Destruction of cytochrome P 450 by secobarbital and other barbiturates containing allyl groups.

Administration of certain commonly used barbiturates containing allyl groups, such as secobarbital, allobarbital, or aprobarbital to rats treated chronically with a microsomal enzyme inducer causes a rapid destruction of the liver microsomal hemoprotein that serves as the terminal oxidase for drug metabolism. In contrast, barbiturates without an allyl group do not have this effect. The decrease in this hemoprotein, cytochrome P(450), by the barbiturates containing an allyl group could also be demonstrated in an in vitro liver microsomal system requiring reduced nicotinamide adenine dinucleotide phosphate. These results suggest that the barbiturates containing an allyl group are converted to a metabolite that leads to the destruction of cytochrome P(450).

Decreased concentration of phenacetin in plasma of cigarette smokers.

The amount of phenacetin in plasma was determined in nine control subjects (nonsmokers) and nine subjects who smoked at least 15 cigarettes per day. The mean plasma concentration of phenacetin at 1, 2, 3(1/2), and 5 hours after its administration was markedly lower in cigarette smokers than in nonsmokers. At 2 hours after the oral administration of 900 milligrams of phenacetin, the plasma concentration (+/- standard error) of unchanged drug was 2.24 +/- 0.73 micrograms per milliliter in the controls and 0.48 +/- 0.28 micrograms per milliliter in the smokers. The rate of excretion in urine of the major metabolite of phenacetin, N-acetyl-p-aminophenol, was the same in both groups. These results indicate for the first time decreased concentrations of a drug in plasma of persons who smoke cigarettes, and the results suggest that the decrease in the amount of Phenacetin in plasma may result from increased metabolism of phenacetin in cigarette smokers.

Intestinal metabolism of phenacetin in the rat: effect of charcoal-broiled beef and rat chow.

The intestinal metabolism of phenacetin in vitro was increased 1100 percent in rats fed charcoal-broiled ground beef in a semisynthetic diet. The intestinal metabolism of phenacetin was increased 200 percent in rats fed a chow diet, as compared to rats fed the semisynthetic diet. The results obtained suggest a need for studies in man to determine whether charcoal-broiled meat and other dietary constituents can stimulate the intestinal metabolism of phenacetin or other drugs and thereby decrease their absorption and bioavailability.

Inhibition of the acute toxicity and adrenocorticolytic effect of 7,12-dimethylbenz(a)anthracene by isopropylvaleramide and allylisopropylacetamide in the rat.

Isopropylvaleramide (IVA) and allylisopropylacetamide (AIA) inhibit hemorrhagic adrenocortical necrosis and mortality caused by 7,12-dimethylbenz(a)anthracene (DMBA) in female Sprague-Dawley rats. Unlike their effect on hepatic microsomal cytochrome P-450, the anti-DMBA action of these compounds does not depend on the presence of the reactive allyl group in the molecule. Similarly, related barbiturates, regardless of whether they contain, like AIA, an allyl group and consequently destroy cytochrome P-450 (secobarbital and aprobarbital) or have, like IVA, saturated side chains and therefore do not effect the microsomal hemoprotein (pentobarbital and phenobarbital), proved ineffective in preventing both adrenal damage and death caused by DMBA. Hence, the protective action of IVA and AIA cannot be attributed to the destruction of the microsomal enzyme system responsible for the activation of DMBA. The toxicity of another carcinogen, dimethylnitrosamine, which also requires metabolic activation by microsomal enzymes, is not influenced by either IVA or AIA. IVA, which counteracts the adrenocorticolytic action of DMBA when given prior to, simultaneously with, or even after this carcinogen, has no discernible effect on hydrocarbon metabolism in vivo or in vitro. IVA is one of the most powerful inhibitors of the acute toxicity of DMBA. It has the simplest aliphatic structure and the smallest molecule among protectors of the adrenals against hydrocarbon-induced damage; its mechanism of action awaits further elucidation.

Phenacetin metabolism: effect of hydrocarbons and cigarette smoking.

The effects of cigarette smoking on phenacetin metabolism in the rat and in man have been investigated. Exposure of rats to cigarette smoke or pretreatment with the polycyclic hydrocarbon, 3,4-benzpyrene (benzo[a]pyrene), resulted in a more rapid disappearance of phenacetin in vivo. Additional studies demonstrated that hydrocarbon and smoking pretreatment of rats enhanced the 0-dealkylation of phenacetin to N-acetyl-p-aminophenol (APAP) by the intestinal mucosa. Cigarette smoking also increased the metabolism of phenacetin in man. The plasma concentration of phenacetin in cigarette smokers was lower than that in nonsmokers, whereas the ratio of the concentration of APAP to that of phenacetin was increased severalfold in the smokers. No difference in plasma half-life of elimination of phenacetin or in the amount of APAP excreted was found between smokers and nonsmokers. The lower blood levels of phenacetin in cigarette smokers could be the result of increased intestinal metabolism of the drug and/or first-pass metabolism in the liver.

High-power potassium titanyl phosphate laser vaporization prostatectomy.

In a search for potential therapeutic strategies for benign prostatic hyperplasia (BPH) that would be associated with less morbidity than transurethral resection of the prostate, various types of laser prostatectomy have been used. Although the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser allows performance of prostatectomy in an almost bloodless field and without absorption of irrigant, the remaining necrotic tissue causes bladder outlet obstruction and related symptoms for 5 to 7 days after treatment. In contrast, the potassium titanyl phosphate (KTP) laser has been found to vaporize tissue with minimal coagulation of the underlying structures. With use of the KTP laser, heat is concentrated into a small volume, the tissue is ablated by rapid vaporization of cellular water, and a 2-mm rim of coagulated tissue is left. After favorable results were obtained in studies of canine prostates and human cadavers, we implemented clinical use of 60-W KTP laser prostatectomy in selected patients. In 10 patients with symptomatic BPH who ranged in age from 52 to 80 years, outpatient KTP laser prostatectomy yielded significantly increased mean peak urinary flow rates (from 8.0 mL/s preoperatively to 19.4 mL/s within 24 hours after the procedure). No patient had hematuria, dysuria, or incontinence after removal of the catheter, and no patient required recatheterization. One patient, however, had urgency, and two other patients became febrile during the 24-hour observation period. Overall, KTP laser vaporization prostatectomy can provide immediate relief from obstructive symptoms of BPH and is not associated with dysuria.

High-power potassium-titanyl-phosphate (KTP/532) laser vaporization prostatectomy: 24 hours later.

OBJECTIVES: To study the feasibility and immediate postoperative outcome of vaporization prostatectomy by high-power potassium-titanyl-phosphate (KTP/532) laser in 10 men with bladder outlet obstruction due to benign prostatic hyperplasia (BPH) and to evaluate their clinical and voiding outcome 24 hours postoperatively. METHODS: The KTP/532 laser at 60 W was produced by a prototype Laserscope generator and delivered through a side-deflecting fiber with a 22F continuous-flow cystoscope. Sterile water was used for irrigation. The prostatic lobes were readily vaporized to within capsular fibers. The mean lasing time was 29 +/- 8 minutes, during which a mean of 104.6 +/- 30 kJ of energy was delivered. RESULTS: The prostate volumes ranged from 22 to 60 mL (mean 38.4 +/- 9.7). None of the 10 patients had any significant blood loss or any fluid absorption. Foley catheters were removed in less than 24 hours postoperatively. All patients were satisfied with their voiding outcome. The mean peak urine flow rate increased from 8 +/- 1.3 mL/s preoperatively to 19.4 +/- 8.4 mL/s (142%, P = 0.003266) 24 hours postoperatively. Postvoid residual volumes remained essentially unchanged from their preoperative levels, as expected (P = 0.767423). One patient had urgency, but none had dysuria, hematuria, or incontinence or required recatheterization. Three patients have returned for 3-month follow-up; all 3 patients have had excellent results and are very satisfied with the outcome. CONCLUSIONS: Our very early and limited experience indicates that high-power KTP/532 laser vaporization prostatectomy is feasible and appears to be safe and effective for quickly relieving bladder outlet obstruction due to BPH. Larger randomized clinical trials to compare this technique with standard transurethral resection of the prostate and more follow-up data are needed to determine its long-term efficacy and durability.

High-power (60-watt) potassium-titanyl-phosphate laser vaporization prostatectomy in living canines and in human and canine cadavers.

OBJECTIVES: We studied the safety and efficacy of 60-W potassium-titanyl-phosphate (KTP) laser prostatectomy in living dogs and compared the efficacy with that in fresh human and dog cadavers. METHODS: Ten dogs underwent 60-W KTP laser prostatectomy and were sacrificed 3 hours (n = 5) or 7 weeks (n = 5) after operation. Two thawed fresh-frozen human cadaver prostates and two thawed fresh-frozen canine prostates were also vaporized with the 60-W KTP laser. All prostates were weighed, measured, serially sectioned, and whole mounted for histologic analysis. RESULTS: In dogs, the in vivo procedure was hemostatic, and no irrigant absorption was detected. Prostatic defects with a mean diameter of 3.0 and 2.5 cm at 3 hours and 7 weeks postoperatively, respectively, were produced. With experience, resection time was reduced to 14 minutes. Of the 5 dogs that were studied for 7 weeks, 4 voided immediately after removal of the urethral catheter on the morning after operation, and 1 dog required recatheterization but voided with a strong stream when the urethral catheter was removed 4 days later. All 5 dogs were continent and had normal erectile function postoperatively. Defects of 2.0 and 2.5 cm were produced in the two human cadaver prostates (weight, 29.5 and 55 g) with resection times of 26 and 54 minutes, respectively. Human and canine cadaver prostates required similar energies for tissue vaporization (15.2 and 13.7 kJ/cm3 cavity created, respectively, P > 0.6), whereas living canine prostates required only 7.0 kJ/cm3 cavity created (P < 0.01 compared with cadaver tissue). CONCLUSIONS: The 60-W KTP laser allows technically easy, safe, rapid, and hemostatic removal of canine prostatic tissue in vivo. Furthermore, there is no difference in the efficacy of KTP laser vaporization between human and canine cadaver prostates. These findings suggest that KTP laser vaporization may be as effective in living human prostates as it is in living dogs, and thus it may be a useful technique in the surgical treatment of human benign prostatic hyperplasia.

Potassium-titanyl-phosphate laser vaporization of the prostate: a comparative functional and pathologic study in canines.

OBJECTIVE: We compared the functional and pathologic results of potassium-titanyl-phosphate (KTP) laser vaporization prostatectomy with those of neodymium:yttrium-aluminum-garnet (Nd:YAG) laser vaporization and coagulation prostatectomy in dogs. METHODS: The prostates of 41 dogs were treated with KTP laser vaporization (n = 21), Nd:YAG laser vaporization (n = 10), or Nd:YAG laser coagulation (n = 10). Dogs were sacrificed 2 days or 8 weeks after treatment. Prostates were weighed, measured, serially sectioned, and whole-mounted for histologic analysis. RESULTS: All techniques were hemostatic, and no irrigant absorption was detected. KTP laser vaporization produced a prostatic defect with a mean diameter of 3.0 and 2.4 cm at 2 days and 8 weeks postoperatively, respectively. Smaller defects (P < 0.0005 at 2 days and P < 0.02 at 8 weeks) were produced by Nd:YAG laser vaporization (2.0 and 1.4 cm, respectively) and coagulation (0.5 and 0.9 cm, respectively). No dog treated with KTP laser vaporization was incontinent or developed urinary retention, including 5 dogs whose urethral catheters were removed within 24 hours of surgery. CONCLUSIONS: KTP laser vaporization prostatectomy not only provides hemostasis similar to that obtained with Nd:YAG laser coagulation, but also removes tissue at the time of operation, allowing dogs to void without straining within 24 hours of treatment. In addition, the procedure is technically simple, and the operator has excellent control over exactly which tissue is removed and which is left intact. These findings suggest that KTP laser vaporization may be useful in the treatment of human benign prostatic hyperplasia.

Partial purification and separation of multiple forms of cytochrome. P-450 and cytochrome P-448 from rat liver microsomes.

1. Partial purification of liver microsomal cytochrome p-450 results in the separation of two forms of cytochrome p-450 from phenobarbital-treated rats and two forms of cytochrome p-44, from 3-methylcholanthrene-treated rats. 2. Each of the four cytochrome fractions had different spectral properties (absolute spectra, CO differences spectra, and ethylisocyanide difference spectra). 3. The hemeprotein in fractions which elute from a DEAE-cellulose column at 100 mKM KCl fraction IV B) are more highly purified than the hemeproteins (fraction IV A) that elute in the column volume. 4. The more highly purified cytochrome fractions (IV B) contain 9-11 moles of cytochrome P-450 or P-448 per mg protein (an approximately 5-7 fold purification over microsomes) and are enzymatically active in the metabolism of a variety of substrates when combined with lipid and NADPH-cytochrome c reductase. These hemeprotein fractions are free of cytochrome b5 and NADPH-cytochrome c reductase, and the hemeproteins are purified approximately 100-fold with respect to phospholipid. The cytochrome P-450 and P-448 are virtually free of epoxide hydrase.