used and standard penetration enhancer laurocapram. In vitro skin permeation studies showed that camphor could significantly facilitate the transdermal absorption of model drugs with differing lipophilicity, and the penetration-enhancing activities were in a parabola curve going downwards with the drug logP values, which displayed the optimal penetration-enhancing efficiency for the weak lipophilic or hydrophilic drugs (an estimated logP value of 0). In vivo skin microdialysis showed that camphor had a similar penetration behavior on transdermal absorption of model drugs. Meanwhile, the partition of lipophilic drugs into SC was increased after treatment with camphor, and camphor also produced a shift of CH2 vibration of SC lipid to higher wavenumbers and decreased the peak area of the CH2 vibration, probably resulting in the alteration of the skin permeability barrier. This suggests that camphor might be a safe and effective penetration enhancer for transdermal drug delivery.

Estrogen target gene regulation and coactivator expression in rat uterus after developmental exposure to the ultraviolet filter 4-methylbenzylidene camphor.

Because the estrogen receptor (ER) ligand type influences transactivation, it is important to obtain information on molecular actions of nonclassical ER agonists. UV filters from cosmetics represent new classes of endocrine active chemicals, including the preferential ER beta ligands 4-methylbenzylidene camphor (4-MBC) and 3-benzylidene camphor. We studied estrogen target gene expression in uterus of Long Evans rats after developmental exposure to 4-MBC (0.7, 7, 24, and 47 mg/kg x d) administered in feed to the parent generation before mating, during pregnancy and lactation, and to the offspring until adulthood. 4-MBC altered steady-state levels of mRNAs encoding for ER alpha, ER beta, progesterone receptor (PR), IGF-I, androgen receptor, determined by real-time RT-PCR in uterus of 12-wk-old offspring. Western-blot analyses of the same tissue homogenates indicated changes in ER alpha and PR but not ER beta proteins. To assess sensitivity to estradiol (E2), offspring were ovariectomized on d 70, injected with E2 (10 or 50 microg/kg sc) on d 84, and killed 6 h later. Acute up-regulation of PR and IGF-I and down-regulation of ER alpha and androgen receptor by E2 were dose-dependently reduced in 4-MBC-exposed rats. The reduced response to E2 was accompanied by reduced coactivator SRC-1 mRNA and protein levels. Our data indicate that developmental exposure to 4-MBC affects the regulation of estrogen target genes and the expression of nuclear receptor coregulators in uterus at mRNA and protein levels.

Circadian activity rhythms in selectively bred ethanol-preferring and nonpreferring rats.

Chronic alcohol intake is associated with dramatic disruptions in sleep and other circadian biological rhythms in both humans and experimental animals. In human alcoholics, these disruptions persist during extended abstinence and appear to promote relapse to drinking. Whereas chronic ethanol intake alters fundamental properties of the circadian pacemaker in unselected rats, nothing is known concerning circadian pacemaker function in selectively bred ethanol-preferring and nonpreferring rats, which are the most widely accepted animal models of genetic predisposition to alcoholism. The present experiments were designed to characterize free-running circadian activity (wheel-running) rhythms under both constant darkness and constant light in selectively bred ethanol-preferring (P, HAD2) and nonpreferring (NP, LAD2) rats. Differences in circadian organization between ethanol-preferring and nonpreferring animals were seen for both pairs of selected lines (P vs. NP; HAD2 vs. LAD2), but these differences were not identical in the two line pairs. For example, although P rats showed shorter free-running periods than NP rats only in constant light, HAD2 rats showed shorter free-running periods than LAD2 rats only in constant darkness. In addition, ethanol-preferring HAD2 rats showed a high rate of rhythm "splitting" that was not seen in any of the other three lines. Taken together, these results suggest that the circadian pacemakers of P and NP rats differ mainly in light sensitivity, whereas those of HAD2 and LAD2 rats differ in their intrinsic period.

Camphor: an herbal medicine causing grand mal seizures.

Camphor is usually used in the USA to repel insects, but it is widely used in other countries as an herb. We report the case of a 52-year-old previously healthy Nepali man who ingested approximately 10 g of pure camphor with therapeutic intention. He developed grand mal seizures, and was evaluated in an emergency room. He failed to recall the camphor ingestion initially, and was treated with phenytoin for new-onset idiopathic seizures. Examining physicians only later found out about his camphor ingestion. Finding the cause of new-onset seizures is often challenging for emergency room physicians, internists and neurologists. In addition to other well-reported causes of secondary seizures, herbal medications and supplements must also be explored.

Broad range of inhibiting action of novel camphor-based compound with anti-hemagglutinin activity against influenza viruses in vitro and in vivo.

Influenza virus continues to remain one of the leading human respiratory pathogens causing significant morbidity and mortality around the globe. Due to short-term life cycle and high rate of mutations influenza virus is able to rapidly develop resistance to clinically available antivirals. This makes necessary the search and development of new drugs with different targets and mechanisms of activity. Here we report anti-influenza activity of camphor derivative 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol (camphecene). In in vitro experiments it inhibited influenza viruses A(H1, H1pdm09, H3 and H5 subtypes) and B with EC50's lying in micromolar range. Due to low cytotoxicity it resulted in high selectivity indices (74-661 depending on the virus). This effect did not depend on susceptibility or resistance of the viruses to adamantane derivatives amantadine and rimantadine. The compound appeared the most effective when added at the early stages of viral life cycle (0-2h p.i.). In direct hemagglutinin inhibition tests camphecene was shown to decrease the activity of HA's of influenza viruses A and B. The activity of camphecene was further confirmed in experiments with influenza virus-infected mice, in which, being used orally by therapeutic schedule (once a day, days 1-5 p.i.) it decreased specific mortality of animals infected with both influenza A and B viruses (highest indices of protection 66.7% and 88.9%, respectively). Taken together, these results are encouraging for further development of camphecene-based drug(s) and for exploration of camphor derivatives as highly prospective group of potential antivirals.

Confirmation of uterotrophic activity of 3-(4-methylbenzylidine)camphor in the immature rat.

In this study we found that the ultraviolet sunscreen component 3-(4-methylbenzylidine)camphor (4MBC) is uterotrophic in immature rats when administered by either subcutaneous injection or oral gavage. These data confirm earlier reports of uterotrophic activity for this agent when administered to immature rats in the diet or by whole-body immersion; however, they are in contrast to negative unpublished immature rat uterotrophic assay results. Data also indicate that 4MBC binds to isolated rat uterine estrogen receptors and shows activity in a human estrogen receptor yeast transactivation assay; however, we considered both of these effects equivocal. In this study, we confirmed the original observation that 4MBC was active as a mitogen to MCF-7 breast cancer cells. We evaluated and discounted the possibility that the estrogenic activity of 4MBC is related to its bulky camphor group, which is of similar molecular dimensions to that of the weak estrogen kepone. Uncertainty remains regarding the mechanism of the uterotrophic activity of 4MBC.