British journal of clinical pharmacology · 2012
Quantification of the spatial distribution of rectally applied surrogates for microbicide and semen in colon with SPECT and magnetic resonance imaging.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка службы здравоохранения СШАНазвание и аннотация: Перевод в очереди
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Cao Ying J, Caffo Brian S, Fuchs Edward J, Lee Linda A, Du Yong, Li Liye, Bakshi Rahul P, Macura Katarzyna, Khan Wasif A, Wahl Richard L, Grohskopf Lisa A, Hendrix Craig W
Аннотация
AIMS: We sought to describe quantitatively the distribution of rectally administered gels and seminal fluid surrogates using novel concentration-distance parameters that could be repeated over time. These methods are needed to develop rationally rectal microbicides to target and prevent HIV infection.
METHODS: Eight subjects were dosed rectally with radiolabelled and gadolinium-labelled gels to simulate microbicide gel and seminal fluid. Rectal doses were given with and without simulated receptive anal intercourse. Twenty-four hour distribution was assessed with indirect single photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging (MRI), and direct assessment via sigmoidoscopic brushes. Concentration-distance curves were generated using an algorithm for fitting SPECT data in three dimensions. Three novel concentration-distance parameters were defined to describe quantitatively the distribution of radiolabels: maximal distance (D(max) ), distance at maximal concentration (D(Cmax) ) and mean residence distance (D(ave) ).
RESULTS: The SPECT/CT distribution of microbicide and semen surrogates was similar. Between 1 h and 24 h post dose, the surrogates migrated retrograde in all three parameters (relative to coccygeal level; geometric mean [95% confidence interval]): maximal distance (D(max) ), 10 cm (8.6-12) to 18 cm (13-26), distance at maximal concentration (D(Cmax) ), 3.8 cm (2.7-5.3) to 4.2 cm (2.8-6.3) and mean residence distance (D(ave) ), 4.3 cm (3.5-5.1) to 7.6 cm (5.3-11). Sigmoidoscopy and MRI correlated only roughly with SPECT/CT.
CONCLUSIONS: Rectal microbicide surrogates migrated retrograde during the 24 h following dosing. Spatial kinetic parameters estimated using three dimensional curve fitting of distribution data should prove useful for evaluating rectal formulations of drugs for HIV prevention and other indications.
METHODS: Eight subjects were dosed rectally with radiolabelled and gadolinium-labelled gels to simulate microbicide gel and seminal fluid. Rectal doses were given with and without simulated receptive anal intercourse. Twenty-four hour distribution was assessed with indirect single photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging (MRI), and direct assessment via sigmoidoscopic brushes. Concentration-distance curves were generated using an algorithm for fitting SPECT data in three dimensions. Three novel concentration-distance parameters were defined to describe quantitatively the distribution of radiolabels: maximal distance (D(max) ), distance at maximal concentration (D(Cmax) ) and mean residence distance (D(ave) ).
RESULTS: The SPECT/CT distribution of microbicide and semen surrogates was similar. Between 1 h and 24 h post dose, the surrogates migrated retrograde in all three parameters (relative to coccygeal level; geometric mean [95% confidence interval]): maximal distance (D(max) ), 10 cm (8.6-12) to 18 cm (13-26), distance at maximal concentration (D(Cmax) ), 3.8 cm (2.7-5.3) to 4.2 cm (2.8-6.3) and mean residence distance (D(ave) ), 4.3 cm (3.5-5.1) to 7.6 cm (5.3-11). Sigmoidoscopy and MRI correlated only roughly with SPECT/CT.
CONCLUSIONS: Rectal microbicide surrogates migrated retrograde during the 24 h following dosing. Spatial kinetic parameters estimated using three dimensional curve fitting of distribution data should prove useful for evaluating rectal formulations of drugs for HIV prevention and other indications.
Предметные рубрики MeSH
Administration, RectalAdultAnti-Infective AgentsCelluloseColonGadoliniumGadolinium DTPAGlycerolHIV InfectionsHomosexuality, MaleHumansMagnetic Resonance ImagingMaleMiddle AgedModels, TheoreticalPentetic AcidPhosphatesPropylene GlycolsSemenSigmoidoscopyTechnetium Tc 99m Sulfur ColloidTomography, Emission-Computed, Single-Photon