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PubMed1992

Improved high-performance liquid chromatographic determination of khellin and visnagin in Ammi visnaga fruits and pharmaceutical formulations.

An improved, simple, selective, and sensitive reversed-phase high-performance liquid chromatographic (HPLC) assay for khellin and visnagin in Ammi visnaga L. fruits was developed by using an internal standardized technique. The HPLC column was a reversed-phase microBondapack C18 column, the mobile phase was water: methanol:acetonitrile (49:49:2), and the flow rate was 1.5 mL/min. Khellin and visnagin were detected and analyzed with a spectrophotometer set at 250 nm. Results of the HPLC analysis indicate a relative standard deviation of less than 0.04%. The analytical procedure was used for the quantification of khellin in various pharmaceutical dosage forms, such as ampules, tablets, and suppositories, with relative standard deviations of 1.2, 1.4, and 1.7%, respectively. As little as 10 ng of khellin or visnagin could be detected accurately in less than 13 min.

Calibration↗
PubMed1991

Effects of khellin on contractile responses and 45Ca2+ movements in rat isolated aorta.

The effects of khellin on contractile responses and 45Ca2+ flux have been studied in rat isolated aortae. Khellin (10(-5)-3.2 x 10(-4) M) produced a concentration-dependent inhibition of noradrenaline (10(-6) M) and high K+ (80 mM)-induced contractions. At 3.2 x 10(-4) M, khellin increased cAMP levels and reduced 45Ca2+ influx in resting tissues and in tissues stimulated by noradrenaline (10(-5) M) and high K+ without affecting basal 45Ca2+ efflux or noradrenaline induced 45Ca2+ efflux. It is concluded that in rat isolated aorta, khellin caused a non-specific inhibition of Ca2+ influx but may also exhibit intracellular actions, thus decreasing the availability of Ca2+ required for activation. One or more of these mechanisms may be related to an increase in intracellular cAMP levels.

Animals↗
PubMed1992

Hypocholesterolemic effect of khellin and methoxsalen in male albino rats.

Khellin (CAS 82-02-0) and methoxsalen (CAS 298-81-7) were examined in male albino rats to evaluate their ability to modify serum lipoprotein cholesterol. Clinical chemistry parameters were also measured to obtain information indicative of possible drug toxicity. The drugs were evaluated in four-week double dose studies. After four weeks at 0.45 mg/100 mg b.wt. for khellin and 0.27 mg/100 g b.wt. for methoxsalen, per day, both drugs significantly lowered low density lipoprotein cholesterol, high density lipoprotein cholesterol and total cholesterol. Very low density lipoprotein cholesterol and triglycerides were not changed. No apparent toxicity was observed as clinical chemistry parameters and body weights were not different compared to control values. Similar results were observed with a lower dose of khellin (0.23 mg/100 g b.wt./d). A dose of 0.13 mg/100 g b.wt./d of methoxsalen had no observable effect in this study. Confirmation of the hypocholesterolemic activity of khellin and methoxsalen in this study enhances the therapeutic potential of these compounds against atherosclerosis.

Animals↗
PubMed1988

Khellin, a naturally occurring furochromone, used for the photochemotherapy of skin diseases: mechanism of action.

Khellin, a naturally occurring furochromone, used in the past as a coronary vasodilator, has recently been used in the photochemotherapeutic treatment of vitiligo and psoriasis. With the aim of elucidating its mechanism of action, the interactions both in ground and excited states between the drug and DNA were studied in vitro. Khellin forms in the dark a molecular complex with DNA. By subsequent irradiation (365 nm) the drug photoconjugates covalently with the macromolecule, although the rate of photobinding is rather low. The in vivo photobinding of khellin to the DNA of Ehrlich ascites tumor cells is also low. In photoaddition with the macromolecule the drug forms inter-strand cross-links, although again in small amounts. The furan side monoadduct between khellin and thymine, formed in the photoreaction between the drug and DNA, was isolated and characterized, and shows a cis-syn configuration.

Animals↗
PubMed1980

Khellin determination in human serum and urine by high-performance liquid chromatography.

A rapid, sensitive, and specific high-performance liquid chromatographic method was developed for the determination of khellin in serum and urine using theophylline as the internal standard. Chromatography was performed on a reversed-phase C18 column with 65% (v/v) methanol as the mobile phase. The assay is capable of measuring khellin concentrations down to 100 ng/ml with a total procedure time of less than 20 min. Oral administration of 60 mg of khellin tablets to two healthy human males was carried out, and the serum samples were analyzed by the described method. Serum concentration-time profiles are presented.

Chromatography, High Pressure Liquid↗
PubMed1985

Active oxygen forms in photoreaction between DNA and furanochromones khellin and visnagin.

The two furanochromones khellin and visnagin react with DNA under irradiation by 365 nm light, forming photoadducts. Recently, the use of khellin as therapeutic agent for skin diseases has been proposed. It is well known that during the formation of photoadducts toxic active oxygen forms are produced. We studied therefore the behaviour of the two furanochromones as producers of 1O-2 and O-2. Our results indicate that visnagin is a strong generator of both superoxide radicals and singlet oxygen, while khellin does not exhibit strong production of OO-2, which is promptly quenched by superoxide dismutase.

Animals↗
PubMed1986

The mechanisms of interaction between furanochromones and DNA. A heteronuclear Overhauser effect study on the khellin-thymidine model system.

The furanochromones khellin and visnagin have been characterised by 1H and 13C mono- and bidimensional NMR spectroscopies. Their strong affinity with DNA was experimentally confirmed by the complete disappearance of the furano-chromones' NMR signals upon additions of DNA. An intermolecular interaction between furanochromones and the thymidyl moieties of DNA, stabilized by the formation of a hydrogen bond between the thymidyl NH hydrogen and the C = O group of khellin or visnagin, is here proposed. This is suggested by the strong donor-acceptor behavior of these two molecular moieties, as pointed out by a selective 1H-13C Overhauser effect study of the khellin-thymidine model system.

Carbon Isotopes↗
PubMed1990

Photosensitization of DNA of defined sequence by furochromones, khellin and visnagin.

The sequence specificity in the in vitro DNA photobinding of khellin and visnagin, two naturally occurring furochromones proposed for chemotherapy of vitiligo, was investigated by using DNA sequencing methodology. The 3'-5' exonuclease associated with the T4 DNA polymerase served as a tool for determining photoadducts distribution on DNA fragments of the lac I gene of Escherichia coli. The photoadduct distribution of psoralen is also studied for comparison. Upon UVA irradiation, visnagin mainly forms monoadducts with thymine and to a lower extent with cytosine. Alternating (A-T)n sequences are hot spots for visnagin photoaddition. This is a property shared with furocoumarins. TTT sites are also quite reactive to visnagin, as they are to methylated angelicins. In contrast, with psoralen derivatives, there is no preferential photobinding in 5'-TpA sites, and 5'-ApT sites react as well. Furthermore, many sites such as T in the GC context, and C in any context, react, although weakly. The visnagin photoadduct distribution resembles very much the photoadduct distribution of methylated angelicins as described by Miolo et al. The photoreaction of these two series of compounds is less sequence dependent than the photobinding of psoralen derivatives as described by Sage and Moustacchi and by Boyer et al. The sequence specificity in khellin-DNA photobinding is the same as for visnagin, even though it forms much fewer photoadducts. The absence of photo-oxidation of DNA after treatment with visnagin or khellin plus UVA suggests that furochromones do not present any photodynamic effect on DNA.

Base Sequence↗
PubMed1993

Photosensitized cleavage and cross-linking of pBR322 DNA with khellin and visnagin.

The naturally occurring furanochromones khellin and visnagin have received considerable attention, largely because of their vasodilatory properties and of their ability (particularly that of khellin) to induce skin pigmentation upon ultraviolet light treatment of patients suffering from vitiligo. There are conflicting statements in the literature on whether or not they are capable of cross-linking DNA photochemically. Supercoiled and linear pBR322 DNA was used to probe this reaction. The results showed that both khellin and, to a greater extent, visnagin photosensitized DNA cross-linking. In addition, both photosensitizers induced extensive DNA cleavage.

Cross-Linking Reagents↗
PubMed2002

Determination of khellin and visnagin in Ammi visnaga fruits by capillary electrophoresis.

A new, simple and rapid capillary electrophoresis method was developed for the identification and quantitative determination of two medically active constituents-khellin and visnagin-in the extracts of Ammi visnaga fruits. Micellar electrochromatographic separation of khellin and visnagin was carried out using 10 mmol/l borate, 50 mmol/l sodium dodecylsulfate, 25% (v/v) acetonitrile at pH 9 as running buffer. Ammi visnaga fruits were extracted with methanol and the extracts were directly injected without any purification and pre-separation processes. Coumarin was used as internal standard for quantitation and the limits of detection for khellin and visnagin were 2.36 and 1.97 microg/ml, respectively using UV detection at 245 nm.

Ammi↗
PubMed1996

Pertussis toxin reverses the inhibition of the adenylyl cyclase system by khellin in HeLa cells.

Khellin, a furochromone structurally related to furocoumarins, is a phototherapeutic agent used against psoriasis and vitiligo. This paper reports that pretreatment of HeLa cells with pertussis toxin reverses both the inhibition of NaF-stimulated adenylyl cyclase activity and the stimulation of GTPase by khellin alone and plus UVA light, as previously reported. Our results demonstrate, for the first time, that khellin is able to elicit an intracellular response by Gi alpha protein.

Adenylate Cyclase Toxin↗
PubMed2005

Nanosecond time-resolved infrared studies of visnagin and khellin triplets and radical ions.

Time-resolved infrared spectroscopy (TRIR) and density functional theory (DFT) calculations were used to directly observe and assign the vibrational spectra of the triplet states of visnagin and khellin, and to investigate their electron-transfer chemistry. The TRIR spectra of triplet visnagin and triplet khellin, and of their radical cations and anions, were obtained upon 266 nm laser flash photolysis in acetonitrile and in deuterated acetonitrile. The radical cations were observed in the presence of chloranil, and the radical anions were formed in the presence of NaI and KSCN. The TRIR spectra are in good agreement with the calculated vibrational spectra. We did not observe the related neutral radicals by TRIR spectroscopy upon laser flash photolysis (LFP) of khellin in the presence of hydroquinone, but we found evidence for the formation of semiquinone and neutral visnagin radicals upon LFP of visnagin and hydroquinone.

Ions↗
PubMed1988

Phototherapeutic, photobiologic, and photosensitizing properties of khellin.

Khellin, whose chemical structure closely resembles that of psoralen, is reported to be an efficient drug for treating vitiligo when combined with ultraviolet A irradiation. Photobiological activity on yeast is found to be much lower than that of bifunctional psoralens such as 5-methoxypsoralen. In vitro experiments reveal that khellin is a poor photosensitizer. It behaves as a monofunctional agent with respect to DNA photoaddition. It does not photoinduce cross-links in DNA in vitro or in Chinese hamster cells in vivo. This behavior may explain the low photogenotoxicity in yeast and the lack of phototoxic erythemal response when treating vitiligo with khellin.

Animals↗
PubMed1983

Preliminary report on the therapeutic effect of khellin in psoriasis.

A double-blind study has been performed to search for the possible effect of khellin in psoriasis. 10 patients were treated orally with khellin and subsequently exposed to sunlight for 4 months; a total of 8 cases responded positively with variable degrees of clearance. None of 10 controls had any response. A relapse-free duration of 3 years was recorded for 6 out of the 8 responders. This study would introduce the nonpsoralen compound khellin as a possible agent for the therapy of psoriasis.

Adolescent↗
PubMed1982

An approach to the treatment of vitiligo by khellin.

An anticipated effect of khellin, related to its chemical structure, in the photochemotherapy of amelanosis has been investigated. In a double-blind clinical study, khellin has been orally administered to 30 vitiligo patients for 4 months with subsequent exposure to natural sunlight. At the end of the trial period, 5 patients out of 30 (16.6%) repigmented 90-100%; 7 cases (23.3%) repigmented 50-60% of the vitiliginous areas treated; 11 (36.6%) repigmented 25% or less, and 7 subjects (23.3%) showed negative response. 30 control subjects failed to repigment at all. The achieved repigmentation was stable after drug cessation for a period of 1 year. These data add a previously unreported effect for the non-psoralen compound, khellin, in the therapy of vitiligo.

Adolescent↗
PubMed2003

Fluorometric determination of khellin in human urine and serum by high-performance liquid chromatography using postcolumn photoirradiation.

For the determination of khellin in urine and serum, fluorometry using HPLC-postcolumn photoirradiation has been developed. Khellin and visnagin of similar structure were separated on a column of Capcell Pak C8. The mobile phase consisted of 40%(v/v) ethanol containing 75 mmol l(-1) H2O2. The postcolumn reagent, 70 mmol l(-1) KH2PO4-NaOH buffer (pH 12.7) containing 50%(v/v) ethanol, were mixed with the mobile phase, which was irradiated with ultraviolet light to induce fluorescence. The fluorescence was monitored with excitation at 378 nm and emission at 480 nm. The calibration graph for khellin was linear over the range of 65 - 2620 ng ml(-1) using an injection volume of 20 microl. The pretreatment of the urine or serum samples consisted of diluting steps or deproteinizing steps using perchloric acid, respectively.

Calibration↗
PubMedDate not supplied

A case study to evaluate the treatment of vitiligo with khellin encapsulated in L-phenylalanin stabilized phosphatidylcholine liposomes in combination with ultraviolet light therapy.

Vitiligo destroys the melanocytes in the epidermis; the inactive melanocytes in the outer root sheaths are not affected. Phosphatidylcholine liposomes are able to target molecules contained in them into the hair follicles. Khellin is activated by UVA and previous studies have shown that a combination of khellin and UVA (KUVA) can be effective in the treatment of vitiligo. The aim of this study was to determine in an open trial the efficacy and safety of treatment with khellin encapsulated in L-phenylalanine stabilized phosphatidylcholine liposomes in combination with UVA/UVB light therapy(KPLUV) in 74 subjects with vitiligo. After a mean treatment period of 12 months (range 10-14 months) 72% of the treated locations had a repigmentation response of 50% to 100%. Repigmentation of 75-100% was achieved on the face in 63%, the back in 59%, the arms in 58%, the trunk in 57%, the legs in 56% and on the hands in 4% of the patients. Side effects were not seen with KPLUV. The patients in the control group, only treated with UVA/B-light, hardly showed any repigmentation. This indicates that the exposure of the skin to UV light alone is not responsible for the results of KPLUV.

Administration, Topical↗
PubMed1985

Comparative effects of khellin and timefurone on serum parameters in normal male cynomolgus monkeys.

Timefurone and khellin (10 mg/kg/day, gavage, 14 days) significantly lowered low density lipoprotein cholesterol, high density lipoprotein cholesterol, and total cholesterol. Khellin-induced changes were significantly greater than those induced by timefurone. Neither drug altered body weights or clinical chemistry parameters. Monkeys treated with khellin, however, exhibited elevated levels of very low density lipoprotein cholesterol and marked emesis, while no changes were observed with timefurone. On the basis of these data, timefurone has a better therapeutic ratio and further study with this promising drug appears warranted.

Animals↗