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Kindle Money Mastery

If you have ever wanted to be able to be an author for a living or as a side hobby, this is the online course for you! This course gives you access to all kinds of ebook and materials on how to make the most of the Amazon Kindle Store to make a huge amount of money! You don't need to be a creative genius, spend Hours on end writing, or even know how to use Kindle! All that you have to do is follow the instructions in this course by Stefan Pylarinos. Stefan built this course based on what he does for a living Every Single DAY. This is REAL information that has been perfected in a real business Why would this NOT work for you? This is how Stefan makes his money Why not you? Just think You can make living money writing Kindle books. And you can learn all about how to get started making money with K Money Mastery! Continue reading...

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Results in the NAc and Striatum

We have measured glutamate receptor subunit mRNA levels and immuno-reactivity in rats treated for 5 d with 5 mg kg of amphetamine or saline and perfused 3 or 14 d after the last injection. For AMPA receptor subunits, quantitative in situ hybridization studies showed no changes in GluR1-3 mRNA levels in the NAc after 3 d, but decreases in GluRl and GluR2 mRNA levels were observed after 14 d (41). Parallel changes were observed at the protein level using quantative immunoautoradiography (42). Similarly, mRNA and protein levels for NR1 in the NAc were not altered by repeated amphetamine at the 3-d withdrawal time, but both were significantly decreased after 14 d of withdrawal (24). The decreased levels of GluR1, GluR2, and NR1 subunits in amphetamine-treated rats may be functionally significant. Single-unit recording studies performed in the NAc of rats treated with the same amphetamine regimen, or a sensitizing regimen of cocaine, revealed that NAc neurons recorded from drug-treated...

Gene Structure and Species Diversity

Rat clones have 95 nucleic acid identity (100 amino acid identity). The mouse and human clones have 90 nucleic acid identity (97 amino acid identity). Rat CB1 probes can be used to detect mouse cannabinoid receptor mRNA (Abood et al. 1993), again indicating conservation among species. However, the human and rat sequences diverge about 60 bp upstream of the translation initiation codon. Furthermore, we have isolated a rat CB1 clone that is identical to the published sequence in the coding region, but diverges about 60 bp upstream of the translation codon (unpublished data). Examination of the 5' untranslated sequence of the mouse CB1 genomic clone indicates a splice junction site approximately 60 bp upstream from the translation start site. This splice junction site is also present in the human CB1 gene (Shire et al. 1995). These data suggest the existence of splice variants of the CB1 receptor as well as possible divergence of regulatory sequences between these genes. A third exon is...

Side Chain Modifications

A variety of side-chain modified analogs of MDMA and MBDB have begun to be examined. Very early studies were of the Ot.a-dimethyl analog, 3,4-methylenedioxyphentermine (figure 8a) and its N-methyl derivative (figure 10). This latter compound proved to lack MDMA-like activity (Shulgin, unpublished). Interestingly, this compound also lacked the ability to stimulate the release of 3H serotonin from prelabeled rat brain synaptosomes (Nichols et al. 1982).

Role of Oxidative and Bioenergetic Stress in MDMA Neurotoxicity

Reactive species that contribute to MDMA toxicity may not be limited to oxygen-based radicals but also may include reactive nitrogen species, for example, nitric oxide and peroxynitrite. Inhibitors of nitric oxide synthase (NOS) provide protection against MDMA-induced dopamine depletion in the mouse (68), as well as 5-HT depletion in the rat (69,70). However, it has not been possible to ascribe the neuroprotective effects of these drugs specifically to the inhibition of NOS, inasmuch as NOS inhibitors, for the most part, markedly attenuate MDMA-induced hyperthermia (69). However, the NOS inhibitor 5-methyl-l-thiocitrulline attenuates MDMA-induced dopamine toxicity in the mouse without modifying MDMA-induced hyperthermia (68). 5-Methyl-l-citrulline also attenuates the long-term depletion of 5-HT, as well as dopamine, in the striatum of the rat following the intrastriatal administration of MDMA and malonate (Gudelsky, unpublished observations). The administration of MDMA also results in...

Biosynthesis of Other Putative Endocannabinoids

Original evidence for the formation of NAD A from arachidonic acid and dopamine or tyrosine (Huang et al. 2002) suggested a biosynthetic pathway common to that of the recently discovered arachidonoyl amino acids (Huang et al. 2001), i.e. from the direct condensation between arachidonic acid and dopamine, or, alternatively, from the condensation between arachidonic acid and tyrosine followed by the transformation of N-arachidonoyl-tyrosine into NADA by the enzymes catalysing dopamine biosynthesis from tyrosine. Preliminary data have shown, however, that NADA cannot be produced from either N-arachidonoyl-tyrosine or N-arachidonoyl-L-DOPA either in vitro, in brain homogenates, or in vivo, and that the lipid formed from tyrosine and arachidonic acid is not NADA (M.J. Walker and V. Di Marzo, unpublished observations). Clearly, further studies are needed to understand the biosynthetic mechanism for this putative endocannabinoid.

Endocannabinoids In The Nervous System

Noticeably, as mentioned in the preceding text, several investigators have demonstrated that 2-AG was rapidly produced in various nervous tissues and cells when challenged with a variety of stimuli. An important aspect is that Ca2+ plays an essential role in the generation of 2-AG (Bisogno et al., 1997 Stella et al., 1997 Kondo et al., 1998). Bisogno et al. (1997) demonstrated that N18TG2 cells generate 2-AG when stimulated with ionomycin and that a large portion of 2-AG was released into the extracellular medium. Di Marzo, Hill, et al. (2000) also reported that the injection of reserpine induced an increase in the level of 2-AG in the globus pallidus in rats. Stella et al. (1997) reported the generation of 2-AG in electrically stimulated rat hippocampal slices and ionomycin-stimulated neurons. They also detected the generation of 2-AG in NMDA-stimulated rat cortical neurons (Stella and Piomelli, 2001). On the other hand, we found that the administration of picrotoxinin, a central...

Similarities among and differences between phenylethylamine compounds

A comparison of MDMA to d-amphetamine, MDA, and DOM can provide an understanding of the pharmacology of MDMA and its abuse liability. While there are differences between MDMA and amphetamine in the subjective effects in humans (Shulgin and Nichols 1978). the similarities in the self-injection and preclinical pharmacology profile between MDMA and d-amphetamine suggest that MDMA has abuse liability. Both MDMA and d-amphetamine maintain self-injection behavior above vehicle control levels, and high doses of both drugs are associated with a cyclic pattern of self-injection over days (Lamb and Griffiths 1987 Griffiths et al. 1976). At doses larger than those needed to maintain self-injections, both MDMA and d-amphetamine suppressed food intake and food-maintained behavior (Lamb and Griffiths 1987 Griffiths et al. 1976) and produced similar changes in gross behavior, such as tracking nonexistent visual objects and repetitive self-grooming (Lamb and Griffiths 1987 Lamb and Griffiths,...

Src Inhibitors Overview

Thorough reviews of Src inhibitor classes from the chemical and biological perspective are already available (e.g., refs. 12-15). Here, we will briefly summarize the updated knowledge on the most promising Src inhibitory compounds and then focus on new unpublished data on Src mechanism of action and in vivo activity. Src inhibitors fall into two broad classes inhibitors of the tyrosine kinase activity (adenosine triphosphate ATP binding domainmediated) and inhibitors of protein-protein (SH2-, SH3-, or substrate binding domain-mediated) interactions. Worth mentioning are the nonpeptidic Src SH2 domain ligands, designed to accumulate in bone via binding of a phosphate group to bone mineral (recently reviewed in ref. 15). However, a big improvement in cellular potency and pharmacokinetic properties of such compounds, linked to their chemical properties, remains a challenge. The kinase inhibitors are still the most promising group in terms of potency, selectivity, and therapeutic...

Pharmacological Profile Of Cannabinoid Receptor Antagonists

Has greatly contributed to further our understanding of these receptors, and to tease out differences between the CBX and CB2 receptors. For example, application of the CB2 antagonist in several pharmacological paradigms used to test for cannabinoid effects, helped characterize a new specific CB2 agonist ( HU-308 ) and the discovery that not only CBX, but also CB2 receptors are involved in blood pressure regulation (Hanus et al., 1999). Effective SR141716A-induced blockade of the CBX receptor-induced activities has been shown for a number of centrally mediated functions (Rinaldi-Carmona et al., 1994 Compton et al., 1996). For example, the CB 1 receptor antagonist blocked A9-THC-induced effects on the tetrad (Adams et al., 1998 Compton et al, 1996 Fride et al, 1998a), A9-THC - or anandamide-induced learning and memory impairment (Brodkin and Moerschbaecher, 1997 Mallet and Beninger, 1998a), and the discriminative properties of A9-THC in rats and monkeys (Wiley et al., 1995b)....

Lactate Production by Parasites

P. falciparum possesses cytochromes, but is not thought to contain them in a functionally organized respiratory chain capable of undertaking oxidative phosphorylation. Hence, when parasites reside in host erythrocytes (which lack mitochondria), their sole energy source is considered to be anaerobic glycolysis (Mi-Ichi et al. 2003). Parasitized red cells make 20-50 times more lactate than uninfected cells (Vander Jagt et al. 1990). In theory this would roughly double red cell lactate production in a person with 2 par-asitaemia. However, this would be unlikely to contribute to the high lactate levels seen in severe malaria, which may occasionally be over 10-fold higher than resting lactate concentrations. Infected red cells produce both d and L-lactate, but concentrations of venous blood D-lactate concentrations are usually low (P. Holloway and S. Krishna unpublished results). This finding does not support the production of lactate by parasites as an important cause of hyperlactataemia...

Chronic Salicylate Toxicity

Acute salicylate poisoning may uncouple oxidative phosphorylation and precipitate lactic acidosis (Stacpoole 1993). Salicylate toxicityhas been associated with hyperlactataemia and hypoglycaemia in a group of Kenyan children with severe malaria (English et al. 1996). There are great variations in prescribing practice between countries, for example in Kumasi, Ghana none of 50 children presenting with severe malaria had detectable salicylate in plasma (T. Agbenyega, S. Krishna and T. Planche, unpublished results). Although chronic salicylate toxicity may be more prevalent in some geographical areas, salicylates are not widely used in children and are unlikely to be a major cause of hyperlactataemia in malaria worldwide.

Biosynthesis of Prostaglandins

In several cellular systems, higher levels of prostaglandin production have been associated with COX-2 expression. In some cells (e.g. WISH) expression of both enzymes yields prostaglandin production from only COX-2, as shown by specific inhibitors (Hulkower and Bell, unpublished observations, 1996 305). In addition COX-1 appears to prefer exogenous arachidonic acid, whereas with endogenous substrate COX-2 metabolism is predominant (298). These phenomena have three possible explanations (1) specific linkage of each enzyme with a specific phospholipase, (2)linkage of COX-2 to an inducible PGE, synthase, and (3) regulation by peroxide tone.

The Haematological Features of Malaria Infection

The bone marrow is typically hypercellular. The most striking findings are of grossly abnormal development of erythroid precursors, or dyserythro-poiesis. The developing erythroid cells typically demonstrate cytoplasmic and nuclear bridging and irregular nuclear outline (Abdalla et al. 1980 Abdalla and Wickramasinghe 1988). These changes are probably central to the pathophysiology of malarial anaemia and are discussed in detail below. Children who present with either acute or chronic malaria have significant suppression of reticulocytes (Casals-Pascual and Roberts, unpublished results). However, it has been firmly established that the proportion of abnormal erythroid precursors and the degree of dyserythropoiesis are much greater in chronic compared to acute infection (Abdalla et al. 1980). These data suggest that the inhibition and abnormal maturation of erythroid precursors may have

Pharmacological determinants

Ongoing experiments with methylenedioxymethamphetamine (MDMA) show a systematic dose-dependent decrease in attack and threat behavior in mice confronting an intruder into their homecage (Miczek et al., unpublished observations). The decrement in aggressive behavior appears to be behaviorally specific it is obtained at MDMA doses (0.3, 1, 3 mg kg) that are lower than those necessary to decrease measures of conditioned performance under the control of schedules of positive reinforcement. Because of species-dependent neurotoxicity, MDMA's effects on aggressive behavior need to be explored in other species, including primates.

Regulatory Issues Affecting Herbal Medicines

Herbal products are regulated differently in other countries. In the United Kingdom, any product not granted a license as a medical product by the Control Agency is treated as a food and cannot carry any health claim or medical advice on the label. Similarly, herbal products are sold as dietary supplements in the Netherlands. In Germany, herbal monographs called the German Commission E monographs are prepared by an interdisciplinary committee using historic information, chemical, pharmacological, clinical and toxicological studies, case reports, epidemiological data and unpublished data from manufacturers. If an herb has an approved monograph, it can be marketed. Australia created a Complementary Medicine Evaluation Committee in 1997 to address regulatory issues regarding herbal remedies, and Canada has created a Natural Health Products Directorate after restructuring Therapeutic Products and Foods Branch in 2000 (8,9).

Noradrenergic Receptor Antagonists

Antagonism of several characteristic effects of amphetamine and cocaine by the alpha adrenergic receptor antagonist prazosin is a most recent example of noradrenergic mechanisms in the actions of psychomotor stimulants (Tessel and Barrett 1986). We investigated whether or not prazosin may attenuate the disruptive effects of amphetamine on social and aggressive behavior in mice and squirrel monkeys (Miczek, unpublished observations). Pretreatment with prazosin (0.4 mg kg) attenuated the disruption of attack

Possible role of other neurotransmitter systems in the antiemetic properties of cannabinoids

Although the cholinergic neurotransmitter system per se is not directly involved in chemotherapy-induced vomiting (see section 2.1), dopaminergic and serotonergic mechanisms do appear to be important downstream in cannabinoids' antiemetic actions. Indeed, in the feline, nabilone dose-dependently prevents emesis produced by the dopamine D2 receptor agonist apomorphine (London et al., 1979). In a similar manner, A9-THC prevents vomiting produced by dopamine D2 D3 receptor agonists such as apomorphine, quinpirole, quinelorane and 7-OH DPAT in the least shrew (Darmani, unpublished observations). In this context, the least shrew seems to be an excellent dopamine animal model of emesis since the cited selective and nonselective dopamine D2 receptor agonists can potently induce emesis in this species, whereas D2 antagonists prevent the induced behavior (Darmani et al., 1999). As discussed earlier, clinical findings further underscore the role of blockade of the dopaminergic system in the...

Replication Transcription and Translation of mtDNA

The mitochondrial ribosomes in malaria parasites have a highly unusual organization multiple rRNA fragments will need to interact in trans to form the core small and large subunit rRNA structures, which will in turn interact with imported ribosomal proteins to form functional ribosomes (Feagin et al. 1992 Vaidya et al. 1993a). At present, little is known about the components and the process underlying the assembly of these bizarre ribosomes. Through a bioinformatics approach, a number of nuclearly encoded putative mitochondrial ribosomal proteins have been identified, and the N-terminal signal of one has been experimentally shown to target a fused GFP to the mitochondrion (Perrault and Vaidya, unpublished data). The parasite mtDNA does not encode any tRNAs or tRNA synthetases, all of which will need to be imported. Genomic sequences do not reveal any tRNA genes other than those for cytoplasmic protein synthesis, thus tRNAs will require dual targeting in malaria parasites. Indeed,...

Ajulemic acid a potent synthetic analog of THC11oic acid

The application of this principle to the CB acids resulted in the molecule called ajulemic acid (Figure 14.1). As predicted, the analog has a pharmacological profile similar to the template molecule but at doses that are considerably lower (Burstein et al, 1992 Dajani et al., 1999 Zurier et al., 1998). Interestingly, it shows an affinity for CBX comparable to that of THC (Rhee et al, 1997) posing something of a dilemma since it lacks the psychotropic actionsofTHC.Whileajulemicacidlikewise inhibits COX-2 mediated PG synthesis, it is becoming apparent that its mechanism of action may be more complex. For example, like THC it stimulates the release of arachidonic acid in cell culture models (Burstein, unpublished data). What can be stated is that it is highly effective as both an analgesic and anti-inflammatory agent and shows no psychotropic action at therapeutic doses. Moreover, it has been subjected to a rigorous screening for toxic effects (S. Miller, personal communication) with...

Validated blind predictions

In CASP II (Critical Assessment of Methods of Protein Structure Prediction Round II), a new prediction section on protein-ligand docking was introduced 154 . Several groups participated and submitted up to three models for some of the seven protein-ligand complexes (see 155-158 for reports). For each target, the 3D structure of the protein and the 2D structure of the ligand was given to the participants. All complexes were unpublished before the submission deadline.

Fiisidic acidformation

Structures are being used to study details of the effects of inhibitors on factor-ribosome interactions. As indicated in Fig. 2, cyclic thiopeptides such as amythiamicin and GE2270 prevent aminoacylated tRNA forming a ternary complex with EF1A-GTP. A computer-modelled 3D structure of EF1A from P. falciparum suggested that the plastidic translational machinery might be affected by these same two inhibitors (Sato et al. 2000). In cultures of P. falciparum, the IC50 for amythiamicin was 10 nM (Clough et al. 1999). Unpublished studies with smaller synthetic derivatives of promothiocin A, a related thiopeptide antibiotic (Bagley et al. 2000), found that inhibition could be achieved, albeit at a lower level, without cyclization of the inhibitor (C.J. Moody and B. Clough, personal communication).

Psychological psychiatric

In a new twist, Wakefield's crusade fuelled further anxiety among parents when he and John O'Leary, director of pathology at Coombe Women's Hospital, Dublin, Ireland, presented unpublished data to the US Senate's congressional oversight committee in Washington on April 6 2000 . The hearing was called by the chairman, Dan Burton, an Indiana Republican, whose grandson has autism and visited the Royal Free Hospital in November last year. At the hearing, six parents of children with autism gave moving testimonies of their children's illness. Scientific evidence was presented by six chosen 'experts'. According to Wakefield's testimony, he has now studied more than 150 children with 'autistic enterocolitis' an unproven association had become a disease and a detailed analysis of the first 60 cases is to be published in the American Journal of Gastroenterology later this year. Wakefield presented uninterpretable fragments of results only and concentrated on refuting studies that had...

Established Emetic Neurotransmitters And More Novel Mediators Of Vomiting

In addition to the discussed established neurotransmitter systems in emetic circuits, a number of other less well-recognized mediators appear to play an important role in the production of emesis. We have recently shown that AA, the common precursor of prostaglandins, thromboxanes, hydroxy -eicosatetraenoic acids (HETEs), hydroperoxyeicosatetraenoic acids (HpETEs), and prostacyclins, is a potent emetic agent in the least shrew (Darmani, 2002b). Moreover, both prostaglandins PGE2 and PGF2 induce vomiting in humans (Karim and Filshe, 1970 Wislicki, 1982), pigs (Wechsung, 1996 De Saedeleer et al., 1992), and the least shrew (Darmani, unpublished findings). Furthermore, prostaglandin synthesis inhibitors such as dexamethasone are used clinically as additive antiemetics for the prevention of vomiting produced by both chemo- and radiotherapy (Ioanidis, 2000 Maranzano, 2001). Stimulation of vanilloid VR1 receptors by agonists such as capsaicin and resiniferatoxin induce vomiting in shrews,...

Cloning and Expression

The baculovirus system, for the reasons mentioned in the above paragraph, is the expression system of choice for tyrosine kinases. However, it is a complicated system that is not very well suited to a high-throughput multiparallel approach. As kinases are expressed intracellularly, and the baculovirus system is a lytic one, there is a fine balance to be made between the multiplicity of infection used and the length of time between infection and harvest. On the one hand, expression levels increase with time, up to a point where the cells start to lyse on the other hand, for some kinases the solubility may be reduced by prolonged infection, presumably owing to the action of phosphatases (P. Ramage, unpublished results) or proteolytic degradation may become significant. When trying to maximize yields, it is useful to be able to carry out analytical affinity chromatography to optimize time of harvest. Similarly, the degree of autophos-phorylation observed will often vary with the...

Tail npentyl group modifications

Anandamide behaves as a partial agonist in the biochemical and pharmacological tests used to characterize cannabimimetics. Although there is no apparent structural similarity between the classical cannabinoids and anandamide, there is considerable evidence suggesting that these two classes of cannabimimetic agents bind similarly to the CBX active site. Chemical and computational data indicate that arachidonic acid, the parent fatty acid of anandamide, favors a bent or looped conformation in which the carbonyl group is proximal to the C14-C15 olefinic bond. This is suggested by the highly regiospecific intramolecular epoxidation of arachidonyl peracid (Corey et al., 1984) and the facile macrolactonization of the C20 hydroxyl methyl arachidonate (Corey et al, 1983). The above experimental results are corroborated by molecular dynamics calculations (Rich, 1993) which indicate that indeed a bent conformation is thermodynamically favorable. In the case of arachidonylethanolamides,...

General Information

The under-reporting of the results of clinical trials in patients with heart failure has been reviewed (7). Some trials that have been unpublished or published only in abstract or preliminary form have involved drugs with positive inotropic effects, such as the phosphodiesterase inhibitor vesnarinone (SEDA-23, 195), the beta-adreno-ceptor partial agonist xamoterol, and the dopamine receptor agonist ibopamine.

The thirdgeneration oral contraceptives a judicial assessment and further evidence

That the issue reached an English court was not surprising, for it was in England that the Committee on Safety of Medicines had written to prescribers in 1995 stating that three unpublished studies on the safety of combined oral contraceptives in relation to venous throm-boembolism had indicated about a two-fold increase in the risk of such conditions compared with the preceding generation of products. This issue of a two-fold increase became crucial to the case. For reasons of causation , as the Judge put it, the claimants had accepted the burden ofproving that the increase in risk was indeed not less than two-fold.

Organs and Systems Cardiovascular

The warning was based on three unpublished studies that had not at the time been formally peer reviewed. All three showed about double the risk of venous throm-boembolism with gestodene and desogestrel products compared with oral contraceptives containing other progestogens. The first, a large WHO collaborative case-control study of cardiovascular disease and oral contraceptives was undertaken in 17 countries. It was completed in July 1995, and involved 829 cases of venous throm-boembolism and 2641 controls from nine countries in which third-generation oral contraceptives had been used (15). The second, from the Boston Collaborative Drug Surveillance Program, was an analysis of the occurrence of venous thromboembolism in a UK general practice cohort of 238 130 women who had received a

Direct Cardiodepressant Effects of Cannabinoids

In agreement with the observations on isolated cardiac preparations, our recent unpublished results using the Millar pressure-volume conductance system (see below and also Figs. 1 and 2) to directly measure cardiac performance in vivo strongly suggest the crucial importance of the cardiac component in the hemo-dynamic effects of cannabinoids. Taken together, the above-mentioned studies suggest that CB1 receptors are present in cardiomyocytes, and cannabinoids may decrease cardiac contractility through both CB1-dependent and CB1-independent mechanisms.

Inhibition of Angiogenesis

To grow beyond minimal size, tumours must generate a new vascular supply (angiogenesis) for purposes of cell nutrition, gas exchange and waste disposal, and therefore blocking the angiogenic process constitutes one of the most promising antitumoural approaches currently available. Immunohistochemical and functional analyses in mouse models of glioma (Blazquez et al. 2003) and skin carcinoma (Casanova et al. 2003) have shown that cannabinoid administration turns the vascular hyperplasia characteristic of actively growing tumours to a pattern of blood vessels characterised by small, differentiated and impermeable capillaries. This is associated with a reduced expression of VEGF and other proangiogenic cytokines (Casanova et al. 2003 Blazquez et al. 2003 Portella et al. 2003), as well as of VEGF receptors (Portella et al. 2003 C. Blazquez and M. Guzman, unpublished results). Interestingly, pharmacological inhibition of ceramide synthesis de novo abrogates the antitumoural effect of...

Oxidation of the 5Position of Deoxyribose and the Chemistry of Butenedialdehyde

The Dedon group recently discovered that 5 '-oxidation of deoxyribose results in the formation a trans -l,4-dioxo-2-butene product that is likely derived by -elimina-tion of a 2 phosphoryl-l,4-dioxobutane residue, as shown in Fig. 22.5 ( Chatter ji, Venkitachalam, and Dedon, submitted for publication). This four-carbon fragment completes the picture of deoxyribose 5'-oxidation chemistry 12 , with partitioning of the reaction pathway to form an accompanying 3'-formylphosphate residue or a nucleoside-5'-aldehyde residue (Fig. 22.5). Again, it was demonstrated that this potent electrophile reacts with dC in a highly efficient manner to form a novel bicyclic oxadiazabicyclooctaimine adduct, as shown in Fig. 22.8 118 , which in preliminary studies was observed in DNA oxidized by ionizing radiation ( Chatter ji and Dedon, unpublished observation). This second example of base adduct formation from deoxyribose oxidation products suggests an important role for this phenomenon in the spectrum...

Activity of EGFR Inhibitors in Combination With Other Chemotherapeutic Agents

Fig. 5. (continued) were determined after 27 d. (A) The response of each individual tumor was assigned to the categories based on changes in volume over the course of the experiment. * p 0.025, Crochan-Mantel-Hansel test with subsequent ranking and allowance for multiple comparisions by Holm's procedure. (B) Tumor volumes and body weights were determined two to three times per week. *p 0.05 vs controls (analysis of variance on ranks and Dunn's test) (R. Brandt and T. O'Reilly, unpublished data).

Invertebrates That Molt Ecdysozoa

McPartland et al. (2000a) and Elphick and Egertova (2001) screened the D. melanogaster genome and found no CBj or CB2 orthologs. The Anopheles gambiae (mosquito) genome also lacked genes with significant identity to CBRs (McPartland, 2004). Similarly, McPartland and Glass (2001) found no orthologs in the genome of the nematode C. elegans. Taken together, these findings led McPartland et al. (2001) to propose that CBRs evolved prior to the hydra-bilaterian divergence, but that they were secondarily lost in the Ecdysozoa. Indeed, G-protein-coupled receptors (GPCRs) gated by other lipids such as prostaglandins and lysophosphatidic acids are not well represented in the Ecdysozoa (unpublished results using HomoloGene, It is difficult to prove a negative, but the null molecular studies were initially supported by pharmacological data. McPartland et al. (2001) found no specific binding of 3H CP55,940 or 3H SR141716A in a panel of insects including D. melanogaster, A. mellifera, Gerris...

Genetically Selected Systems of Malaria Resistance

New World and Asian strains of P. falciparum were efficiently encapsulated by the resistant mosquito line, but P. falciparum strains of African origin were not (Collins et al. 1986). Similarly, the African species P. ovale and P. malariae (along with close simian relative P. brasilianum) also failed to be efficiently encapsulated. The geographic range ofAn. gambiae is limited to sub-Saharan Africa. Thus, one interpretation is that parasites sympatric with An. gambiae have evolved local adaptations to evade recognition or effector functions of the encapsulation response. However, because these observations were made using cultured parasite strains and laboratory mosquito colonies, the genetic fidelity of either to their original natural populations could be questioned. Encapsulation of P. falciparum has been observed in wild An. gambiae in Africa (K. D. Vernick, unpublished results Schwartz and Koella 2002), and thus it is a natural phenotype even in the sympatric combination, although...

Fitness Costs and Evolution of Malaria Resistance

A related consideration is that the lack of robust natural resistance may at least in part result from indirect or direct parasite modulation of host defenses. Indirect effects could result from bloodmeal-related factors. For example, some malaria-responsive An. gambiae genes are transcriptionally regulated by an infected bloodmeal beginning before actual ookinete invasion of the midgut (J. Xu, J. Li, F. Oduol, M. Riehle, and K.D. Vernick, unpublished results Bonnet et al. 2001 Tahar et al. 2002). This early expression could represent a response to soluble parasite-produced immune elicitors, to the quality of the bloodmeal derived from an infected vertebrate host, or to immune signaling molecules from the infected vertebrate host that might influence mosquito immune signaling pathways (Luckhart et al. 2003). Finally, the parasite may actively and directly manipulate components of host defenses. This mechanism has numerous precedents, for example insect polydnavirus proteins that...

Accessing the Plasmodium Liver Stage Proteome

The first large-scale dataset for analyzing gene expression during Plasmodium exoerythrocytic development utilized laser capture microdissection (LCM) techniques to target and extract P. yoelii parasite material for the construction and subsequent sequencing of a malaria liver-stage EST library (Sacci et al., unpublished results). LCM was applied to 40-h P. yoelii exo-erythrocytic schizonts preserved as cryosections. The liver schizonts were purified with minimal contamination from the invaded hepatocyte. Approximately 1,500 schizonts were meticulously isolated, parasite RNA was extracted, and a cDNA library was constructed. Sequencing of 2,628 of the P yoelii EST clones identified 1,662 sequences with significant homologies to known sequences by BLASTN analysis. Validation of the purity of the LCM parasite sample was achieved upon the same sequence analysis where only 1 of the total sequences (16 out of 1,346) shared homology to mouse derived sequence databases. Since the 40-h...

Perspectives in Credentialing the Plasmodium Genome Proteome

Acknowledgements We wish to thank our colleagues J. Aguiar, D. Bacon, F. Huang, and J. Russell for support and communication of unpublished data. We are grateful to J. Yates and L. Florens for critical reading of this review. The opinions expressed are those of the authors and do not reflect the official policy of the Department of the Navy, Department of Defense, or the US government.

CYP2D Enzyme in Brain

An uneven distribution of CYP2D activity was also observed in preliminary studies of dissected monkey (C. Aethiops) brain (Tyndale et al., unpublished data). Subcellular preparations of the nucleus accumbens, amygdala, and parietal cortex oxidized sparteine at rates of 300 to 600 picomoles per milligram of protein per hour (pmol mg protein hour). (By contrast, the rate in monkey hepatic microsomes was 62,000 pmol mg protein hour). The rate in striatum, hippocampus, and temporal and olfactory cortex was approximately 75 pmol mg protein hour. The spinal cord, frontal cortex, midbrain, medulla, and cerebellum had negligible activity. CYP2D activity in monkey brain displayed the stereoselective inhibition by quinidine and quinine that is characteristic of monkey liver CYP2D and human liver CYP2D6. Regional variation in the distribution of CYP2D messenger ribonucleic acid (mRNA) in rat and human brain has also been observed (Tyndale et al., unpublished observations). There is molecular...

Enantioselective Cannabinergic Ligands

WIN-55,212-2, the (+)-enantiomer binds with high affinity to CB1 (1.9 nM) and CB2 (0.3 nM) whereas its (-)-isomer, WIN-55,212-3 does not bind significantly to CB1 and CB2 (both 1000 nM) (Pertwee 1997 Xie et al. 1995). The aminoalkylin-dole AM1241 exhibits high CB2 selectivity (Ibrahim et al. 2003 Malan et al. 2001). Enantiomeric resolution of this ligand using chiral AD column gave the eutomer R-(+)-AM1241, which shows higher CB2 affinity and selectivity (CB1 139.7 nM CB2 1.4 nM) than S-(-)-AM1241 (CB1 2049 nM CB2 160.5 nM). Recently, the asymmetric synthesis of R-(+)-AM1241 was carried out (A. Zvonok and A. Makriyannis, unpublished results).

PDGF in Malignant Disease

Perivascular and stromal expression of the PDGF-P-receptor has been found in more than 90 and 50 , respectively, of common human solid tumors (T. Sjoblom, et al., unpublished observation). Furthermore, several lines of evidence suggest that paracrine PDGF stimulation has a role in tumor formation, making PDGF-P-receptors candidate targets for anti-angiogenic and antistro-mal therapy.

The Blast furnace of Disillusion

World sharing and discovery of parallel realities fills the DMT afternoons of 'Grade and Zarkov', she a published anthropologist, he an established and successful investment analyst. Sex swingers in the 1970s, they became psychedelic voyagers in the 1980s and self-published their

Dependence of the Extent of Neurotoxicity on Dose Route of Administration and Species

Compared with rats, nonhuman primates seem to be more sensitive to MDMA neurotoxicity, suffering more damage at lower doses (Insel et al. 1989 RicaurteandMcCann 1992 Ricaurte etal. 1992 Ali etal. 1993 Fischer et al. 1995 see also De Souza et al. 1990 for slighdy different results). Many MDMA neurotoxicity studies have used squirrel monkeys as subjects. The threshold dose for producing long-term 5-HT depletions in this species is between 2.5 and 5 mg kg of oral MDMA. Two weeks after a single 5.0 mg kg oral MDMA dose, 5-HT levels declined to 83 percent of control levels in the hypothalamus and 79 percent of controls in the thalamus but were not changed in other examined brain regions (Ricaurte et al. 1988a). In contrast, no long-term serotonergic changes were seen in squirrel monkeys after 2.5 mg kg of MDMA was given orally every two weeks for four months (Ricaurte unpublished observations, cited in Vollenweider et al. 1999a). The therapeutic dose of 125 mg of MDMA in a 150-pound person...

Antimicrobial Activity of Furamidine and Analogs

As previously noted, furamidine has been shown to be effective against three different organisms in animal models. The effectiveness against trypanosomes was described sometime ago in both murine and simian models 32, 33 . More recently, Hall and co-workers have demonstrated the efficacy of furamidine using one intravenous dose of 2.5 pmol kg 1 against a mouse model of the disease (see summary in Tab. 16.6). In this study mice were infected with T. brucei brucei S427 clone 22 and were treated 72 h post infection. Mean survival time of untreated controls was 5.8 days and treated animals surviving 63 days were deemed cured (J. E. Hall, unpublished results). bDr J. E. Hall, unpublished results. cRef. 18 . dRef. 25 . e Dr K. Werbovetz. unpublished results. fDr C. C. Dykstra, unpublished results. gRef. 25 . hDr S. Franzblau, unpublished results.

Physical Barrier Peritrophic Matrix

Some authors have suggested that ookinete-secreted protease(s), acting synergistically with parasite-produced chitinase, are important in parasite penetration of the peritrophic matrix (Abraham and Jacobs-Lorena 2004 Langer and Vinetz 2001 Shen 1998). Recent evidence from our laboratory suggests, for the first time, that Plasmodium ookinetes secrete an aspartic protease, plasmepsin, the first reported presence of plasmepsins in a stage of the malaria parasite other than asexual blood stages. Aspartic protease inhibitors, peptidomimetic inhibitors (noncleavable peptides mimicking the hemoglobin chain cleavage site), and anti-plasmepsin monoclonal antibodies significantly impair ookinete invasion of the mosquito midgut, in the P. gallinaceum-Ae. aegypti model system (Li, Dame, J.M. Vinetz, unpublished results). The P. gallinaceum plasmepsin is secreted as well as localized to the surface of the apical complex of the ookinete (unpublished results), suggesting a role for this protease in...

Drug Drug Interactions Aspirin

The WASH pilot study (Warfarin Aspirin Study in Heart Failure) compared the effects on cardiovascular events of warfarin and aspirin, and on antithrombotic therapy in patients with heart failure, most of whom were also taking an ACE inhibitor. Patients taking aspirin had more events and hospitalizations related to worsening heart failure than patients in the two other groups (unpublished data, reported at the 1999 annual meeting of the European Society of Cardiology, John Cleland, personal communication). The authors speculated that this may have been related to a negative interaction between ACE inhibitor therapy and aspirin, which would counteract the beneficial effects of ACE inhibitors. The Warfarin-Antiplatelet Trial in Chronic Heart Failure (WATCH) is indirectly addressing the issue. It is based on the hypothesis that warfarin or clopidogrel (an antiplate-let agent that acts by a pathway independent of cyclo-oxygenase) may be preferred to aspirin as antithrombotic therapy in...

Plasmodium Iron Sources and Pathways

P. falciparum lacks a ferroportin, ferritin, metallothione, ferroxamine-based transport systems, or ferredoxin or bacterial iron siderophore orthologs in the sequence database (Rasoloson et al. 2004). Loyevsky has charatereized a Plasmodium iron regulatory protein (gb AJ012289 PF13_0229) demonstrating that it can bind mammalian IREs and also P. falciparum IREs which are different from the mammalian consensus sequence (Loyevsky et al. 2001, 2003). A DMT-1 ortholog (PFE1185w) localized to the plasma membrane and has not yet been expressed for functional characterization (D.J. Sullivan, unpublished results).

Levosalbutamol levalbuterol

There has been a systematic review of the literature and of unpublished trials with single and chronic doses of inhaled salmeterol 100 g from the GlaxoSmithKline databases (51M). The analysis covered data available until early 1999. Of 44 trials that included a salmeterol 100 g treatment arm, data on systemic effects were available from 19 trials that were subsequently included in a pooled weighted analysis. In the chronic dose studies in 1504 patients who

Covalent Binding Probes

A significant improvement in the design of these new probes was the introduction of a 125I-substituent in the ligand without compromising its high receptor affinity (e.g., AM1708, 70, Fig. 19) (Khanolkar et al. 2000 A.D. Khanolkar, G.A. Thakur, and A. Makriyannis, unpublished). These radio-iodinated probes have served as valuable tools for receptor purification and characterization of the CB1 and CB2 receptors (A. Makriyannis and W. Xu unpublished). Currently, a variety of mono- and bifunctional covalent ligands with hybrid cannabinoid structures (71, Fig. 19) (Chu et al. 2003), as well as endocannabinoid-like compounds (C. Li and A. Makriyannis, unpublished) are being used to elucidate the binding motifs

Prodrug Approaches for Furamidine

We have also prepared a number of carbamates, including some which are double pro-drugs, of 17 as part of our continuing effort to develop pro-drug approaches for diamidines to achieve better oral activity (J. E. Hall, unpublished results). Table 16.13 also includes the data for the most promising of these carbamates, which are of comparable effectiveness to the oxime pro-drugs in the rat model for P. carinii Thus, we have developed two effective pro-drug types for furamidine. As previously noted, one of these 2,5-bis 4-(methoxyamidino)phenyl furan (20, DB289), is currently undergoing phase II clinical trials.

How To Detect And Remove Antibody Interference

Hama Dilution

Dilution linearity study with the specimen is the simplest way to document interference when observed values after dilution deviate significantly from the target values. Figure 1 illustrates the effect of successive dilutions of a HAMA containing sample (spiked with 32 g mL of theophylline but observed value was 59 g mL) compared to a serum-based calibrator for the assay (60 g mL) for a theophylline immunoassay that uses mouse anti-theophylline antibody. The HAMA in the specimen interfered with the assay and initial value observed was 59 g mL. After successive dilutions (with the assay diluent), the interfering antibody was diluted enough and with high dilution the interference was minimal (Datta, unpublished data). However, dilutions do not always correct the analyte value in the sample because of increased imprecision in the low end of the assay and the matrix effect between the calibrator matrix and the matrix of the original specimen.

Role of Vanilloid TRPV1 Receptors in the Cardiovascular Effects of Cannabinoids

2004) and is unaffected by the CB1 antagonist SR141716 in rats (Varga et al. 1995). Bolus intravenous injections of anandamide may reach high enough plasma concentrations for a few seconds to activate TRPV1 receptors, which may explain the above findings. Indeed, the phase I transient hypotension and bradycardia do not appear when anandamide is injected slowly to limit its peak plasma concentration (Z. Jarai, J.A. Wagner, G. Kunos, unpublished observations). In contrast, the prolonged hypotensive phase of the anandamide response is characterized by decreased cardiac contractility and total peripheral resistance (TPR), which are similar in TRPV1+ + and TRPV1- - mice and were completely antagonized by SR141716, implicating CB1 receptors (Pacher et al. 2004). In agreement with this observation, the sustained hypotensive and bradycardic effects of cannabinoids are totally absent in mice lacking the CB1 receptor (Ledent et al. 1999 Jarai et al. 1999). Thus, TRPV1 receptors are not involved...

See also Angiotensin II receptor antagonists General Information

An updated review of the pharmacology and therapeutic use of irbesartan in cardiovascular disorders has been published, including a brief section on drug tolerability, which referred to an unpublished postmarketing surveillance study in which 14 of the patients (1232 of 9009) had mostly mild adverse events (2). No further details were given on the nature of the adverse events.

The Chronic Mouse MPTPProbenecid Model

We have tested two doses of MPTP at 15 mg kg and 25 mg kg (as MPTP HCl salt form), respectively. With probenecid, MPTP at 15 mg kg produces about 60 DA depletion without recovery for at least 6 mo (43), and at 25 mg kg, it causes a nearly 80 loss of DA 6 mo later (40). The latter dose appears to be the maximally tolerated dose when given with probenecid. All the treated animals survive under this regimen. Either increasing the dose of MPTP higher than 25 mg kg with the same dose of probenecid in this chronic protocol, or injecting the animals with MPTP at 25 mg kg plus probenecid on a daily basis results in significant death of animals (unpublished results).

Mutated receptors and binding site models Chimeric CBICB2 receptors

Cyp2c9 Thc Binding Site

Studies (see below) contradict this supposition. Furthermore, the chimeric receptors were functional, since they have been shown to transduce a CP 55,940-mediated signal to G proteins (unpublished data). Although the chimeric constructs provided no clues as to the CP 55,940 binding site, they permitted us to use 3H CP 55,940 as a universal ligand for competition binding assays. The wild-type hCBx and hCB2 receptors have different binding affinities for WIN 55212-2 (IC50 7 0nM and 3nM, respectively) and for SR 141716A (IC50 6nM and 1000nM, respectively) (Shire et al., 1996a) and SR 144528 (IC50 1000nM and 2.5nM, respectively). These differences may reflect recognition of distinct subtype specific amino acid residues present in the two receptors. As CB2 receptor regions replaced those of the CBX receptor in the chimeras, so the competition binding affinities of these three ligands with respect to 3H CP 55,940 were modified (Shire et al., 1996a an unpublished data). The results led us to...

Folate antagonistic antimetabolites

Ten publications listing more than 110 pregnancies with exposure during the first trimester refer to the so-called low-dose therapy for rheumatic diseases. However, with the exception of a recently published small prospective study from France (Lewden 2004) and our own unpublished data, all listed eases represent retrospective reports or, at best, small prospective case studies describing a maximum of four pregnancies (Ostensen 2000, Donnenfeld 1994).

Neuronal Actions of Amphetamine in the Rat Brain

The effects of amphetamine on catecholamine terminal excitability are very similar to the effects of direct-acting agonists. Nigrostriatal dopamine neurons, for example, show a decrease in terminal excitability following the systemic administration of doses of amphetamine ranging from 0.25 to 5.0 mg kg, IV (Groves et al. 1981). Direct infusions of amphetamine into the terminal fields also decrease excitability. A similar decrease in excitability is seen after the administration of the direct-acting D2 agonist apomorphine (Tepper et al. 1984) and the D1 agonist SKF 38393 (unpublished data). The action of amphetamine may be blocked by dopamine antagonists, including haloperidol, fluphenazine, and sulpiride, as well as by pretreatment with the dopamine synthesis blocker a-imetbylparatyrosine (Tepper et al. 1984). These actions of amphetamine occur only in regions of the dopamine axon containing presynaptic autoreceptors infusions of amphetamine into the medial forebrain bundle were...

Conazole antimycotics for systemic use

In a prospectively studied controlled cohort of 226 women, firsttrimester exposure to low-dosage regimens (150 mg d) of fluconazole for vaginal candidiasis did not appear to cause an increased risk of malformations (Mastroiacovo 1996). In an unpublished (to date) ongoing prospective study by the European Network of Teratology Information Services (ENTIS) concerning the new systemic conazole antimycotics, preliminary data on 191 fluconazole-exposed pregnancies give no indication of an increased risk of malformations. Fluconazole was mostly used very early in pregnancy on a short-term basis and in low doses (Vial 2001). In several other studies, based on linkage of prescription databases with birth registries, first-trimester exposure to low dosage regimens of fluconazole for vaginal candidiasis did not appear to cause an increased risk of malformations. These studies included more than 400 first-trimester exposures (fick 1999, Sorensen 1999, Inman 1994).

Neurochemical Pathology Of Cocaine Delirium

Neurochemistry Addiction

Figure 6.2 In vitro autoradiographic maps of 3H WIN 35,428 labeling of the DA transporter in coronal sections of the striatum. (A) Representative age-matched and drug-free subject, (B) cocaine overdose victim, and (C) cocaine delirium victim. The brain maps illustrate the adaptive increase in DA transporter density over the striatum in the cocaine overdose victim. Note the lack of any apparent elevation for the victim presenting with agitated delirium. Since the DA transporter regulates the synaptic concentration of neurotransmitter, the lack of a compensatory upregulation may result in a DA overflow following a cocaine binge. Elevated synaptic Da with repeat exposures may kindle the emergence of the agitated delirium syndrome. Gray scale codes are shown in panel B (black high densities gray intermediate light gray to white low densities). Abbreviations Cd, caudate NA, nucleus accumbens Pt, putamen. Figure 6.2 In vitro autoradiographic maps of 3H WIN 35,428 labeling of the DA...

Inhibitors of Endocannabinoid Inactivation

- N-arachidonoyl-serotonin (AA-5-HT, Bisogno et al. 1998), which is not particularly potent (IC50 values in the low pM range), but was tested against CBi and CB2 receptors and PLA2 enzymes and found to be inactive, and is suitable for use in vivo (V. Di Marzo, unpublished observations) so far, it has not been possible to enhance its inhibitory potency by chemical modification (Fowler et al. 2003). - OMDM-1 and OMDM-2 are the first selective inhibitors of AEA cellular uptake to be developed from a fatty acid other than arachidonic acid, i.e. oleic acid (Ortar et al. 2003). For this reason, and also because it is more stable to hydrolysis in rat brain homogenates, OMDM-2 appears to exert a more long-lasting inhibition of spasticity in mice with experimental allergic encephalomyelitis (de Lago et al. 2004b), and to improve several motor and immunological parameters of the disorder (C. Guaza and V. Di Marzo, unpublished observations).

Methylergometrine methylergonovine

A potentially negative influence on milk production due to prolactin antagonism is known. For breastfed infants themselves, the preparation seems to be tolerated in the overwhelming majority of cases. It should, however, be mentioned that the author has received to date 15 case descriptions involving ergotism-like symptoms in breastfed children (particularly restlessness, vomiting, and diarrhea). This cannot be explained in light of the above-mentioned limited transfer. Experiences with accidental direct administration of methylergometrine, owing to a mix-up of the medication in the delivery room, also argue against a toxic risk via the mothers milk, In such cases, ergotism-like symptoms were first observed after a dosage that was 150-200 times above that transferred through mother's milk (Hoffmann-Walbeck 2001. Poison Control Center Berlin, unpublished observations). However, hypersensitivity, or the transfer of individual higher doses via breast milk, cannot be ruled out. In this...

Other Metabolic Reactions

Some lipoxygenase products being still capable of binding to both CB1 and CB2, and cyclooxygenase-2 products being inactive (Edgemond et al. 1998 Berglund et al. 1999 Maccarrone et al. 2000b van der Stelt et al. 2002). Indeed, recent pharmacological data point to the existence of distinct, non-cannabinoid receptor, specific molecular targets for both prostaglandin-ethanolamides (prostamides), in particular prostamide F2a (Matias et al. 2004), and prostaglandin E2 glycerol ester (Nirodi et al. 2004). Prostamides, however, are rather stable to further metabolism, except for prostamide E2, which undergoes slow dehydration isomerization to prostamide B2 (Kozak et al. 2001), whereas prostaglandin E2 glyceryl ester is instead rapidly hydrolysed in rat, but not human, plasma (Kozak et al. 2001). None of these compounds is a substrate for the endocannabinoid transporter or FAAH (Matias et al. 2004 V. Di Marzo and L. Marnett, unpublished data). Regarding lipoxygenase products of AEA and 2-AG,...

Src Inhibitors Activity In Vitro

Cells were treated with increasing compound concentrations to determine IC50 values. Cellular kinase activities were measured by immunoblotting of kinase-specific immunoprecipi-tates or whole-cell lysates with phosphotyrosine of phospho-kinase-specific antibodies. The data are derived from refs. 18, 37, or are our unpublished data. Nd, not determined EGFR, epidermal growth factor receptor PDGFR, platelet-derived growth factor receptor FGFR, fibroblast growth factor receptor IGFR, insulin-like growth factor receptor PKC, protein kinase C. Cells were treated with increasing compound concentrations to determine IC50 values. Cellular kinase activities were measured by immunoblotting of kinase-specific immunoprecipi-tates or whole-cell lysates with phosphotyrosine of phospho-kinase-specific antibodies. The data are derived from refs. 18, 37, or are our unpublished data. Nd, not determined EGFR, epidermal growth factor receptor PDGFR, platelet-derived growth factor receptor FGFR, fibroblast...

The Cytochrome CYP2D6 Genetic Polymorphism

At least 30 drugs, many of them derived from plant alkaloids, have subsequently been shown to be oxidized by CYP2D6, including tricyclic antidepressants, some neuroleptics, beta blockers, and antiarrhythmic agents such as perhexiline, flecainide, and encainide. Several drugs of abuse including codeine (Chen et al. 1988), hydrocodone (Otton et al. 199 a) oxycodone (Otton et al., unpublished observation), dextromethorphan (Schmid et al. 1985), and p-methoxyamphetamine (PMA) (Kitchen et al. 1979) are known to be metabolized by this enzyme. CYP2D6-mediated metabolism of these drugs is known to be a major source of pharmaco-kinetic variation and variation in drug effect.

Clinical Experience With Mdmaassisted Psychotherapy

GG I had heard in late 1982 that MDMA was being used recreationally at parties in New York City. At that point, I decided to start writing up the results that I had found with the people to whom I had given it. I knew that if it were being used at parties, it very likely would be scheduled. I already had asked everyone to fill out a complete pre-session questionnaire then I designed a similar questionnaire that I could send to people after their sessions. For some people, it was a couple of years later that I got the follow-up data. I started collecting it, assembling it, and organizing it, and I worked on that part time for almost a year to get it in a format to be printed. It was self-published in late 1983, and then it was published in th e, Journal of Psychoactive Drugs in 1986, after a conference on MDMA that summer.

Mosquito Transcriptome and Proteome

EST libraries highly enriched for repressed and induced sequences of the immune transcriptome of whole An. gambiae mosquitoes (Oduol et al. 2000) were spotted on microarrays and expression profiles were analyzed (J. Xu, J. Li, F. Oduol, M. Riehle and K.D. Vernick, unpublished results). Transcrip-tional profiles in response to the Gram-negative bacterial immune elicitor lipopolysaccharide were almost entirely distinct from the response to malaria or injury. A significant coexpressed cluster of genes was induced by injury but repressed by malaria infection, suggesting that a counter-inflammatory response maybe caused by malaria parasites. The repression began soon after the infective bloodmeal, before ookinete invasion of the midgut epithelium, and expanded during midgut invasion, indicating the existence of malaria-related molecular signals that may prime the mosquito host for infection. There is an effort underway to catalog the hemolymph proteome of An. gambiae by mass spectrometry...

The Coffee botanical family Rubiaceae

Such as the Tea plant family (Theaceae), the Guarana plant family (Sapinidaceae) and the Cola plant family (Sterculiaceae). The plants of the Guarana family have one additional alkaloid, guaranine (Table 10). Purine alkaloids have a biological and according to recent (still unpublished) clinical results, also a positive and prophylactic effect in decreasing the risk of Parkinson's disease, for example in the case of caffeine. From Waltheria douradinha St. Hill belonging to the Cola family, walterione A, a tryptophan-derived alkaloid, has been discovered147. This alkaloid has important biological potential. Staerk et al.50 noted five alkaloids isolated from the species Corynanthe pachyceras K. Schum., a member of the Rubiaceae family. Corynantheidine, corynantheine, dihydrocorynantheine, a-yohimbine and corynanthine were isolated from the bark of this species and all these alkaloids demonstrate powerful bio and ecoimpacts (leishmanici-dal, antiplasmodial and cytotoxic activity). Other...

In vivo properties of putative aberrant oxidative metabolites of 5ht and da

Investigations into the neurotoxicology and neuropharmacology of putative aberrant oxidative metabolites of 5-HT and DA are at a very preliminary stage. 5-HEO, the major product of the in vitro HO-mediated oxidation of 5-HT, is not toxic (lethal) when administered into the brains of mice weighing 30 grams (g) at doses as high as 100-200 micrograms (g) (Dryhurst et al., unpublished results). However, several other intermediates products of this reaction are active in the brain. For example, T-4,5-D is lethal when injected into the brains of mice (Wong et al. 1993). Furthermore, intracerebroventricular injections of T-4,5-D into rat brain have been claimed to evoke long-lasting decreases in 5-HT levels in the hippocampus, striatum, and cortex reduced activity of tryptophan hydroxylase (Chen et al. 1992) and degeneration of nerve terminals (Crino et al. 1989). 7-S-Glu-T-4,5-D is also lethal (median lethal dose (LD50) 21 g) when administered into mouse brain, evoking extreme excitation...

Identification of Substrates Inhibitors of Human Hepatic CYP2D6

Because of (-)-cocaine's extremely high affinity for hepatic CYP2D6 (Ki 0.07 M), this drug is not metabolized by CYP2D6. The authors incubated (-)-cocaine with cloned human CYP2D6 enzyme expressed in yeast. Using a gas chromatography mass spectrometry assay, no detectable ecgonine, ecgonine methyl ester, ecgonidine, ecgonidine methyl ester, norecgonidine methyl ester, norecgonine methyl ester, benzoylecgonine, o-m-p-hydroxycocaine, or norcocaine was formed during the incubations (Otton et al., unpublished observations).

A potent irreversible inhibitor of anandamide amidase

Very recently the authors developed a novel anandamide amidase inhibitor, AM374, whose potency in vitro and in neuroblastoma cells significantly exceeds that of other compounds developed to date as well as PMSF. In intact neuroblastoma cells, AM374 was found to dramatically increase the level of undegraded anandamide 55-fold at 10 nM. Interestingly, its affinity for the CB1 receptor was approximately tenfold weaker than anandamide (Deutsch and Makriyannis, unpublished data).

Outstanding Questions in Ookinete Biology of Fundamental Biological Interest

Al. 2003 Florens et al. 2002 Le Roch et al. 2003). Notably absent from these analyses are studies of ookinetes, primarily because this developmental stage of P. falciparum cannot be obtained in vitro and has not been able to be obtained ex vivo from mosquito midguts in quantities sufficient for gene expression or proteomic analysis. Recent advances have been made in the proteomic analysis of Plasmodium zygotes, ookinetes, and proteins secreted extracellularly. Ookinetes of P. berghei, the genome sequence of which has recently been completed, have been an important model parasite for studies of transmission from the proteomic point of view (Trueman et al. 2004 Raine et al. 2004). Similarly, comparative proteomics of P. gallinaceum zygotes and ookinetes as well as secreted released proteins of P. gallinaceum ookinetes is currently underway (K.P. Patra, G. Cantin, J.M. Vinetz, et al., unpublished results). These promise to accelerate the delineation of mechanisms of cell biology...

Introduction and background

Also, although nicotine- 1(5)-iminium forms a p-methylthiophenol adduct (Brandange and Lindblom 1979a), the iminium does not bind to nucleophilic polyamino acids except polycysteine, and this only in the presence of O2 (Obach and Van Vunakis 1988). Unpublished studies from the authors' laboratory indicate that simple cyclic iminium species form stable covalent adducts with typical bionucleophiles only under special conditions, and no evidence has been obtained for the persistent binding of iminium species directly under physiologic conditions.

Immunotherapy for treatment of drug overdose

After careful consideration for the structure-activity relationship of arylcyclohexylamines, monoclonal antibodies against a PCP-like hapten acid) were generated (McClurkan et al. 1993). These antibodies bind to PCP, TCP, and PCE with a greater affinity than the binding of these ligands to the PCP receptor (Owens, unpublished observation). The development of antibody-based approaches for treating drug classes, rather than just one specific drug, is an exciting possibility and could provide a prototypic model for designing immunotherapeutic approaches for other classes of drugs of abuse.

Findings in Prospective Clinical MDMA Studies

Few peer-reviewed reports are available that examine volunteers in clinical MDMA studies for evidence of neurotoxic changes. This section therefore significantly relies on unpublished data kindly supplied by researchers who are in the process of preparing reports on their findings. The reader is advised to consider this discussion as preliminary and subject to revision in more definitive peer-reviewed publications.

Pharmacokinetics And Administration Of Compounds

Effect of formulation on plasma and tumor levels of PKI166. PKI166 was formulated in 5 DMSO 95 Tween-80 (0.5 ) NaCl (0.9 ) or 30 NMP 70 PEG300. 100 mg kg was administered to mice bearing subcutaneous A431 tumors. At selected times mice were sacrificed (n 4 per data point) and plasma and tumor concentrations of PKI166 determined by reversed-phase high-performance liquid chromatography (T. O'Reilly and J. Brueggen, unpublished data). DMSO, dimethyl sulfoxide. Fig. 1. Effect of formulation on plasma and tumor levels of PKI166. PKI166 was formulated in 5 DMSO 95 Tween-80 (0.5 ) NaCl (0.9 ) or 30 NMP 70 PEG300. 100 mg kg was administered to mice bearing subcutaneous A431 tumors. At selected times mice were sacrificed (n 4 per data point) and plasma and tumor concentrations of PKI166 determined by reversed-phase high-performance liquid chromatography (T. O'Reilly and J. Brueggen, unpublished data). DMSO, dimethyl sulfoxide.

Variations Of Harmala Alkaloids In Samples Of B Caapi

Another item of phytochemical interest is the remarkable change in harmala profiles over various samples of B. caapi, which seem to be similar in apparent morphology. In some of the thirty-five samples of B. caapi analyzed, fairly high amounts of THH and or harmine are present, which seems to have a direct impact on the overall quality of the tea. In particular, experienced drinkers seem to prefer those teas where THH concentrations were high, relative to harmine and harmaline. They explained that such teas delivered more force to the experience. Overall, harmine concentrations were found to be highest in the analytical analysis. This was followed closely by THH, then lesser amounts of harmaline (unpublished results).

Harmala Alkaloids From Banisteriopsis Caapi

THH is another major alkaloid in B. caapi. I have also detected this alkaloid in the leaves of Calliandra pentandra, which are sometimes added to ayahuasca by the Shuar in Equador, where it is reported to enhance the visionary effects of this brew (Fericgla 1996). This is a bit surprising, as THH is not remarkably psychoactive on its own, even after MAO inhibition (unpublished results). THH, like other 1-methyl-tetrahydro-S-carbolines, probably serves to further increase serotonin concentrations by weakly inhibiting serotonin's reuptake into presynaptic neurons after MAO inhibition by harmine (Airaksinen 1980). This effect is not trivial, as the reuptake mechanism and MAO metabolism

Novel Endothelial Endocannabinoid Receptor

More recently, a non-CB1 non-CB2 site was also postulated to exist on gluta-matergic terminals in the mouse hippocampus, where its activation by cannabi-noids inhibits glutamatergic transmission and excitatory postsynaptic potentials (EPSPs) (Hajos et al. 2001). Similar to the endothelial site, the site in the hippocampus is susceptible to inhibition by SR141716, but it can be activated by the synthetic cannabinoid WIN55,212-2 (Hajos et al. 2001). A similarly WIN55,212-2-sensitive, but SR141716-insensitive, non-CB1 non-CB2 site that can activate guano-sine triphosphate (GTP)yS labeling in brain membranes has been identified in CB1 knockout mice (Breivogel et al. 2001) and in astrocytes, where its stimulation inhibits cyclic adenosine monophosphate (cAMP) production (Sagan et al. 1999). Since the endothelial site is insensitive to WIN55,212-2 in the rat mesentery (Wagner et al. 1999) or in the rabbit aorta (Mukhopadhyay et al. 2002), and abn-cbd does not inhibit glutamatergic EPSPs in...

Neurotransmission via Monoamines and Acetylcholine

Cannabinoids inhibit noradrenaline release in the brain. A Guinea-pig hippocampal slices were preincubated with 3H noradrenaline and superfused.The electrically (0.3 Hz) evoked tritium overflow (which represents quasi-physiological noradrenaline release) was inhibited by WIN55212-2 but not affected by its enantiomer WIN55212-3. The concentration-response curve of WIN55212-2 (WIN) was shifted to the right by a low concentration of the CB1 receptor antagonist SR 141716 (pA2 8.2) but hardly affected by a high concentration oftheCB2 144528 did not affect, noradrenaline release. In another series of experiments, not shown here, slices were superfused with K+-rich (2.5 x10-2 M) Ca2+-free medium containing tetrodotoxin 10-6 M under this experimental condition WIN inhibited tritium overflow evoked by re-introduction of Ca2+ 1.3 x10-3 M (in a manner sensitive to SR 141716 3.2 x10-7), suggesting that the CB1 receptors are located presynaptically on the noradrenergic axon terminals. B...

Discussion

The present study showed that a single injection of heroin increases the relative number of apoptotic cells in the spleen, but does not change the number of necrotic cells in the spleen. The effect of heroin on apoptosis is stable over time in culture, since the heroin-induced increase in apoptotic cells was present in both fresh and cultured splenic mononuclear cells. Additional studies indicate that the effect of heroin on apoptosis also is stable over time in vivo. In particular, an increase in the relative number of apoptotic cells was present when splenic mononuclear cells were isolated one hour or three hours after the injection of heroin (Fecho, How and Lysle, unpublished observations). These results suggest that heroin is producing a very specific and long-lasting change in the rate of leukocyte apoptosis in the spleen. An interesting, though unresolved, question concerns the relationship between the decrease in total leukocytes and the increase in apoptotic cells in the...

Mefloquine

As yet, experience with first-trim ester use of mefloquine for prophylaxis in several hundred pregnancies gives no indication for a teratogenic potential in humans (Schlagenhauf 1999, Philips-Howard 1998, unpublished experience by the European Network of Teratology Information Services, ENTIS). More extensive experience with mefloquine prophylaxis in the second and third trimesters of pregnancy gave no clear indication for mefloquine-associatcd adverse effects (Schlagenhauf 1999, Philips-Howard 1996).

TKD Mutations

Like FLT3-ITD receptors, FLT3-TKD mutations induce ligand-independent receptor activation and confer growth factor independence in 32D cells (80). However, it remains to be established whether FLT3-TKD receptors phospho-rylate the same substrates as and signal in a similar manner to FLT3-ITD receptors. Given the fact that FLT3-D835 mutations are not associated with a significant decrease on the overall survival of AML patients, FLT3-TKD mutations might be less tumorigenic than FLT3-ITD mutations, even though FLT3-D835Y receptors display a higher level of intrinsic tyrosine kinase activity than FLT3-ITD receptors (Scheijen and Griffin, unpublished results).

Conclusions

The balance between toxication and detoxication may also vary considerably between different tissues. For example, whereas microsomal rates of conversion of nicotine to the 1(5)-iminium ion for rabbit liver and lung are comparable on a per weight basis, nicotine is oxidized at a higher rate by lung microsomes than by liver microsomes when one corrects for the much smaller P-450 content of lung microsomal protein (McCoy, unpublished data). The higher rate of nicotine metabolism in the rabbit lung results from the enrichment in P-450 isozymes which preferentially metabolize nicotine to the 1(5)-iminium ion, for example, CYP2B4 and CYP4B1, which account for 90 percent of lung P-450 content (Serabjit-Singh et al. 1979) but less than 20 percent of the liver total P-450 content (Lu and West 1980). Further studies (Flammang 1994) demonstrate very low aldehyde oxidase activity in rabbit lung compared to liver, and also very low MND activity in lung compared to liver, as also reported by Obach...

Baseline

Of attack in the later phase (Miczek, unpublished observations). Also, higher amphetamine doses that decreased attack behavior at the start of an encounter did not lead to any rebound in the later phases, even during 28-minute encounters. Apparently, once an aggressive interaction has been initiated, and the opponent reacts with defensive and flight responses, amphetamine does not increase further the rate of aggressive behavior within the same encounter.

FLT3 and cKit

Kit is also a target of Gleevec, and a recent structure of this kinase in complex with the drug at 1.65 A (Cowan-Jacob, Fendrich, et al., unpublished data), which is used in the treatment of gastrointestinal stromal tumors, shows that it binds to Kit in a very similar manner to Abl kinase (Fig. 7). The Kit A-loop adopts an

Conclusion

The present data demonstrate that the amphetamine analogs MDA and MDMA influence the extrapyramidal neuropeptide systems in a METH-line manner (figures 4 and 5). As already discussed, the METH effects on these peptide systems are dopaminergically mediated, thus, it is likely that the amphetamine designer drugs also influence SP, NT, and Dyn extrapyramidal pathways by enhancing extrapyramidal dopaminergic activity. In support of this conclusion, we have observed that blockade of D1 receptors with SCH 23390 completely blocks the increases in striatal NT and Dyn induced by MDMA treatment (unpublished observation). This finding is consistent with observations that MDMA and MDA stimulate the release of striatal DA from tissue slices (Schmidt et al. 1987) and intact animals (Yamamoto and Spanos 1988). In addition, Stone et al. (1986) reported that treatments with MDA and MDMA resulted in increases in striatal concentrations of homovanillic acid, a DA metabolite, which reflects the extent of...

Future Work

Although the analysis summarized here has increased significantly the number of transport proteins predicted to be present in P. falciparum, it is very likely that more parasite-encoded transport proteins remain to be uncovered. Search criteria were targeted towards identifying transporters with seven or more TMDs however, many of the polypeptides which form ion channels possess six or fewer TMDs and several types of transporters also contain six or fewer TMDs. The fact that four putative channels (two putative K+ channels 34,121 and two other putative ion channels, both with seven or more TMDs) have been identified 73 Allen RJW, unpublished indicates that these types of transport proteins are indeed present in the P. falciparum permeome.

Cell Growth Arrest

It has been suggested that cannabinoids produce their growth-inhibiting effects on skin and prostate cancer cells at least in part by attenuating epidermal growth factor receptor tyrosine kinase activity (Casanova et al. 2003) and or by lowering epidermal growth factor receptor expression (Casanova et al. 2003 Mimeault et al. 2003). Furthermore, the antiproliferative action of cannabinoids in breast, prostate and thyroid cancer cells might involve a decrease in the activity and or expression of prolactin (De Petrocellis et al. 1998), nerve growth factor (Melck et al. 2000) or type 1 vascular endothelial growth factor (VEGF) tyrosine kinase receptors (Portella et al. 2003). In addition, cannabinoids inhibit the type 2 VEGF tyrosine kinase receptor in glioma cells (C. Blazquez and M. Guzman, unpublished results). Taken together, these observations indicate that attenuation of signalling through tyrosine kinase receptors may constitute a common mechanism of cannabinoid antiproliferative...

Laevis Oocytes

Two groups have reported the cloning and functional expression in oocytes of a P. falciparum nucleoside transporter, designated PfNTl 14 or PfENTl 81 . The two studies differed significantly in the reported properties of the transporter. Carter et al. measured a Km of 13 M for adenosine, while Parker et al. reported a Km of 320 M. Carter et al. reported that the transporter was unable to transport nucleobases, whereas Parker et al. reported that it transported nucleobases efficiently, with Km values similar to that for adenosine, as well as accepting the antiviral nucleoside analogues 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine and 2',3'-dideoxyinosine, none of which are transported by mammalian equilibrative nucleoside transporters. Carter et al. reported the transporter to be inhibited by 10 M dipyridamole, whereas in the study by Parker et al. it was not. Preliminary studies from our own laboratory have essentially reproduced the findings of Parker et al. with regard to...

Virodhamine

O-Arachidonoylethanolamine was identified in rat brain and named virodhamine (Porter et al. 2002). This compound is similar to anandamide in being formed from arachidonic acid and ethanolamine, but virodhamine contains an ester linkage rather than anandamide's amide linkage. Like anandamide, it appears to act as a partial agonist. However, a microdialysis study suggested that while its tissue concentrations are similar to anandamide, it is released in much higher amounts. The existence of this compound has not been independently verified, and this author has been unable to detect it in rat brain extracts using ultrasensitive LC MS MS (liquid chromatography tandem mass spectrometry) methods developed using the synthetic compound (J.M. Walker, unpublished observations). Additional confirmatory studies of the existence of virodhamine are needed upon which further study of its potential role in pain modulation would be warranted.

Alcohol ethanol

Based on three studies on female fertility (Eggert 2004, Tolstrup 2003, Jensen 1998), it is concluded that there is a dose-effect relationship between alcohol consumption effects and female fertility. There are indications that consumption of less than lOg d ethanol might decrease female fertility (e.g. time to pregnancy). For effects on male fertility, only one published study (Hassan 2004) is available in which effects on fertility are described. Earlier, Rouquette (1957), in Paris, wrote an unpublished thesis on this topic. Based on this study, it can be concluded that there are indications that consumption of less than 10 g d of ethanol might also decrease male fertility.

Endocannabinoids

N-Pentyl Group Tail Modifications Although there is no apparent structural similarity between the classical cannabinoids and anandamide, there is considerable evidence suggesting that these two classes of cannabimimetic agents bind similarly to the CB1 active site (Barnett-Norris et al. 2002 A. Makriyannis and C. Li, unpublished results). There is ample chemical and computational evidence indicating that arachidonic acid, the parent fatty acid of anandamide, favors a bent or looped conformation in which the carbonyl group is proximal to the C14-C15 olefinic bond. The chemical evidence for such a conformation includes the highly regiospecific intramolecular epoxidation of arachidonoyl peracid (Corey et al. 1984) and the facile macrolactonization of C20 hydroxyl methyl arachidonate (Corey et al. 1983). These experimental results are corroborated by molecular dynamics calculations (Rich 1993) that indicate that indeed a bent conformation is thermodynamically favorable. In the case of...

Itraconazole

Cardiovascular Unpublished studies in dogs and healthy human volunteers have suggested that itraconazole has a negative inotropic effect the mechanism is unknown. A systematic analysis of data from the FDA's Adverse Event Reporting System (AERS) identified 58 cases suggestive of congestive heart failure in patients taking itraconazole (32c). A simultaneous search did not identify any cases of congestive heart failure in patients taking fluconazole and ketoconazole, ruling out the possibility of a class effect. In consequence, the labelling of itraconazole has been revised. Itraconazole is now contraindicated for the treatment of onychomycosis in patients with evidence of ventricular dysfunction. For systemic fungal infections, the risks and benefits of itraconazole should be reassessed if signs or symptoms of congestive heart failure develop.

Band

Earlier, we observed (unpublished data) that band 3 (- -) mouse erythrocytes were completely resistant to P. falciparum (3D7 strain) invasion in culture when band 3 (+ -) and wild-type mouse erythrocytes obtained showed a typical invasion profile known for mouse erythrocytes (Klotz et al. 1987). Similarly, band 3 (- -) mice were refractory to blood-stage infection by rodent malaria P. yoelii 17XL whereas band 3 (+ -) and wild-type mice became infected at a comparable rate (our unpublished data). These band 3 (- -) mouse erythrocytes display a secondary loss of GPA and protein 4.2 in the erythrocyte membrane as a consequence of the targeted disruption of the erythroid band 3 (AE1) gene (Southgate et al. 1996 Hassoun et al. 1998). Protein 4.2 (- -) mice (Peters et al. 1999) showed a normal course of P. yoelii 17XL infection similar to the wild-type (our unpublished data). These observations argue that band 3 could be a crucial host receptor either independently or in conjunction with...

Snuffing in Mexico

Now we give attention to Mexico and the archaeological evidence for an ancient snuffing complex that dates back at least to the second millennium BC, apparently became extinct as a major technique of ritual intoxication before AD 1000, and today survives only in remote mountain areas of Oaxaca and Guerrero, where some curers are said to inhale the pulverized seeds of the morning glory (T. Knab, personal communication, based on the unpublished field notes of the late botanist Thomas McDougall). It has always seemed puzzling that the early Spanish missionaries, who were certainly alert to the many manifestations of ritual intoxication, seem not to have seen any evidence of snuffing, even in areas adjacent to the well-developed snuffing complex of the Caribbean island cultures. Powdered tobacco is mentioned, but there is nothing to suggest that it, or any other hallucinogen, was inhaled as snuff.

Migraini Ddications

Uterine contractions and perfusion disturbances in the placenta (Fox 2005, Silberstein 2004). Individual cases of birth defects due to vascular disruption and stillbirths have been observed (Hughes 1988, Schaet'er unpublished observations). Epidemiological studies have not, as yet, documented a clear increase in the rate of birth defects (Raymond 1995). The other ergotamine derivatives, which arc available in oral form, lisuride and methysergide, are not well studied for their tolerability during pregnancy, and should also be avoided (Fox 2005, Silberstein 2004).

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