The potential agents from food for preventing leukopenia induced by benzene: garlic preparations.

Leukopenia is the early clinical manifestation of benzene poisoning. The aim of our research was to evaluate the preventive effects of three kinds of garlic preparations on benzene induced leukopenia. The mouse model of Leukopenia was established with benzene orally. At the same time, mice were administrated with garlic homogenate (GH), garlic oil (GO) or diallyl trisulfide (DATS) as preventional measures. The counts of white blood cells (WBC), the organ indexes, pathological examinations, blood biochemical parameters, weight gains, and food intakes were evaluated to observe the protective effect and potential adverse events. The results demonstrated that the counts of WBC increased by 144.04%, 140.07%, and 148.34%, respectively, after intervention by GH (400 mg/kg), GO (60 mg/kg) and DATS (30 mg/kg), compared with that in the model group. The spleen and thymus indexes in the benzene model group were 44.99% and 54.04% lower than those in the blank control group, the number of spleen nodules reduced and the thymus atrophy, which were restored by three garlic preparations at different degree. The results suggested that the three preparations all could prevent the leukopenia and protect the organ injuries induced by benzene. However, the spleen index and weight gains revealed that GH and GO brought more adverse events than DATS.

DADS suppresses human esophageal xenograft tumors through RAF/MEK/ERK and mitochondria-dependent pathways.

Diallyl disulfide (DADS) is a natural organosulfur compound isolated from garlic. DADS has various biological properties, including anticancer, antiangiogenic, and antioxidant effects. However, the anticancer mechanisms of DADS in human esophageal carcinoma have not been elucidated, especially in vivo. In this study, MTT assay showed that DADS significantly reduced cell viability in human esophageal carcinoma ECA109 cells, but was relatively less toxic in normal liver cells. The pro-apoptotic effect of DADS on ECA109 cells was detected by Annexin V-FITC/propidium iodide (PI) staining. Flow cytometry analysis showed that DADS promoted apoptosis in a dose-dependent manner and the apoptosis rate could be decreased by caspase-3 inhibitor Ac-DEVD-CHO. Xenograft study in nude mice showed that DADS treatment inhibited the growth of ECA109 tumor in both 20 and 40 mg/kg DADS groups without obvious side effects. DADS inhibited ECA109 tumor proliferation by down-regulating proliferation cell nuclear antigen (PCNA). DADS induced apoptosis by activating a mitochondria-dependent pathway with the executor of caspase-3, increasing p53 level and Bax/Bcl-2 ratio, and downregulating the RAF/MEK/ERK pathway in ECA109 xenograft tumosr. Based on studies in cell culture and animal models, the findings here indicate that DADS is an effective and safe anti-cancer agent for esophageal carcinoma.

Chk1, but not Chk2, is responsible for G2/M phase arrest induced by diallyl disulfide in human gastric cancer BGC823 cells.

Diallyl disulfide (DADS) has been shown to cause G2/M phase cell cycle arrest in several human cancers. Here we demonstrate a mechanism by which DADS induces G2/M phase arrest in BGC823 human gastric cancer cells via Chk1. From cell cycle gene array results, we next confirmed that cyclin B1 expression was decreased by DADS, while the expression of p21, GADD45α and p53 were increased. Despite the lack of change in Chk1 gene expression in response to DADS according to the array analysis, intriguingly overexpression of Chk1, but not Chk2, exhibited increased accumulation in G2/M phase. Moreover, overexpression of Chk1 promoted the effect of DADS-induced G2/M arrest. Augmented phosphorylation of Chk1 by DADS was observed in Chk1-transfected cells, followed by downregulation of Cdc25C and cyclin B1 proteins. In contrast, phosphorylated Chk2 showed no obvious change in Chk2-transfected cells after DADS treatment. Furthermore, knockdown of Chk1 by siRNA partially abrogated DADS-induced downregulation of Cdc25C and cyclin B1 proteins and G2/M arrest. In contrast, knockdown of Chk2 did not show these effects. Therefore, these data indicate that DADS may specifically modulate Chk1 phosphorylation, and DADS-induced G2/M phase arrest in BGC823 cells could result in part from Chk1-mediated inhibition of the Cdc25C/cyclin B1 pathway.

Delirium due to intoxication from the novel synthetic tryptamine 5-MeO-DALT.

Synthetic tryptamines have gained popularity for their hallucinogenic properties, unscheduled status, and availability from "head shops" and through the internet. Here, we present a case of synthetic tryptamine-induced delirium secondary to 5-MeO-DALT ingestion in a previously healthy young male. 5-MeO-DALT led to the hospitalization of our patient after ingestion of a standard dose, presenting with extreme agitation, tachycardia, diaphoresis, and combativeness leading to physical restraint and intravenous sedation. A search of PubMed, Ovid, and Google Scholar for keywords of "5-MeO-DALT," "5-methoxy-N,N-diallyltryptamine," or "Lucy-N-Nate" found no case reports or clinical articles in the literature. Rapid emergence and commercialization of this novel synthetic tryptamine 5-MeO-DALT points to the importance of health care and forensic professionals keeping abreast of the latest drugs of abuse and their clinical features. The authors hope this report leads the way in disseminating the potential risks associated with unscheduled and unregulated substances, synthetic tryptamines such as 5-MeO-DALT in particular.

Effect of Nigella sativa and Allium sativum coadminstered with simvastatin in dyslipidemia patients: a prospective, randomized, double-blind trial.

Dyslipidemia plays an important role in the provocation of cardiovascular disease. Psoriasis was associated with metabolic disorder and therefore the present study was performed to evaluate the therapeutic effect of combination of blackseed with garlic as a treatment for dyslipidemia. A randomized, double-blind, placebo controlled, two arms parallel study consisted of 4 week diet stabilization period that included a 4 week base line evaluation phase, followed by an 8 week treatment period. The study comprised men (n=127) and women (n=131) aged 24 to 57 years, who met the NCEP ATP III criteria for drug treatment of hyperlipidemia and dietary intervention. Three hundred patients were randomized to treatment and 258 completed the study. The lipid profile included total cholesterol, HDL-C, Non-HDL-C, LDL-C, and Triglyceride. There were no significant differences between the two treatment groups at the baseline for triglyceride, HDL, Non-HDL, LDL and total cholesterol. Following 8 weeks treatment with simvastatin plus placebo the reduction in Non-HDL, triglyceride, LDL and total cholesterol following treatment course was statistically highly significant (P= <0.01). However, the increase in HDL was significant (P=0.02). Patients who received simvastatin, plus black seed and garlic for 8 weeks of treatment show significant differences between baseline and after treatment course for all tested profiles (P=<0.01). This comparison of mean values reveals a high significant difference (P=<0.01) for cholesterol, triglyceride, Non-HDL, and LDL, and significant difference (P=0.03) for HDL between the two treatment groups. This study suggests that the evaluated combination was effective in correction of dyslipidemia. Large scale clinical trials comparing different doses are warranted.

Efficacy and tolerability of diphenyl-dimethyl-dicarboxylate plus garlic oil in patients with chronic hepatitis.

OBJECTIVE: To investigate the hepatoprotective effect, safety and tolerability of oral preparation comprising dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB) plus garlic oil (GO) in chronic hepatitis patients. METHODS: In this double-blind, placebo-controlled clinical trial conducted for 6 weeks with 1-week follow-up, a total of 88 patients with histologically confirmed chronic hepatitis and persistently elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were enrolled and randomly assigned to one of 4 treatment groups: placebo (Group A) and 3 escalating dose groups (2, 3, or 6 study drug capsules a day) (Groups B - D). Each study drug capsule contains 25 mg DDB plus 50 mg GO. Efficacy was assessed by monitoring changes in the circulating activities of ALT and AST as surrogate markers for liver injury. Safety and tolerability were assessed based on the evaluation of clinically adverse events and laboratory test results. RESULTS: Of 88 patients, 83 took at least one dose of study drug and 79 completed the study without any protocol violation. The majority of patients (81/83, 98%) had been infected with HBV. The proportions of patients whose ALT levels returned to normal ranges at Week 6, a primary outcome, were significantly different among 4 groups: 16% (3/19), 41% (9/22), 52% (11/21), and 88% (15/17) in Groups A, B, C, and D, respectively (p < 0.001). The proportions were significantly higher in Groups C (p = 0.022) and D (p < 0.001) but not in Group B compared to Group A. Interestingly, the proportion of Group D was higher than that of Group C (p = 0.034), suggesting a dose-response effect of DDB plus GO on the decrease of ALT levels. The mean ALT levels started to decrease from Week 1 in patients treated with DDB plus GO, whereas no decrease was seen in placebo group. The mean AST levels had a decreasing trend in all doses of DDB plus GO groups. Notably, patients treated with 6 capsules of DDB plus GO daily exhibited the statistically significant decrease in AST levels from Week 3. However, there was no difference in the proportions of patients with the AST decrease to normal ranges after 6-week therapy among 4 groups. The effects of DDB plus GO on decreases in ALT and AST levels lasted until 1 week after completion of treatment. Additionally, the ratios of ALT to AST gradually decreased in patients treated with DDB plus GO over time, suggesting higher degrees of reduction in ALT than in AST in those groups. No clinically meaningful adverse events and laboratory abnormalities were observed during the study period. CONCLUSIONS: The 6-week treatment of DDB plus GO lowered serum aminotransferase activities in patients with chronic hepatitis induced by HBV and/or HCV and was well tolerated. For the treatment of viral hepatitis patients, the optimal dose of this preparation was 3 to 6 capsules per day.

Dillapiole as antileishmanial agent: discovery, cytotoxic activity and preliminary SAR studies of dillapiole analogues.

In this paper, the isolation of dillapiole (1) from Piper aduncum was reported as well as the semi-synthesis of two phenylpropanoid derivatives [di-hydrodillapiole (2), isodillapiole (3)], via reduction and isomerization reactions. Also, the compounds' molecular properties (structural, electronic, hydrophobic, and steric) were calculated and investigated to establish some preliminary structure-activity relationships (SAR). Compounds were evaluated for in vitro antileishmanial activity and cytotoxic effects on fibroblast cells. Compound 1 presented inhibitory activity against Leishmania amazonensis (IC(50) = 69.3 µM) and Leishmania brasiliensis (IC(50) = 59.4 µM) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC(50) = 99.9 µM for L. amazonensis and IC(50) = 90.5 µM for L. braziliensis) and 3 (IC(50) = 122.9 µM for L. amazonensis and IC(50) = 109.8 µM for L. brasiliensis) were less active than dillapiole (1). Regarding the molecular properties, the conformational arrangement of the side chain, electronic features, and the hydrophilic/hydrophobic balance seem to be relevant for explaining the antileishmanial activity of dillapiole and its analogues.

Effect of diallyl trisulfide on the pharmacokinetics of dipyridamole in rats.

This study was aimed to evaluate the effect of diallyl trisulfide (DATS), a major component derived from garlic used to inhibit platelet thromboxane formation, on the pharmacokinetics of dipyridamole. Pharmacokinetic parameters of dipyridamole were determined in rats following intragastric (80 mg/kg suspension or 40 mg/kg solution) or intravenous (3 mg/kg) administration of dipyridamole with coadministration (20 mg/kg) and long-term pretreatment of DATS (10 or 20 mg/kg/day for 15 consecutive days). In addition, everted gut sac models were used to assess transepithelial transport of dipyridamole and the effect of DATS on the intestinal absorption of dipyridamole. After coadministration and long-term pretreatment of DATS, significantly lower Cmax and AUC(0-24 h) were observed for intragastric administration of dipyridamole, whereas little change was noted after intravenous dipyridamole administration. After adding DATS (10 and 50 µg/mL) in the everted gut sacs, absorption of dipyridamole was remarkably decreased in the ileum and jejunum (p < 0.01). In conclusion, DATS reduced the oral exposure of dipyridamole in rats likely by the modification of the dissolution rate and intestinal absorption of dipyridamole, indicating that combined use of DATS or DATS-containing supplements with dipyridamole may require caution as low plasma concentrations of dipyridamole may lead to a subtherapeutic effect of this agent.

Effect of diallyl trisulfide on the pharmacokinetics of nifedipine in rats.

This study aimed to evaluate the effect of diallyl trisulfide (DATS), a major component derived from garlic, on the pharmacokinetics of nifedipine. Pharmacokinetic parameters of nifedipine were determined in rats following an oral gavage (3 mg/kg) or intravenous administration (0.75 mg/kg) of nifedipine with co-administration of DATS (20 mg/kg) and long-term pretreatment of DATS (20 mg/kg/d for 15 consecutive days). Compared to the control groups, higher C(max) and AUC(0-24 h) were observed for oral gavage of nifedipine after short-term and long-term pretreatment of DATS, whereas those for intravenous nifedipine were little changed. The oral bioavailabilities of nifedipine were remarkably enhanced via the concomitant use of DATS. In conclusion, DATS increased the oral exposure of nifedipine in rats likely by the modification of intestinal metabolism of nifedipine, indicating that combined use of DATS or DATS-containing supplement with nifedipine may require caution because high plasma concentrations may lead to an undesired toxicity of this agent. Practical Application: Patients suffering from cardiovascular disease should take caution in combined use of DATS or DATS-rich garlic supplement with nifedipine because long-term treatment of DATS could lead high plasma concentrations of nifedipine.

The composition of oil phase modulates venous irritation of lipid emulsion-loaded diallyl trisulfide.

INTRODUCTION: In this study, a nanoemulsion system (LE) was investigated for intravenous delivery of diallyl trisulfide (DT), which was a lipophilic and venous irritant drug for systemic therapy of bacterial and fungal infection. METHODS: Egg phospholipid was chosen as the only emulsifier, soybean oil, medium chain triglyceride (MCT), and olive oil were used as the oil phases, forming stable DT LEs (o/w) with small particle sizes. The venous irritation of DT LEs was evaluated by in vitro human umbilical cord endothelial cells (HUV-EC CRL 1730) tolerance model with the intracellular ATP and GTP concentrations as the indices. RESULTS: The intracellular ATP and GTP reduction changed with the incorporation of a variety of oils, which were strongly related with the free DT concentration of DT LEs. DISCUSSION: It was deduced that the free DT concentrations of LEs made of various oils depended on the particle sizes of the DT LEs. In conclusion, the oil phases modulated the free DT concentrations by forming DT LEs with different particle sizes, and optimization of the oil phase was an effective method to alleviate the venous irritation of DT LEs.

Efficacy of niosomal formulation of diallyl sulfide against experimental candidiasis in Swiss albino mice.

AIM: We developed a niosomal formulation of diallyl sulfide (DAS), a garlic oil component, and evaluated its efficacy against experimental candidiasis in mice. METHODS: DAS-bearing niosomes prepared from sorbitan monoester surfactants were evaluated for drug entrapment efficiency, release kinetics, toxicity, size, zeta-potential and others. Mice challenged with Candida albicans were treated with various DAS formulations. The efficacy of the formulations was assessed on the basis of reduction in mortality and decrease in residual fungal load in vital organs, such as liver and spleen, of treated mice. RESULTS: Niosomal DAS (12 mg/kg body weight) significantly reduced fungal load and mortality in treated animals compared with the free form of DAS. Niosomal DAS was also found to be free of toxic manifestations, as revealed by histopathological studies, as well as liver/kidney function tests. CONCLUSION: Incorporation of DAS in niosomes enhances its antifungal efficacy. Further studies are needed to optimize the current findings to develop an efficient nature-derived alternative antifungal therapeutic strategy.

[Patterns of biochemical disorders under exposure to neurotoxic chemicals varying in nature].

The article covers results of examination of workers engaged into chemical production and contacting neurotoxic factors varying in nature. Findings are disorders of cholesterol metabolism in individuals engaged into vinylchloride and metallic mercury production, modified protein metabolism, activated lipid peroxidation and depressed antioxidant

Reduced allergy rates in atopic eczema to contact allergens used in both skin products and foods: atopy and the 'hapten-atopy hypothesis'.

BACKGROUND: Food allergy is strongly associated with atopy. This retrospective study investigates whether atopic status affects responses to contact allergens also found in food. We compared incidences of atopic dermatitis/eczema (AD) in subjects who were patch-test positive (PT+) to diallyl disulfide from handling garlic and parabens used as a skin cream/ointment and food preservative with the incidence in those subjects who were PT+ to chemicals encountered at skin surfaces (lanolin and nickel). RESULTS: 36,658 patients with eczema/dermatitis were patch tested (1980-2006). 10,326 (28.2%) had AD. 13/83 (15.6%) PT+ subjects to diallyl disulfide/garlic had AD (AD/total population versus AD/diallyl disulfide PT+, P = 0.011). 54/239 parabens PT+ had AD (22.6%), while 181/608 lanolin PT+ had AD (29.8%) (P < 0.05). CONCLUSIONS: Contact allergy to haptens with oral and skin exposure is reduced in AD compared with non-AD, unlike food protein hypersensitivity. Lanolin frequency was not decreased. Possible explanations include (i) confounding factors, e.g. AD subjects handle garlic less than non-AD subjects, or (ii) AD patients tolerate haptens efficiently, secondary to their atopic status, or (iii) oral tolerance of haptens antagonizes tolerance of food proteins, contributing to development of atopy (hapten-atopy hypothesis). The recent upsurge of atopy took place when gut exposure to haptens in processed foods increased dramatically.

The soil ecotoxicology of 1,3-dichloropropene under commercial growing conditions.

Soil fumigants are used extensively in the protection of crops against parasitic nematodes and other soil borne pests. The active ingredient in Telone II soil fumigant is 1,3-Dichloropropene (1,3-D) which has a wide range of uses in Europe as a pre-plant nematocide. During the use of soil fumigants such as 1,3-D a range of non-target soil dwelling organisms has the potential to be exposed and impacted. We report here the results of a field study conducted in Italy to assess the impact of 1,3-D applications to soil-dwelling non-target organisms. This study was conducted under conditions of commercial tomato growing either without (untreated control) or with an application of 1,3-D at 224 kg a.i./hectare. Samples of arthropods and earthworms were taken before and up to 12 months after application to measure season long effects. A soil sample was taken at 4.5 months and a soil function test performed. By evaluating the effects of 1,3-D both in the Laboratory and under field conditions equivalent to commercial practices it was concluded that applications of 1,3-D would not adversely effect soil arthropods, but may have an effect on earthworms and soil microflora. These effects were, however, transient as full recovery was observed within six months of application for earthworms and 4.5 months for soil microflora. Consequently, the risk to non-target soil micro- and macro-organisms was considered acceptable according to current risk assessment guidelines within the European Union.

Effects of garlic oil on platelet aggregation: a double-blind placebo-controlled crossover study.

The use of antiplatelet therapies decreases the incidence of mortality in persons prone to cardiovascular events. Several in vitro studies suggest that garlic may decrease platelet aggregation. We aimed to test the acute effects of garlic on platelet aggregation in 14 healthy volunteers using a randomised, double-blind, placebo-controlled, crossover research method. The active agent tested was solvent-extracted garlic oil incubated in ethanol to obtain organosulphur compounds that demonstrate the highest antiplatelet activity when tested in vitro. Platelet aggregation was induced ex vivo by adrenaline, collagen or adenosine diphosphate (ADP). Four hours after consuming one large dose of oil derived from 9.9 g garlic, there was little or no effect in the reduction of platelet aggregation. Platelet aggregation induced by adrenaline was reduced slightly but significantly (P<0.05; 12% reduction). The oil had no effect on collagen- or ADP-induced aggregation. The results of this controlled trial indicate that this type of garlic oil should not be relied on in persons with conditions in which reductions in platelet aggregation are desired or necessary.

Use of gloves in protection from diallyl disulphide allergy.

Contact dermatitis, particularly affecting the fingertips, is a recognized presentation of garlic allergy. There have been no recommendations in the literature with respect to the type of gloves that offer the best protection against diallyl disulphide, the major allergen in garlic and onion. In fact, we have found that diallyl disulphide penetrates most commercially available glove types. Silver laminate gloves offered only slightly better protection.