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Integration of herbal medicine into modern medical practices: issues and prospects.

The integration of herbal medicine into modern medical practices including cancer treatments must take into account the interrelated issues of quality, safety, and efficacy. Quality is the paramount issue because it can affect the efficacy and/or safety of the herbal products being used. Current product quality ranges from very high to very low due to intrinsic, extrinsic, and regulatory factors. Intrinsically, species differences, organ specificity, diurnal and seasonal variations can affect the qualitative and quantitative accumulation of active chemical constituents in the source medicinal plants. Extrinsically, environmental factors; field collection methods such as cultivation, harvest, post-harvest transport and storage; manufacturing practices; inadvertent contamination and substitution; and intentional adulteration are contributing factors to the quality of herbal medicinal products. Source plant materials that are contaminated with microbes, microbial toxins, environmental pollutants, or heavy metals; or finished products that are adulterated with foreign toxic plants or synthetic pharmaceutical agents can lead to adverse events. Substandard source materials or finished products will yield therapeutically less effective agents. Herbal medicine quality can also be attributed to regulatory practices. In a number of countries, herbal medicines are unregulated, which has led to product quality differences. Product quality improvement may be achieved by implementing control measures from the point of medicinal plant procurement under good agricultural practices (GAPs) and the manufacture of the finished botanical products under good manufacturing practices (GMPs), plus post-marketing quality assurance surveillance. The lack of pharmacological and clinical data on the majority of herbal medicinal products is a major impediment to the integration of herbal medicines into conventional medical practices. For valid integration, pharmacological and especially, clinical studies, must be conducted on those plants lacking such data. Adverse events, including drug-herb interaction must also be monitored to promote a safe integration of efficacious herbal medicine into conventional medical practices.

Delivery of Health Care, Integrated↗

The harmful potential of herbal and other plant products.

Herbs, herbal products, food additives and other dietary supplements derived from plants are widely consumed in many countries. The literature on intoxications from such behaviour is increasing. This article reviews some of the factors predisposing to intoxication from the use of herbs, with examples drawn largely from pyrrolizidine alkaloid-containing plants. Poisonings occur because of the misidentification of a plant, or the unknown or ignored toxicity of a correctly identified plant. Factors contributing to problems include the difficulties of identifying chopped, processed herbs or plant mixtures, persistent use of a toxic plant, variability in the toxic constituents of a plant, problems of nomenclature, adulteration and the difficulty in establishing the chronic toxic potential of a plant. Certain users of herbs are at high risk of intoxication. These include chronic users, those consuming large amounts or a great variety, the very young, fetuses, the elderly, the sick, the malnourished or undernourished and those on long term medication. Members of certain cultural groups in North America are also at higher risk. Certain plant toxins may be gender-selective in their action. To encourage discussion, some approaches to regulation are suggested, and some commonsense guidelines are given.

Humans↗

Authentic identification of stigma Croci (stigma of Crocus sativus) from its adulterants by molecular genetic analysis.

Stigma Croci, stigma of Crocus sativus L., is a precious traditional Chinese medicine, which is commonly used to activate blood circulation and to dissipate blood stasis. Three plant species, Carthamus tinctorius L., Hemerocallis fulva (L.) L. and Hemerocallis citrina Baroni, could carry the name Stigma Croci in the commercial markets of South East Asia. However, C. sativus is the only one that has proven its effectiveness, while the others could act as adulterants. The authentic identification of C. sativus on the market is difficult. By using molecular genetic method, the spacer domains of 5S-rRNA were cloned from the genomic DNAs that were isolated from C. sativus, C. tinctorius, H. fulva and H. citrina. The cDNAs encoding the spacer domains, about 300 to 500 bp, were sequenced. The nucleotide sequences of these four species showed great diversity, which could serve as markers for authentic identification of Stigma Croci to distinguish from its substitution and counterfeit.

Drugs, Chinese Herbal↗

Structure elucidation of a novel analogue of sildenafil detected as an adulterant in an herbal dietary supplement.

A new analogue of sildenafil was detected in an herbal dietary supplement, which was sold over the internet and promoted as a product for the enhancement of sexual performance. The structure of the compound was established using LC-MS, UV spectroscopy, MS-MS, and NMR. In addition, the compound was cleaved at its sulfonamide S-N bond yielding a sulfonic acid and an amine, which were independently characterized using LC-MS, GC-MS, and derivatization. The compound, named methisosildenafil, is a novel synthetic analogue of sildenafil in which the N-methylpiperazine moiety has been replaced with 2,6-dimethylpiperazine.

Chromatography, Liquid↗

High ethanol preferring rats fail to show dependence following short- or long-term ethanol exposure.

AIMS: The high ethanol preferring (HEP) rat shows high total ethanol consumption, high spontaneous activity and high consumption of novel tastants. Because these animals consume large quantities of ethanol daily, we sought to determine whether they could become alcohol-dependent by repeated exposures of varying lengths and withdrawals of alcohol, both in short- and long-term ethanol exposure. METHODS: Male and female HEP rats were subjected to short (14 days) or long (20 weeks) exposure to 10% ethanol in a two choice (vs. water) test. During the short- and long-term ethanol exposures, the animals were repeatedly deprived of ethanol for 5 days followed by reinstatement of the two-choice test. Moreover, pharmacological interventions (morphine and naltrexone), adulteration of ethanol by quinine and addition of saccharine to water were applied to test the lability of a possible alcohol deprivation effect. RESULTS: In every case, deprivation produced a high initial intake of ethanol that lasted 0.5 h, but thereafter no significant increase in alcohol consumption, compared to predeprivation. Even after several months of continuous drinking of large amounts of ethanol, the animals were sensitive to adulteration of the alcohol solution by quinine, that reduced the intake, and still preferred a saccharine solution when presented as a free choice with the alcohol solution. Pretreatment with morphine increased ethanol consumption in the first 0.5 h following deprivation, whereas naltrexone reduced it. CONCLUSIONS: Taste reinforcement is probably a major component of alcohol drinking by the HEP rats, and that while these rats consume large quantities of ethanol both in the short- and long-term, they do not show a robust alcohol deprivation effect.

Alcohol Drinking↗

Diethylene glycol poisoning in Nigerian children.

Between June and September 1990, 47 children died at Jos University Teaching Hospital, Nigeria from ingestion of paracetamol syrup adulterated with diethylene glycol. Most of the children presented with anuria, fever, vomiting, diarrhoea and convulsions. Signs on admission were tachycardia, acidotic breathing, pallor, oedema and hepatomegaly. Laboratory findings included hyperkalaemia, acidosis, elevated creatinine level and hypoglycaemia. Management consisted of correction of dehydration and acidosis plus administration of antibiotics when indicated. None of the children had dialysis. All died within 2 weeks of admission. Proper government supervision of pharmaceutical companies and their agencies is urgently needed in order to prevent any future occurrence of such tragic deaths.

Acetaminophen↗

Plasticizers as contaminants in commercial ethanol.

A batch of 95% ethanol caused unusually strong disordering of biomembranes, which could be detected either by fluorescence anisotropy in synaptosomal membranes or by electron paramagnetic resonance spectroscopy in erythrocyte membranes. The contaminated batches of ethanol were visibly fluorescent when evaporated on filter paper. The adulterants were separated by capillary gas chromatography and the ubiquitous pollutant dioctylphthalate was identified by its low resolution electron impact mass spectrum. The remaining peaks, which were not recognized by any of the available mass spectral libraries, were identified by high resolution electron impact and chemical ionization mass spectrometry and low resolution tandem mass spectrometry using fast atom bombardment ionization; they were triethylene glycol esters and aryl phosphates. All the contaminants are industrial plasticizers. Distillation resulted in loss of the strong disordering properties of the alcohol.

Animals↗

Protoporphyrin hepatopathy. Effects of cholic acid ingestion in murine griseofulvin-induced protoporphyria.

Short-term effects of cholic acid ingestion on hepatic accumulation, fecal excretion, and blood levels of protoporphyrin were studied in vivo in griseofulvin-induced protoporphyric mice. Experimental mice that received feed with 2% griseofulvin and 0.5% cholic acid were compared with control mice that received feed with 2% griseofulvin for 4 wk. Five mice from each group were assessed each week for liver and blood porphyrin levels. Fecal protoporphyrin was compared weekly in the total pooled output of each population. Mean protoporphyrin levels were significantly lower for liver (P less than 0.0001), erythrocytes (P less than 0.05), and plasma (P less than 0.05), and higher for feces (P less than 0.001) for the mice that were fed cholic acid. Microscopic protoporphyrin deposits, inflammation, necrosis, and dysplasia were more severe in livers of control mice. A second experimental design compared four regimens in the feed given to all mice after 1-wk induction with 2% griseofulvin: (a) 0.5% cholic acid, (b) no adulterant, (c) 2% griseofulvin and 0.5% cholic acid, and (d) 2% griseofulvin. No difference in protoporphyrin removal from livers of mice in groups 1 and 2 was observed after 1 and 2 wk of these regimens. The apparent reduction in hepatic protoporphyrin content in mice of group 3 as compared with group 4 at weeks 2 and 3 was not significant at P less than 0.05. These data suggest that in selected circumstances, hepatic protoporphyrin secretion may be enhanced in protoporphyric disease states by bile salt supplementation.

Animals↗

Changes in place of origin of heroin seized in Denmark from 1981 to 1986. "Chemical fingerprint" of 138 samples.

Hundred thirty-eight samples of heroin weighing more than 0.1 g seized between 1981 and 1986 were characterized according to their contents of opium alkaloids, adulterants, and diluents together with their form and color. The "chemical fingerprint" was used to establish a change in the heroin during the period. As compared to the first few years covered by the survey, a predominant number of the samples at the end of the period were in the base form and contained the opium alkaloids papaverine and noscapine. In particular, the concentration of noscapine as related to the heroin content of each sample had increased considerably, indicating Pakistan or Iran as being the places of origin of most of the heroin seized in Denmark at the end of the period.

Chemical Phenomena↗

Methadone and metabolite urine concentrations in patients maintained on methadone.

As regulatory control over methadone maintenance relaxes, the need for methods of monitoring compliance will increase. In community clinics, monitoring would most likely involve immunoassays of outpatients' trough urine specimens. There are no published norms for such data. Therefore, we determined concentrations of methadone in 1093 urine specimens collected thrice weekly in 27 outpatients during up to 17 weeks of observed methadone ingestion (35 to 80 mg/day) using a semiquantitative homogeneous enzyme immunoassay (CEDIA). We used a separate CEDIA assay to measure methadone's main metabolite, 2-ethylidene-3,3-diphenylpyrrolidine (EDDP), which may help detect compliance in fast metabolizers or patients who adulterate samples to simulate compliance. Methadone concentrations were more variable than those of EDDP. Concentrations of methadone were < 100 ng/mL in one specimen, between 100 and 300 ng/mL in 27, and >or= 300 ng/mL in all others. EDPP concentrations were >or= 100 ng/mL in all specimens, suggesting that EDDP should be detectable in urine from compliant patients. Methadone and EDDP concentrations significantly increased with methadone dose and (in one participant with poor clinic attendance) significantly decreased following missed methadone doses. Nevertheless, variability was too great to permit estimation of methadone dose (or detect a single missed administration) from any single specimen.

Drug Monitoring↗

Seizure of illicitly produced para-fluorofentanyl: quantitative analysis of the content of capsules and tablets.

A gas chromatography/mass spectrometry (GC/MS) method for the quantification of para-fluorofentanyl (pFF) in powder and powdered samples was developed and validated. The method was applied on a seizure of capsules and tablets, that had been confiscated at an illicit production site in the Netherlands. The investigated capsules and tablets contained pFF in the range of 33.8-408.7 microg. As caffeine was detected as being an adulterant, a HPLC/UV method for the quantification of caffeine in capsules and tablets was also validated and applied. Caffeine was detected in the range of 25.6-108 mg per capsule or tablet. Based on an extrapolation of pharmacological and toxicological data of fentanyl, it can be argued that the highest detected single dose of pFF could be lethal, when administered orally. However, the large variability of the doses observed for pFF could mislead abusers, potentially leading to multiple doses and thus overdosing.

Caffeine↗

Effects of T-2 toxin on saccharin aversion and food consumption in adult rats.

The present experiment used a saccharin aversion paradigm to evaluate the potential aversive action of T-2 toxin, a trichothecene mycotoxin that induces emesis and weight loss. Adult male rats were fed either a control diet or a diet adulterated with 640 ppm lithium chloride (positive control) or with 2.5, 5.0 or 10.0 ppm T-2 toxin and given access to a 0.1% saccharin solution and to tap water during four training days. The rats were then shifted to the control diet during three extinction days. Moderate saccharin aversion induced by the positive control diet and the 5.0 and 10.0 ppm T-2 diets was apparent on the third day of exposure and the aversion to the saccharin solution abated during the extinction trials. Saccharin aversion was evident at levels of T-2 toxin that did not induce obvious tissue pathology.

Animals↗

Cocaine-induced heart disease: mechanisms and pathology.

Cocaine use has increased in recent years, in part as a result of the increased availability of "crack," the inexpensive freebase form. Although it is used medicinally and initially was considered a relatively safe street drug, cocaine clearly has addictive potential as well as adverse health consequences even in low doses. Some of its most serious adverse effects involve the cardiovascular system. Understanding the cellular mechanisms of the action of cocaine on the heart allows insight into the pathophysiology of its adverse effects. Blockade of sodium channels accounts for cocaine's anesthetic effects and acts directly on myocytes to impair action potential generation and conduction, predisposing to dysrhythmias. Blockade of neurotransmitter reuptake has many deleterious effects, including dysrhythmogenesis via increased intracellular calcium, myocardial ischemia via vasospasm and increased myocardial oxygen demand, and contraction band necrosis also via increased intracellular calcium. In addition, alterations in platelet-endothelial cell function predispose to coronary artery thrombosis and ischemia. Alterations in immune function of natural killer cells may, among other effects, predispose to the development of myocarditis, the etiology of which is probably multifactoral. Finally, a direct toxic effect of cocaine on myocytes may, in some cases, produce heart muscle dysfunction. These multiple mechanisms of action combined with the deleterious effects of often-present adulterants give rise to an unpredictable, variable, and potentially life-threatening cardiovascular response to cocaine administration.

Anesthesia, Local↗

Eating induced by injections of 2-deoxy-D-glucose in neurologically intact hypodipsic rats.

Neurologically intact rats were presented with a 0.2% (w/v) quinine adulterated water supply, and they failed to meter fluid consumption homeostatically in accordance with the elevated food intake that followed glucoprivation induced by 250, 500, and 750 mg/kg injections of 2-deoxy-D-glucose (2DG). These animals, nevertheless, were statistically indistinguishable from controls in the amount of food eaten following the 2DG treatments. These data suggest that the hypodipsia produced by some brain lesions is not a sufficient stimulus to produce the deficient glucoprivic feeding that accompanies such lesions; therefore, future lesion investigations that simultaneously yield hypodipsia and reduced eating in response to 2DG need not employ hypodipsic neurologically intact controls.

Animals↗

Chemical analysis of Radix Astragali (Huangqi) in China: a comparison with its adulterants and seasonal variations.

Radix Astragali (root of Astragalus; Huangqi) is a popular traditional Chinese medicine, and Astragalus membranaceus and A. membranaceus var. mongolicus are two commonly used species; however, there are many Astragalus species that could act as adulterants of Radix Astragali. To find the chemical composition of Radix Astragali, the main constituents including flavonoids, saponins, polysaccharides, amino acids, and trace elements were determined in two Radices Astragali, A. membranaceus and A. membranaceus var. mongolicus, and its eight adulterants, Astragalus propinquus, Astragalus lepsensis, Astragalus aksuensis, Astragalus hoantchy, Astragalus hoantchy subsp. dshimensis, Astragalus lehmannianus, Astragalus sieversianus, and Astragalus austrosibiricus. The results showed that the amounts of main constituents such as isoflavonoids and astragalosides varied in different species. In distinction, A. membranaceus and A. membranaceus var. mongolicus contained a higher amount of astragaloside I and IV. In addition, the main constituents of A. membranaceus var.mongholicus changed according to seasonal variation and age of the plant. The chemical composition of different species of Astragalus would provide useful information for the quality control of Radix Astragali.

Amino Acids↗

Component analysis of illicit heroin samples with GC/MS and its application in source identification.

A novel method based on GC/MS and GC for component analyses of seized illicit heroin was established by using SKF525A as an internal standard. The main components in illicit heroin products such as heroin, O3-acetylmorphine, monoacetylcodeine, and O6-acetylmorphine were determined quantitatively and the organic adulterants such as paracetamol, acetaminophen caffeine and theophylline were detected qualitatively using the developed method. With these obtained data, 500 seized illicit heroin samples were divided into nine groups. The decomposition pattern of heroin was studied. The dependencies of both the decomposition pattern and the content ratios of monoacetylcodeine to heroin and monoacetylcodeine to O6-acetylmorphine on the source of the seized illicit heroin were observed. This information was used to develop a novel method for its source identification. The examination results were in agreement with the practical cases, thus providing significant information for detection of criminal cases involving illicit heroin.

Acetaminophen↗

[Very low temperature (quick freezing) and pseudo-stabilization of the chemical composition of food of plant origin].

The consequences of freezing at -18, -30 degrees C are presented: slowing down or acceleration of enzymatic or non enzymatic reactions, concentration effect, consequences of the death of cells, (time--temperature relation). The most characteristic examples of nutritive value adulterations are presented: ascorbic and dehydroascorbic acids, other vitamins, derivatives of the insaturated fatty acids oxidation, changes in proteins. Other damages more related to sensorial quality are summarized: "chlorophyll, phenolic substances, aroma, pectins. These chemical changes occurring at low temperatures are generally less important than the losses in nutritional value of frozen plant products related to the necessary treatments preceding or following cold storage. Particularly, the losses during blanching and thawing (drip) are discussed. Finally, quick freezing as it is used now industrially does not exactly stabilize the nutritive quality of plant products but protects this quality satisfactorily. Progress is however possible, concerning the cold treatments (storage temperature lowering) and especially the losses before and after freezing and storage (blanching, transport, distribution, thawing).

Drug Stability↗

Do young heroin users in Madrid, Barcelona and Seville have sufficient knowledge of the risk factors for unintentional opioid overdose?

To identify the self-perceived reasons for unintentional opioid overdose of young heroin users in three Spanish cities and their agreement with objective risk factors for overdose. Computer-Assisted Personal Interviews (CAPI) were held with 991 street-recruited current heroin users aged 18-30. The general reasons for overdose and the reasons for the last overdose suffered were explored with open-ended (OEQs) and pre-coded questions (PCQs). Limited knowledge of overdose risk factors was defined as mention of fewer than two objective risk factors for unintentional overdose in the OEQ. Univariate, bivariate, and logistic regression methods were used. 77.8% (Seville), 64.9% (Madrid) and 57.2% (Barcelona) of participants have limited knowledge of overdose risk factors. Residence in Seville and not having attended courses or meetings on overdoses were significantly associated with limited knowledge, after adjusting for other factors. The most frequently identified general reasons in OEQ or PCQ were using heroin in large amounts (66.8%), together with tranquilizers (62.0%), adulterated (60.7%), or purer than usual (57.6%). Most reasons were selected more frequently in PCQ than in OEQ, especially rapid injection of the entire dose and using heroin shortly after using tranquilizers or alcohol, by injection, or after a period of abstinence. The results were similar for overdoses suffered by participants. Most young heroin users do not have sufficient knowledge of overdose risk factors, especially the use of heroin by injection, after a period of abstinence, or together with alcohol or methadone. Specific informational or educational programs adapted to the local context are critically needed.

Adolescent↗