Computational modeling to predict effect of treatment schedule on drug delivery to prostate in humans.

PURPOSE: To evaluate a computational approach that incorporates experimental data in preclinical models to depict doxorubicin human tissue pharmacokinetics. EXPERIMENTAL DESIGN: Beagle dogs were given 2 mg/kg doxorubicin as i.v. bolus, 4-h infusion, or 96-h infusion. Concentrations in plasma, prostate (target tissue), heart (toxicity), and major tissues for disposition were determined and modeled. Model parameters were obtained after the bolus injection with model validation based on the 4-h and 96-h infusion data. Clinical pharmacokinetic data and scale-up gave doxorubicin profiles in human prostate and heart. RESULTS: In agreement with in vitro results, tissues were best modeled with two compartments, one rapidly and one slowly equilibrating. The developed tissue distribution model predicted concentrations for all three administration regimens well, with an average deviation of 34% (median, 29%). Interspecies scale-up to humans showed that the change from a bolus injection to a slow, 96-h infusion (a) had different effects on the drug partition and accumulation in heart and prostate, and (b) lowered the peak concentration in the plasma by approximately 100-fold but had relatively little effect on maximal heart concentration ( approximately 33% lower). The simulated drug exposure in a human prostate was above the exposure required to inhibit tumor proliferation but was 30 to 50 times below that needed for cell death. CONCLUSION: The present study shows a computation-based paradigm for translating in vitro and in vivo preclinical data and to estimate and compare the drug delivery and pharmacokinetics in target tissues after different treatment schedules.     

Intraprostatic chemotherapy: distribution and transport mechanisms.

PURPOSE: The present study evaluated the tissue distribution and targeting advantage of intraprostatic chemotherapy. EXPERIMENTAL DESIGN: We studied the delivery and spatial distribution of a fluorescent drug, doxorubicin, in the prostate of beagle dogs, after intraprostatic or i.v. administration. Drug concentrations were measured using high-performance liquid chromatography and confocal fluorescence microscopy. RESULTS: I.v. and intraprostatic injections yielded qualitatively and quantitatively different doxorubicin distribution in the prostate. A relatively homogeneous distribution was found after i.v. administration, whereas intraprostatic injection yielded a highly heterogeneous distribution with >10-fold higher concentrations localized in a cone-shaped glandular lobule bound by fibromuscular stroma, compared with other parts of the prostate. Compared with i.v. injection, intraprostatic injection yielded, on average, approximately 100-fold higher tissue-to-plasma concentration ratio, ranging from 963-fold near the injection site to 19-fold in the contralateral half of the prostate. The drug distribution within the prostate further suggests an important role for acinar flow in intraprostatic drug transport. CONCLUSIONS: Intraprostatic administration represents a viable option to deliver high drug concentrations within the prostate. The results further suggest the fibromuscular stroma separating the prostatic lobules as a major barrier to drug transport and convective flow as an important drug transport mechanism in the prostate.     

Verbal learning in Alzheimer's dementia.

Many recent findings in Western countries suggest that episodic recall is the most sensitive discriminator between patients with mild Alzheimer disease (AD) and the normal elderly, while semantic memory tends best to differentiate between moderate and severe AD patients. The present study is the first to examine in detail the episodic memory of Chinese AD patients in Hong Kong with a locally developed list learning test, comparing procedures that do or do not encourage the use of semantic organization. The performance of 28 AD patients was compared to that of 30 normal controls. AD patients did significantly worse in terms of acquisition and retention and also benefited significantly less from external organization cues. In the discriminant function analysis, the rate of forgetting in the random condition and the total retention score in the blocked condition were found to be the best predictors for differentiating between AD patients and controls. On the other hand, in the differentiation between mild and moderate AD, semantic clustering in the blocked condition was found to be the best predictor. Results of the present study were discussed in the light of the previous findings reported in the Western countries and the neuropathological changes of AD patients.     

Effect of Bupivacaine and Levobupivacaine on Exocytotic Norepinephrine Release from Rat Atria

Background: The cardiotoxic mechanism of local anesthetics may include interruption of cardiac sympathetic reflexes. The authors undertook this investigation to determine if clinically relevant concentrations of bupivacaine and levobupivacaine interfere with exocytotic norepinephrine release from cardiac sympathetic nerve endings.

Methods: Rat atria were prepared for measurements of twitch contractile force and 3[H]-norepinephrine release. After nerve endings were loaded with 3[H]-norepinephrine, the tissue was electrically stimulated in 5-min episodes during 10 10-min sampling periods. After each period, a sample of bath fluid was analyzed for radioactivity and 3[H]-norepinephrine release was expressed as a fraction of tissue counts. Atria were exposed to buffer alone during sampling periods 1 and 2 (S1 and S2). Control atria received saline (100 [mu]l each, n = 6 atria) in S3-S10. Experimental groups (n = 6 per group) received either bupivacaine or levobupivacaine at concentrations (in [mu]M) of 5 (S3-S4), 10 (S5-S6), 30 (S7-S8), and 100 (S9-S10).

Results: Bupivacaine and levobupivacaine decreased stimulation-evoked fractional 3[H]-norepinephrine release with inhibitory concentration 50% values of 5.1 +/- 0.5 and 6.1 +/- 1.3 [mu]m. The inhibitory effect of both local anesthetics (~70%) approached that of tetrodotoxin. Local anesthetics abolished the twitch contractions of atria with inhibitory concentration 50% values of 12.6 +/- 5.0 [mu]m (bupivacaine) and 15.7 +/- 3.9 [mu]m (levobupivacaine). In separate experiments, tetrodotoxin inhibited twitch contractile force by only 30%.     

Growth hormone resistance in uremia

Growth retardation is a major complication in children with uremia. Protein restriction, calorie deficit, metabolic acidosis, renal osteodystrophy, and endocrinologic disturbances contribute to the growth failure. The effect of these factors on growth retardation can be attenuated in part by therapy with vitamin D metabolites, adequate nutrition, alkalization, and dialysis. Linear growth in children with uremia is markedly retarded despite normal or increased levels of circulating serum growth hormone. An increased growth hormone level in children with uremia is due to normal growth hormone secretion from the pituitary gland and impaired growth hormone clearance in the kidney. However, the elevated growth hormone level does not lead to a commensurate rise in serum insulin-like growth factor I (IGF-I); the serum IGF-I level is decreased or normal in relation to the degree of renal failure. This discrepancy suggests growth hormone resistance in the liver in uremia. Recent molecular techniques open a new era in studying the gene expression for growth hormone or IGF-I. There is no doubt today that growth hormone treatment has the beneficial effect of growth promotion in children with uremia, which also suggests endogenous growth hormone resistance in target organs or target cells in uremia.     

Neural cell adhesion molecules are present in the fetal human primary olfactory pathway.

Olfactory tissues from human fetuses (17.5-28 weeks of gestation) were stained by immunofluorescence for neural cell adhesion molecules (N-CAMs). Staining for N-CAMs was most prominent in the olfactory nerve bundles in the lamina propria, while in the olfactory epithelium, it was present on the olfactory receptor neurons and globose basal cells. The basal cells proper and supporting cells lacked N-CAMs. In the olfactory bulb, only the olfactory nerve and glomerular layers showed moderate labeling for N-CAMs. Western blot analysis showed that the N-CAMs of the fetal human primary olfactory pathway consisted of three molecular isoforms, N-CAM180, N-CAM140 and N-CAM120.     

Biomarker monitoring of a population residing near uranium mining activities.

We investigated whether residents residing near uranium mining operations (target population), who are potentially exposed to toxicants from mining waste, have increased genotoxic effects compared with people residing elsewhere (reference population). Population surveys were conducted, and 24 target and 24 reference residents were selected. The selected subjects and controls were matched on age and gender and they were nonsmokers. Blood samples were collected for laboratory studies. The standard cytogenetic assay was used to determine chromosome aberration frequencies, and the challenge assay was used to investigate DNA repair responses. We found that individuals who resided near uranium mining operations had a higher mean frequency of cells with chromosome aberrations and higher deletion frequency but lower dicentric frequency than the reference group, although the difference was not statistically significant. After cells were challenged by exposure to gamma-rays, the target population had a significantly higher frequency of cells with chromosome aberrations and deletion frequency than the reference group. The latter observation is indicative of abnormal DNA repair response in the target population.