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Prevalence of complementary and alternative medicine use among HIV patients for perceived lipodystrophy.

BACKGROUND: Complementary and alternative medicine (CAM) use is common among some patients who test positive for human immunodeficiency virus (HIV). Changes in body-fat distribution can occur in some patients on prolonged highly active antiretroviral therapy. Currently, there are fewer effective treatments for the condition. Patients with lipodystrophy may be turning to CAM. OBJECTIVE: The objective was to investigate the prevalence and perceived benefit of CAM use for perceived body-shape changes among a cohort of HIV-positive patients. DESIGN/SETTING/SUBJECTS: We surveyed a cross-sectional convenience sample of 74 patients from urban and suburban HIV outpatient clinics in Baltimore, MD, who indicated concerns about body-shape changes. The survey instrument was developed based on validated questionnaires previously used in clinical trials and published work. RESULTS: CAM use including both supplements and visits to CAM providers was 74% in our study population. In multivariate analysis, users of CAM were more likely to be men (p = 0.016) and to have noticed bodyshape changes after taking HIV medications (p = 0.012). However, very few subjects reported using CAM specifically for lipodystrophy changes. CAM use was more commonly reported for "general health." CAM was primarily more conventional, such as multivitamins or minerals, but several subjects reported using meditation and/or prayer (38%), ginseng (Panax spp.) (3%), St John's wort (Hypericum perforatum) (1%), and acupuncture (1%). More conventional CAM, such as exercise, diet, and vitamins as well as meditation/prayer were perceived to be effective for lipodystrophy as well as for improving the overall sense of well-being. CONCLUSIONS: The rate of CAM use among the HIV-positive population is high and is primarily used to improve general health.

Adult↗

The methodological quality of randomized controlled trials of homeopathy, herbal medicines and acupuncture.

BACKGROUND: To investigate the methodological quality of randomized controlled trials in three areas of complementary medicine. METHODS: The methodological quality of 207 randomized trials collected for five previously published systematic reviews on homeopathy, herbal medicine (Hypericum for depression, Echinacea for common cold), and acupuncture (for asthma and chronic headache) was assessed using a validated scale (the Jadad scale) and single quality items. RESULTS: While the methodological quality of the trials was highly variable, the majority had important shortcomings in reporting and/or methodology. Major problems in most trials were the description of allocation concealment and the reporting of drop-outs and withdrawals. There were relevant differences in single quality components between the different complementary therapies: For example, acupuncture trials reported adequate allocation concealment less often (6% versus 32% of homeopathy and 26% of herb trials), and trials on herbal extracts had better summary scores (mean score 3.12 versus 2.33 for homeopathy and 2.19 for acupuncture trials). Larger trials published more recently in journals listed in Medline and in English language scored significantly higher than trials not meeting these criteria. CONCLUSION: Trials of complementary therapies often have relevant methodological weaknesses. The type of weaknesses varies considerably across interventions.

Acupuncture Therapy↗

Natural and complementary therapies for substance use disorders.

PURPOSE OF REVIEW: To review recent studies that have examined the efficacy of natural and complementary therapies as treatments for substance use disorders and their complications. RECENT FINDINGS: Despite increasing interest in natural and complementary therapies for substance use disorders, rigorous clinical studies in this area are few in number. Recent clinical studies, although preliminary, have reported potential therapeutic effects for hypericum in the treatment of smoking cessation, for prickly pear extract in the prevention of alcohol hangover and magnesium supplementation as an adjunct to methadone treatment. Other clinical studies have reported negative findings for ginkgo as an adjunctive treatment for cocaine dependence, for artichoke in prevention of alcohol hangover, and acupuncture for alcohol withdrawal. Relevant findings from animal studies are also discussed. Neither vitamin E nor Liv 52 had a useful effect in alcohol-related liver disease. A study of silymarin in baboons, which was undertaken in an attempt to untangle the conflicting findings of human studies, reported a potential for this compound to prevent liver injury. There is increasing awareness of safety issues associated with complementary therapies. Safety issues pertinent to substance use treatment are discussed in this review. SUMMARY: Several pharmacological and psychosocial treatments for substance use disorders are solidly evidence-based and improve both individual and public health outcomes. At this stage, there remains insufficient evidence to support the use of natural and complementary therapies as a primary intervention for substance use disorders. Further clinical trials are required to clarify the potential role of particular agents.

Journal Article↗

Molecular cloning and characterization of norcoclaurine synthase, an enzyme catalyzing the first committed step in benzylisoquinoline alkaloid biosynthesis.

(S)-Norcoclaurine synthase (NCS) (EC 4.2.1.78) catalyzes the condensation of 3,4-dihydroxyphenylethylamine (dopamine) and 4-hydroxyphenylacetaldehyde (4-HPAA) as the first committed step in the biosynthesis of benzylisoquinoline alkaloids such as morphine, sanguinarine, and berberine, in plants. A molecular clone encoding NCS was isolated from a meadow rue (Thalictrum flavum ssp. glaucum) cell suspension culture cDNA library. Heterologous expression of the NCS cDNA, truncated to remove a putative signal peptide, produced a recombinant protein with NCS activity. Recombinant NCS showed sigmoidal saturation kinetics for dopamine (Hill coefficient=1.98), hyperbolic saturation kinetics for 4-HPAA (Km of 700 microm), and pH and temperature optima of 7.0 and 40 degrees C, respectively, all similar to the purified, plant-derived enzyme. NCS exhibits 28-38% identity, and putative structural homology, with the Bet v 1 allergen and pathogenesis-related (PR)10 protein families. NCS also displays 35% identity with the enzyme (HYP1) responsible for hypericin biosynthesis in St John's wort (Hypericum perforatum). The novel catalytic functions of NCS and HYP1 define a new class of plant secondary metabolic enzymes within the Bet v 1 and PR10 protein families. Weaker homology was also detected between NCS and proteins identified in the latex of Papaver somniferum (opium poppy), and in Arabidopsis thaliana. A family of three to five NCS genes is abundantly expressed in the rhizome, followed by petioles and roots of T. flavum. NCS transcripts were localized to the immature endodermis and pericycle in roots, and the protoderm of leaf primordia in rhizomes; thus, the sites of NCS gene expression and berberine accumulation are temporally and spatially separated in roots and rhizomes respectively.

Alkaloids↗

Antispasmodic and bronchodilator activities of St John's wort are putatively mediated through dual inhibition of calcium influx and phosphodiesterase.

The crude extract of aerial parts of St John's wort (Hypericum perforatum) (Hp.Cr) and its fractions were studied in vitro for its possible spasmolytic and bronchodilator activities to rationalize some of its medicinal uses. In rabbit jejunum preparations, Hp.Cr caused a concentration-dependent relaxation of both spontaneous and K+ (80 mm)-induced contractions at a similar concentration range (0.1-1.0 mg/mL), similar to that produced by papaverine, whereas verapamil was relatively potent against K+-induced contractions. Hp.Cr shifted the Ca2+ concentration-response curves (CRCs) to the right, similar to that caused by papaverine or verapamil and also caused leftward shift of isoprenaline-induced inhibitory CRCs, similar to papaverine. In guinea-pig tracheal preparations, Hp.Cr caused relaxation of carbachol and K+-induced contractions at similar concentrations (0.01-0.3 mg/mL) and also shifted the isoprenaline-induced inhibitory CRCs to the left, similar to that caused by papaverine. In rabbit aorta preparations at rest, Hp.Cr produced a moderate vasoconstriction, while exhibited vasodilator effect against phenylephrine and K+-induced contractions. Papaverine and verapamil also produced similar non-specific vasodilation, but were devoid of any vasoconstrictor effect. Hp.Cr caused suppression of atrial force of contractions at concentrations about 20 times higher than those that produced inhibitory effect in smooth muscle preparations, similar to papaverine. These results suggest that the spasmolytic effects of Hp.Cr are mediated through dual inhibition of calcium influx and phosphodiesterase (PDE)-like mechanisms, which might explain the medicinal use of St John's wort in the disorders of gastrointestinal and respiratory tracts. Furthermore, the presence of Ca2+ antagonist and PDE inhibitory-like constituents might also be contributing to some extent in the well established use of plant in depression.

Animals↗

Novel therapeutic and diagnostic applications of hypocrellins and hypericins.

Hypocrellins and hypericins, structurally related plant pigments isolated from Hypocrella bambuase and Hypericum respectively, are known photodynamic agents. This review summarizes certain significant advances in the photophysics, photochemistry and photobiology of these pigments in the last 2 years and discusses their prospects as novel therapeutic and diagnostic agents in the future. Recently, certain unique properties of hypocrellins and hypericins have been explored for a variety of therapeutic and diagnostic applications. In particular, substantial progress has been made in both anticancer and antiviral applications (especially anti-human immunodeficiency virus). The promising anticancer and antiviral results obtained both in vitro and in vivo have led to intensive investigation into their photo-physical and photochemical processes, especially kinetic studies of their intramolecular proton transfer. These compounds offer the potential for a highly sensitive fluorescent redox sensor for investigation of a variety of cellular events. The biomedical advances of hypocrellins and hypericins have been further promoted by significant progress in their chemical synthesis and the recent commercialization of hypocrellins A and B and hypericin.

Animals↗

In vitro metabolism of hyperforin in rat liver microsomal systems.

Hyperforin is an important active component of St. John's wort (Hypericum perforatum) that has been suggested to be responsible for the St. John's wort antidepressive effects and herbal-drug interactions. In this study, the in vitro metabolism profile of hyperforin was investigated using liver microsomes from male and female Sprague-Dawley rats, with or without induction by phenobarbital or dexamethasone. Four major Phase I metabolites, named 19-hydroxyhyperforin, 24-hydroxyhyperforin, 29-hydroxyhyperforin, and 34-hydroxyhyperforin, were isolated by high performance liquid chromatography and identified by mass spectrometry and NMR. Results suggest that hydroxylation is a major biotransformation of the hyperforin pathway in rat liver and that inducible cytochrome P450 3A (CYP450 3A) and/or CYP2B may be the major cytochrome P450 isoforms catalyzing these hydroxylation reactions.

Animals↗

Pharmacokinetics, safety, and antiviral effects of hypericin, a derivative of St. John's wort plant, in patients with chronic hepatitis C virus infection.

Hypericin is a natural derivative of the common St. Johns wort plant, Hypericum perforatum. It has in vitro activity against several viruses, including bovine diarrhea virus, a pestivirus with structural similarities to hepatitis C virus (HCV). We conducted a phase I dose escalation study to determine the safety and antiviral activity of hypericin in patients with chronic HCV infection. The first 12 patients received an 8-week course of 0.05 mg of hypericin per kg of body weight orally once a day; 7 patients received an 8-week course of 0.10 mg/kg orally once a day. At the end of the 8-week period of treatment, no subject had a change of plasma HCV RNA level of more than 1.0 log(10). Five of 12 subjects receiving the 0.05-mg/kg/day dosing schedule and 6 of 7 subjects receiving the 0.10-mg/kg/day dosing schedule developed phototoxic reactions. No other serious adverse events associated with hypericin use occurred. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 h, respectively, for the doses of 0.05 and 0.1 mg/kg) and mean area under the curve determinations of 1.5 and 3.1 microg/ml x hr, respectively. In sum, hypericin given orally in doses of 0.05 and 0.10 mg/kg/d caused considerable phototoxicity and had no detectable anti-HCV activity in patients with chronic HCV infection.

Adolescent↗

Systematic reviews of herbal medicines--an annotated bibliography.

OBJECTIVE: To provide a comprehensive collection and a summary of systematic reviews of clinical trials on herbal medicines. METHODS: Potentially relevant reviews were searched through the register of the Cochrane Complementary Medicine Field, the Cochrane Library, Medline, and bibliographies of articles and books. To be included articles had to review prospective clinical trials of herbal medicines; had to describe review methods explicitly; had to be published; and had to focus on treatment effects. Information on conditions, interventions, methods, results and conclusions was extracted using a pretested form and summarized descriptively. RESULTS: From a total of 79 potentially relevant reviews preselected in the screening process 58 met the inclusion criteria. 30 of the reports reviewed ginkgo (for dementia, intermittent claudication, tinnitus, and macular degeneration), hypericum (for depression) or garlic preparations (for cardiovascular risk factors and lower limb atherosclerosis). The quality of primary studies was criticized in the majority of the reviews. Most reviews judged the available evidence as promising but definitive conclusions were rarely possible. CONCLUSIONS: Systematic reviews are available on a broad range of herbal preparations prescribed for defined conditions. There is very little evidence on the effectiveness of herbalism as practiced by specialist herbalists who combine herbs and use unconventional diagnosis.

Clinical Trials as Topic↗

Treatment of depression.

Depressions are the most common psychiatric diseases. For treatment, plant extracts have been used for thousands of years: examples are extracts from the (sleeping) poppy (opium), deadly nightshade (Atropa belladonna), Indian hemp (hashish), henbane (hyoscyamine), thorn apple (scopolamine), and St. John's wort (hypericum oil). In addition, psychotherapeutic measures, like playing music, dancing, playing theatre, and also the temple sleep, were used. In the 19th century, the introduction of brome (1826), codeine (1832), chloral hydrate (1869), and paraldehyde (1882), as well as the barbiturates (at the turn of the century) introduced significant improvements in pharmacotherapy. The modern thymoleptica therapy started in 1957 with the introduction of imipramine. Now about 40 active antidepressants are marketed. New drug developments should be characterized mainly by an improvement in tolerance.

Antidepressive Agents↗

Systematic reviews of complementary therapies - an annotated bibliography. Part 2: herbal medicine.

BACKGROUND: Complementary therapies are widespread but controversial. We aim to provide a comprehensive collection and a summary of systematic reviews of clinical trials in three major complementary therapies (acupuncture, herbal medicine, homeopathy). This article is dealing with herbal medicine. Potentially relevant reviews were searched through the register of the Cochrane Complementary Medicine Field, the Cochrane Library, Medline, and bibliographies of articles and books. To be included articles had to review prospective clinical trials of herbal medicines; had to describe review methods explicitly; had to be published; and had to focus on treatment effects. Information on conditions, interventions, methods, results and conclusions was extracted using a pre-tested form and summarized descriptively. RESULTS: From a total of 79 potentially relevant reviews pre-selected in the screening process 58 met the inclusion criteria. Thirty of the reports reviewed ginkgo (for dementia, intermittent claudication, tinnitus, and macular degeneration), hypericum (for depression) or garlic preparations (for cardiovascular risk factors and lower limb atherosclerosis). The quality of primary studies was criticized in the majority of the reviews. Most reviews judged the available evidence as promising but definitive conclusions were rarely possible. CONCLUSIONS: Systematic reviews are available on a broad range of herbal preparations prescribed for defined conditions. There is very little evidence on the effectiveness of herbalism as practised by specialist herbalists who combine herbs and use unconventional diagnosis.

Herbal Medicine↗

Herbal remedies in the United States: potential adverse interactions with anticancer agents.

PURPOSE: Interest in the use of herbal products has grown dramatically in the Western world. Recent estimates suggest an overall prevalence for herbal preparation use of 13% to 63% among cancer patients. With the narrow therapeutic range associated with most anticancer drugs, there is an increasing need for understanding possible adverse drug interactions in medical oncology. METHODS: In this article, a literature overview is provided of known or suspected interactions of the 15 best-selling herbs in the United States with conventional allopathic therapies for cancer. RESULTS: Herbs with the potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome p450 isozymes) and/or the drug transporter P-glycoprotein include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), St John' s wort (Hypericum perforatum), and kava (Piper methysticum). All of these products participate in potential pharmacokinetic interactions with anticancer drugs. CONCLUSION: It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care.

Antineoplastic Agents↗

Nelumbinis Semen reverses a decrease in hippocampal 5-HT release induced by chronic mild stress in rats.

Depression is associated with a dysfunctional serotonin system. Recently, several lines of evidence have suggested that a very important evoking factor in depression may be a serotonin deficit in the hippocampus. This study assessed the antidepression effects of Nelumbinis Semen (NS) through increasing serotonin concentrations under normal conditions and reversing a decrease in serotonin concentrations in rat hippo-campus with depression-like symptoms induced by chronic mild stress (CMS). Using an in-vivo microdialysis technique, the serotonin-enhancing effect of NS on rat hippocampus was investigated and its effects compared with those of two well-known antidepressants, Hypericum perforatum (St John's wort) and fluoxetine (Prozac). Rats were divided into five groups: saline-treated normal, without CMS; saline-treated stress control; NS-, St John's wort- and fluoxetine-treated rats under CMS for 8 weeks or no stress treatment. NS and fluoxetine significantly increased serotonin in normal conditions and reversed a CMS-induced decrease in serotonin release in the hippocampus (P<0.05 compared with normal group or control group under CMS). These results suggest that NS increases the serotonin levels normally decreased in depression, resulting in an enhancement of central serotonergic transmission and possible therapeutic action in depression. It is suggested that NS may present an antidepressant effect through enhancement of serotonin.

Animals↗

Phytomedicine research in Germany.

In Germany since 1980, more than 300 clinical studies have been carried out with standardized phytopharmaceuticals, including Crataegus, Silybum, Ginkgo, Hypericum, Sabal, Urtica, Kava-Kava, Allium sativum, Valeriana, Aesculus, Echinacea, and Viscum drugs. These studies assessed the efficacy of phytopharmaceuticals for the treatment of moderate or moderately severe diseases and prevention. Several comparative clinical trials showed that these phytopharmaceuticals had full therapeutic equivalence with chemotherapeutics and had the simultaneous advantage of being devoid of any adverse effects. The mechanism of action of herbal drugs and their extract preparations, which differ in many respects from that of synthetic drugs or mono substances, can be characterized as a polyvalent action and interpreted as additive or, in some cases, potentiating. Currently, a rationale for the observed reversal effects and optimal effects with very low doses after a long-term application has not been developed, but is under investigation by systematic research at the molecular level.

Clinical Trials as Topic↗

Naturopathic treatment for ear pain in children.

OBJECTIVE: Otitis media is 1 of the most frequent diseases of early infancy and childhood and 1 of the most common reasons for children to visit a physician. In the past 2 decades, there has been a substantial increase in the diagnosis of otitis media worldwide. In the United States, 93% of all children have had at least 1 episode of acute otitis media (AOM) by 7 years of age. Otalgia is the hallmark of AOM. Most affected children either complain of earache or manifest behavior that the parents interpret as indicating ear pain. Treatment of the ear pain early in the course of AOM decreases both parental anxiety and the child's discomfort and accelerates the healing process. The objective of this study was to determine the efficacy and tolerability of naturopathic versus traditional treatment for the management of otalgia commonly associated with AOM in children. METHODS: The study was designed as a double-blind trial in an outpatient community clinic. A total of 171 children who were aged 5 to 18 years and had otalgia and clinical findings associated with middle-ear infection were studied. The children were randomly assigned to receive treatment with Naturopathic Herbal Extract Ear Drops (NHED) or anesthetic ear drops, with or without amoxicillin. On enrollment, the children were assigned by computer-numbered randomization to receive NHED (contents: allium sativum, verbascum thapsus, calendula flores, hypericum perfoliatum, lavender, and vitamin E in olive oil) 5 drops 3 times daily, alone (group A) or together with a topical anesthetic (amethocaine and phenazone in glycerin) 5 drops 3 times daily (group B), or oral amoxicillin 80 mg/kg/d (maximum 500 mg/dose) divided into 3 doses with either NHED 5 drops 3 times daily (group C) or topical anesthetic 5 drops 3 times daily (group D). A double-blind design was used, and all ear drops were placed in identical bottles. Treatment was initiated by the nurse in all cases. A single physician (M.S.) evaluated and treated all of the patients included in the study and recorded all of the data. The presence or absence of ear pain was assessed over 3 days with a visual analog scale. Ear pain was assessed by a specially devised observational instrument based on previous reports. One side of the instrument consisted of a linear numbered scale, from 1 (no pain) to 10 (worst possible pain), and a corresponding color scale, ranging from blue to dark red. The reverse side contained a scale of 5 facial expressions, ranging from broad smile (no pain) to a sad and crying face (worst possible pain), and a corresponding color scale, ranging from blue to dark red. RESULTS: There were no significant between-group differences in patient age or gender, degree of fever, main symptoms, associated symptoms, and severity or laterality of acute otitis media. Each group had a statistically significant improvement in ear pain over the course of the 3 days. Patients who were given ear drops alone had a better response than patients who were given ear drops together with amoxicillin. Results were better in the NHED group than in the controls. Nevertheless, the findings indicated that the pain was mostly (80%) self-limited and could be explained simply by the time elapsed. The American Academy of Otolaryngology-Head and Neck Surgery guidelines recommend topical medications as the first line of treatment for ear pain in the absence of systemic infection or serious underlying disease. Because no evidence was found that systemic antibiotics alone improved treatment outcome, if antibiotics do not change the natural course of otitis media, then the main goal of treatment, as in the present study, should be to alleviate the ear pain. The alternative, naturopathic herbal extract medications, may offer many new possibilities in the management of ear pain associated with AOM. Primary care physicians should be aware that at least 10% of their patients may have tried 1 or more forms of alternative/complementary medicine before presenting for consultation. As it was widely reported in the medical literature, these herb, these herbal extracts have the potential to meet all of the requirements of appropriate medication that could be routinely used in the pediatric patient, namely in vitro bacteriostatic and bacteriocidal activity against common pathogens, immunostimulation ability, antioxidant activity, and anti-inflammatory effects. They are also well-absorbed with good penetration into the tissue surrounding the tympanic membrane. They have been found to enhance local immunologic activity. Finally, herbal extracts are well-tolerated (owing to their long elimination time), easy to administer, and less expensive than the new antibiotics. There are no documented side effects. On the basis of our findings that the group with the most significant treatment effects (NHED with topical anesthetic) explained only 7.3% of the total pain reduction, we propose that sometimes the general practitioner or pediatrician needs to give the human body a chance to repair itself. Nevertheless, if the physician believes that there is an indication for some treatment, especially if the parents are anxious, then a local treatment such as one used in our study might be adequate. CONCLUSIONS: This study suggests that in cases of ear pain caused by AOM in children in which active treatment, besides a simple 2- to 3-day waiting period, is needed, an herbal extract solution may be beneficial. Concomitant antibiotic treatment is apparently not contributory.

Acute Disease↗

Photosensitized structural modifications of the lens protein alpha-crystallin: do all modifications impair chaperone-like activity?

Among chaperone-like functioning proteins, the lens alpha-crystallins are of particular interest because they are not renewed, and even minor alterations can hurt their function of maintaining the proper refractive index and avoiding cataract formation in the lens. Several reports have suggested the occurrence of remarkable structural modifications in lens proteins in the presence of endogenous and exogenous sensitizers upon exposure to light. In particular, it has been shown in vitro that hypericin, the active ingredient of Hypericum, can bind to and, in the presence of light, cause the photopolymerization of alpha-crystallin. On the basis of these results it has also been suggested that a subsequent significant impairment of the protein function can occur. Using absorption and emission spectroscopic techniques, as well as circular dichroism, we have studied the structural modifications of alpha-crystallin resulting from its interaction with hypericin after irradiation with visible light. To investigate the chaperone-like function of alpha-crystallin, the heat-induced aggregation kinetics of another lens protein, betaLow-crystallin, was monitored by measuring the apparent absorption due to scattering at 360 nm as a function of time, and no apparent damage to its functional role was observed. Spectroscopic results, on the contrary, show a prominent reduction in both tryptophan and hypericin fluorescence emission intensity after light irradiation, suggesting an alteration in the tryptophan microenvironment and a high degree of packing of the chromophore due to photoinduced modification of the molecular framework. Control experiments on alpha-crystallin structurally modified by light in the presence of hypericin indicated that the protein still retains its ability to chaperone both lens crystallins and insulin.

Animals↗

Potentiation of photodynamic therapy with hypericin by mitomycin C in the radiation-induced fibrosarcoma-1 mouse tumor model.

Hypericin, a polycyclic quinone obtained from plants of the genus Hypericum, has been shown to be a promising photosensitizer. We investigated the combination of hypericin-photodynamic therapy (PDT) and a bioreductive drug mitomycin C (MMC) in the present study. The radiation-induced fibrosarcoma-1 tumors were exposed to laser light (120 J/cm2 at 595 nm) 24 h after an intravenous injection of hypericin (1 mg/kg). Hypericin-PDT alone significantly decreased tumor perfusion and oxygen tension as demonstrated by India ink staining technique and OxyLite pO2 measurement, respectively. The in vivo-in vitro cell-survival assay revealed about 60% direct tumor cell killing immediately after PDT. No significant delayed tumor cell death was observed after PDT, which suggests that vascular damage does not contribute significantly to the overall tumor cell death. Injection of a 2.5 mg/kg dose of MMC 20 min before light application significantly decreased tumor cell survival and delayed tumor growth compared with PDT or MMC alone. No greater skin reaction was observed after the combination of MMC and PDT than after PDT alone. Our study demonstrates that combining hypericin-PDT with MMC can be effective in enhancing tumor response with little side effect.

Animals↗

Characterization of apoptosis induced by photodynamic treatment with hypericin in A431 human epidermoid carcinoma cells.

Hypericin is a naturally occurring metabolite extracted from Hypericum plants and is regarded as a promising photosensitizing agent for applications in the frame of photodynamic treatment (PDT). This treatment procedure is based on the light-induced formation of reactive oxygen species and subsequent destruction of target cells. We used an in vitro model system consisting of human epidermoid carcinoma cells (A431) and hypericin as a photosensitizer to study the time- and dose-dependent characteristics of hypericin-PDT-based induction of cytotoxicity and apoptotic cell death. The induction of apoptosis by hypericin-PDT was found to follow a strict dose-dependent manner with a transition to necrotic cell death at higher doses. Apoptosis was analyzed by characteristical biochemical and morphological markers (activation of caspases, nuclear fragmentation and membrane blebbing). Time-course analysis of an almost homogenous apoptotic population of cells (at 1.44 J/cm2) showed a rapid increase in nuclear fragmentation and activation of caspases reaching a maximum at 5 hr after irradiation. Using specific caspase substrates, significant activation of caspase-2, -3, -6, and -9 was found. Mitochondrial involvement during hypericin-PDT-induced apoptosis could be proven by a rapid reduction of the mitochondrial membrane potential; interestingly, the level of intracellular adenosine-5'-triphosphate (ATP) remains at control level for up to 6 hr post irradiation suggesting upregulation of glycolysis as a compensating mechanism of energy supply. Our data contribute to a deeper understanding of the processes involved in apoptotic cell death following photodynamic treatment with hypericin.

Adenosine Triphosphate↗