Experiences with dose finding in patients in early drug development: the use of biomarkers in early decision making.

With the increasing cost and complexity of drug development, biomarkers will play an increasing role in the early phases. Biomarkers can be classified into target, mechanistic, or outcome with varying degrees of linkage to disease or treatment effect. They can be used to determine proof of concept by characterising the efficacy or safety profiles, or determining differentiation from any competitor drugs. PK/PD modelling of biomarker data for novel and marketed compounds can be used to predict outpatient dose response. Subsequent simulations may replace or reduce the size and cost of larger phase 2b outpatient studies. Two examples of biomarkers and PK/PD modelling used to characterise dose response are presented. Penile plethysmography (RigiScan Plus) in male erectile dysfunction and phenylephrine challenge urethral pressure in benign prostatic hyperplasia are used to reduce time and cost to reach major exploratory development decision points in these indications.

The value of a travel history in urology.

We report a case of a young British woman who contracted urinary schistosomiasis while on holiday in Africa, having swum in Lake Malawi. A travel history would have been helpful in reaching the diagnosis earlier. The diagnosis was made after biopsy of an unusual bladder mucosal lesion and effective treatment given but it could easily have been missed, with the disease's resulting sequelae.

Laser Doppler perfusion imaging: a method for measuring female sexual response.

To develop a new noninvasive technique to measure vulval blood flow changes during sexual arousal; 18 healthy volunteers between the age of 20 and 33 years were studied. Each subject underwent two experimental sessions at least 2 weeks apart to coincide with the proliferative and luteal phases of her menstrual cycle. An initial laser Doppler perfusion imaging (LDPI) scan of the vulva was performed. The subject was then given a chapter of erotic fiction to read and a repeat LDPI scan was performed immediately after. The percentage change in flux were calculated: the clitoral skin blood flow increased by 26.4% (P < 0.05), labial skin blood flow by 24.9% (P < 0.05) and the posterior fourchette skin blood flow by 35.3% (P < 0.05). LDPI can detect changes in vulval perfusion during the sexual arousal response and could be used to compare healthy subjects with female sexual dysfunction patients, as well as for assessing the benefits of any treatment for this condition.

'Raver's' haematuria.

Strenuous exertion is a recognized cause of haematuria but full investigation is still required to exclude any serious underlying pathology. Heavy exercise and amphetamine abuse can both cause rhabdomyolysis and acute renal failure. The recent popularity of 'rave parties' has highlighted these problems in young people who attend the all-night dance parties where a minority of them abuse drugs such as amphetamines. We describe a case of rhabdomyolysis following ingestion of amphetamines during a rave party, where the patient was diagnosed early, presenting acutely with frank haematuria.

Microscopic haematuria: urological investigation using a standard protocol.

OBJECTIVE: To determine which patients with asymptomatic microscopic haematuria (AMH) should be investigated to exclude significant urological pathology. PATIENTS AND METHODS: The study comprised a prospective audit of a standard protocol for investigating all patients referred with haematuria over one year in a haematuria clinic in the urology department serving Tayside, Scotland. Investigations included urine culture and cytology, flexible cystoscopy, and upper tract imaging which consisted of both excretory urography and renal ultrasonography in many of the patients. RESULTS: A total of 381 patients with microscopic haematuria was investigated. No malignancy was found in any < 50 years of age (n = 131); in patients aged > 50 years the overall incidence of malignancy was 7.5% (19/250). The asymptomatic patients in this group had a lower incidence (5%, 6/126) of malignancy than the symptomatic patients (10.5%, 13/124) but this difference did not reach statistical significance. There was no statistically significant difference in the incidence of urological malignancy between men and in women with microscopic haematuria. During the same period, 233 patients were referred with frank haematuria; in these patients, those aged < 50 years had a 10% incidence of malignancy (6/60), while in those aged > 50 years the incidence was 34.5% (60/173). A total of 18 patients (4.7%) with microscopic haematuria had upper tract calculi, comprising 5.3% (7/131) of patients aged < 50 years and 4.4% (11/250) of those > 50 years with microscopic haematuria. CONCLUSIONS: The investigation of older patients with microscopic haematuria (and all those with frank haematuria) is well justified, as malignancy will be found in a significant proportion even if they are asymptomatic. The benefit of a full urological investigation of younger patients with microscopic haematuria is debatable.

Extraperitoneal laparoscopic dismembered fibrin-glued pyeloplasty: medium-term results.

OBJECTIVE: To assess the feasibility and results of performing retroperitoneoscopic dismembered fibrin-glued pyeloplasty in a clinical series of patients with pelvi-ureteric junction (PUJ) obstruction. PATIENTS AND METHODS: A balloon-dissecting four-port extraperitoneal laparoscopic approach was used in each of nine patients (aged 21-60 years) to dismember the PUJ over a previously placed double-pigtail stent, insert stay sutures to appose the urothelium and complete the pelvi-ureteric anastomosis using fibrin glue. Anastomoses were assessed by diuresis renography 3 months after surgery and at yearly intervals thereafter. RESULTS: Eight of the nine attempted procedures were completed successfully in a median (range) operating time of 180 (150-230) min. The median (range) post-operative parenteral opiate requirement was 0 (0-80) mg morphine sulphate and the post-operative hospitalization was 2 (2-4) nights. A shortened fibrotic ureter prevented the laparoscopic completion of the second case, which was converted to an open procedure. Follow-up imaging after 1-2 years showed satisfactory upper tract drainage in those cases completed successfully. One patient developed a renal pelvic calculus that was treated by extracorporeal shock wave lithotripsy. CONCLUSION: This technique is associated with a significantly shorter operating time than historical laparoscopic controls, and with a significantly lower post-operative opiate analgesic requirement and shorter post-operative hospitalization than in a contemporaneous series of patients undergoing open pyeloplasty. However, longer term follow-up is needed to fully assess the performance of these anastomoses.

Candidal urinary tract infection as a cause of pneumaturia.

Colonization of the urinary tract by Candida species occurs particularly in diabetic or immunocompromised patients. We report the cases of two patients presenting with pneumaturia and urinary tract infection who were initially thought to have colovesical fistulae. In both patients a diagnosis of emphysematous pyelonephritis or cystitis due to candidal infection was subsequently made. These cases serve as a reminder of this rare presentation of a not uncommon urinary tract infection.