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Inorganic compounds have been known and used since antiquity. Dynameron is the largest Byzantine medical manuscript divided into 24 sections, in accordance with the letters of the Hellenic alphabet, which contains 2667 recipes. The majority of them contain ingredients of plant origin, followed by animal origin, while fewer inorganic substances are quoted. In the present study, the latter ones are listed. Moreover, the information on the uses of inorganic ingredients in the treatment of many diseases in the late Byzantine era is presented and their evaluation in light of the modern Pharmacology and Toxicology. © 2021 The Authors

Ethnopharmacological relevance: Dynameron is a Byzantine medical compendium, divided into 24 sections, in accordance with the letters of the Greek alphabet. Being the largest medical and pharmaceutical book ever written in Byzantium, Dynameron contains 2667 recipes intended to treat many pathological conditions. A lot of information convey to us through prescriptions. In addition to plants, Nikolaos Myrepsos proposes the use of many animals, animal parts and animal by-products, for the treatment of various diseases. This article presents for the first time a full account of the animal products included in Dynameron. Aim of the study: In continuation to our previous studies, this paper focuses on the use of animal products in composite medicines described in Dynameron. An effort was made to trace down the use of similar or identical animal products in texts of earlier medical writers. Recording recipes with animals or animal products intended for use in everyday medical practice highlights the timeless belief in their healing properties. Materials and methods: Our main source of material is the recent digital edition of Nikolaos Myrepsos’ Dynameron. This huge treatise was written in the 13th century and reflects in many ways the long medical tradition of the Greek, the Hellenistic and the Roman eras, having also received influences from the materia medica of Arabic medicine. In addition, information from dictionaries and databases were cross-checked to confirm and classify the animals and their products and to identify them. For the various pathological conditions these products are meant for, we have used the current medical terminology. Results: In the present study, we could identify the therapeutic use of 93 animals. In several instances, Myrepsos suggests the use of specific organs of an animal, and for that reason he includes in his treatise 16 anatomical parts of different animals. Moreover, Dynameron comprises also 34 animal by-products, such as milk and honey. Medicines of animal origin are used in recipes concerning diseases of the respiratory, the digestive, the cardiovascular and the urinary system, as well as gynecological diseases, and ailments of the eyes, the ears and the skin. Conclusions: Of the 2667 recipes of Dynameron, 344 recipes contain medicines of animal origin, which can be detected in totally 769 citations. In addition, 626 citations for animal by-products are found in 268 recipes. Honey and milk are quoted in 2136 recipes, mostly as excipients. Dietary instructions are present on many occasions, reflecting the attitude for a healthy everyday life, similar to the modern beliefs pertaining to food as an essential factor for a good health. © 2021 Elsevier B.V.

Oleuropein (OLE), a main constituent of olive, exhibits antioxidant and hypolipidemic effects, while it reduces the infarct size in chow- and cholesterol-fed rabbits. Peroxisome proliferator-activated receptor α (PPARα) has essential roles in the control of lipid metabolism and energy homeostasis. This study focused on the mechanisms underlying the hypolipidemic activity of OLE and, specifically, on the role of PPARα activation in the OLE-induced effect. Theoretical approach using Molecular Docking Simulations and luciferase reporter gene assay indicated that OLE is a ligand of PPARα. The effect of OLE (100 mg/kg, p.o., per day, ×6 weeks) on serum triglyceride (TG) and cholesterol levels was also assessed in adult male wild-type and Ppara-null mice. Molecular Docking Simulations, Luciferase reporter gene assay and gene expression analysis indicated that OLE is a PPARα agonist that up-regulates several PPARα target genes in the liver. This effect was associated with a significant reduction of serum TG and cholesterol levels. In contrast, OLE had no effect in Ppara-null mice, indicating a direct involvement of PPARα in the OLE-induced serum TG and cholesterol reduction. Activation of hormone-sensitive lipase in the white adipose tissue (WAT) and the liver of wild-type mice and up-regulation of several hepatic factors involved in TG uptake, transport, metabolism and clearance may also contribute in the OLE-induced TG reduction. In summary, OLE has a beneficial effect on TG homeostasis via PPARα activation. OLE also activates the hormone sensitive lipase in the WAT and liver and up-regulates several hepatic genes with essential roles in TG homeostasis. © 2018 Elsevier Inc.

Ethnopharmacological relevance Dynameron is a Byzantine medical compendium, divided into 24 sections, the “Elements”, containing 2667 recipes, most of which inherited by previous physicians of the classic ancient Greek and Hellenistic, and imperial Roman periods. Aim of the study In continuation to our previous study concerning the first and largest chapter of the “Element Alpha” of Nikolaos Myrepsos׳ Dynameron (Valiakos et al., 2015), this paper focuses on the plants quoted in the recipes of the eight following chapters entitled “About Salts”, “About Honeypacks” and “About Spreads”, all belonging to the same “Element Alpha” “About Antitussives” and “About Suppositories” belonging to the “Element Beta” “About women's Cathartics” belonging to the “Element Gamma” “About Drossaton” and “About Diachrisma”, both belonging to the “Element Delta”. Materials and methods Our main primary source material was the codex kept in the National Library of France (in Paris) under the number grec. 2243, which is the older and larger codex of Dynameron (Valiakos et al., 2015). Results The present study led us to the interpretation of 277 plants under different names, among which we recognized 57 medicinal plants listed by the European Medicines Agency, one of them with negative monograph (i.e. Chelidonium majus). In addition, there are identified taxa related to those quoted by EMA as herbal medicines. The plants appearing in the examined Elements belong to various families of which the most frequent are: Apiaceae 10.11%; Lamiaceae 7.22%; Asteraceae 6.86%; Rosaceae 6.5% and Fabaceae 6.14%. Conclusions A total of 277 species have been catalogued, most of which are referred in our previous publication (Valiakos et al., 2015). Among them, 56 plants still play a very important role in medical practice, as they are used as traditional herbal medicines (www.ema.eu). This evidence is a proof that the use of medicinal plants remains valuable from the ancient times until today. The recipes, in contrast to older medical compendia, contain precise measurements of ingredients and dosages for every drug, which seem to reflect empirical logic. © 2017 Elsevier Ireland Ltd

Ethnopharmacological relevance:This paper focuses on the plants quoted in the recipes of the first chapter entitled "About the Antidotes" belonging to the first and largest section "Element Alpha" of Nikolaos Myrepsos' Dynameron, a medieval medical manuscript. Nikolaos Myrepsos was a Byzantine physician at the court of John III Doukas Vatatzes at Nicaea (13th century). He wrote in Greek a rich collection of 2667 recipes, the richest number known in late Byzantine era, conventionally known as Dynameron and divided into 24 sections, the "Elements". The only existing translation of this work is in Latin, released in 1549 in Basel by Leonhart Fuchs. Since no other translation has ever been made in any language, this work still remains poorly known. Materials and Methods:Our primary source material was the codex written in 1339 and kept in the National Library of France (in Paris) under the number grec. 2243. For comparison, all the other codices, which contain the entire manuscript, have also been studied, namely the codices EBE 1478 (National Library of Greece, Athens), grec. 2237 and grec. 2238 (both in Paris), Lavra Ε 192 (Mont Athos, Monastery of Megisti Lavra), Barocci 171 (Oxford) and Revilla 83 (Escorial). Results: The exhaustive study of the "About the Antidotes" led us to the interpretation of 293 plant names among which we recognized 39 medicinal plants listed by the European Medicines Agency, (Herbal Medicines, www.ema.eu); the therapeutic indications of some of them provided by Myrepsos were similar or related to their current ones, as given in their monographs. The plants belong to various families of which the most frequent are: Apiaceae 10.6%; Lamiaceae 9.2%; Asteraceae 8.9%; Fabaceae 6.8% and Rosaceae 5.1%. The most frequently mentioned plants even under several different names are the following: Apium graveolens L., Crocus sativus L., Nardostachys jatamansi (D. Don) DC., Zingiber officinale Roscoe, Rosa centifolia L., Syzygium aromaticum (L.) Merr. & L.M. Perry, Papaver somniferum L., Costus sp., Petroselinum crispum (Mill.) Fuss, Anethum graveolens L., Foeniculum vulgare Mill., Daucus carota L. Conclusions: This research led us to the conclusion that the content of "About the Antidotes" is a valuable source for the study of recipes based mainly on medicinal plants, most of them inherited from classic ancient Greek and Hellenistic periods. © 2015 Elsevier Ireland Ltd.All rights reserved.

Disulfiram is used in the treatment of chronic alcoholism, because of the unpleasant symptoms it provokes after ethanol intake. The underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the liver aldehyde dehydrogenases. In addition, it is known that disulfiram also has some neurotoxic properties. The aim of our study was to investigate the relationship between the pharmacological and neurotoxicological properties of disulfiram with respect to the doses applied. Increasing doses of disulfiram (25, 50, 75, 100 and 150 mg/kg) were administered intraperitoneally to Wistar rats and the hepatic enzyme activities of alcohol and aldehyde dehydrogenases were measured. Also, in two brain subregions (midbrain and hypothalamus) the levels of noradrenaline, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were determined. The higher dose of disulfiram (150 mg/kg) produced lethal effects in all treated animals. Aldehyde dehydrogenase activities were inhibited by disulfiram in a dose-dependent way, while alcohol dehydrogenase was not affected at all. Concerning the levels of brain biogenic amines, disulfiram produced a significant reduction in noradrenaline and an increase in dopamine levels in both structures of the brain, in a dose-dependent way. However, the lowest dose applied (25 mg/kg) had no effects on brain catecholamines. It is known that high doses of disulfiram may cause severe encephalopathy and peripheral neuropathy in humans, which could be attributed to the impairment of the metabolism of brain biogenic amines, due to inhibition of dopamine-beta-hydroxylase. Our experimental data show that disulfiram affects the level of brain biogenic amines at dose levels higher than those inhibiting the activity of aldehyde dehydrogenase. Therefore, in clinical practice 'disulfiram reaction' could still be achieved with a low dosage regimen not producing neurotoxicity Pharmacol Toxicol

Malassezia yeasts are commensal microorganisms, which under insufficiently understood conditions can become pathogenic. We have previously shown that specific strains isolated from diseased human skin can preferentially produce agonists of the aryl hydrocarbon receptor (AhR), whose activation has been linked to certain skin diseases. Investigation of skin scale extracts from patients with Malassezia-associated diseases demonstrated 10-to 1,000-fold higher AhR-activating capacity than control skin extracts. Liquid chromatography-tandem mass spectrometry analysis of the patients' extracts revealed the presence of indirubin, 6-formylindolo[3,2-b]carbazole (FICZ), indolo[3,2-b]carbazole (ICZ), malassezin, and pityriacitrin. The same compounds were also identified in 9 out of 12 Malassezia species culture extracts tested, connecting their presence in skin scales with this yeast. Studying the activity of the Malassezia culture extracts and pure metabolites in HaCaT cells by reverse transcriptase real-time PCR revealed significant alterations in mRNA levels of the endogenous AhR-responsive genes Cyp1A1, Cyp1B1, and AhRR. Indirubin-and FICZ-activated AhR in HaCaT and human HepG2 cells with significantly higher, yet transient, potency as compared with the prototypical AhR ligand, dioxin. In loco synthesis of these highly potent AhR inducers by Malassezia yeasts could have a significant impact on skin homeostatic mechanisms and disease development. © 2013 The Society for Investigative Dermatology.

Early maternal deprivation (MD) is an animal model of neurodevelopmental stress associated with a variety of abnormalities during adulthood. The present study investigated specific behavioral, neurochemical and neurobiological parameters related to dopaminergic and serotonergic function in adult rats subjected to early life MD. Behavioral responses, including the reaction to novelty, the response to d-amphetamine (d-AMP) and the susceptibility to apomorphine (APO) were evaluated in adulthood. Dopamine (DA) and serotonin (5-HT) levels, their metabolites along with their turnover ratios were assessed in distinct rat brain regions. The impact of MD on DARPP-32 protein, D2 and 5-HT2A receptor expression was also estimated in the same brain regions during adulthood. Our results indicated that MD rats were more reactive to novelty behavior and more sensitive to dopaminergic agonists compared to controls. MD rats displayed elevated dopaminergic and serotonergic function in the amygdala and prefrontal cortex, whereas in the striatum only the dopaminergic activity was also increased. Interestingly, MD induced a region-dependent modulation of D2, 5-HT2A receptor and DARPP-32 protein expression. Our findings clearly indicated that early MD stress produces long term behavioral impairments and region-dependent modifications in various neurochemical and neurobiological indices of dopaminergic and serotonergic function in brain regions holding critical roles in the pathophysiology of central nervous system disorders. © 2013. Published by Elsevier B.V.

The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague-Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7-ethoxyresorufin-O-dealkylase (EROD) and 16α-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(α)pyrene (B(α)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(α)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity. © 2010 Elsevier Inc.

This study explored the behavioural, neurochemical and molecular effects of 9-tetrahydrocannabinol (9-THC) and WIN55,212-2, in two rat phenotypes, distinguished on the basis of their vertical activity upon exposure to a novel environment, as high responders (HR) and low responders (LR). Motor effects were assessed under habituated vs. non-habituated conditions. Dopaminergic activity and DARPP-32 phosphorylation were measured in the dorsal striatum, nucleus accumbens, prefrontal cortex and amygdala. These cannabinoids influenced motor activity in a biphasic manner, i.e. low doses stimulated, whereas high doses suppressed motor activity. Dopamine (DA) biosynthesis was increased in most brain regions studied following 9-THC administration mainly in HR rats, and low-dose WIN55,212-2 increased DA biosynthesis in HR rats only. Both high and low doses of 9-THC increased DARPP-32 phosphorylation in most brain regions studied in both phenotypes, an effect that was also observed following high-dose WIN55,212-2 administration only in the striatum. The present results provide further support for a key role of cannabinoids in the regulation of motoric responses and elements of dopaminergic neurotransmission and reveal their complex differential effects in distinct rat phenotypes, as seen with other drugs of abuse. Copyright © 2009 CINP.

Ejc Supplements

Aim: To determine the safe dose range and pharmacokinetics of metronomic oral vinorelbine and obtain preliminary data on biomarkers and efficacy in patients with advanced cancer. Methods: Successive cohorts of patients received escalated doses of oral vinorelbine given thrice a week until disease progression, unacceptable toxicity (UT), or consent withdrawal. UT was any grade 4 toxicity, or grade 2 or 3 toxicity that would result to longer than 2-week break during the first 2 months of treatment. Blood samples were collected for pharmacokinetics and quantification of angiogenesis regulatory proteins. Results: Sixty-two patients (median age, 60 years) enrolled at six dose levels from 20 to 70 mg and received treatment for median 12.25 weeks (range, 2-216+). Unacceptable toxicity occurred in two of six patients treated at 60 mg (leucopenia grade 4 and epistaxis grade 2) and in one at 70 mg (leucopenia grade 2). The upper metronomic dose was 50 mg. Objective antitumor response documented in eight cases and 32% of patients experienced disease stability for minimum 6 months. Three responders (renal cancer, medullary thyroid carcinoma, and Kaposi sarcoma) received nonstop treatment for over 3 years without overt toxicity. Low pretreatment levels of circulating interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor were found predictors of efficacy. Steady-state concentrations of vinorelbine and its active metabolite ranged from 0.5 to 1.5 ng/mL. Conclusions: Metronomic administration of oral vinorelbine is feasible at doses up to 50 mg thrice a week and can yield sustainable antitumor activity without overt toxicity, probably through antiangiogenic mechanism. Further clinical investigation is warranted. (Clin Cancer Res 2009;15(20):6454–61)

Choline is an essential nutrient that seems to be involved in a wide variety of metabolic reactions and functions in both humans and rodents. Various pathophysiological states have been linked to choline deprivation (CD). The aim of the present study was to determine the effect of CD upon biochemical, histological and metabolic alterations induced by drugs that affect hepatic functional integrity and various drug metabolizing systems via distinct mechanisms. For this purpose, paracetamol (ACET) or phenobarbital (PB) were administered to male Wistar rats that were fed with standard rodent chow (normally fed, NF) or underwent dietary CD. The administration of ACET increased the serum aspartate aminotransferase levels in NF rats, while CD restricted this increase. On the other hand, ACET suppressed alkaline phosphatase levels only in CD rats. Moreover, CD prevented the PB-induced increase of the mitotic activity of hepatocytes. The administration of ACET down-regulated CYP1A2 and CYP2B1 expression in CD rats, while up-regulating them in NF rats. The administration of PB suppressed CYP1A2 apoprotein levels in CD rats, whereas the drug had no effect on NF rats. The PB-induced up-regulation of CYP2B, CYP2E1 and CYP1A1 isozymes was markedly higher in CD than in NF rats. In addition, PB increased glutathione-S-transferase activity only in CD rats. Hepatic glutathione content (GSH) was suppressed by ACET in NF rats, whereas the drug increased GSH in CD rats. Our data suggest that CD has a significant impact on the hepatic metabolic functions, and in particular on those related to drug metabolism. Thus, CD may modify drug effectiveness and toxicity, as well as drug-drug interactions, particularly those related to ACET and PB. Copyright © 2008 John Wiley & Sons, Ltd.

Aims: This study investigated the role of the cannabinoid CB1 receptor agonist, WIN 55,212-2, on motor activity. Subsequently, the effects of a low, stimulatory dose of WIN 55,212-2 and cocaine, as a positive control, were evaluated using a conditioned place preference (CPP) procedure. Upon completion of CPP, in rats that had been treated with WIN 55,212-2, dopaminergic status and spontaneous and d-amphetamine-induced motor activity were assessed. Main methods: Sprague-Dawley rats were evaluated for habituated motor activity following WIN 55,212-2 (0, 0.1, 0.3, 1 mg/kg, i.p.) administration. A stimulatory dose of WIN 55,212-2 (0.1 mg/kg, i.p.) and cocaine (20 mg/kg, i.p.) was selected to assess CPP behaviour. Upon completion of CPP, in one group, tissue levels of dopamine and its metabolites were measured in distinct brain regions (dorsal striatum, nucleus accumbens, prefrontal cortex, amygdala, hippocampus) using High Performance Liquid Chromatography with electrochemical detection. In another group, spontaneous and d-amphetamine-induced motor activity was evaluated in an open-field apparatus. Key findings: The lowest dose of WIN 55,212-2 increased motor activity but did not produce CPP. As expected, cocaine induced clear CPP. Dopaminergic status was increased in a region-specific way and motor activity was enhanced following a challenge of d-amphetamine in rats that had been administered with WIN 55,212-2 during conditioning. Significance: A stimulatory effect of WIN 55,212-2 on motor activity was not accompanied by place preference. Upon completion of the CPP procedure, this dose was found to induce region-specific hyperdopaminergia along with a greater sensitivity to a subsequent challenge dose of d-amphetamine. © 2009 Elsevier Inc. All rights reserved.

Increased activity of CYP2E1 has been associated with increased risk of chemically-mediated cancers, through enhanced activation of a variety of procarcinogens. In this context, inhibition of CYP2E1 is potentially of significance in xenobiotic toxicity. The aim of the present study was to test the hypothesis that quinacrine inhibits hepatic CYP2E1. For this purpose, disulfiram (75 mg/kg i.p) as an inhibitor and isoniazid (100 mg/kg i.p) as an inducer of CYP2E1, as well as quinacrine (50 mg/kg i.p) were administered to Wistar rats and the hepatic activity of CYP2E1 was measured. The expression of CYP2E1 was further assessed by Western blot analysis. As expected, disulfiram inhibited, while isoniazid induced the activity and expression of the enzyme. Interestingly, treatment with quinacrine resulted in a significant decrease of CYP2E1 activity and expression. To investigate any similarities in the inhibition of CYP2E1 by quinacrine and disulfiram, molecular modeling techniques were adopted and revealed that quinacrine molecule anchors inside the same binding pocket of the protein where disulfiram is also attached. Finally, as assessed by the sister chromatid exchanges (SCE) assay, quinacrine was demonstrated to reduce the mutagenic effects of the tobacco-specific N-nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is known to be converted to active mutagen in the liver principally through CYP2E1. We suggest that these antimutagenic effects of quinacrine could be possibly attributed, at least in part, to its ability to block the bioactivation of NNK, mainly by the inhibition of CYP2E1. Our results, even preliminary, indicate that quinacrine as an inhibitor of CYP2E1 might be protective against chemically-induced toxicities such as NNK-induced mutagenicity. Arch Toxicol

Eur J Obstet Gynecol Reprod Biol

Journal URL: http://journals.lww.com/behaviouralpharm/pages/default.aspx

The aim of the present study was to investigate the course of levodopa induced dyskinesia (LID) development in parkinsonian rats treated with several different levodopa dosing regiments. Administration of 6.25 mg/kg levodopa once daily did not induce any dyskinesia for the first 12.5 +/- 2.5 days. Then, LID gradually increased in intensity reaching an AIMs score on day 40 of 6.3 +/- 0.9. Treatment with 6.25 mg/kg of levodopa qid resulted in the rapid appearance of LID with a mean latency of 2 days and an AIMs score of 19.9 +/- 2.9 on day 10. Levodopa (25 mg/kg) once daily induced severe LID from the second day of treatment reaching an AIMs score of 35 +/- 3.2. In summary, the worst way for delivering levodopa was through intermittent administration of high doses. The daily cumulative dose of levodopa was found more important for LID induction than the total amount of levodopa received. In contrast, the best way to administer levodopa in respect to prevention/delay of LID was "low dopaminergic stimulation" with one low daily dose, instead of trying to achieve "continuous dopaminergic stimulation" using several levodopa doses throughout the day. The benefits of this strategy offered protection against severe dyskinesia even if subsequently subjects were switched to high dose levodopa. Mov Disord

The potential involvement of catecholamines and in particular of alpha(2)-adrenoceptor-related signalling pathways, in the regulation of drug-metabolizing enzymes by stress was investigated in Wistar rats after exposure to the environmental pollutant benzo(alpha)pyrene. For this purpose, total cytochrome P450 content, the CYP1A2 mRNA levels, 7-methoxyresorufin-O-dealkylase (MROD), 7-pentoxyresorufin-O-dealkylase (PROD) and p-nitrophenol hydroxylase activity levels were determined in the livers of rats exposed to repeated restraint stress after treatment with benzo(alpha)pyrene coupled with pharmacological manipulations of peripheral and/or central catecholamines and alpha(2)-adrenoceptors. The data show that stress is a significant factor in the regulation of CYP1A2 induction and that catecholamines play a central role in the stress-mediated modulation of hepatic CYP1A2 inducibility by benzo(alpha)pyrene. The up-regulating effect of stress on benzo(alpha)pyrene-induced CYP1A2 gene expression was eliminated after a generalized catecholamine depletion with reserpine. Similarly, in a state where only peripheral catecholamines were depleted and central catecholamines remained intact after guanethidine administration, the up-regulating effect of stress was eliminated. It is apparent that stress up-regulates the induction of CYP1A2 by benzo(alpha)pyrene mainly via peripheral catecholamines, while central catecholamines hold a minor role in the regulation. Pharmacological manipulations of alpha(2)-adrenoceptors appear to interfere with the effect of stress on the regulation of CYP1A2 inducibility. Either blockade or stimulation of alpha(2)-adrenoceptors with atipamezole and dexmedetomidine respectively, eliminated the up-regulating effect of stress on CYP1A2 benzo(alpha)pyrene-induced expression, while it enhanced MROD activity. In contrast, stress and pharmacological manipulations of catecholamines and alpha(2)-adrenoceptors did not affect total P450 content, the CYP2B1/2-dependent PROD and the CYP2E1-dependent p-nitrophenol hydroxylase activities. In conclusion, stress is a significant factor in the regulation of the CYP1A2 inducibility by benzo(alpha)pyrene, which in turn is involved in the metabolism of a large spectrum of toxicants, drugs and carcinogenic agents. Although the mechanism underlying the stress effect on CYP1A2 induction has not been clearly elucidated, it appears that peripheral catecholamines hold a predominant role, while central catecholamines and in particular, central noradrenergic pathways hold a minor role. Basic Clin Pharmacol Toxicol

Drug Metabolism Reviews

Behav Pharmacol

The aim of this study was to investigate the effect of benzo(alpha)pyrene (B(alpha)P), a representative polycyclic aromatic hydrocarbon (PAH), on dopaminergic activity in brain. (B(alpha)P) altered dopaminergic activity in discrete regions of the rat brain, including the hippocampus, hypothalamus, caudate putamen and nucleus accumbens. Specifically, B(alpha)P increased DA levels in the hippocampus and DA turnover in the caudate putamen. In addition, B(alpha)P suppressed DA levels in the caudate putamen and DA turnover in the nucleus accumbens. B(alpha)P also altered the effect of several dopaminergic agents, L-DOPA, sulpiride and bromocriptine, on DA activity. In particular, B(alpha)P enhanced the L-DOPA-induced increase in the DA turnover ratio in the caudate putamen and increased DA levels in the nucleus accumbens. B(alpha)P also reversed the sulpiride-induced increase of DA turnover in the nucleus accumbens and the bromocriptine-induced increase of DA turnover in the hippocampus. In addition, DA turnover was increased by B(alpha)P in the nucleus accumbens and caudate putamen and DA levels were suppressed in the nucleus accumbens of bromocriptine treated rats, though the drug alone had no effect. These changes indicate that exposure to B(alpha)P and related compounds may affect dopaminergic function in discrete brain regions that are implicated in cognitive functions, psychosis, depression and Parkinson's disease, and may possibly interfere with their pharmacological intervention. Neurotoxicology

Background: Although protracted intravenous 5-fluorouracil is superior to bolus regimens in terms of tumour exposure to the drug during DNA synthesis as well as activity and safety, the oral fluoropyrimidine capecitabine is administered intermittently. In this phase I study, we investigated an alternative, dose-intense continuous regimen. Materials and methods: Oral capecitabine was administered twice daily continuously with weekend breaks, in patients with advanced solid tumours refractory to standard therapy. Dose escalation proceeded from 1,331 to 2,510 mg/m2 daily. Dose limiting toxicity (DLT) consisted of any grade-3 or 4 adverse event except for alopecia and skin toxicity resolving within 7 days. Results: Twenty-five heavily pretreated patients participated in the study. No DLT occurred in the first four cohorts. Two out of four patients developed grade III diarrhoea in the fourth week of capecitabine at 2,510 mg/m2 (DLT). The most common toxic episodes during all cycles of treatment were grade 1-2 fatigue, skin erythema, abdominal cramps, nausea, constipation and neutropenia. Disease regression was seen in three and stabilisation with clinical benefit in ten patients (clinical benefit response 54%). Pharmacokinetic studies of capecitabine and metabolites in four patients at 2,250 mg/m2 daily showed rapid absorption, short plasma half-lives with the exception of FBAL and absence of accumulation or conversion saturation during the course of therapy. At this dose, administered dose intensity in eight patients was 99.3% of the planned one. Conclusions: Weekday on-weekend off capecitabine maximizes cytotoxic impact on tumour cells during S-phase by safely simulating protracted fluoropyrimidine therapy at a recommended dose (2,250 mg/m2) close to that of the intermittent schedule and clearly higher than the continuous one of 1,331 mg/m2. © 2007 Springer-Verlag. 60 5 733 739

Movement Disorders

CYP1A2, a principal catalyst for metabolism of various therapeutic drugs and carcinogens, among others, is in part regulated by the stress response. This study was designed to assess whether catecholamines and in particular adrenergic receptor-dependent pathways, modulate benzo(alpha)pyrene (B(alpha)P)-induced hepatic CYP1A2. To distinguish between the role of central and peripheral catecholamines in the regulation of CYP1A2 induction, the effect of central and peripheral catecholamine depletion using reserpine was compared to that of peripheral catecholamine depletion using guanethidine. The effects of peripheral adrenaline and L-DOPA administration were also assessed. The results suggest that alterations in central catecholamines modulate 7-methoxyresorufin O-demethylase activity (MROD), CYP1A2 mRNA and protein levels in the B(alpha)P-induced state. In particular, central catecholamine depletion, dexmedetomidine-induced inhibition of noradrenaline release and blockade of alpha(1)-adrenoceptors with prazosin, up-regulated CYP1A2 expression. Phenylephrine and dexmedetomidine-induced up-regulation may be mediated, in part, via peripheral alpha(1)- and alpha(2)-adrenoceptors, respectively. On the other hand, the L-DOPA-induced increase in central dopaminergic activity was not followed by any change in the up-regulation of CYP1A2 expression by B(alpha)P. Central noradrenergic systems appeared to counteract up-regulating factors, most likely via alpha(1)- and alpha(2)-adrenoceptors. In contrast, peripheral alpha- and beta-adrenoceptor-related signaling pathways are linked to up-regulating processes. The findings suggest that drugs that bind to adrenoceptors or affect central noradrenergic neurotransmission, as well as factors that challenge the adrenoceptor-linked signaling pathways may deregulate CYP1A2 induction. This, in turn, may result in drug-therapy and drug-toxicity complications. Life Sci