Tobramycin pharmacokinetics in patients with cystic fibrosis before and after bilateral lung transplantation.

STUDY OBJECTIVES: To compare the pharmacokinetics (PK) of tobramycin in patients with cystic fibrosis (CF) before and after bilateral lung transplantation, in order to evaluate optimal dosing practices post transplant. DESIGN: Retrospective, single-center, chart review study, in which tobramycin concentrations from CF patients were used to calculate PK parameters, including elimination rate constant, half-life, volume of distribution (Vd), area under the curve (AUC), and clearance before and after lung transplantation. SETTING: Medical school-affiliated teaching hospital. PATIENTS: Eight patients with CF, who received a bilateral lung transplant from January 1, 2005 through August 1, 2009 (4 males, 4 females; mean age 26.3 years). INTERVENTIONS: None. MAIN RESULTS: Sixty-nine sets of pre- (n=52) and post transplant (n=17) tobramycin concentrations were available. PK parameters were significantly altered post transplant. Elimination rate constant decreased 38% from 0.26±0.1 to 0.16±0.1 h(-1) (P<0.001), with a related increase of 200% in half-life from 2.8±0.8 to 8.4±8.7 h (P<0.001). Clearance decreased 25% post transplant from 67.3±32.3 to 50.2±15.9 mL/min (P=0.04). No statistically significant change occurred in AUC or Vd after transplant, although a trend was seen toward increased Vd. Dosage requirements after transplantation were significantly lower, 10.7±2.5 and 7.6±1.6 mg/kg/day, pre and post transplant, respectively (P<0.001). Concentrations were also evaluated in 2 time periods: 0-3 weeks and ≥6 weeks post transplant, based on available data. Clearance and Vd ≥6 weeks post transplant did not significantly differ from pre-transplant values (P=0.28 and 0.54, respectively), suggesting that these changes may be temporary. CONCLUSIONS: The results suggest that tobramycin PK are altered in patients with CF after bilateral lung transplantation, although no clear trend was seen owing to inter-patient variability. We propose that PK parameters should be reassessed during each treatment course post transplant.

Effects of ovarian follicle ablation on FSH, oestradiol and inhibin A concentrations and growth of other follicles in sheep.

The aim of this study was to examine the effect of removal of the largest follicle or all visible follicles during the first follicle wave on subsequent follicular growth, steroid, inhibin A and gonadotrophin secretion in sheep. On day 4.5 of a synchronized oestrous cycle, ewes (n = 18) were assigned to one of three groups which underwent either no treatment (control), ablation of the largest follicle (largest follicle aspirated and cauterized via laparotomy) or ablation of all follicles (all visible follicles ablated). Between day 0 and day 10 of the oestrous cycle, blood samples were collected every 8 h and ovaries were examined daily using transrectal ultrasonography. The lifespan of the second largest follicle (number of days > 3 mm in diameter) was longer (6.7 +/- 0.9 days; P < 0.05) and the maximum diameter tended to be greater (4.8 +/- 0.3 mm; P = 0.07) in ewes in which the largest follicle was ablated than in the control ewes (3.8 +/- 0.4 days; 4.2 +/- 0.3 mm). There was no difference in the day of emergence of the second follicular wave between groups (day 6.9 +/- 0.4). However, the peak of the transient increase in FSH concentrations after ablation was earlier (day 5.67 +/- 0.15; P < 0.05) in ewes in which all follicles were ablated than in control ewes (day 6.72 +/- 0.36); the timing in ewes that had only the largest follicle ablated was intermediate (day 6.11 +/- 0.28). Serum inhibin A concentrations were about three-fold lower (P < 0.05) in both follicle ablation groups than in the control group. The numbers of follicles 2-3 mm in diameter during the first 3 days of the second follicular wave were greater in 'ablated ewes' (both groups had 2.6 +/- 0.2 follicles day-1) than in control ewes (1.7 +/- 0.3 follicles day-1). It is concluded that: (i) transient increases in FSH concentrations precede the emergence of follicle waves; (ii) ablation of all follicles on day 4.5 after oestrus advanced the timing of the next peak in FSH concentrations and the numbers of small follicles associated with the development of the second follicular wave; and (iii) ablation of the largest follicle resulted in an increase in the lifespan of the second largest follicle, indicating a regulatory role of large dominant follicles over smaller subordinate follicles.

Ovulation of aged follicles does not affect embryo quality or fertility after a 14-day progestagen estrus synchronization protocol in ewes.

The aim was to examine the effect of ovulation of aged follicles on embryo quality and fertility in ewes. In Experiment 1, ewes (n = 39) received a prostaglandin analogue on Day 6 of the cycle and then received either a progestagen sponge from Day 6 to 20 after estrus (Single sponge) or a progestagen sponge on Day 6 that was replaced on Day 11 and 16 and removed on Day 20 (Multiple sponges). In a subgroup of ewes, the growth of ovarian follicles was characterised using ultrasonography. Fertile rams were introduced 48 hours after sponge withdrawal; we slaughtered the ewes on Day 5 of pregnancy and recovered the embryos. The mean age of the ovulatory follicles was greater in ewes that received a single sponge compared with multiple sponges (8.7+/-0.8 days, range 4 to 14, versus 4.5+/-0.7 days, range 3 to 6; P<0.05). However, the groups did not differ (P>0.05) in ovulation rate (2.4+/-0.3 corporal lutea per ewe) or the proportion of good quality embryos recovered (71 to 82%; developed to the early morula stage or further). In Experiment 2, ewes (570 in total) received treatments similar to those in Experiment 1 but were kept until lambing. Ewes that received a single sponge came into heat earlier (P<0.05) than those that received multiple sponges, but > or = 97% of ewes in all groups (P>0.05) were bred by 48 to 72 hours after ram introduction. There was no difference (P>0.05) between groups for the proportion of ewes that lambed to first service (80 to 86%) or the number of lambs per ewe (1.94+/-0.08 lambs). We conclude that when luteolysis occurs at the beginning of progestagen synchronisation, ewes will ovulate aged follicles, but that compared to shorter duration follicles, these follicles produce oocytes that are equally competent to be fertilised and develop into good quality embryos and full-term lambs.

Progestagen synchronisation in the absence of a corpus luteum results in the ovulation of a persistent follicle in cyclic ewe lambs.

Progestagens are widely used to synchronise oestrous in sheep but the effects on follicular dynamics are not clear. We tested the hypothesis that when luteolysis occurs early during progestagen synchronisation prolonged growth of the ovulatory follicle will occur. Cyclic ewe lambs (40.0+/-0.3 kg) were divided into three groups: eight ewes (Long group) received a progestagen sponge (60 mg medroxyprogesterone acetate) from Days 5 to 19 after oestrous and eight ewes (Short group) received a progestagen sponge on Day 5 which was replaced on Day 10 and again on Day 15, and removed on Day 19 after oestrous. On Days 6 and 7, ewes in both groups received prostaglandin. A third group (n=5, Control) did not receive any treatment. The growth and development of follicles > or =2 mm in diameter were characterised using daily transrectal ultrasonography. On Day 18, blood samples were collected every 12 min for 8 h from five ewes in the Long and Short groups. Data were analysed by ANOVA. The maximum diameter and age (emergence to ovulation) of the ovulatory follicle was greater (P<0.01) in ewes in the Long group (7. 4+/-0.2 mm and 12.1+/-0.6 days) than in ewes in the Short group (6. 3+/-0.2 mm and 5.1+/-0.5 days) and Control group (6.3+/-0.4 mm and 6. 8+/-0.6 days). On Day 18 of the cycle, LH pulse frequency and oestradiol concentrations were greater (P<0.05) in ewes in the Long group (3.2+/-1.1 pulse per 8 h and 1.15+/-0.09 pg ml(-1)) than the Short group (0.8+/-0.4 pulses per 8 h and 0.54+/-0.08 pg ml(-1)). We suggest that the negative feedback efficacy of a long-term progestagen sponge decreased with time and led to an increase in LH pulse frequency and prolonged growth of the ovulatory follicle. We conclude that, in the absence of luteal progesterone, synchronisation with a single progestagen sponge for 14 days resulted in higher LH pulse frequency and ovulation of a persistent follicle with a larger maximum diameter, compared with controls.

Etiology of the pulmonary pathophysiology associated with inhalation injury.

This study describes an experimental model of smoke inhalation injury in sheep in which the same pathophysiologic alterations occur as with clinical inhalation injury in man. Diffuse pulmonary mucosal sloughing with atelectasis and emphysema with concomitant development of pulmonary edema results in a decrease in arterial oxygen and progressive pulmonary deterioration which results in a substantial mortality. Increased pulmonary edema fluid is shown to be caused by an increased microvascular permeability to protein with pulmonary lymph and tracheobronchial fluid, a filtrate of plasma. Concomitant with this increase in microvascular permeability is an influx of neutrophils, release of proteolytic enzymes and an identified presence of the metabolite of the prostanoid thromboxane A2 which are postulated as contributors to the progressive pulmonary dysfunction post inhalation injury.

Superficial bladder tumors (stage pTa, grades 1 and 2): the importance of recurrence pattern following initial resection.

We treated 414 new patients with stage pTa, grades 1 and 2 bladder tumors by transurethral resection between 1970 and 1982. All of the patients with grade 3 or previous upper tract tumors, or who had been treated at some stage with intravesical chemotherapy were excluded. Followup for 5 or more years was available in 188 of the patients. There was a low increase in T stage (6 per cent). Of the patients followed for 5 or more years 46 per cent remained free of tumor. Only 16 per cent of the patients had multiple tumors at presentation and 20 per cent had tumors of 10 gm. or more. These factors were associated with a worse prognosis. Patients free of tumor at 3 months had an 80 per cent chance of having no further recurrences and this rate remained the same up to 2 years from the start of the disease. Patients with a recurrence at 3 months were much less likely to remain free of tumor, and had a higher chance of recurrence at every future visit.

Bladder neck contracture following prostatectomy.

In an 11-year period, 49 patients developed bladder neck contracture after prostatectomy--an incidence of 0.86%. This complication was found to be more common after resection of small fibrous hyperplastic prostates. The best results for treatment of the contracture were obtained after bladder neck incision, which gave a 9% incidence of recurrence; after transurethral resection of the bladder neck contracture the recurrence rate was 46%, and after bladder neck dilatation it rose to 100%.

A 15-year follow-up of 406 consecutive spinal cord injuries.

A follow-up of 406 traumatic spinal cord injuries admitted from 1967 to 1982 is presented. Forty patients died, only two (5% of deaths and 0.5% of the series) from renal complications. Twenty-seven died from pulmonary or cardiovascular causes, complete and cervical lesions being the most significant factors in mortality. Early and continued active urological treatment aimed at the provision of low pressure bladder drainage to protect the upper tract. The management and results are critically discussed.

Ureterovaginal fistula: a report of 12 cases and review of the literature.

Ureterovaginal fistula is an uncommon complication of pelvic operations, seen most often after Wertheim's hysterectomy. We report 12 cases of ureterovaginal fistulas seen during a 20-year period, all of which followed operations for benign gynecologic conditions. Most patients had no urinary symptoms until the sudden onset of incontinence 1 to 4 weeks postoperatively. Diagnosis was established readily by a combination of excretory urography, cystography, cystoscopy, retrograde pyeloureterography and dye studies. In our series only 1 patient was treated by primary nephrectomy, while 11 underwent ureteroneocystostomy: 2 with a Boari flap and 9 by a direct method. Reconstruction failed in 2 patients, 1 of whom required a secondary nephrectomy.

Tuberculous stricture of ureter.

Tuberculous stricture of the ureter is not uncommon in centers which treat large numbers of patients with urinary tuberculosis. Ninety-seven such strictures were seen in 92 patients over a twenty-five-year period. All patients were treated with appropriate antituberculous chemotherapy. Transurethral dilatation of the ureteral stricture was done on 80 ureters. Dilatation was successful in 51 ureters (64%) and failed to relieve the strictures in 29. Technical difficulties prevented dilatation of 17 ureters. We believe that transurethral dilatation should be attempted on all tuberculous ureteral strictures and that other procedures should be employed only if dilatation fails.

The treatment of ureteric stones: report on 1120 patients.

A consecutive series of 1120 patients with ureteric stones is presented. Conservative and surgical treatment is discussed and the results of ureteric catheterisation, dilatation, transurethral manipulation and extraction, ureteric meatotomy and ureterolithotomy are presented.

Urological disability in quadriplegia: a study of treatment and follow-up in 92 patients.

The urological aspects of a series of 92 quadriplegic patients are presented. The types of operations done to relieve outlet obstruction and the long-term follow-up with particular emphasis upon the urographic findings and the incidence of pyelonephritis are described and discussed.

Primary nonfunctioning carcinoma of adrenal cortex.

Two cases of nonfunctioning adrenocortical carcinomas are presented. The clinical features, operative findings, and histopathologic appearances are discussed. It is believed that these tumors are difficult to diagnose because of their vague presentation. Intravenous urography with nephrotomography is the most valuable method of detecting these tumors, and surgery remains the best treatment.

Early and late management of the neuropathic bladder in spinal cord injury patients.

Early and late management of neuropathic bladders in 562 consecutive patients with spinal cord injuries is described. Indications for an operation to relieve outlet obstruction by transurethral resection and external sphincterotomy are outlined, and the management of urinary infection and incontinence is discussed. Approximately 30 per cent of all spinal cord injury patients had outlet obstruction for which either external sphincterotomy, transurethral resection or both procedures were necessary. Operations appeared to be required more frequently in patients with complete and thoracic lesions, and more than 1 operation may be necessary to achieve satisfactory bladder emptying.

Epodyl in management of noninvasive vesical neoplasms.

A prospective study to assess the effects of triethylene glycol diglyceridyl ether (Epodyl) in the management of superficial noninvasive vesical neoplasm (T1) is presented. Apart from a few local side effects, the response of the tumor to Epodyl was very good as assessed up to three years. Further long-term studies are being done.

Transurethral removal of bladder stone: the place of litholapaxy.

The surgical management of 652 cases of bladder stone, with particular reference to the value of litholapaxy, is discussed. The majority of cases can be treated by closed methods--litholapaxy and transurethral removal. Those cases treated by closed methods have a reduced postoperative complication and morbidity rate, a shorter operating time, and a reduced period of hospitalisation. Provided the necessary skill is acquired, it is concluded that litholapaxy is a safe and efficient method of dealing with bladder stones.

Closed renal trauma.

A series of 76 cases of closed renal trauma is presented. The clinical and radiological features are described and the indications for conservative and surgical treatment discussed.