Effect of Pulicaria mauritanica on Glucose Metabolism and Glycogen Content in Streptozotocin-Induced Diabetic Rats.

AIMS: The study aimed to assess the antihyperglycemic activity of Pulicaria mauritanica. BACKGROUND: Pulicaria mauritanica is a medicinal and aromatic plant used for the treatment of many diseases such as inflammation, diabetes, and intestinal disorders. OBJECTIVE: The main goals of this present paper were to confirm the antihyperglycemic capacity of aqueous extract from Pulicaria mauritanica in normoglycemic and diabetic rats over a period of time (7 days of treatment). METHODS: The effect of the aqueous extract of Pulicaria mauritanica from aerial parts (AEPM) on glucose and lipid metabolism was tested using an acute test (single dose during 6 hours) and subchronic assay (repeated oral administration for seven days) at a dose of 60 mg/kg and the serum glucose levels were measured in normoglycemic and streptozotocin(STZ)-induced diabetic rats. In addition, the glycogen content in the liver, extensor digitorum longus (EDL), and soleus was evaluated. The antioxidant activity, phytochemical screening, and quantification of some secondary metabolites of this extract were also performed. RESULTS: AEPM at a dose of 60 mg/kg reduced the plasma glucose concentrations significantly in STZ-induced diabetic rats after a single oral administration (p<0.05). This lowering effect became more significant during the repeated oral administration in hyperglycemic rats (p<0.0001). Also, the findings showed that this plant exhibited a significant increase in liver and skeletal soleus muscle glycogen content in diabetic rats. AEPM revealed a remarkable antioxidant activity in addition to the presence of polyphenol compounds such as flavonoids, tannins, saponins, sterols, glucides, terpenoids, quinones, anthraquinones, and mucilage. CONCLUSION: The study shows that AEPM exhibits antihyperglycemic activity in diabetic rats, and it increases liver and muscle glycogen content.

Reactive metabolite of gefitinib activates inflammasomes: implications for gefitinib-induced idiosyncratic reaction.

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been approved for non-small cell lung cancer. Although EGFR TKIs are less toxic than traditional cytotoxic therapies, they cause many severe idiosyncratic drug reactions. Reactive metabolites can cause cellular damage with the release of danger-associated molecular patterns (DAMPs), which is thought to be involved in immune activation. Inflammasomes can be activated by DAMPs, and this may be a common mechanism by which DAMPs initiate an immune response. We tested the ability of afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib to induce the release of DAMPs that activate inflammasomes. Human hepatocarcinoma functional liver cell-4 (FLC-4) cells were used for bioactivation of drugs, and the detection of inflammasome activation was performed with the human macrophage cell line, THP-1 cells. Gefitinib is known to be oxidized to a reactive iminoquinone metabolite. We found that the supernatant from the incubation of gefitinib with FLC-4 cells for 7 days led to increased caspase-1 activity and production of IL-1ß by THP-1 cells. In the supernatant of FLC-4 cells with gefitinib, the heat shock protein (HSP) 40, 70 and 90 were significantly increased. In addition, activated THP-1 cells secreted high mobility group box 1 (HMGB1) protein. These results support the hypothesis that the reactive iminoquinone metabolite can cause the release of DAMPs from hepatocytes, which in turn, can activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by gefitinib, which in some patients, can cause immune-related adverse events.

Pharmacokinetics and derivation of an anticancer dosing regimen for the novel anti-cancer agent isobutyl-deoxynyboquinone (IB-DNQ), a NQO1 bioactivatable molecule, in the domestic felid species.

Isobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB-DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable anticancer agent. First, using feline oral squamous cell carcinoma (OSCC) as a comparative cancer model, expressions of NQO1 were characterized in not only human, but also feline OSCC tissue microarrays. Second, IB-DNQ mediated cytotoxicity in three immortalized feline OSCC cell lines were studied under dose-dependent and sequential exposure conditions. Third, the feasibility of administering IB-DNQ at doses predicted to achieve cytotoxic plasma concentrations and biologically relevant durations of exposure were investigated through pharmacokinetic and tolerability studies in healthy research felines. Intravenous administration of IB-DNQ at 1.0-2.0 mg/kg achieved peak plasma concentrations and durations of exposure reaching or exceeding predicted in vitro cytotoxic concentrations. Clinical adverse side effects including ptyalism and tachypnea exhibited during and post-IV infusion of IB-DNQ were transient and tolerable. Additionally, IB-DNQ administration did not produce acute or delayed-onset unacceptable hematologic, non-hematologic, or off-target oxidative toxicities. Collectively, the findings reported here within provide important safety and pharmacokinetic data to support the continued development of IB-DNQ as a novel anticancer strategy for NQO1 expressing cancers.

On mechanisms of reactive metabolite formation from drugs.

Idiosyncratic adverse drug reactions (IADRs) cause a broad range of clinically severe conditions of which drug induced liver injury (DILI) in particular is one of the most frequent causes of safety-related drug withdrawals. The underlying cause is almost invariably formation of reactive metabolites (RM) which by attacking macromolecules induc eorgan injuries. Attempts are being made in the pharmaceutical industry to lower the risk of selecting unfit compounds as clinical candidates. Approaches vary but do not seem to be overly successful at the initial design/synthesis stage. We review here the most frequent categories of mechanisms for RM formation and propose that many cases of RMs encountered within early ADME screening can be foreseen by applying chemical and metabolic knowledge. We also mention a web tool, SpotRM, which can be used for efficient look-up and learning about drugs that have recognized IADRs likely caused by RM formation.

Allergic contact dermatitis to plants: understanding the chemistry will help our diagnostic approach.

Allergic contact dermatitis due to plants is common. Potentially allergenic plants and plant products are found in many everyday environments, such as the home, the garden, the workplace, and recreational settings. By improving our knowledge of allergenic plant-derived chemical compounds, we will be better positioned to identify novel allergens. We review the most relevant chemical allergens that contribute to plant allergic contact dermatitis and propose a clinical classification system based on 5 major families of chemical sensitizers: α-methylene-γ-butyrolactones, quinones, phenol derivatives, terpenes, and miscellaneous structures (disulfides, isothiocyanates, and polyacetylenic derivates). We also describe the different clinical pictures of plant allergic contact dermatitis and review currently available patch test materials. A better understanding of the specific allergens involved in plant allergic contact dermatitis will help to predict cross-reactivity between different plant species or families.

Pharmacokinetic properties of hydroxysafflor yellow A in healthy Chinese female volunteers.

ETHNOPHARMACOLOGICAL RELEVANCE: Hydroxysafflor yellow A (HSYA) was isolated from the dried flower of Carthamus tinctorius L. which was extensively used in traditional Chinese medicine to treat diseases due to blood stasis. However, there have been few detailed pharmacokinetic studies about HSYA on human beings. AIM OF THE STUDY: The aim was to investigate the pharmacokinetic characteristics of HSYA in healthy Chinese female volunteers. MATERIALS AND METHODS: The volunteers were given intravenous infusion of single doses of safflor yellow injection (containing HSYA 35, 70 and 140 mg) in separate trial periods with 1 week washout period. The concentration levels of HSYA in plasma were determined with HPLC. Various pharmacokinetic parameters were estimated from the plasma concentration versus time data using non-compartmental methods. RESULTS: The C(max) values were 2.02+/-0.18, 7.47+/-0.67 and 14.48+/-4.71 microg/mL after the administration of single doses of 35, 70, and 140 mg of HSYA, respectively. The corresponding values of AUC(0-15 h) were 6.57+/-1.20, 25.90+/-4.62 and 48.47+/-12.11 microg/(mL h(-1)), and the values of t(1/2) were 3.21+/-1.26, 3.33+/-0.68 and 2.98+/-0.09 h. The Student-Newman-Keuls test results showed that C(max) and AUC(0-15 h) were both linearly related to dose. CONCLUSIONS: In this study, the pharmacokinetic properties of HSYA are based on first-order kinetics over the dose range tested.

[Dermatitis Caused by Hair Dye (Quinone Produced by the Action of Aqueous Hydrogen Peroxide on p-Phenylenediamine Hydrochloride), by Juan de Azúa]. / Dermitis producida por una tintura para el pelo. (Quinona resultante de la acción del agua oxigenada sobre el clorhidrato de parafenileno-diamina), por Juan de Azúa.

In the first issue of Actas Dermo-Sifiliográficas, Juan de Azúa published a magnificent article on contact dermatitis caused by hair dyes, which reflects his profound knowledge of allergy and how the skin responds to chemical stimuli. It gives a brilliant description of irritative and allergic dermatitis, although without naming the allergic form explicitly. Of note is how he is concerned about the composition of <>; so much so that he contacted the local laboratory to determine their chemical composition and how they work. It is a delight to study the case histories and treatments administered to these 15 patients. During the months of treatment, he reports trying different officinal formulas that, although unknown to most of today's dermatologists, nevertheless managed to cure the patients in the end.

The induction of heat shock proteins as a potential strategy to treat neurodegenerative disorders.

Neurodegenerative diseases, whether acute or chronic, are a tremendous medical problem in the modern world. Therapies are rare and only applied after a vast amount of neurons are lost. Many efforts have been made to develop new strategies to treat these disorders, but so far, there has been no breakthrough. A characteristic shared by some experimental neuroprotective substances is the induction of the heat shock response, in particular the expression of the heat shock proteins Hsp70 and Hsp27. These Hsps protect cells from cell death induced by various noxious stimuli and inhibit various cellular death pathways. Gene therapy, transgenic mice and drugs inducing Hsps in the brain decrease the infarction area after ischemia and protect neurons and nonneuronal cells of the brain. Furthermore, recent data hint toward a protective role of Hsps in chronic neurological diseases. The induction of Hsps as a possible treatment for stroke, Alzheimer's disease and Huntington's disease is discussed.

Initiating activity of 4-chlorobiphenyl metabolites in the resistant hepatocyte model.

We recently reported that several mono- to tetrachlorinated biphenyls have initiating activity in the livers of Fischer 344 rats. In the present study, we investigated the metabolic activation of one of those compounds, 4-chlorobiphenyl (PCB 3). Monohydroxy (400 micromol/kg), dihydroxy (200 micromol/kg), and quinone (100 micromol/kg) metabolites of PCB 3 were evaluated for their initiating activity. Fischer 344 male rats were fasted for 4 days; 24 h after feeding again, they were injected (ip) with metabolites, vehicle, or diethylnitrosamine (DEN, 20 or 40 mg/kg). All animals were treated with selection agents as follows: three daily p.o. doses of 2-acetylaminofluorene (2-AAF, 30 mg/kg), followed by a single p.o. dose of carbon tetrachloride (2 ml/kg) and three additional daily treatments of 2-AAF. Rats were killed 2 weeks after the last 2-AAF intubation. Livers were evaluated for changes in morphology, and the number and volume of gamma-glutamyl transpeptidase-positive foci were measured. Of the metabolites tested, only one monohydroxy and one quinoid metabolite showed initiating activity. The metabolic activation of PCB 3, therefore, proceeds via parahydroxylation and oxidation to the ortho 3,4-quinone, the ultimate carcinogen. This is the first report to demonstrate that specific PCB metabolites possess initiating activity in the rodent liver in vivo. The results support the conclusion that 4-OH PCB 3 and 3,4-BQ PCB 3 act as proximate and ultimate carcinogenic metabolites resulting from the bioactivation of PCB 3 in rat liver.

Oxidative DNA damage induced by benz[a]anthracene metabolites via redox cycles of quinone and unique non-quinone.

Benz[a]anthracene (BA) is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) that are ubiquitous environmental pollutants. PAH carcinogenesis is explained by DNA adduct formation by PAH diol epoxide and oxidative DNA damage by PAH o-quinone. Benz[a]anthracene-trans-3,4-dihydrodiol (BA-3,4-dihydrodiol) is a minor metabolite but shows higher mutagenicity and tumorigenicity than parent BA. We confirmed that a BA o-quinone type metabolite, benz[a]anthracene-3,4-dione (BA-3,4-dione), induced oxidative DNA damage in the presence of cytochrome P450 reductase. Interestingly, we found that BA-3,4-dihydrodiol nonenzymatically caused Cu(II)-mediated DNA damage including 8-oxo-7,8-dihydro-2'-deoxyguanosine formation and the addition of NADH enhanced DNA damage. BA-3,4-dihydrodiol induced a double-base lesion of C and G at the 5'-ACG-3' sequence complementary to codon 273 of the human p53 tumor suppressor gene, which is known as a hotspot. The DNA damage was inhibited by catalase and bathocuproine, indicating the involvement of H(2)O(2) and Cu(I). Time-of-flight mass spectroscopic study suggested that BA-3,4-dihydrodiol undergoes Cu(II)-mediated autoxidation leading to the formation of its hydroxylated form of BA-3,4-dihydrodiol, capable of causing oxidative DNA damage. It is noteworthy that BA-3,4-dihydrodiol can nonenzymatically induce DNA damage more efficiently than BA-3,4-dione with metabolic activation. In conclusion, oxidative DNA damage induced by BA-3,4-dihydrodiol not only via quinone-type redox cycle but also via a new type of redox cycle participates in the expression of carcinogenicity of BA and BA-3,4-dihydrodiol.

Analgesia Preventiva en un modelo experimental de dolor visceral / Pre-emptive analgesia in an experimental model of visceral pain

Objetivo. Evaluar la eficacia de la analgesia preventiva inducida por estimulación eléctrica nerviosa transcutánea (TENS) sobre la respuesta constrictora abdominal (RCA) evocada por Perezona en el ratón. Material y Métodos. Se emplearon 64 ratones macho de la cepa CD-1 dividido en 8 grupos (n=8 cada grupo). El grupo I recibió la perezona 5 mg/kg Intraperitoneal (IP), el grupo II recibió el vehículo de la perezona (aceite de maíz Los grupos IV al VIII se sometieron a diferentes frecuencias de TENS (10,20,40,80 y 160 Hz), durante 30 minutos, posteriormente se les administró perezona 5 mg/kg IP registrando el número de RCA en 20 minutos. Resultados. A los resultados obtenidos se le aplicó la prueba de Kruskal-Wallis siendo estadísticamente significativo los valores de p>0.05, encontrando eficacia antinociceptiva preventiva del TENS en los grupos IV al VII con p<0.05 con respecto a los grupos controles (I y II). El grupo III (vehículo) no registró capacidad para inducir RCA. Conclusiones. Los hallazgos señalan que las frecuencias bajas de TENS (10,20,40 y 80 Hz) son más eficaces para inducir un efecto antinociceptivo en este modelo experimental con relación a las frecuencias altas, (160 Hz) con p>0.05. Se concluye que el TENS es un procedimiento eficaz como analgésico preventivo

Preclinical assessment of hypocrellin B and hypocrellin B derivatives as sensitizers for photodynamic therapy of cancer: progress update.

Hypocrellins are perylenequinone pigments with substantial absorption in the red spectral region and high singlet oxygen yield. They are available in pure monomeric form and may be derivatized to optimize properties of red light absorption, tissue biodistribution and toxicity. In vitro screening of synthetic derivatives of the naturally occurring compound, hypocrellin B (HB), for optimal properties of cyto-(dark) toxicity and phototoxicity resulted in selection of three compounds for preclinical evaluation: HBEA-R1 (ethanolaminated HB), HBBA-R2 (butylaminated HB) and HBDP-R1 [2-(N,N-dimethylamino)-propylamine-HB]. Extinction coefficients at 630 nm (epsilon 630) are 6230, 6190 and 4800, respectively; and 1O2 quantum yields, phi, 0.60, 0.32 and 0.42. Intracellular uptake is essentially complete within 2 h (HBEA-R1, HBBA-R2) and 20 h (HBDP-R1). Greatest uptake is associated with lysosomes and Golgi. The HBEA-R1 and HBBA-R2 elicit phototoxicity in vitro primarily via the type II mechanism, with some type I activity under stringently hypoxic conditions. Transcutaneous phototherapy with HBEA-R1 permanently ablates EMT6/Ed tumors growing in the flanks of Balb/c mice, with minimal cutaneous effects. The HBBA-R2 does not elicit mutagenic activity in strains TA98 and TA100 of Salmonella typhimurium. Further development of selected hypocrellin derivatives as photosensitizers for photodynamic therapy is warranted.

Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent.

The plasma pharmacokinetics of the anti-tumor antibiotic geldanamycin (GM: NSC 122750), a naturally occurring benzoquinoid ansamycin, was characterized in mice and a beagle dog. Concentrations of GM well above 0.1 microgram/ml, which was typically effective against neoplastic cell lines responsive to the drug in vitro, were achieved in the plasma of the mice and the dog treated by i.v. injection. However, the systemic duration of the drug was relatively short. Plasma levels decayed below 0.1 microgram/ml within 3-4 h after administration of the apparent maximum tolerated doses, which were approximately 20 mg/kg for the mice and 4 mg/kg for the dog. The drug exhibited linear pharmacokinetic behavior within the dose ranges studied. However, there were significant interspecies differences in its disposition. Whereas the mean biological half-life of GM was slightly longer in the mice (77.7 min) than in the dog (57.9 min), its mean residence time in the dog (46.6 min) was more than twofold greater than that observed in the mice (20.7 min). Nevertheless, the drug was cleared from plasma much faster by the dog (49.4 ml/min per kg) than by the mice (30.5 ml/min per kg). These apparent anomalies were principally associated with differences in the relative significance of the terminal phase upon overall drug disposition. The liver appeared to be the principal target organ of acute drug toxicity in the dog. Doses of 2.0 and 4.2 mg/kg both produced elevations in serum levels of the transaminases and other indicators of liver function characteristic of acute hepatic necrosis. Additional effects included symptoms of minor gastrointestinal toxicity and alterations in serum chemistry parameters consistent with less severe nephrotoxicity. Drug-related toxicity appeared to be reversible. In consideration of the potential for acute hepatotoxic reactions to GM, as well as to the other benzoquinoid ansamycins based upon structural analogy, additional pharmacological and therapeutic information is required to ascertain whether these compounds are viable candidates for clinical development.

Mahogany discoloration of the skin due to the defensive secretion of a millipede.

An 8-year-old boy developed a sudden mahogany discoloration of his skin after exposure to defensive secretions of a millipede. The mechanisms and the composition of the secretion and other clinical features are briefly reviewed.

Primin standard patch testing: 5 years experience.

From 1 November 1984 to 1 November 1989. 3075 patients (1949 female and 1126 male) were patch tested with the European standard series, including primin 0.01% pet. 57 positive reactions were obtained (1.8%). About 95% of the patients with positive patch tests were female. 60% of the patch-test-positive patients were above age 60 and 35% above 70 years. The test was negative in all under the age of 20 and rarely positive under the age of 35 years. Only 2 patients had probable patch test sensitization observed 8 and 14 days after application of the test material. 41% of the patients with positive reactions had current primula dermatitis at the time of patch testing. The frequency and high degree of current relevance justify inclusion of primin in the standard series, at least in certain geographical regions. The patch test concentration of 0.01% pet. seems to be correct.

Contact allergy to Australian blackwood (Acacia melanoxylon R.Br.): isolation and identification of new hydroxyflavan sensitizers.

Australian blackwood is known to be an important cause of allergic contact dermatitis in Australia. Previous investigations have shown that 2,6-dimethoxy-1,4-benzoquinone and acamelin are 2 of the responsible, but weak, sensitizers. When these 2 quinones are lacking, which is occasionally found, the wood still possesses allergenic properties. The present re-examination led to the isolation and identification of 4 hydroxyflavans, of which 3 proved to be allergens. Melacacidin, known to be the main constituent of these flavan derivatives in the heartwood, was isolated and its sensitizing capacity in guinea pigs determined. It showed a moderate sensitizing power. Melacacidin occurs abundantly in 125 Australian and 3 African Acacia species.

Phase I and pharmacokinetic studies with the pentacyclic pyrroloquinone mitoquidone.

Mitoquidone (MTQ) is the first member of a new group of pentacyclic pyrroloquinones developed for clinical evaluation as a potential anticancer agent. MTQ demonstrated good activity in a range of experimental solid tumour models, but was weakly active against standard prescreens such as the P388 murine leukaemia. Bone marrow suppression or other significant toxicity was not observed in preclinical studies. Twenty-seven patients were treated with MTQ given as a 4-h infusion either once every 21 days (150-600 mg/m2), once a week (200 mg/m2 per week), or as 5 daily doses repeated every 28 days (60-180 mg/m2 per day). The major adverse events encountered included nausea and vomiting (in virtually all patients), dyspnoea, tumour-related pain, and thrombocytopenia in several patients with pretreatment bone-marrow impairment. Phase I studies were suspended without a maximum tolerated dose being reached because of formulation difficulties. There were no major responses, although stable disease was observed in a number of patients with gastrointestinal malignancies. Temporary remission of B-symptoms occurred in two patients with lymphoma. The plasma pharmacokinetics of MTQ were investigated using an HPLC assay with fluorescence detection. Linear pharmacokinetics were observed with a terminal plasma half-life of 2.9 +/- 2.1 h (n = 18 doses). The volume of distribution was 3.4 +/- 2.6 l/kg and plasma clearance was 629 +/- 469 ml/min per m2. Several soluble analogues with similar antitumour activity are currently under investigation.