Identification of a GBR12935 homolog,LR1111, which is over 4,000-fold selective for the dopamine transporter,relative to serotonin and norepinephrine transporters

The di-substituted piperazines, GBR12909 (1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-4-[3-phenylpropyl]piperazine) and GBR12935 (1-[2-(diphenyl-methoxy)-ethyl]-4-(3-phenylpropyl)piperazine), are potent and selective (20-to 100-fold) inhibitors of [³H]dopamine reuptake, relative to [³H]5-HT and [³H]norepinephrine uptake. The GBR12935 analog, 1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)homopiperazine (LR1111), was synthesized as part of a systematic structure-activity study of analogs of GBR12935 and GBR12909. LR1111 differs from GBR12935 by the addition of a methylene group into the piperazine ring to yield a compound with a seven-member homopiperazine ring. The IC50 values for LR1111 at the dopamine, norepinephrine, and serotonin transporters were 7.2 nM, 34, 072 nM, and greater than 20,000 nM, respectively, whereas the IC50 values of GBR12935 were 3.7 nM, 289 nM, and 1261 nM for these same transporters. This demonstrates that the addition of a single methylene group in the piperazine ring results in a compound with similar affinity but significantly higher selectivity for the dopamine transporter. LR1111 increased motoric activity in rats after intravenous administration. These indicate that LR1111 is a potent and highly selective inhibitor of the dopamine transporter. Published 1993 Wiley-Liss, Inc.     

Protection against cocaine toxicity in mice by the dopamine D3/D2 agonist R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol [(+)-PD 128,907

Cocaine abuse is a public health concern with seizures and death being one consequence of overdose. In the present study, dopamine D(3/)D(2) receptor agonists dose dependently and completely prevented the convulsant and lethal effects of cocaine. The D(3)-preferring agonists R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol) [(+)-PD 128,907], (+)-7-hydroxy-dipropylaminotetralin, and the mixed D(3/)D(2) agonists quinpirole and quinelorane were all effective against cocaine toxicity in mice. The anticonvulsant effects of these compounds occurred at doses below those that produced motor impairment as assessed in the inverted screen test. Protection against the convulsant effects of the selective dopamine uptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy] ethyl]-4-[3-phenyl-propyl]piperazine (GBR 12909) was also conferred by (+)-PD 128,907. The possible selectivity of the effects of (+)-PD 128,907 (3 mg/kg) for these dopaminergic compounds was demonstrated by its general lack of protective efficacy against a host of convulsants acting through other neural mechanisms [pentylenetetrazol, (+)-bicuculline, and picrotoxin, 4-aminopyridine, and t-butylbiclyclophosphoorothionate, N-methyl-d-aspartate, kainate, pilocarpine, nicotine, strychnine, aminophylline, threshold electric shock, and 6-Hz electrical stimulation]. Direct and correlational evidence suggests that these effects were mediated by D(3) receptors. Protection was stereospecific and reversible by an antagonist of D(3) receptors [3-[4[1-(4-[2[4-(3-diethyamino-propoxy)-phenyl]-benzoimidazol-l-yl]-butyl)-1H-benzoimidazol-2-yl]-phenoxy]-propyl)-diethyl-amine; PD 58491] but not D(2) receptors [3[[4-(4-chlorophenyl)-4 hydroxypipeidin-1-yl]methyl-1H-indole; L-741,626]. Anticonvulsant potencies were positively associated with potencies in a functional assay of D(3) but not D(2) receptor function. Together, these findings suggest that the prevention of cocaine convulsions and lethality by (+)-PD 128,907 may be due to D(3) receptor-mediated events.     

Malaria and HIV co-infection in pregnancy in sub-Saharan Africa: impact of treatment using antimalarial and antiretroviral agents

Malaria and HIV infection represent severe public health problems in sub-Saharan Africa, and pregnant women are at increased risk because the two diseases intersect in pregnancy, causing adverse perinatal outcome. As access to antiretroviral drugs is increasing in the sub-region, and new combinations of antimalarial drugs are being implemented while more are being evaluated, there is potential for interactions between these therapies. In this report, the impact of treatment using antimalarial and antiretroviral agents in pregnant women with malaria and HIV co-infection was reviewed, using scientific publications identified through a Medline Entrez-Pubmed search with reference to sub-Saharan Africa. The safety and operational feasibility of use of antimalarial and antiretroviral agents to treat co-infected pregnant women were evaluated. Although use of these therapies was shown to improve the health of pregnant women with co-infection, low adherence, poor-quality drugs, resource scarcity, lack of infrastructure and inadequate treatment in sub-Saharan Africa continue to hamper treatment outcome. The absence of studies on interaction between antimalarials and antiretrovirals, as well as mounting evidence of treatment failure due to drug resistance and adverse drug reactions, in most parts of sub-Saharan Africa, make the establishment of new guidelines for the prevention of malaria and HIV infection during pregnancy imperative.     

Artemisinin-based combination therapy for uncomplicated malaria in sub-Saharan Africa: the efficacy, safety, resistance and policy implementation since Abuja 2000

Following increased resistance of malaria parasites to conventional drugs in the malarial regions of the world, the WHO is promoting artemisinin-based combination therapy (ACT) for treating uncomplicated malaria. The objective of this report is to review the available scientific information on the efficacy, safety, resistance and policy implementation of ACT as it relates to sub-Saharan Africa since the Abuja 2000 Roll Back Malaria initiative. To achieve this, a Medline search was performed to identify scientific publications relevant to the review. The data reviewed indicated that ACT proved very effective in the treatment of uncomplicated Plasmodium falciparum malaria in the region. ACT was shown to be effective, safe and tolerable and no resistance has been detected so far. However, the major challenges to its widespread use in the region include its high cost, low drug quality and poor healthcare delivery systems, among others. It is absolutely imperative for sub-Saharan African countries to establish an effective national antimalarial drug policy which will provide safe, effective, high-quality, accessible and affordable antimalarial drugs such as ACT to the populations at risk of malaria but, at the same time, promote rational drug use in order to delay or prevent the development of antimalarial drug resistance.     

PD 158771, a potential antipsychotic agent with D(2)/D(3) partial agonist and 5-HT(1A) agonist actions. I. Neurochemical effects

The neurochemical effects of a novel dopamine (DA) D(2)-like and serotonin (5-HT) 5-HT(1A) agonist, PD 158771, are described. PD 158771 exhibited affinities for human D(2L), D(3) and D(4.2) receptors expressed in Chinese hamster ovary (CHO)-K1 cells with K(i) (nM) values of 5.2, 13.7 and 34.8 respectively. PD 158771 showed high affinity for cloned human 5-HT(1A) (K(i) = 2.6 nM) and rat hippocampal 5-HT(1A) receptors (K(i) = 3.5 nM). Weaker affinities were observed at alpha 1-adrenergic (K(i) = 43 nM), histamine H(1) (IC(50) = 30 nM), 5-HT(2A) (K(i) = 24.5 nM) and sigma (sigma) -1 binding sites (K(i) = 24.5 nM). In measures of in vitro functional activity, PD 158771 stimulated [(3)H]thymidine uptake in CHO p-5 cells transfected with hD(3) receptors with a maximal effect of 23% relative to quinpirole. In hD(2)L, the corresponding value was 60% with an EC(50) of 29 nM, again indicating partial DA agonist action of PD 158771. In vivo, PD 158771 produced a dose-related decrease in DA synthesis in the striatum and mesolimbic regions of rat brain treated with gamma-butyrolactone (GBL), indicating a DA autoreceptor agonist action. In animals not treated with GBL, PD 158771 produced a dose-related decrease in DA synthesis and extracellular DA. A decrease in 5-HT synthesis in several brain areas was observed consistent with an agonist response. Further support for DA autoreceptor agonist action is that PD 158771 produced a partial inhibition of the firing of substantia nigra zona compacta DA neurons, an effect reversed by haloperidol. In conclusion, PD 158771 exhibited affinities for DA and 5-HT receptors, appears to possess DA and 5-HT agonist actions; and it could provide improved antipsychotic profile with minimal side effects.     

Biomass solid fuel and acute respiratory infections: the ventilation factor

Biomass solid fuel smoke is linked to acute respiratory infections (ARI). In future, its use will likely increase among poor households, and better ventilation is one important measure that can reduce this health impact. The authors aimed to study the extent to which improvement in ventilation-related factors reduces the fraction of ARI attributable to exposure to biomass smoke in children under 5 years old. An explorative study was carried out in 2004 by applying a questionnaire on 51 households randomly selected from a health district in Burkina Faso. The prevalence of exposure in the population was estimated using ventilation coefficients, and proportions of households with different stove types and locations. An attributable fraction of 0.56 (95% CI: 0.47-0.62) was estimated using the traditional formula for attributable fraction, and 0.26 (95% CI: 0.19-0.31) after weighting exposure by ventilation coefficients, stove type and location. Two scenarios were created: (1) Assuming that most households cooked inside, the fraction becomes 0.54 (95% CI: 0.45-0.61). (2) Assuming that indoor ventilation and cooking device are improved by 20%, the fractions decreased slightly. Improving cooking devices and indoor ventilation reduces the fraction of ARI in children under 5 years attributable to exposure to biomass smoke, but a higher reduction is achieved by cooking outdoors.