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Minocycline Diffusion into Benign Prostatic Hyperplasia
Vol. 118, October Printed in U.SA.
THE JOURNAL OF UROLOGY
Copyright © 1977 by The Williams & Wilkins Co.
MINOCYCLINE DIFFUSION INTO BENIGN PROSTATIC HYPERPLASIA TERRY W. HENSLE, GEORGE R. PROUT, JR. and PAMELA GRIFFIN From the Urological Service, Massachusetts General Hospital and the Department of Surgery, Harvard Medical School, Boston, Massachusetts
ABSTRACT
lipid soluble tetracycline that has generated interest in the treatment of chronic was evaluated for its possible ability to be concentrated in benign prostatic hyperplasia. Drug levels in the prostate, plasma, fat, muscle and urine were measured in patients undergoing prostatectomy after preoperative intravenous minocycline. The concentrations of the drug in prostate and serum were dose (4.16 versus 3.01 µg. per gm.), while drug levels in striated muscle and fat were consistently lower (2.92 and 0.77 µ.,g. per gm.). Higher preoperative doses of the drug yielded higher tissue levels. Drug delivery closer temporally to the operation serum and prostatic levels as opposed to striated muscle and fat, suggesting a diffusion of the drug into benign prostatic hyperplasia. is a semisynthetic tetracycline that recently has generated interest in dealing with chronic prostatitis. 1." The drug has a broad antibacterial spectrum with a high degree of activity against the bacterial cell wall.1. 3 Minocycline, like all tetracyclines, is 70 to 80 per cent protein-bound in ~-·------· but it is the most lipid soluble T.<>TT!'lf'v,c, available. The drug is dissociated as an other tetracyclines but it does have dissociation constants of 7. 8 and 9 .3. 4 These characteristics enable minocycline to diffuse readily across the epithelium of the prostatic acinus. The characterization of physical properties necessary for antibiotic diffusion into the prostate has been defined and an animal model demonstrating minocycline con-
p.m. on the evening before the operation, followed by another dose of 100 mg. intravenously on call to the operating room at 10 a.m. on the day of the operation, for a total dose of 300 mg. preoperatively. Eight of the 20 patients studied received more than the protocol dosage of minocycline, receiving 300 mg. at night and 200 mg. immediately preoperatively (fig. 1 and table 1). Tissue for study taken at the operation included prostatic adenoma, fat and striated muscle, as well as serum and urine. The excised prostatic tissue was washed repeatedly with saline TABLE
1. Concentrations of minocycline in benign prostatic
hyperplasia and other tissues Pt. No.
10
6.95
0.74
FIG. 1. Concentrations of minocycline in benign prostatic hyperplasia and oth2r tissues.
centration in the canine prostate has been developed." These experimental data along with recent clinical evidence of minocycline's effectiveness in the control and treatment of chronic prostatitis in the human 2 ' 7 prompted us to design a study that would yield data concerning the concentration of minocycline in benign nr,,Q,,,,,,.. hyperplasia. MATERIALS AND METHODS
Twenty pw""'·""" undergoing open prostatectomy for benign hyperplasia were studied prospectively. In this study group 200 mg. minocycline were given intravenously at 10 Accepted for publication December 10, 1976. Supported in part by a grant from Lederle Laboratories. 609
168--80 113-85 191-08 000-72 040-87* 003-94* 052-73* 194-79 007-72*· t 052-42*· t 026-82*· t 150-90 034-29 147-85* 178-68* 166-69 181-85 099-90 179-52 198-65 Mean Standard deviation Standard error
Prostate Muscle Fat (µ,g./gm.) (µ,g./gm.) (µ.g./gm.) 2.84 2.99 1. 74 2.82 3.62 3.61 5.78 3.27 11. 70 7.23 7.14 3.95 4.85 2.14 4.57 3.39 2.63 3.03 3.00 2.83 4.16 ±2.32 ±0.52
3.57 0.76 0.83 0.29 <0.15 3.60 4.52 0.33 6.67 2.83 2.71 3.29 ' 43 15.70 2.54 2.79 1.97 2.17 0.67 2.63 2.97 ±3.41 ±0.76
<0.15 0.26 <0.15 <0.15 1.26 <0.15 0.86 1.34 1.44 0.68 1.17 3.18 <0.15 0.27 0.72 0.36 <0.15 1.69 <0.15 0.44 0.74 ±0.77 ±0.17
Serum (µ.g./ml.) 2.24 3.26 2.26 <0.025 4.97 0.45 3.36 3.35 5.19 10.00 6.64 2.81 4.23 3.13 5.36 4.84 3.55 3.34 3.32 3.81 ±2.19 ±0.87
Urine (µ,g./ml.) 8.7d
6.95
2.10 3.01 4.85 1.58 2.14 7.89 19.40 9.07 25.02
1.50 0.92 4.11 6.95 ±7.12 ±1.90
* 500 mg. total preoperative dose- 300 mg. at night and 200 mg. immediately preoperatively. t Second dose given in operating room in the immediate preoperative period. and then, using fresh gloves and instruments, the tissue was incised and an uncontaminated portion of adenoma was sub-mitted for determination of drug concentration. This method totally eliminated the chance of urinary contamination of the tissue to be analyzed. The samples of fat and striated muscle (rectus) were taken prior to incision into the prostatic capsule specifically to avoid urinary contamination. All samples of tissue and urine were frozen promptly, as was the serum after centrifugation at 65 times the force of gravity for 10 minutes.
610
HENSLE, PROUT AND GRIFFIN TABLE
10
2. Concentrations ofminocycline in 8 patients who received 500
mg. total dose preoperatively
7.49
rrg/gm
Serum Fat Prostate Muscle (µ,g./gm.) (µ,g./gm.) (µ,g./gm.) (µ,g./ml.)
Pt. No. 040-87 003-94 052-73 007-72 052-42 026-82 147-85 178-68 Mean Standard deviation Standard error
5
0
3.62 3.61 5.78 11.70 7.23 7.14 2.14 4.57 5.72 ±3.00 ±1.06
<0.15 3.60 4.52 6.67 2.83 2.71 15.70 2.54 4.84 ±4.76 ±1.68
1.26 <0.15 0.86 1.44 0.68 1.17 0.27 0.72 0.82 ±0.46 ±0.16
4.97 0.45 3.36 5.19 10.00 6.64 3.13 5.36 4.89 ±2.79 ±0.99
Urine (µ,g./ml.) 2.10 4.85 1.58 2.14 9.07 25.20 7.49 ±9.12 ±3.72
~-s, TABLE
00 -Q,-9
3. Concentrations of minocycline in 3 patients who received
their final dose just prior to operation*
Fm. 2. Concentrations of minocycline in 8 patients who received 500 mg. total dose preoperatively.
Prostate Muscle Fat Serum Urine (µ,g./gm.) (µ,g./gm.) (µ,g./gm.) (µ,g./ml.) (µ,g./ml.)
Pt. No. 007-72 052-42 026-82 Mean Standard deviation Standard error
11.70 7.23 7.14 8.69 ±2.61 ±1.51
6.67 2.83 2.71 4.07 ±2.25 ±1.30
1.44 0.68 1.17 1.10 ±0.39 ±0.23
5.19 10.00 6.64 7.28 ±2.47 ±1.43
4.85 1.58 2.14 2.86 ±1.75 ±1.01
* Total dose 500 mg., 200 mg. preoperatively. TABLE
rrg/gm
4. Concentrations of minocycline in 12 patients who received 300 mg. total dose preoperatively Pt. No.
Fm. 3. Concentrations of minocycline in 3 patients who received their final dose just before operation. Total dose 500 mg., 200 mg. preoperatively.
10 6.57
rrg/
5
0.68
Fm. 4. Concentrations of minocycline in 12 patients who received 300 mg. total dose preoperatively.
All samples analyzed were delivered frozen to Lederle Laboratories, Pearl River, New York. Bacillus cereus was used as a standard in the cylinder plate assay method for tetracyclines. 8
194-79 150-90 034-29 166-69 181-85 099-90 179-52 198-65 168-80 113-85 191-08 000-72 Mean Standard deviation Standard error
Urine Fat Serum Prostate Muscle (µ,g./gm.) (µ,g./gm.) (µ,g./gm.) (µ,g./ml.) (µ,g./ml.) 3.27 3.95 4.85 3.39 2.63 3.03 3.00 2.83 2.84 2.99 1.74 2.82 3.11 ±0.75 ±0.22
0.33 3.29 1.43 2.79 1.97 2.17 0.67 2.63 3.57 0.76 0.83 0.29 1. 73 ±1.17 ±0.34
1.34 3.18 <0.15 0.36 <0.15 1.69 <0.15 0.44 <0.15 0.26 <0.15 <0.15 0.68 ±0.94 ±0.27
3.35 2.81 4.23 4.84
3.01 7.89 19.40
3.55 3.34 3.32 2.24 3.26 2.26 <0.025 3.02 ±1.25 ±0.38
1.50 0.92 4.11 8.74 6.95 6.57 ±5.95 ±2.10
striated muscle were present but consistently lower, with an average of 2.97 µ,g. per gm. Little minocycline was concentrated in fat, with an average of 0. 77 µ,g. per gm. and urinary concentrations were most variable, with wide differences between individual patients and a mean value of6.95 µ,g. per ml. urine. The patients who received 500 mg. minocycline preoperatively, rather than the 300 mg. protocol dose, had significantly higher drug concentrations in the prostate, serum and muscle as might be expected (fig. 2 and table 2) but the concentration ratio, prostate to serum of 1 to 1, remained unchanged. It is interesting that those patients who received minocycline just before the operation and close temporally to tissue sampling had high levels of the drug in the serum and prostate (fig. 3 and table 3) in comparison to the regular protocol patients (fig. 4 and table 4), and the concentrations of drug in muscle and fat of these patients were not significantly different from levels found in patients receiving the drug 2 to 3 hours preoperatively, suggesting rather rapid equilibration of the drug from serum to prostate in comparison to muscle and fat.
RESULTS
DISCUSSION
Individual and mean concentrations of minocycline in prostatic tissue, serum, urine, fat and striated muscle are tabulated in figure 1 and table 1. At the time of sampling minocycline levels in the prostate and serum were virtually identical with 4.16 and 3.81 µ,g. per gm., respectively. Drug levels in
The inability of most antibiotics to reach the prostatic parenchyma has long been a problem. The general characteristics necessary for antibiotic diffusion in the prostate have been defined previously. s, 7 These include 1) a high degree of solubility, 2) a proper degree of ionization (high dissociation con-
MINOCYCLINE DIFFUSION INTO BENIGN PROSTATIC HYPERPLASIA
stant) to assure the presence of enough uncharged portion of the to diffuse across the prostatic epithelium and 3) non-protein-bound drug free in plasma to diffuse into if the first 2 requirements are met. with a high degree of lipid high constants (7.8 and 9.3) and 20 to 30 per cent unbound form of the drug in plasma, meets all the characteristics that would favor prostatic tissue concentration. The most single factor in minocycline's increased ability to enter the prostate is its lipid solubility. Because of minocycline's increased activity as measured by partition coefficients at the ofprostatic fluid (pH 6.6) it is 30 times more soluble than other tetracyclines. Tissue levels in our studies indicate that m,mc,""" concentration in the prostate is time and Patients larger doses of minocycline and those receiving the more proximate to their surgical procedure had higher of in the serum and prostate. The serum-to-prostate ratio remained in the 1 to 1 range despite time and dose These data do not answer the question as to the for - ... ·- ,..-of drug between plasma and and between prostatic parenchyma and prostatic We do know that in man 10 hours after an initial loading dose of minocycline there appears to be not only drug present in prostate but some degree of concentration with reference to However, the p values are not significant and the concentration ratio of serum to prostate remained ap1 to 1. rn animal model, found a high degree of drug concentration in the prostatic parenchyma but not in nr,c,Q
611
cycline are indicated to determine the fate of the antibiotic after entering the prostate. The data of the current study plus evidence of the long half-life of minocycline (13.6 hours), low mean inhibitory concentration in plasma (minimal inhibitory concentration equals 0.02 µ.g. per ml.) 8 and a broad gram-negative antibacterial spectrum suggest that minocycline may be valuable in dealing with chronic bacterial infections in the prostate. For these same reasons, minocycline also may be useful as a prophylactic agent to control bacteremia during prostatec· tomy. The assays were done by Mr. Dornbush. REFERENCES
1. Klastersky, J. and Daneau, D.: Bacteriological evaluation of minocycline, a new tetracycline. Chemotherapy, 17: 51, 1972. 2. Brannan, W.: Treatment of chronic prostatitis. Comparison of minocycline and doxycycline. Urology, 5: 626, 1975. 3. Steigbigel, N. H., Reed, C. W. and Finland, M.: Susceptibility of common pathogenic bacteria to seven tetracycline antibiotics in vitro. Amer. J. Med. Sci., 255: 179, 1968. 4. Hess!, J. M. and Stamey, T. A.: The passage of tetracyclines across epithelial membranes with special reference to prostatic epithelium. J. Urol., 106: 253, 1971. 5. Winningham, D. G., Nemoy, N. J. and Stamey, T. A.: Diffusion of antibiotics from plasma into prostatic fluid. Nature, 219: 139, 1968. 6. Fair, W. R.: Diffusion of minocycline into prostatic secretion in dogs. Urology, 3: 339, 1974. 7. Stamey, T. A., Meares, E. M., Jr. and Winningham, D. G .. Chronic bacterial prostatitis and the diffusion of drugs into prostatic fluid. J. Urol., 103: 187, 1970. 8. Steers, E., Foltz, E. L. and Graves, B. S.: An inocula replicating apparatus for routine testing of bacterial susceptibility to antibiotics. Antibiot. Chemother., 9: 307, 1959.
THE JOURNAL OF UROLOGY
Copyright © 1977 by The Williams & Wilkins Co.
MINOCYCLINE DIFFUSION INTO BENIGN PROSTATIC HYPERPLASIA TERRY W. HENSLE, GEORGE R. PROUT, JR. and PAMELA GRIFFIN From the Urological Service, Massachusetts General Hospital and the Department of Surgery, Harvard Medical School, Boston, Massachusetts
ABSTRACT
lipid soluble tetracycline that has generated interest in the treatment of chronic was evaluated for its possible ability to be concentrated in benign prostatic hyperplasia. Drug levels in the prostate, plasma, fat, muscle and urine were measured in patients undergoing prostatectomy after preoperative intravenous minocycline. The concentrations of the drug in prostate and serum were dose (4.16 versus 3.01 µg. per gm.), while drug levels in striated muscle and fat were consistently lower (2.92 and 0.77 µ.,g. per gm.). Higher preoperative doses of the drug yielded higher tissue levels. Drug delivery closer temporally to the operation serum and prostatic levels as opposed to striated muscle and fat, suggesting a diffusion of the drug into benign prostatic hyperplasia. is a semisynthetic tetracycline that recently has generated interest in dealing with chronic prostatitis. 1." The drug has a broad antibacterial spectrum with a high degree of activity against the bacterial cell wall.1. 3 Minocycline, like all tetracyclines, is 70 to 80 per cent protein-bound in ~-·------· but it is the most lipid soluble T.<>TT!'lf'v,c, available. The drug is dissociated as an other tetracyclines but it does have dissociation constants of 7. 8 and 9 .3. 4 These characteristics enable minocycline to diffuse readily across the epithelium of the prostatic acinus. The characterization of physical properties necessary for antibiotic diffusion into the prostate has been defined and an animal model demonstrating minocycline con-
p.m. on the evening before the operation, followed by another dose of 100 mg. intravenously on call to the operating room at 10 a.m. on the day of the operation, for a total dose of 300 mg. preoperatively. Eight of the 20 patients studied received more than the protocol dosage of minocycline, receiving 300 mg. at night and 200 mg. immediately preoperatively (fig. 1 and table 1). Tissue for study taken at the operation included prostatic adenoma, fat and striated muscle, as well as serum and urine. The excised prostatic tissue was washed repeatedly with saline TABLE
1. Concentrations of minocycline in benign prostatic
hyperplasia and other tissues Pt. No.
10
6.95
0.74
FIG. 1. Concentrations of minocycline in benign prostatic hyperplasia and oth2r tissues.
centration in the canine prostate has been developed." These experimental data along with recent clinical evidence of minocycline's effectiveness in the control and treatment of chronic prostatitis in the human 2 ' 7 prompted us to design a study that would yield data concerning the concentration of minocycline in benign nr,,Q,,,,,,.. hyperplasia. MATERIALS AND METHODS
Twenty pw""'·""" undergoing open prostatectomy for benign hyperplasia were studied prospectively. In this study group 200 mg. minocycline were given intravenously at 10 Accepted for publication December 10, 1976. Supported in part by a grant from Lederle Laboratories. 609
168--80 113-85 191-08 000-72 040-87* 003-94* 052-73* 194-79 007-72*· t 052-42*· t 026-82*· t 150-90 034-29 147-85* 178-68* 166-69 181-85 099-90 179-52 198-65 Mean Standard deviation Standard error
Prostate Muscle Fat (µ,g./gm.) (µ,g./gm.) (µ.g./gm.) 2.84 2.99 1. 74 2.82 3.62 3.61 5.78 3.27 11. 70 7.23 7.14 3.95 4.85 2.14 4.57 3.39 2.63 3.03 3.00 2.83 4.16 ±2.32 ±0.52
3.57 0.76 0.83 0.29 <0.15 3.60 4.52 0.33 6.67 2.83 2.71 3.29 ' 43 15.70 2.54 2.79 1.97 2.17 0.67 2.63 2.97 ±3.41 ±0.76
<0.15 0.26 <0.15 <0.15 1.26 <0.15 0.86 1.34 1.44 0.68 1.17 3.18 <0.15 0.27 0.72 0.36 <0.15 1.69 <0.15 0.44 0.74 ±0.77 ±0.17
Serum (µ.g./ml.) 2.24 3.26 2.26 <0.025 4.97 0.45 3.36 3.35 5.19 10.00 6.64 2.81 4.23 3.13 5.36 4.84 3.55 3.34 3.32 3.81 ±2.19 ±0.87
Urine (µ,g./ml.) 8.7d
6.95
2.10 3.01 4.85 1.58 2.14 7.89 19.40 9.07 25.02
1.50 0.92 4.11 6.95 ±7.12 ±1.90
* 500 mg. total preoperative dose- 300 mg. at night and 200 mg. immediately preoperatively. t Second dose given in operating room in the immediate preoperative period. and then, using fresh gloves and instruments, the tissue was incised and an uncontaminated portion of adenoma was sub-mitted for determination of drug concentration. This method totally eliminated the chance of urinary contamination of the tissue to be analyzed. The samples of fat and striated muscle (rectus) were taken prior to incision into the prostatic capsule specifically to avoid urinary contamination. All samples of tissue and urine were frozen promptly, as was the serum after centrifugation at 65 times the force of gravity for 10 minutes.
610
HENSLE, PROUT AND GRIFFIN TABLE
10
2. Concentrations ofminocycline in 8 patients who received 500
mg. total dose preoperatively
7.49
rrg/gm
Serum Fat Prostate Muscle (µ,g./gm.) (µ,g./gm.) (µ,g./gm.) (µ,g./ml.)
Pt. No. 040-87 003-94 052-73 007-72 052-42 026-82 147-85 178-68 Mean Standard deviation Standard error
5
0
3.62 3.61 5.78 11.70 7.23 7.14 2.14 4.57 5.72 ±3.00 ±1.06
<0.15 3.60 4.52 6.67 2.83 2.71 15.70 2.54 4.84 ±4.76 ±1.68
1.26 <0.15 0.86 1.44 0.68 1.17 0.27 0.72 0.82 ±0.46 ±0.16
4.97 0.45 3.36 5.19 10.00 6.64 3.13 5.36 4.89 ±2.79 ±0.99
Urine (µ,g./ml.) 2.10 4.85 1.58 2.14 9.07 25.20 7.49 ±9.12 ±3.72
~-s, TABLE
00 -Q,-9
3. Concentrations of minocycline in 3 patients who received
their final dose just prior to operation*
Fm. 2. Concentrations of minocycline in 8 patients who received 500 mg. total dose preoperatively.
Prostate Muscle Fat Serum Urine (µ,g./gm.) (µ,g./gm.) (µ,g./gm.) (µ,g./ml.) (µ,g./ml.)
Pt. No. 007-72 052-42 026-82 Mean Standard deviation Standard error
11.70 7.23 7.14 8.69 ±2.61 ±1.51
6.67 2.83 2.71 4.07 ±2.25 ±1.30
1.44 0.68 1.17 1.10 ±0.39 ±0.23
5.19 10.00 6.64 7.28 ±2.47 ±1.43
4.85 1.58 2.14 2.86 ±1.75 ±1.01
* Total dose 500 mg., 200 mg. preoperatively. TABLE
rrg/gm
4. Concentrations of minocycline in 12 patients who received 300 mg. total dose preoperatively Pt. No.
Fm. 3. Concentrations of minocycline in 3 patients who received their final dose just before operation. Total dose 500 mg., 200 mg. preoperatively.
10 6.57
rrg/
5
0.68
Fm. 4. Concentrations of minocycline in 12 patients who received 300 mg. total dose preoperatively.
All samples analyzed were delivered frozen to Lederle Laboratories, Pearl River, New York. Bacillus cereus was used as a standard in the cylinder plate assay method for tetracyclines. 8
194-79 150-90 034-29 166-69 181-85 099-90 179-52 198-65 168-80 113-85 191-08 000-72 Mean Standard deviation Standard error
Urine Fat Serum Prostate Muscle (µ,g./gm.) (µ,g./gm.) (µ,g./gm.) (µ,g./ml.) (µ,g./ml.) 3.27 3.95 4.85 3.39 2.63 3.03 3.00 2.83 2.84 2.99 1.74 2.82 3.11 ±0.75 ±0.22
0.33 3.29 1.43 2.79 1.97 2.17 0.67 2.63 3.57 0.76 0.83 0.29 1. 73 ±1.17 ±0.34
1.34 3.18 <0.15 0.36 <0.15 1.69 <0.15 0.44 <0.15 0.26 <0.15 <0.15 0.68 ±0.94 ±0.27
3.35 2.81 4.23 4.84
3.01 7.89 19.40
3.55 3.34 3.32 2.24 3.26 2.26 <0.025 3.02 ±1.25 ±0.38
1.50 0.92 4.11 8.74 6.95 6.57 ±5.95 ±2.10
striated muscle were present but consistently lower, with an average of 2.97 µ,g. per gm. Little minocycline was concentrated in fat, with an average of 0. 77 µ,g. per gm. and urinary concentrations were most variable, with wide differences between individual patients and a mean value of6.95 µ,g. per ml. urine. The patients who received 500 mg. minocycline preoperatively, rather than the 300 mg. protocol dose, had significantly higher drug concentrations in the prostate, serum and muscle as might be expected (fig. 2 and table 2) but the concentration ratio, prostate to serum of 1 to 1, remained unchanged. It is interesting that those patients who received minocycline just before the operation and close temporally to tissue sampling had high levels of the drug in the serum and prostate (fig. 3 and table 3) in comparison to the regular protocol patients (fig. 4 and table 4), and the concentrations of drug in muscle and fat of these patients were not significantly different from levels found in patients receiving the drug 2 to 3 hours preoperatively, suggesting rather rapid equilibration of the drug from serum to prostate in comparison to muscle and fat.
RESULTS
DISCUSSION
Individual and mean concentrations of minocycline in prostatic tissue, serum, urine, fat and striated muscle are tabulated in figure 1 and table 1. At the time of sampling minocycline levels in the prostate and serum were virtually identical with 4.16 and 3.81 µ,g. per gm., respectively. Drug levels in
The inability of most antibiotics to reach the prostatic parenchyma has long been a problem. The general characteristics necessary for antibiotic diffusion in the prostate have been defined previously. s, 7 These include 1) a high degree of solubility, 2) a proper degree of ionization (high dissociation con-
MINOCYCLINE DIFFUSION INTO BENIGN PROSTATIC HYPERPLASIA
stant) to assure the presence of enough uncharged portion of the to diffuse across the prostatic epithelium and 3) non-protein-bound drug free in plasma to diffuse into if the first 2 requirements are met. with a high degree of lipid high constants (7.8 and 9.3) and 20 to 30 per cent unbound form of the drug in plasma, meets all the characteristics that would favor prostatic tissue concentration. The most single factor in minocycline's increased ability to enter the prostate is its lipid solubility. Because of minocycline's increased activity as measured by partition coefficients at the ofprostatic fluid (pH 6.6) it is 30 times more soluble than other tetracyclines. Tissue levels in our studies indicate that m,mc,""" concentration in the prostate is time and Patients larger doses of minocycline and those receiving the more proximate to their surgical procedure had higher of in the serum and prostate. The serum-to-prostate ratio remained in the 1 to 1 range despite time and dose These data do not answer the question as to the for - ... ·- ,..-of drug between plasma and and between prostatic parenchyma and prostatic We do know that in man 10 hours after an initial loading dose of minocycline there appears to be not only drug present in prostate but some degree of concentration with reference to However, the p values are not significant and the concentration ratio of serum to prostate remained ap1 to 1. rn animal model, found a high degree of drug concentration in the prostatic parenchyma but not in nr,c,Q
611
cycline are indicated to determine the fate of the antibiotic after entering the prostate. The data of the current study plus evidence of the long half-life of minocycline (13.6 hours), low mean inhibitory concentration in plasma (minimal inhibitory concentration equals 0.02 µ.g. per ml.) 8 and a broad gram-negative antibacterial spectrum suggest that minocycline may be valuable in dealing with chronic bacterial infections in the prostate. For these same reasons, minocycline also may be useful as a prophylactic agent to control bacteremia during prostatec· tomy. The assays were done by Mr. Dornbush. REFERENCES
1. Klastersky, J. and Daneau, D.: Bacteriological evaluation of minocycline, a new tetracycline. Chemotherapy, 17: 51, 1972. 2. Brannan, W.: Treatment of chronic prostatitis. Comparison of minocycline and doxycycline. Urology, 5: 626, 1975. 3. Steigbigel, N. H., Reed, C. W. and Finland, M.: Susceptibility of common pathogenic bacteria to seven tetracycline antibiotics in vitro. Amer. J. Med. Sci., 255: 179, 1968. 4. Hess!, J. M. and Stamey, T. A.: The passage of tetracyclines across epithelial membranes with special reference to prostatic epithelium. J. Urol., 106: 253, 1971. 5. Winningham, D. G., Nemoy, N. J. and Stamey, T. A.: Diffusion of antibiotics from plasma into prostatic fluid. Nature, 219: 139, 1968. 6. Fair, W. R.: Diffusion of minocycline into prostatic secretion in dogs. Urology, 3: 339, 1974. 7. Stamey, T. A., Meares, E. M., Jr. and Winningham, D. G .. Chronic bacterial prostatitis and the diffusion of drugs into prostatic fluid. J. Urol., 103: 187, 1970. 8. Steers, E., Foltz, E. L. and Graves, B. S.: An inocula replicating apparatus for routine testing of bacterial susceptibility to antibiotics. Antibiot. Chemother., 9: 307, 1959.