Dinucleotide analogues as inhibitors of thymidine kinase, thymidylate kinase, and ribonucleotide reductase.

P1-(Adenosine-5')-Pn-(thymidine-5') tri-, tetra-, penta-, and hexaphosphates (ApnT) plus the analogues with a methylene group alpha, beta to the thymidine residue (ApncpT) were synthesized by coupling the appropriate two nucleotides, having activated one by morpholine. These were tested as potential dinucleotide inhibitors of thymidine kinase, thymidylate kinase, and ribonucleotide reductase. All three enzymes bind ATP and thymidine or its nucleotides and therefore might be inhibited by dinucleotides containing adenosine and thymidine. Ap5T and Ap6T strongly inhibited all three enzymes (IC50 = 2.4-20 microM). Ap4cpT and Ap5cpT also strongly inhibited the two kinases (IC50 = 4-20 microM) but were much weaker inhibitors of the reductase (IC50 = 130 and 230 microM).

A reappraisal of the effect upon thymidine kinase of thymidine derivatives carrying large groups at the 5'-position.

Several thymidine derivatives with hydrophobic 5'-substituents, linked by chemically stable amide and ether links, were synthesized as potential thymidine kinase inhibitors. None of these was active nor were several derivatives of thymidine 5'-acetate, which were previously reported to be inhibitors. It was shown that the apparent inhibition by the latter compounds was due to their facile hydrolysis in aqueous solution with release of thymidine. These results must cast doubt on any conclusions drawn from biological studies with 5'-esters of thymidine.

Inhibition of human leukaemic thymidylate kinase and L1210 ribonucleotide reductase by dinucleotides of adenosine and thymidine and their phosphonate analogues.

Dinucleotides of adenosine and thymidine in the ApnT series (n = 3,4,5 and 6) and their corresponding phosphonate analogues, where a methylene group replaces the oxygen between the alpha and beta phosphorus atoms adjacent to thymidine, have been evaluated as inhibitors of human leukaemic thymidylate kinase (dTMP kinase, EC 2.7.4.9) and ribonucleotide reductase (EC 1.17.4.1) from L1210 cells. Ap3T, Ap4T, Ap2cpT and Ap3cpT were poor inhibitors of both enzymes. Ap5T, Ap6T and their phosphonate analogues were potent inhibitors of dTMP kinase, possibly acting as bisubstrate analogues (IC50 values: Ap5T, 7.9 microM; Ap4cpT, 5.8 microM; Ap6T, 5.4 microM; Ap4cpT, 4.0 microM). For CDP reductase, where these compounds may bridge activity/effector sites on the M1 subunit of the enzyme, Ap5T and Ap6T were inhibitors with IC50 values of 14.4 microM and 20.3 microM respectively. The phosphonate series of compounds was far less active. The thymidine moiety of the compounds was essential for inhibition since Ap5A was inactive against both enzymes. dTTP, although a poor inhibitor of thymidylate kinase was a potent negative effector of CDP reductase (IC50, 19.3 microM). Significantly, Ap5T was not hydrolysed to release dTTP under the conditions of the assay. These studies show that the activities of both enzymes may be modulated by nucleotide analogues.

Ketoconazole for prevention of postoperative penile erection.

OBJECTIVES: To determine if ketoconazole, an inhibitor of testosterone synthesis, can prevent postoperative spontaneous erections in patients undergoing penile surgery. METHODS: Ketoconazole was administered to 8 patients, aged 14 to 42 years, who underwent penile surgery. All patients received ketoconazole 400 mg orally three times daily starting on the day of surgery. Liver function tests were obtained preoperatively and after the completion of treatment. RESULTS: Ketoconazole successfully prevented erections in all patients. None of the patients demonstrated liver function abnormalities. CONCLUSIONS: Ketoconazole is a reliable method to prevent postoperative penile erection. With the proper monitoring of liver function tests and the avoidance of drug interactions, ketoconazole therapy also appears to be safe.

Distal urethroplasty and glanuloplasty procedure: results of 512 repairs.

OBJECTIVES: We describe the distal urethroplasty and glanuloplasty (DUG) procedure, a modification of the Thiersch-Duplay method, and report indications, outcomes, and complications. METHODS: In all, 512 children with glanular, coronal, or subcoronal hypospadias variants underwent the DUG procedure. RESULTS: Follow-up demonstrated excellent functional performance and cosmetic appearance. Complications included 5 fistulae, 2 meatal stenoses, and 4 distal breakdowns of the distal neourethra. The incidence of complications requiring secondary procedures was 2.1% for the entire group. CONCLUSIONS: The DUG repair has allowed us to repair virtually all distal hypospadias variants using the Thiersch-Duplay method. The combined use of the Heineke-Mikulicz meatoplasty in patients with a stenotic meatus and the glanuloplasty as described by Zaontz has allowed the DUG repair to achieve excellent cosmetic and functional results.

Fibrous hamartoma of infancy: a report of two cases in the genital region.

OBJECTIVES: Fibrous hamartoma of infancy (FHI) is an uncommon subcutaneous proliferative lesion usually found in the upper portions of the body, particularly in males during the first 2 years of life. We report 2 cases of FHI in the genital region. METHODS: We retrospectively reviewed the charts of children treated at Children's Hospital and Health Center, with FHI located in the genital region. RESULTS: We report 2 cases of FHI in the genital region, 1 involving the scrotum and 1 the labium majus. CONCLUSIONS: FHI should be considered in the differential diagnosis of genital masses in children. The histologic features are characteristic, local excision of the tumor is curative, and the local recurrence rate is low.

Distal hypospadias.

Distal hypospadias, where the urethral meatus is located subcoronal or more distal, is one of the most common congenital anomalies in males. The embryology and etiology of hypospadias, timing of repair, surgical techniques, anesthesia for and complications of hypospadias repair are reviewed.

Pediatric urology facts and figures. Data useful in the management of pediatric urologic patients.

This article includes facts and figures useful in the management of pediatric urologic patients. A formulary of commonly used drugs as well as modified doses for use in renal insufficiency is provided. In addition, data on bowel preparations, vital signs, hypertension, creatinine clearance, Tanner stages, and stretched penile length are provided.

Hematuria in children. A practical approach.

The investigation of hematuria in children should never be allowed to pose a greater risk to the child's health than does the problem itself. For this reason, angiography and cystoscopy are rarely employed in the evaluation. The evaluation of the child should proceed methodically and rest firmly on a well-taken history and results of physical examination. The microscopic examination of the urinary sediment is the cornerstone of the evaluation process and can itself suggest the origin of the hematuria. Red cell casts, if present, indicate glomerulonephritis and obviate further urologic evaluation. Genitourinary imaging should be tailored to each clinical situation.

Neonatal circumcision.

Circumcision remains the most common operation performed in males in the United States. When performed by an experienced operator, circumcision is usually a safe and simple operation. The medical benefits of circumcision appear to exceed the risks of the procedure. The history, embryology, indications, techniques, and complications of neonatal circumcision are discussed.

Carcinoma of the breast metastatic to the ureter presenting with flank pain and recurrent urinary tract infection.

Urinary tract infection in the female patient is not an uncommon finding. Flank pain associated with urinary tract infection is usually due to calculus disease or pyelonephritis. In patients with history of breast carcinoma, metastasis to the periureteral area with resulting obstruction should be considered. The incidence of metastatic breast carcinoma presenting in this fashion is as high as 7.8 per cent. This case shows a patient with metastatic lobular carcinoma of the breast with ureteral obstruction, causing flank pain and recurrent urinary tract infection. This report emphasizes the importance of long-term follow-up in patients with history of breast cancer, especially invasive lobular carcinoma, and the high degree of suspicion required to diagnose and institute proper therapy.

Appendiceal cecoplication: a modification of the Malone antegrade colonic enema procedure.

Bowel dysfunction is common in patients with neurogenic bladder dysfunction. In 1990 Malone combined the principles of antegrade colonic washout and the Mitrofanoff nonrefluxing catheterizable channel to produce a continent colonic stoma, the antegrade colonic enema (ACE) procedure. This procedure provides a catheterizable channel through which antegrade washouts are given to provide efficient colonic emptying. We present our modification of the ACE procedure, the appendiceal cecoplication.