Quantitative pharmacogenetics of nortriptyline: a novel approach.

OBJECTIVE: To quantitatively model nortriptyline clearance as a function of the cytochrome P450 (CYP) 2D6 genotype and to estimate the contribution of genotype to the interindividual variability in steady-state plasma concentration and metabolic clearance. DESIGN: Modelling study using data from two previously published studies. PARTICIPANTS: 20 healthy volunteers receiving single oral doses of nortriptyline and 20 patients with depression on steady-state oral treatment. METHODS: A total of 275 nortriptyline plasma concentrations were analysed by standard nonlinear regression and nonlinear mixed effect models. The pharmacokinetic model was a 1-compartment model with first order absorption and elimination. All participants had previously been genotyped with respect to the CYP2D6 polymorphism. RESULTS: A model in which the intrinsic clearance is a linear function of the number of functional CYP2D6 genes and hepatic blood flow is fixed to 60 L/h gave the closest fit of the pharmacokinetic model to the data. Stable estimates were obtained for population pharmacokinetic parameters and interindividual variances. Assuming 100% absorption, the model allows systemic clearance and bioavailability to be estimated. Bioavailability was found to vary between 0.17 and 0.71, depending on the genotype. Using the frequency distribution of CYP2D6 genotype with the above results we estimate that, in compliant Swedish individuals on nortriptyline monotherapy, the number of functional CYP2D6 genes could explain 21% of the total interindividual variance in oral clearance of nortriptyline and 34% of that in steady-state plasma concentrations. CONCLUSION: Nonlinear mixed-effects modelling can be used to quantify the influence of the number of functional CYP2D6 genes on the metabolic clearance and plasma concentration of drugs metabolised by this enzyme. Gene dose has a significant impact on drug pharmacokinetics and prior knowledge of it may aid in predicting plasma concentration of the drug and thus tailoring patient-specific dosage regimens.

[Non-specific symptoms and primary hyperparathyroidism]. / Ukarakteristiske symptomer og primaer hyperparatyreoidisme.

Primary hyperparathyroidism is diagnosed with increasing incidence. Many patients are misinterpreted as being asymptomatic, but they do indeed suffer from a broad variety of non-specific symptoms. Investigations show that patients with primary hyperparathyroidism may be lethargic, apathic, demented and depressed. Many suffer from bone and joint pain. Surgical treatment can be done with few complications and a high cure rate, resulting in reversal of symptoms. Since symptoms do not correlate with S-Ca++ or S-parathyroid hormone and since the symptoms can be attributed to many other causes, we need more research to find those patients, who will benefit from surgical treatment.

[Primary hyperparathyroidism with serum parathyroid hormone within the normal range]. / Primaer hyperparatyreoidisme med S-parathyreoideahormon i normalområdet.

Patients with primary hyperparathyroidism (PHPT) often suffer from muscle and bone pain, are often easily fatigued and may show depressive signs. We present a case of a 50 year-old man with PHPT with muscle pain and fatigue. After parathyroidectomy the symptoms resolved. Preoperatively he had a normal serum-parathyroid hormone (PTH) and an increased ionized serum-calcium. Postoperatively the PTH level increased, though still within the normal range.

[Prevalence of depressive disorders among frail elderly, assessed by psychogeriatricians, general practitioners and geriatricians]. / Praevalens af depressionssygdom blandt svage aeldre, vurderet ved gerontopsykiater, praktiserende laeger og geriater.

UNLABELLED: The prevalence of depressive disorders (D) in 70 years of age or older frail elderly was studied. Two hundred and eleven (81%) recipients of Municipal Home Help Service (frail elderly) in a rural area of Jutland were included and screened by the Geriatric Depression Scale-15 (GDS). If participants had: a) a GDS-score > or = 5 points or/and b) a history of depression, further evaluation was given by: 1) general practitioners (GPs) (implicit criteria), 2) a psycho-geriatrician (ICD-10 criteria), and 3) a geriatrician with the Hamilton Test for Depression. Prevalence rates for D among the evaluators: 15-18%. The diagnostic agreement was only fair. IN CONCLUSION: 18% of the studied population fulfilled the ICD-10 research criteria for depression. The GDS may help GPs in diagnosing depression among frail elderly. False GDS negatives, found among GDS negatives with a history of depression, should be evaluated thoroughly when identifying depression in the target group.

Eosinophilic cystitis--diagnosis and treatment in Denmark.

OBJECTIVE: The purpose of this study was to evaluate the incidence, diagnostic criteria and treatment of eosinophilic cystitis (EC) in Denmark during the period 1989-94. MATERIAL AND METHODS: A questionnaire was sent to all Danish departments of surgery, urology and pathology. RESULTS: Fifty-six cases of EC were diagnosed in the departments of surgery and urology, and 135 patients were diagnosed in the departments of pathology. The therapy was most often steroid instillation in the bladder or peroral antihistamines. Success rates of treatment were reported to be acceptable. CONCLUSION: The questionnaire confirmed that EC is a rare disease, which is often confused with other bladder diseases. We recommend strict histological criteria combined with clinical information when making the diagnosis of EC. Therapy is generally symptomatic. A diagnostic code number from the Danish Health Board is needed.

[Eosinophilic cystitis. A survey]. / Eosinofil cystit. En enquete.

The purpose of this study was to evaluate the incidence, diagnostic criteria and treatment of eosinophilic cystitis in the period 1989-94 in Denmark. A questionnaire was sent to all Danish surgical, urological and pathological-anatomical departments. Fifty-six patients were diagnosed as having eosinophilic cystitis at the surgical departments and 135 patients were diagnosed at the pathological-anatomical departments. The treatment was most often instillation of steroids in the bladder or oral antihistamine. Success of treatment was generally acceptable. The questionnaire confirmed that eosinophilic cystitis is a rare disease. We recommend the pathological-anatomical departments to use certain diagnostic criteria for eosinophilic cystitis. The treatment is symptomatic. A diagnostic number from the Danish Health Board is needed.

Bladder diverticulectomy: operative technique.

We present a simple technique of bladder diverticulectomy. Etiology, pathogenesis, diagnosis, and treatment of bladder diverticula are discussed. We recommend this technique for common use, since it is safe and time-saving.

Pyelitis cystica.

We present four cases of pyelitis cystica. Aetiology, pathogenesis, diagnoses, treatment and differential diagnosis are discussed. We recommend follow-up until malignant disease has been excluded.

Papillary transitional cell tumour in the vagina.

A case of non-invasive transitional cell tumours in the vagina in a 62-year-old woman is presented. Earlier, the patient had a left nephroureterectomy and a cystectomy performed due to invasive transitional cell tumours. The tumours in the vagina were located in an otherwise normal stratified squamous epithelium.

Single incision, endoscopically assisted nephroureterectomy for tumours of the upper urinary tract.

In five patients undergoing nephroureterectomy for urothelial tumour of the upper urinary tract, the lower end of the ureter was resected by resectoscope (rip and pluck procedure). We recommend this technique for common use, since it is safe and time-saving.

Oestrogen receptor investigations in bladder tumours.

Transitional cell tumours of the bladder in 12 men and 12 women were investigated for oestrogen receptors. All tumours and surrounding urothelium were found to be receptor-negative.

Paget's disease in a squamous metaplasia of the urinary bladder. The first published case of a disease which is usually found in the epidermis.

Extramammary Paget's disease is usually found in epidermis and is often associated with malignancy in visceral organs. We report the first case with Paget's disease developed in metaplastic squamous epithelium in the urinary bladder.

Renal cell carcinoma: prognostic factors.

OBJECTIVE: To establish the prognostic value of a series of pre-operative, per-operative and histopathological parameters in relation to renal cell carcinoma (RCC). PATIENTS AND METHODS: This retrospective study involved a consecutive series of 76 patients (46 men and 30 women with a mean age of 65.3 years [range 44-91]) with a histologically confirmed diagnosis of RCC. Patients who were admitted over the period 1980-1984 were included. Data such as erythrocyte sedimentation rate (ESR), alkaline phosphatase level, histological tumour grade, degree of necrosis and presence of tumour vessels were evaluated in relation to actuarial survival. RESULTS: The ESR and alkaline phosphatase level at the time of diagnosis of RCC, the histological tumour grade, degree of necrosis and presence of tumour vessels on angiography were all found to affect the actuarial length of survival significantly (P < or = 0.05 log-rank test). Macroscopic tumour demarcation estimated per-operatively by the surgeon or after surgery by the pathologist, microscopic demarcation, vascular density on histological examination, tumour diameter and vascular density on angiography were found not to affect actuarial survival significantly. CONCLUSION: The value of establishing simple and reliable diagnostic indicators for patients with RCC is stressed.

Accessory urethra in a male. Case report.

A 19-year-old man presented with an unusual accessory urethra located on the shaft of the penis. The diagnosis was stated by biopsy.

[Vasectomy: who regrets it and why?]. / Vasektomi: hvem har fortrudt og hvorfor?

In order to determine the real percentage of sterilised men who regretted their sterilisation and for which reasons, a retrospective questionnaire survey was conducted in 1990-1991 on 244 men sterilised between 1980 and 1983. Information was also collected from their case records. 7.4% of the sterilised men regretted their decision. Of these, 39% were younger than 30, and 94% had started a relation with another woman. The lower age limit for sterilisation according to the law is 25 years, 37% found this age limit too low and 6% found it too high. We conclude that it should be considered whether the legal lower age limit for sterilisation is too low. It is important to thoroughly inform the patient about problems in sexual relations and alternative methods of contraception before he decides on sterilisation.

PIP: During January 1980-February 1983, a total of 421 men were referred to the urological department of Bispebjerg Hospital, Copenhagen, for vasectomy operations, of whom 19 opted out. In 1990, questionnaires were mailed out to 367 of these men. 246 (68%) returned them, but 2 were incomplete, thus a sample was left for analysis of 244 men who had been sterilized 8-10 years before. The inquiry concerned the percentage of regret among them and its causes. 18 (7.4%) regretted their decision, of whom 7 (39%) had been under 30 years of age at the time of operation. In contrast, of the remaining 226 who did not regret it, only 27 (12%) were under 30. A total of 61 (25%) established a new relationship after sterilization. 17 of those who regretted vasectomy had a new relationship, constituting 94% of all those regretting. 37% of the whole sample thought that the legal age limit for sterilization was low, 57% thought it was acceptable, and 6% thought it was too high. At the time of sterilization, 235 (96%) were in steady relationship and 9 were single. 50% of men who regretted their decision and subsequently underwent sterilization reversal operations were under 30 years of age with a median age of 29, compared to 39 years for those regretted it but did not attempt sterilization reversal. The average number of children before sterilization was 2.1, among those regretting it was 2.6, and among those not regretting 2.1. Among the causes of sterilization 210 (86%) cited the desire not to have more children, 120 (49%) cited their relationship, and some referred to the many side effects of oral contraceptives, previous miscarriage, complicated birth, and the desire to have a better sex life. The questions concerning changes in sex life was answered by 77 (32%) as better, 157 (64%) experienced no change, and 10 (4%) said it had become worse. 166 patients (68%) were satisfied with prior instruction from their physician, 161 (66%) from the department, and 217 (89%) had been counseled with at least one case illustration.

Stripping of the distal ureter in association with nephroureterectomy. Evaluation of the method.

Nephroureterectomy is the standard treatment for transitional cell tumours of the renal pelvis. A single-incision surgical technique with use of a vein stripper to remove the distal ureter is evaluated. The method proved to be safe. There was no evidence of increased immediate or long-term risks, including extravesical recurrence of tumour. The method can be recommended for patients with renal pelvic papilloma and probably also for tumours in the upper part of the ureter, but should not be used when there is tumour in the distal ureter.

Prostatic abscess. A review of literature and a presentation of 5 cases.

Abscess of the prostate has become increasingly rare due to modern antibiotics and a decreasing incidence of gonococcal infections. It is still difficult to diagnose the disorder on clinical grounds. Ultrasound examination is recommended. The preferred treatment is nowadays transurethral prostatic resection. We report 5 cases from a urologic department, during a period of 12 years.

Urinary excretion patterns of pseudouridine and beta-aminoisobutyric acid in patients with tumours of the urinary bladder.

The preoperative and postoperative values of urinary pseudouridine:creatinine (phi:C) and beta-aminoisobutyric acid:creatinine (beta AIB:C) were estimated, in 192 patients with urothelial tumours of the bladder, 92 of whom had not previously been diagnosed. Urinary phi:C ratio correlated with the grade of tumour cell dysplasia (being highest in dysplasia grade 3), and to a lesser extent with the clinical stage. The treatment had no major influence on the excretion ratios. Decreased ratios, or those within the reference range, were associated with a better prognosis than increased ratios, and if both were increased at the same time the risk for progression of the disease was high. The biological tumour markers pseudouridine and beta-aminoisobutyric acid may be helpful in the diagnosis of tumours in the upper urinary tract, and in the follow-up of patients with tumours of the bladder.

Squamous cell metaplasia of the bladder urothelium. A retrospective study of 36 patients.

In a retrospective study of 28 women and eight men with squamous cell metaplasia in different parts of the bladder, including the trigone, no histopathological differences were observed among the regions. All the five (female) patients with parakeratosis had a concomitant invasive bladder tumour. Thirty-eight% of all the patients had a simultaneous neoplastic tumour. The metaplastic lesions were investigated for keratin in 13 patients, and all were positive. In seven out of eight patients, the urothelium adjacent to the squamous cell metaplasia was also positive for keratin, indicating a direct transformation of the urothelium to squamous cell epithelium. The metaplastic cells were investigated for oestrogen receptors in five men and five women, and all were negative, suggesting no relationship between estrogens and squamous cell metaplasia of the bladder. Squamous cell metaplasia in the bladder is not considered a premalignant condition. However, metaplasia and neoplastic tumours are often associated with chronic tissue damage, and the presence of metaplasia may give a warning of conditions that can also cause cancer.