Anticocaine catalytic antibodies have no affinity for RTI compounds: Implications for treatment

Kuhar, MJ; Fi, Carroll; Bharat, Narine; Dw, Landry

doi:10.1002/syn.1072

Cited by 6 publications

(6 citation statements)

References 13 publications

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“…Our study suggests that women in Mbale District have the perceived stigma of HIV/AIDS as described by Bharat et al[ 29 ]. The perceived stigma of HIV/AIDS is informed by enacted stigma in the society usually in the form of gossip, blame, avoidance of physical contact, discrimination, neglect and rejection.…”

Section: Discussionsupporting

confidence: 61%

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Antenatal HIV testing in rural eastern Uganda in 2003: incomplete rollout of the prevention of mother-to-child transmission of HIV programme?

Karamagi

Tumwine

Tylleskär

et al. 2006

BMC Int Health Hum Rights

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BackgroundUganda began to implement the prevention of mother-to-child transmission (PMTCT) of HIV programme in 2000, and by the end of 2003 it had expanded to cover 38 of the 56 districts including Mbale District. However, reports from Mbale Hospital showed that less than 10% of pregnant women accepted antenatal HIV testing. We therefore conducted a study to determine the proportion of pregnant women who tested for HIV and the gaps and barriers in PMTCT implementation.MethodsThe study was a cross sectional household survey of women aged 18 years or more, with children aged one year or less, who resided in Mbale Town or in the surrounding Bungokho County. We also conducted in-depth interviews with six health workers in Mbale Hospital.ResultsIn 2003, we interviewed 457 women with a median age of 24 years. The prevalence of antenatal HIV testing was 10 percent. The barriers to antenatal HIV testing were unavailability of voluntary counselling and testing services (44%), lack of HIV counselling (42%) and perceived lack of benefits for HIV infected women and their infants. Primipara (OR 2.6, 95% CI 1.2–5.8), urban dwellers (OR 2.7, 95% CI 1.3–5.8), women having been counselled on HIV (OR 6.2, 95% CI 2.9–13.2), and women with husbands being their primary confidant (OR 2.3, 95% CI 1.0–5.5) were independently associated with HIV testing.ConclusionThe major barriers to PMTCT implementation were unavailability of PMTCT services, particularly in rural clinics, and poor antenatal counselling and HIV testing services. We recommend that the focus of the prevention of mother-to-child transmission of HIV programme should shift to the district and sub-district levels, strengthen community mobilization, improve the quality of antenatal voluntary counselling and HIV testing services, use professional and peer counsellors to augment HIV counselling, and ensure follow-up care and support for HIV positive women and their infants.

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Section: Discussionsupporting

confidence: 61%

“…In addition, the stigma related to HIV/AIDS is often superimposed on pre-existing stigmas of affected people[ 27 ]. Bharat et al[ 29 ] have identified three different types of HIV/AIDS stigma namely:…”

Section: Discussionmentioning

confidence: 99%

Antenatal HIV testing in rural eastern Uganda in 2003: incomplete rollout of the prevention of mother-to-child transmission of HIV programme?

Karamagi

Tumwine

Tylleskär

et al. 2006

BMC Int Health Hum Rights

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“…Pharmacokinetic antagonism of cocaine could be implemented by administration of a molecule, such as an anti-cocaine antibody, which binds tightly to cocaine so as to prevent cocaine from crossing the blood−brain barrier . A more potent blocking action could also be implemented by administration of a more stoichiometric agent such as a catalytic antibody, an artificial enzyme, that not only binds but also degrades cocaine and thereby frees itself for further binding. ,, To further the development of catalytic antibodies for hydrolysis of cocaine, ,− we sought to understand the mechanism underlying hydrolysis by natural cocaine esterases. Also, natural esterases could themselves be useful therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Fundamental Reaction Mechanism for Cocaine Hydrolysis in Human Butyrylcholinesterase

Chen

Zheng²,

Landry³

2003

J. Am. Chem. Soc.

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139

284

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Butyrylcholinesterase (BChE)-cocaine binding and the fundamental pathway for BChE-catalyzed hydrolysis of cocaine have been studied by molecular modeling, molecular dynamics (MD) simulations, and ab initio calculations. Modeling and simulations indicate that the structures of the prereactive BChE/substrate complexes for (-)-cocaine and (+)-cocaine are all similar to that of the corresponding prereactive BChE/butyrylcholine (BCh) complex. The overall binding of BChE with (-)-cocaine and (+)-cocaine is also similar to that proposed with butyrylthiocholine and succinyldithiocholine, i.e., (-)- or (+)-cocaine first slides down the substrate-binding gorge to bind to Trp-82 and stands vertically in the gorge between Asp-70 and Trp-82 (nonprereactive complex) and then rotates to a position in the catalytic site within a favorable distance for nucleophilic attack and hydrolysis by Ser-198 (prereactive complex). In the prereactive complex, cocaine lies horizontally at the bottom of the gorge. The fundamental catalytic hydrolysis pathway, consisting of acylation and deacylation stages similar to those for ester hydrolysis by other serine hydrolases, was proposed on the basis of the simulated prereactive complex and confirmed theoretically by ab initio reaction coordinate calculations. Both the acylation and deacylation follow a double-proton-transfer mechanism. The calculated energetic results show that within the chemical reaction process the highest energy barrier and Gibbs free energy barrier are all associated with the first step of deacylation. The calculated ratio of the rate constant (k(cat)) for the catalytic hydrolysis to that (k(0)) for the spontaneous hydrolysis is approximately 9.0 x 10(7). The estimated k(cat)/k(0) value of approximately 9.0 x 10(7) is in excellent agreement with the experimentally derived k(cat)/k(0) value of approximately 7.2 x 10(7) for (+)-cocaine, whereas it is approximately 2000 times larger than the experimentally derived k(cat)/k(0) value of approximately 4.4 x 10(4) for (-)-cocaine. All of the results suggest that the rate-determining step of the BChE-catalyzed hydrolysis of (+)-cocaine is the first step of deacylation, whereas for (-)-cocaine the change from the nonprereactive complex to the prereactive complex is rate-determining and has a Gibbs free energy barrier higher than that for the first step of deacylation by approximately 4 kcal/mol. A further analysis of the structural changes from the nonprereactive complex to the prereactive complex reveals specific amino acid residues hindering the structural changes, providing initial clues for the rational design of BChE mutants with improved catalytic activity for (-)-cocaine.

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“…Anticocaine catalytic antibodies, which serve as circulating peripheral blockers of cocaine that prevent its action in the brain, provide an alternative medication for cocaine abuse. , We found that several 3-phenyltropane analogues did not possess affinity for the anticocaine catalytic antibody 15A10, suggesting that the two types of treatments could be used together …”

Section: (1) Monoamine Transporters As Target For Addiction Therapymentioning

confidence: 88%

“…13,71 We found that several 3-phenyltropane analogues did not possess affinity for the anticocaine catalytic antibody 15A10, suggesting that the two types of treatments could be used together. 72 Thus, the 3-phenyltropane analogues could give the benefits associated with the substitution therapy, while the antibody would simultaneously reduce the effects of cocaine in the event of a relapse.…”

mentioning

confidence: 99%

Anticocaine catalytic antibodies have no affinity for RTI compounds: Implications for treatment

Cited by 6 publications

References 13 publications

Antenatal HIV testing in rural eastern Uganda in 2003: incomplete rollout of the prevention of mother-to-child transmission of HIV programme?

Antenatal HIV testing in rural eastern Uganda in 2003: incomplete rollout of the prevention of mother-to-child transmission of HIV programme?

Fundamental Reaction Mechanism for Cocaine Hydrolysis in Human Butyrylcholinesterase

2002 Medicinal Chemistry Division Award Address: Monoamine Transporters and Opioid Receptors. Targets for Addiction Therapy

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