Patient with a sudden drop in blood pressure.
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Animals↗
Biomedical subjects
Donald W Landry
Publications and source records attributed to Donald W Landry.
Vasopressin deficiency in the syndrome of irreversible shock.
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Humans↗
Structure determination of a cocaine hydrolytic antibody from a pseudomerohedrally twinned crystal.
Few examples of pseudomerohedrally twinned macromolecular crystals have been described in the literature. This unusual phenomenon arises when a fortuitous unit-cell geometry makes it possible for twinning to occur in a space group that ordinarily does not allow twinning. Here, the crystallization, structure determination and refinement of the cocaine hydrolytic antibody 15A10 at 2.35 A resolution are described. The crystal belongs to space group P2(1), with two molecules in the asymmetric unit and unit-cell parameters a = 37.5, b = 108.4, c = 111.3 A and beta fortuitously near 90 degrees; the refined twinning fraction is alpha = 0.43. Interestingly, the non-crystallographic symmetry (NCS) and twin operators are nearly parallel, which appears to be a relatively frequent situation in protein crystals twinned by merohedry or pseudomerohedry.
Antibodies↗
Anticocaine catalytic antibodies.
Cocaine mediates its reinforcing and toxic actions through a "loss of function" effect at multiple receptors. The difficulties inherent in blocking a pleiotropic blocker pose a great obstacle for the classical receptor-antagonist approach and have contributed to the failure (to date) to devise specific treatments for cocaine overdose and addiction. As an alternative, we have embarked on an investigation of catalytic antibodies, a programmable class of artificial enzyme, as "peripheral blockers" -- agents designed to bind and degrade cocaine in the circulation before it partitions into the central nervous system to exert reinforcing or toxic effects. We synthesized transition-state analogs of cocaine's hydrolysis at its benzoyl ester, immunized mice, prepared hybridomas and developed the first anticocaine catalytic antibodies with the capacity to degrade cocaine to nonreinforcing, nontoxic products. We subsequently identified several families of anticocaine catalytic antibodies and found that the most potent antibody possessed sufficient activity to block cocaine-induced reinforcement, organ dysfunction and sudden death in rodent models of addiction, toxicity and overdose, respectively. With the potential to promote cessation of use, prolong abstinence and provide a treatment for acute overdose, the artificial enzyme approach comprehensively responds to the problem of cocaine.
Animals↗
Aptamer-based colorimetric probe for cocaine.
Complex of an anti-cocaine aptamer and the dye diethylthiotricarbocyanine behaves as a colorimetric sensor with attenuation in absorbance at 760 nm for cocaine in the concentration range of 2-600 muM. Mechanistic studies indicate an intermolecular displacement of the dye as the mechanism of action of the sensor. As the dye is insoluble in buffer, cocaine binding can be followed with the unaided eye as displaced dye precipitates and supernatant decolorizes.
Base Sequence↗
Covalent modification of proteins by cocaine.
Cocaine covalently modifies proteins through a reaction in which the methyl ester of cocaine acylates the epsilon-amino group of lysine residues. This reaction is highly specific in vitro, because no other amino acid reacts with cocaine, and only cocaine's methyl ester reacts with the lysine side chain. Covalently modified proteins were present in the plasma of rats and human subjects chronically exposed to cocaine. Modified endogenous proteins are immunogenic, and specific antibodies were elicited in mouse and detected in the plasma of human subjects. Covalent modification of proteins could explain cocaine's autoimmune effects and provide a new biochemical approach to cocaine's long-term actions.
Acylation↗
Restoration of renal function in shock by perfusion of the renal artery with venous blood: a counterintuitive approach.
OBJECTIVE: Acute renal failure (ARF) in low-flow states may be reversed by increasing renal perfusion. When hemodynamics are maximized, renal perfusion can only be improved by shunting a higher proportion of cardiac output to the kidney; however, in low-flow states, this reduces already compromised systemic pressure and perfusion to other organs. Increasing perfusion using venous blood (VB) would be an attractive option because decreased systemic pressure and perfusion to other organs could be avoided. However, it is not known whether VB can provide adequate oxygen delivery to restore or maintain renal function. We studied whether antegrade VB perfusion of the kidney via the renal artery would restore urine output (UO) and glomerular filtration rate (GFR) in hypoperfused ARF. DESIGN: Shock was induced in six dogs via a hemorrhagic protocol resulting in a systolic blood pressure of 50-70 mm Hg, a mixed venous oxygen saturation of 25% to 40%, and a UO <10% of baseline. After 60 mins of shock, the left renal artery was cannulated under fluoroscopy and perfused at pressures of 100-150 mm Hg for 30 mins with VB drawn from the vena cava and delivered by an extracorporeal pump system. The right kidneys were controls and remained hypoperfused. RESULTS: All VB-perfused kidneys recovered renal function after a sustained period of shock and marked oliguria: UO from 0.7 +/- 1.6 mL/hr to 101 +/- 58 mL/hr (p <.01); GFR from approximately 0 to 70.3 +/- 55 mL/min (p =.04). The control kidneys' UO (0.7 +/- 1.6 mL/hr) and GFR (0 mL/min) remained unchanged throughout the study. The experimental kidneys were able to extract oxygen from VB (O2 saturation, 31 +/- 7% to 16 +/- 4%; p =.01). CONCLUSION: When flow is controlled, kidneys in hypoperfused ARF can extract sufficient oxygen from antegrade VB perfusion to restore renal function (UO and GFR).
Acute Kidney Injury↗