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PHARMACOKINETICS |
From the Division of Clinical Pharmacology, Department of Medicine, School of Medicine (Dr Cao, Ms Radebaugh, Mr Fuchs, Dr Hendrix); Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland (Dr Caffo); and the Department of Biostatistics, School of Medicine, Vanderbilt University, Nashville, Nashville, Tennessee (Dr Choi).
Address for correspondence: Dr. Craig W. Hendrix, Harvey 502, 600 N. Wolfe Street, Baltimore, MD, 21287; e-mail: chendrix{at}jhmi.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Male genital tract • semen • quantitative clinical pharmacology • modeling • pharmacokinetics
Quantitative assessment of drug concentration in the lumen of the accessory glands, however, was not undertaken until recently.14,15 The male genital tract is composed of glands with distinct anatomical and functional properties. For example, the prostate gland produces acidic fluid and prostate-specific antigen (PSA), while the seminal vesicles produce basic fluids and fructose. During ejaculation, the prostate fluid is released before the release of seminal vesicles, and the fluid from each gland is not completely mixed before emerging out of the urethra with ejaculation. Thus, discrete fractions of seminal ejaculate can be collected, and each collected fraction has a different relative contribution from each of these major accessory glands. The concentration of chemicals unique to the major glands in each fraction can then be measured and used as the marker for the determination of the glandular drug concentration based on the drug concentration in each fraction. This is the basis of the quantitative noninvasive method for the determination of drug concentrations in prostate and seminal vesicles, which we developed based on the split ejaculate method first described by Lundquist for the evaluation of biochemical composition of these glands.16
This noninvasive assessment offers great advantages over other possible methods, including biopsy, prostate massage, and seminal vesicular aspiration. These other methods are invasive and not amenable to repeated sampling within a single dosing interval. In addition, prostate massage can be contaminated by the fluid from seminal vesicles. Biopsies assess both intracellular and interstitial drug concentration, but are not necessarily an efficient way to assess drug concentration in glandular secretions. Building on the split ejaculate collection technique,16 our 5-fraction method combined with a multilevel statistical model has the potential to provide precise estimation of glandular drug concentration noninvasively.14,15 Indirect validation of this method was carried out with 2 probe drugs, chloroquine and salicylate.14 Chloroquine is a weak base and might achieve higher concentration in acidic luminal fluid of prostate. Salicylate, the major metabolite of aspirin, is a weak acid and might achieve higher concentration in basic luminal fluid of seminal vesicles. Both of these assumptions are based on the pH-pKa partition hypothesis and could be significantly modified by other factors, including membrane transporters.
Although in our earlier study the estimated salicylate level in seminal vesicles was indeed significantly different from that in prostate (the mean with 95% credible interval of prostate-to-seminal vesicles ratio: 0.38 [0.12-0.73]), the estimated chloroquine level was not (the mean with 95% credible interval of prostate-to-seminal vesicles ratio: 4.4 [0.14-31]). We may have failed to detect a chloroquine gradient even if the model accurately estimated the true chloroquine concentration in both prostate and seminal vesicles, if our anticipated prostate-to-seminal vesicle gradient was not correct. Our estimates were based only on glandular pH differences, and glandular concentrations of chloroquine may be significantly affected by factors other than pH. For example, chloroquine is a substrate of some membrane transporters, which could be located differentially among accessory glands. Alternatively, the precision of our statistical model could be too low to detect a true prostate-to-seminal vesicle chloroquine concentration difference.
This study was designed to advance and further validate our noninvasive method for the assessment of the pharmacokinetics of physiological subcompartments of the male genital tract. To improve the method, we attempted to increase the precision of our statistical model by fitting 2 drugs simultaneously (rather than each drug individually as in our previous study) to estimate the fraction of ejaculate from each gland. To avoid the membrane transporter issues possibly confounding our chloroquine results, we chose desipramine instead of chloroquine, as desipramine is not known to be a substrate of membrane transporters. Desipramine is a basic drug with pKa 10.4, while salicylate is an acidic metabolite of aspirin with pKa 2.8. We expected, based on the pH-pKa partition hypothesis, that desipramine would be ion-trapped in the prostate, while salicylate would be ion-trapped in the seminal vesicles. Aspirin was used again, as in the previous model development study,14 to enable a direct comparison between this study and the previous one to test the reproducibility of our method.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The study was completed within 1 day in the out-patient setting for each subject. Eligible volunteers were given a single oral dose of desipramine 100 mg and a single oral dose of 975 mg aspirin concurrently. The desipramine dose was selected to achieve a peak concentration similar to the steady-state peak concentration with the typical 25 mg q6h starting dose. Semen and blood samples were collected 2.5 h after dosing. Subjects were instructed to masturbate and ejaculate their semen into a 5-compartment plastic collection tray in a single pass across the long axis of the tray, as described by Ndovi, et al.14,15 Pre-ejaculate that appeared at the urethral orifice was to be wiped away prior to ejaculation. The collection tray was then closed. Seven mL of blood were collected in a green top Vacutainer tube within 5 min after the semen sample was produced. Participants were evaluated for any adverse events and then discharged.
The closed collection device with freshly collected semen was placed in a negative flow hood for 30 min to allow the semen to liquefy. The liquefied semen was transferred with positive displacement pipettes into a sterile 1.5 mL conical centrifuge tube. The volume of each fraction of split ejaculate was measured and recorded. The sample was then centrifuged at 800 g for 10 min at 4°C. Twenty µL of seminal plasma was transferred into another sterile 1.5 mL cryotube for fructose assay. Another 10 µL was taken and diluted at 1:20 000 with PSA diluents (Beckman Coulter, Fullerton, Calif). Blood samples were delivered to the processing laboratory on ice immediately after being drawn. The blood samples were then centrifuged at 1500 g for 10 min at 4°C. The plasma was collected into two 3.6 mL cryovials. All processed semen and blood samples were stored at -70 °C until analysis.
Assay of Fructose and Prostate-specific Antigen (PSA)
The concentration of fructose and PSA in seminal plasma was determined as previously described.14,15 For fructose assay, the seminal plasma (20 µL) was first deproteinated with 1.8% (w/v) ZnSO4.7H2O (60 µL) and 0.1 M NaOH (40 µL). The fructose level in the sample was then measured with an Assay Kit (FA-20, Sigma-Aldrich, Inc., St Louis, Mo) based on the coupled enzymatic conversion of fructose to 6-phosphogluconate with spectrophotometric readout at 340 nm, which we modified to be used with 96-well format and validated for use in human seminal plasma.
The assay was done in triplicate (10 µL deproteinated seminal plasma per well) and had a linear range from 0.125 to 5 mM. Since there was a 6-fold dilution for deproteination, the actual minimum quantifiable limit was 0.75 mM with 20 µL seminal plasma. The intra-day and inter-day coefficient of variation of the quality control samples was less than 6%.
A commercial PSA assay, Hybritech PSA (Beckman Coulter), was validated for use with seminal plasma. The assay was a 2-site immunoenzymatic ("sandwich") method using mouse monoclonal antibody in alkaline phosphatase conjugate and paramagnetic particles coated with a second mouse monoclonal antibody. A chemiluminescent substrate was added to produce light directly proportional to the amount of PSA in the sample. The only modification required for use with seminal plasma was an initial 20 000-fold dilution. The day-to-day variability of the quality control samples was less than 3%, and measurements for standard curves all had a coefficient of variation of less than 15%.
Assay of Desipramine and Salicylate
Assay of desipramine and salicylate was performed by BASi (BAS Analytics, Ltd., Warwickshire, United Kingdom). Desipramine was extracted from 200 µL of blood plasma or 20 µL of seminal plasma (diluted to 200 µL with blank seminal plasma) with C18 solid-phase extraction cartridges. D4-desipramine was used as the internal standard. The cartridges were loaded under basic conditions, washed sequentially at pH8 and pH4, and eluted with acidified methanol. The chromatographic separation was performed on a Luna CN 5 micron 2 x 50 mm column supplied by Phenomenex (Macclesfield Cheshire, United Kingdom). The mobile phase consisted of 1% formic acid in 40% aqueous methanol (v/v) at a flow rate of 0.2 mL/min. The retention time was 2.3 min. Desipramine was detected with tandem mass spectroscopy with ion spray interface in positive mode, monitored for the m/z transition 267
72 (27172 for internal standard). The calibration standards were from 0.2 to 100 ng/mL. The lower limit of quantification was 0.2 ng/mL with 200 µL of blood plasma or 2 ng/mL with 20 µL of seminal plasma. The assay accuracy of calibration standards was within 15% of the actual value. The intra-run precision, calculated with the coefficient of variation, was within 16%, and inter-run precision was within 10%.
Salicylate was extracted from 50 µL of blood or seminal plasma through liquid-liquid partition into acidified methyl-tertiary-butyl ether. M-hydroxybenzoic acid was used as the internal standard. The chromatographic separation was performed on a Luna CN 5 micron 2 x 50 mm column from Phenomenex. The mobile phase consisted of 1% acetic acid in 20% aqueous acetonitrile (v/v) at a flow rate of 0.2 mL/min. The retention time was 2.0 min (1.5 min for internal standards). Detection was performed with tandem mass spectroscopy with ion spray interface in negative mode, monitored for the m/z transition 13793 for both salicylate and internal standards. The calibration standards were from 25 to 10 000 ng/mL. The lower limited of quantification was 25 ng/mL with 50 µL blood or seminal plasma sample. The assay accuracy was within 15% of the actual value. Both intra-day and inter-day precision was within 10%.
Statistical Analysis
Estimation of drug and biomarker level in the plasma of the whole seminal ejaculate. The drug and biomarker level in the plasma of the whole semen ejaculate was calculated by the sum of the amount of drug or biomarker in each fraction divided by the total plasma volume. Data are summarized by medians and range, unless otherwise noted.
Estimation of drug and biomarker level in the plasma from prostate and seminal vesicles. A latent-variable statistical model, improved based on our previous work,14,17 was used for the estimation of drug and biomarker concentration in the prostate and seminal vesicles. The improvement was to combine the underlying mechanisms with all relevant data into a single model for both probe drugs, instead of 1 model for 1 drug. Thus the precision of estimate was increased, as indicated by the narrower credible interval. Specifically, we assumed that
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was the inverse of variance; and f is the contribution of seminal vesicular fluid to the volume of a given fraction. The parameters were estimated through Bayesian inference using Gibbs sampling which was implemented in WinBUGS 1.4 (BUGS Project, MRC Biostatistics Unit, Cambridge, United Kingdom). The priors for mean glandular drug concentration were constrained to be positive. |
RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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3 fractions with semen volume of 0.2 mL each, which were the prespecified fraction and volume requirement. Among them, 4 provided 5 fractions; 8 (including 1 repeat subject who did not provide enough semen volume at first) provided 4 fractions; and 3 provided 3 fractions. Two subjects (7.4%; 1 was HIV-positive) provided 3 fractions with volume of 0.175 mL each and were also included for the assay of drug concentrations. Among the other 10 (37 %) subjects, 2 could not produce semen samples, and 8 did not provide enough number of fractions that met prespecified volume requirements. Nine (33%) subjects, including 1 HIV-positive subject, reported sexual dysfunction. Among them 5 had erection delayed for >10 min (1 could not erect at all, and another also reported less forceful ejaculation). Two reported less semen volume than usual. One could not sustain an erection and thus could not provide a semen sample. One could not ejaculate. None of these sexual side effects existed prior to the study and all resolved after completing the study.
Drug and Biomarker Level in Seminal Ejaculates
The calculated PSA and fructose concentrations in the plasma of the whole semen ejaculate were 1.1 (0.49-4.6) mg/mL and 12 (1.7-22) mM, respectively. The salicylate concentration in seminal plasma of the whole ejaculate and in blood plasma was 7.3 (3.1-11) µg/mL [mean with 95% confidence interval (CI), 7.3 (6.1-8.5)] and 67 (47-86) µg/mL [mean with 95% CI, 66 (61-71) µg/mL], respectively. The desipramine concentration in the whole seminal and blood plasma was 7.7 (1.9-18) ng/mL (after excluding an extreme outlier of 45 ng/mL) and 30 (5.5-42) ng/mL, respectively.
The fructose and PSA level in fractions of split seminal ejaculate appeared negatively correlated in 12 out of 17 subjects (71%). A negative correlation between fructose and PSA was expected if there were no measurement errors. Among 5 seemingly positive correlations, 3 were driven by one fraction. Such influential points were also seen in subjects with apparent negative correlation, suggesting relatively large measurement errors. The coefficient of variation of fructose level in fractions of individual subjects (median with range) was 24% (7.8-64). The coefficient of variation of PSA was 37% (11-113).
Salicylate appeared negatively correlated with PSA in 14/17 (82%) subjects. Desipramine appeared positively correlated with PSA concentrations in 12/17 (76%) subjects. Similar trends, although less prominent, were seen when the fructose levels were compared with salicylate (apparent positive correlation, 65%) and desipramine (apparent negative correlation, 65%). Thus, it was evident that desipramine had higher concentration in prostate and salicylate had higher concentration in seminal vesicles.
Drug and Biomarker Level in Accessory Glands of the Male Genital Tract
Salicylate concentration (median with 95% credible interval) was 2.0 (0.093-6.5) mM in the prostate and 9.9 (8.2-12) mM in the seminal vesicles with a prostate-to-seminal vesicles concentration ratio of 0.20 (0.0087-0.75) (Table I). Desipramine concentration was 27 (8.3-52) mg/mL in the prostate and 7.6 (4.1-11) mg/mL in the seminal vesicles with a prostate-to-seminal vesicles concentration ratio of 3.6 (0.91-9.9) (Table I). The contribution of seminal vesicular fluid to the whole ejaculate (f) was 79% (55%-96%). The PSA concentration in the prostate was 4.3 (0.79-7.2) mg/mL; the fructose concentration in seminal vesicles was 15 (11-19) mM. The probability of the prostate-to-seminal vesicles ratio of desipramine being more than 1 was estimated to be more than 0.90. The probability of the prostate-to-seminal vesicles ratio of salicylate being less than 1 was estimated to be more than 0.995.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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3.6 for desipramine and 0.20 for salicylate, consistent with the above qualitative assessments. The proportion of subjects who reported sexual side effects was one third, which was unexpected. Since participants in our previous study with chloroquine and salicylate14 did not report these side effects, we thought that desipramine was likely the cause. The normal starting dose of desipramine in clinical practice is 25 mg q6h. The accumulation index of this regimen is close to 4.6 assuming first-order kinetics for a single dose with a terminal half-life of 17 h18 or more assuming proportionately greater increase in plasma desipramine concentration than the increase in oral dosage.19 Thus, the maximum plasma desipramine concentration after a single 100-mg dose would be at least 13% less than the steady-state peak concentration on the common starting dosing regimen. The fact that our subjects had difficulty in erection, difficulty in ejaculation, or low ejaculation volume suggests that desipramine might alter the physiological process of semen ejaculation. It also suggests that a therapeutic or subtherapeutic dose of desipramine was associated with sexual dysfunction even in persons without depression. In clinical practice, desipramine has been reported to be associated with anorgasmia20 and anhedonic ejaculation21 and contributes to the increased incidence of sexual dysfunction during treatment with antidepressants.22-24 A separate manifestation of this dysfunction might have been the greater-than-expected variability in measured concentrations and the fructose-PSA correlation. The negative fructose-PSA correlation consistently seen in the majority of subjects and a fundamental assumption of our split ejaculate method would be highly sensitive to the sequence and timing of release of gland contents from the seminal vesicles and the prostate. Therefore, a change in the normal physiology of ejaculation could influence statistical estimations.
If the distribution of desipramine and salicylate is solely governed by an ion-trapping mechanism, the prostate-to-seminal vesicles ratio of desipramine and salicylate would be 10
pH with pH as the pH difference between these 2 glands. Thus, if the pH in prostate is 6.6 and the pH in seminal vesicles is 7.8, the prostate-to-seminal vesicles ratio of desipramine concentration would be 16 and that of salicylate would be 1/16 or 0.063. Overall, our estimation was qualitatively consistent with the expected theoretical trend. Several factors may account for the deviation from the magnitude of the expected value. First, the pH in prostate in vivo may be more basic than generally thought while the pH in seminal vesicles in vivo may be more acidic, making the pH closer to 0.25 Also, the variance of in vivo glandular pH is unknown. Second, half of the split-ejaculate samples in this study were largely (>80% of fraction volume) from seminal vesicles. Thus, the difference in the relative amount of prostate and seminal vesicles fluid from fraction to fraction might be too small while the variation due to measuring/handling errors may be too large, resulting in a small signal-noise ratio. Such small volume contribution from prostate might be particularly problematic for the estimation of prostatic salicylate concentration, which was relatively low as compared with that in seminal vesicles. Third, the differential influence of biochemical properties of glandular fluid, such as lipid solubility and protein binding, may partially cancel out the impact of pH-pKa partitioning. Fourth, the anatomic structure between blood and each gland relevant to drug diffusion and the potential for active drug transport may be different in prostate and seminal vesicles which may also alter ratios based solely on pH-pKa partitioning. Fifth, several physiologic variables may contribute to distinct glandular drug concentration-time profiles and our non-steady-state sampling would be insensitive to these differences. Finally, whether desipramine and aspirin modify each other's distribution into and clearance out of the male genital tract is currently unknown.
In a study on the concentration-time course of healthy volunteers,26 the peak salicylate level of 49 µg/mL was achieved 2.5 h after oral administration of 975 mg aspirin. In this study we found that the blood salicylate level was 66 (61-71) µg/mL (mean with 95% CI) 2.5 h postdosing, which was slightly, but statistically insignificantly, higher than 55 (47-63) µg/mL achieved at 1 h postdosing in our previous study.14 Similarly, the 95% credible intervals of salicylate concentration in prostate and seminal vesicles were largely overlapping with those in our previous study. The prostate-to-seminal vesicles ratio of salicylate in this study was also comparable to our previous report (95% credible interval, 0.0087-0.75 in this study vs 0.12-0.73 in the previous study). The wider credible interval of prostate-to-seminal vesicles ratio of salicylate found in this study was likely due to the fact that the current dataset was more variable overall than that in our previous study, possibly due to the negative impact of desipramine on physiological process of semen ejaculation as mentioned previously. This was especially noticeable in the relationships between fructose and PSA where only 71% were negatively correlated in this current study in contrast to 93% of subjects in the previous study.14 Moreover, the contribution from seminal vesicles (80%) was higher than that in our previous study (56%). Despite the increase in the variability of our data, the statistical inference for aspirin concentrations in the individual glands in this study was comparable to what we have reported.14
We previously found that the prostate-to-seminal vesicles concentration ratio of chloroquine (95% credible interval) was from 0.14 to 31,14 wider than what was found with desipramine in this study, which was 0.91 to 10. Our chloroquine study did not allow us to confidently determine whether the imprecise estimate was drug-specific (ie, chloroquine concentration gradient was not largely driven by pH-pKa partitioning, but by some other chloroquine-specific mechanisms such as active transport) or our Bayesian method-specific (ie, the premise for our Bayesian model was not generalizable). Since the pKa of both chloroquine and desipramine is far below pH 6.6, if the dominant mechanism of distribution is pH-related ionization, their prostate-to-seminal vesicles concentration ratios are expected to be equal. Using the same model as for chloroquine, we estimated the prostate-to-seminal concentration ratio of desipramine in this noisier dataset to be 0.67 to 10, which was narrower than the estimation for chloroquine. Therefore, the wider credible interval found in our previous study was likely chloroquine-specific, due to factors such as the differential distribution of chloroquine-transporting and chloroquine-trapping mechanisms. Another possibility for our success with desipramine and our consistent salicylate results despite a more variable dataset may be related to our methodological improvement introduced with this study. We modeled all 4 variables (PSA, fructose, desipramine, and salicylate) together in this study, instead of only 3 variables in our previous model. We obtained even more precise estimate for desipramine, as seen with narrow credible interval (0.91-10). This was because, for a given fraction, the desipramine concentration was determined not only by the glandular desipramine level but also by the relative volume contribution of the 2 glands whose estimates should also depend on the salicylate concentration, which serves as a biological mechanism in terms of modeling as shown in equation 4. In other words, our estimate for f was also informed by salicylate concentrations of each fraction.
Our quantitative methods are robust. Although not reported, we also tested 2 other potential distribution models—lognormal distribution for PSA and desipramine and lognormal distribution for all concentration measures—to evaluate the sensitivity of our differentiation of drug concentrations in prostate versus seminal vesicles. The results were similar except for the boundary of 95% credible interval of prostatic PSA and salicylate level. With the assumption of the lognormal distribution, the lower boundary of 95% credible interval of prostatic salicylate concentration estimate was close to 0, suggesting that salicylate concentrations were indeed very low or not lognormally distributed in the population. Alternatively, the prostatic fluid volume is relatively small and presumably more subject to the variation from handling and measurement. Thus, we recommend that the ejaculates be well split for the application of our methods.
In summary, our 5-fraction split ejaculation method combined with a Bayesian latent-variable model provided quantification of drug concentrations in the prostate distinct from concentrations in the seminal vesicles. Further direct validation can be performed by comparison of more invasive direct methods such as biopsy and seminal vesicles cannulation. Our method is applicable for drug development and rational therapeutics for diseases of the accessory glands of the male genital tract.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This work was supported in part by a Mid-Career Investigator Award in Patient-Oriented Research (NIH K24 AI01825), General Clinical Research Center (NIH M01RR000052-430919, 5M01RR000052-430852), Johns Hopkins University Center for AIDS Research (NIH P30 AI042855), HIV Prevention Trials Network Central Laboratory (NIH U01 AI46745, U01AI068613), the American Society of Clinical Pharmacology and Therapeutics (the ASCPT Young Investigator Award), and the NIH Fellowship Training Program in Clinical Pharmacology (5T32GM066691-02).
This work has been presented in the doctoral thesis for Dr. Cao, Johns Hopkins University, Graduate Training Program in Clinical Investigation, 2007.
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REFERENCES |
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