Inhalational induction of general anaesthesia for elective caesarean: ethical acceptability in treatment-resistant needle phobia?

We describe the anaesthetic management of a parturient who, due to a severe needle phobia, requested an inhalational induction of general anaesthesia for an elective caesarean section. If general anaesthesia is indicated, conventional practice in the UK is to perform a rapid sequence induction via an intravenous route of drug administration to allow rapid intubation of the trachea. This is because obstetric patients are considered to have a 'full stomach' due to the effects of pregnancy and labour on gastric emptying, and a higher risk of aspiration with consequent maternal and fetal adverse outcomes. Despite a thorough consent process highlighting these significant risks, the patient insisted on an inhalational induction of anaesthesia. We present the case and discuss the ethical dilemma (relating to patient care) in situations in which decisions made by patients deviate from medical recommendations.

Quantitative systems pharmacology: a promising approach for translational pharmacology.

Biopharmaceutical companies have increasingly been exploring Quantitative Systems Pharmacology (QSP) as a potential avenue to address current challenges in drug development. In this paper, we discuss the application of QSP modeling approaches to address challenges in the translational of preclinical findings to the clinic, a high risk area of drug development. Three cases have been highlighted with QSP models utilized to inform different questions in translational pharmacology. In the first, a mechanism based asthma model is used to evaluate efficacy and inform biomarker strategy for a novel bispecific antibody. In the second case study, a mitogen-activated protein kinase (MAPK) pathway signaling model is used to make translational predictions on clinical response and evaluate novel combination therapies. In the third case study, a physiologically based pharmacokinetic (PBPK) model it used to guide administration of oseltamivir in pediatric patients.

Bottom-up Meets Top-down: Complementary Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling for Regulatory Approval of a Dosing Algorithm of Valganciclovir in Very Young Children.

Population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) models are frequently used to support pediatric drug development. Both methods have strengths and limitations and we used them complementarily to support the regulatory approval of a dosing algorithm for valganciclovir (VGCV) in children <4 months old. An existing pediatric PBPK model was extended to neonates and showed that potential physiological differences compared with older children are minor. The PopPK model was used to simulate ganciclovir (GCV) exposures in children with population typical combinations of body size and renal function and to assess the effectiveness of an alternative dosing algorithm suggested by the US Food and Drug Administration. PBPK and PopPK confirmed that the proposed VGCV dosing algorithm achieves similar GCV exposures in children of all ages and that the alternative dosing algorithm leads to underexposure in a substantial fraction of patients. Our approach raised the confidence in the VGCV dosing algorithm for children <4 months old and supported the regulatory approval.

A Physiologically Based Pharmacokinetic Model for Ganciclovir and Its Prodrug Valganciclovir in Adults and Children.

A physiologically based pharmacokinetic (PBPK) model has been developed for ganciclovir and its prodrug valganciclovir. Initial bottom-up modeling based on physicochemical drug properties and measured in vitro inputs was verified in preclinical animal species, and then, a clinical model was verified in a stepwise fashion with pharmacokinetic data in adult, children, and neonatal patients. The final model incorporated conversion of valganciclovir to ganciclovir through esterases and permeability-limited tissue distribution of both drugs with active transport processes added in gut, liver, and kidney. A PBPK model which accounted for known age-related tissue volumes, composition and blood flows, and renal filtration clearance was able to simulate well the measured plasma exposures in adults and pediatric patients. Overall, this work illustrates the stepwise development of PBPK models which could be used to predict pharmacokinetics in infants and neonates, thereby assisting drug development in a vulnerable patient population where clinical data are challenging to obtain.

Physiologically based pharmacokinetic modeling in drug discovery and development: a pharmaceutical industry perspective.

The application of physiologically based pharmacokinetic (PBPK) modeling has developed rapidly within the pharmaceutical industry and is becoming an integral part of drug discovery and development. In this study, we provide a cross pharmaceutical industry position on "how PBPK modeling can be applied in industry" focusing on the strategies for application of PBPK at different stages, an associated perspective on the confidence and challenges, as well as guidance on interacting with regulatory agencies and internal best practices.

Biorelevant media for transport experiments in the Caco-2 model to evaluate drug absorption in the fasted and the fed state and their usefulness.

In this work we developed and characterized transport media that simulate the composition of micellar phase of intestinal fluids in the fasted and, especially, in the fed state and are appropriate for evaluating intestinal drug permeability characteristics using the Caco-2 model (FaSSIF-TM(Caco) and FeSSIF-TM(Caco), respectively). Media composition was based on FaSSIF-V2 and FeSSIF-V2 and recently reported data on total lipid concentrations in the micellar phase of contents of the upper small intestine in the fasted and the fed state and was adapted for cell culture compatibility. Permeation data were evaluated by compartmental kinetic modeling. Permeability coefficients, P, of hydrophilic drugs were not affected by media composition. In contrast, P values of a series of lipophilic compounds measured with FaSSIF-TM(Caco) and FeSSIF-TM(Caco), and reflecting transport by diffusion were smaller than those obtained with a purely aqueous reference transport medium, aq-TM(Caco), following the rank order aq-TM(Caco)>FaSSIF-TM(Caco)>FeSSIF-TM(Caco). The decline of permeability values was stronger as lipophilicity of the compounds increased. Compared with values estimated using aq-TM(Caco), permeability was reduced, depending on the compound, by more than 20- to 100-fold when measured with FeSSIF-TM(Caco) whereas compound ranking in regard to the permeability characteristics was also affected. The impact of reduced P value on flux through the mucosa, hence on drug absorption, in combination with the drug amount loaded on colloidal particles needs to be taken into consideration in PBPK modeling especially when the food effect is evaluated.

Attainment of metabolic goals in the integrated UK islet transplant program with locally isolated and transported preparations.

The objective was to determine whether metabolic goals have been achieved with locally isolated and transported preparations over the first 3 years of the UK's nationally funded integrated islet transplant program. Twenty islet recipients with C-peptide negative type 1 diabetes and recurrent severe hypoglycemia consented to the study, including standardized meal tolerance tests. Participants received a total of 35 infusions (seven recipients: single graft; 11 recipients: two grafts: two recipients: three grafts). Graft function was maintained in 80% at [median (interquartile range)] 24 (13.5-36) months postfirst transplant. Severe hypoglycemia was reduced from 20 (7-50) episodes/patient-year pretransplant to 0.3 (0-1.6) episodes/patient-year posttransplant (p < 0.001). Resolution of impaired hypoglycemia awareness was confirmed [pretransplant: Gold score 6 (5-7); 24 (13.5-36) months: 3 (1.5-4.5); p < 0.03]. Target HbA1c of <7.0% was attained/maintained in 70% of recipients [pretransplant: 8.0 (7.0-9.6)%; 24 (13.5-36) months: 6.2 (5.7-8.4)%; p < 0.001], with 60% reduction in insulin dose [pretransplant: 0.51 (0.41-0.62) units/kg; 24 (13.5-36) months: 0.20 (0-0.37) units/kg; p < 0.001]. Metabolic outcomes were comparable 12 months posttransplant in those receiving transported versus only locally isolated islets [12 month stimulated C-peptide: transported 788 (114-1764) pmol/L (n = 9); locally isolated 407 (126-830) pmol/L (n = 11); p = 0.32]. Metabolic goals have been attained within the equitably available, fully integrated UK islet transplant program with both transported and locally isolated preparations.

Colorectal complications of end-stage renal failure and renal transplantation: a review.

AIM: End-stage renal failure (ESRF) and renal transplant recipients are thought to be associated with an increased risk of colorectal complications. METHOD: A review of the literature was performed to assess the prevalence and outcome in both benign and malignant colorectal disease. RESULTS: No prospective randomized studies assessing colorectal complications in ESRF or renal transplant were identified. Case series and case reports have described the incidence and management of benign colorectal complications. Complications included diverticulitis,infective colitis, colonic bleeding and colonic perforation. There was insufficient evidence to associated iverticular disease with adult polycystic kidney disease.Three population-based studies have shown up to a twofold increased incidence of colonic cancer but not rectal cancer for renal transplant recipients. Bowel cancer screening (as per the general population) by faecal occult blood testing appears justified for renal transplant patients; however, evidence suggests that consideration of starting screening at a younger age may be worthwhile because of an increased risk of developing colonic cancer.Two population-based studies have shown a threefold and 10-fold increased incidence of anal cancer for renal transplant recipients. A single case­control study demonstrated significant increased prevalence of anal human papilloma virus (HPV) and intraepithelial neoplasia (AIN)in patients with established renal transplants. CONCLUSIONS: Despite the lack of high-level evidence,ESRF and renal transplantation were associated with colorectal complications that could result in major morbidity and mortality. Bowel cancer screening in this patient group appears justified. The effectiveness of screening for HPV, AIN and anal cancer in renal transplant recipients remains unclear.

The outcomes of living donor renal transplants with multiple renal arteries: a large cohort study with a mean follow-up period of 10 years.

BACKGROUND: Living donor kidney transplants with multiple arteries are presumed to be associated with an increased risk of complications. OBJECTIVES: The aim of the study was to compare the outcomes in living donor transplantation with the specific intention of comparing long-term outcomes in which the donor kidney had 1 or more renal arteries. The study was undertaken in 2 large transplant centers. METHODS: A retrospective analysis of 201 living donor kidney transplants with multiple arteries that were performed between January 1985 and December 2004 was undertaken. We recorded patient and graft survivals, urological and vascular complications. Kaplan-Meier survival estimates were calculated, and 2-tailed Student t-test was used to compare outcomes. P < .05 was considered statistically significant. RESULTS: Graft and patient survival at 1 year were 93% and 97% and at 5 years were 87% and 92%. The most common complications were vascular (8.9%), followed by urological (6%), acute tubular necrosis (5.5%), and posttransplant hypertension (4.0%). There was significantly higher incidence of acute tubular necrosis (ATN) in multiple-artery transplants. CONCLUSION: In this large cohort of patients studied, apart from a higher incidence of ATN and vascular complications, it appears that the number of renal arteries did not have any adverse impact on the outcomes. The findings from this study suggest that live donor kidneys with multiple renal arteries can be safely utilized for renal transplantation.

Predicting pharmacokinetics of drugs using physiologically based modeling--application to food effects.

Our knowledge of the major mechanisms underlying the effect of food on drug absorption allows reliable qualitative prediction based on biopharmaceutical properties, which can be assessed during the pre-clinical phase of drug discovery. Furthermore, several recent examples have shown that physiologically based absorption models incorporating biorelevant drug solubility measurements can provide quite accurate quantitative prediction of food effect. However, many molecules currently in development have distinctly sub-optimal biopharmaceutical properties, making the quantitative prediction of food effect for different formulations from in vitro data very challenging. If such drugs reach clinical development and show undesirable variability when dosed with food, improved formulation can help to reduce the food effect and carefully designed in vivo studies in dogs can be a useful guide to clinical formulation development. Even so, such in vivo studies provide limited throughput for screening, and food effects seen in dog cannot always be directly translated to human. This paper describes how physiologically based absorption modeling can play a role in the prediction of food effect by integrating the data generated during pre-clinical and clinical research and development. Such data include physicochemical and in vitro drug properties, biorelevant solubility and dissolution, and in vivo pre-clinical and clinical pharmacokinetic data. Some background to current physiological absorption models of human and dog is given, and refinements to models of in vivo drug solubility and dissolution are described. These are illustrated with examples using GastroPlus to simulate the food effect in dog and human for different formulations of two marketed drugs.

Interpreting regulatory authority guidance on immunosuppressive therapy for renal transplantation: a response to the UK's National Institute for Clinical Excellence (NICE).

AIMS: A group of UK consultant transplant physicians and surgeons (the Consensus Group) met to consider the implications and interpretation of the National Institute for Clinical Excellence's (NICE) Technology Appraisal No. 85 on the use of immunosuppressive therapy for renal transplantation in adults. METHODS: This group considered what the implications of these guidelines might be for clinical practice and consensus was developed on those areas which were potentially open to different interpretations. A wider survey of nephrologists and transplant surgeons throughout the UK was also performed to gauge the impact of the NICE recommendations. RESULTS AND CONCLUSIONS: The outcome of the discussions of the Consensus Group are presented with particular reference to the recommendations of how to respond to calcineurin inhibitor (CNI) intolerance. The survey suggested that the publication of this NICE guidance has resulted in relatively few changes in prescribing practice: UK transplant centers continue to use a wide range of locally developed protocols for immunosuppressive therapy. These include the use of agents such as mycophenolate mofetil (MMF) and sirolimus, despite the fact that both drugs appeared to receive only conditional acceptance in the NICE Guidelines.

Challenges and opportunities with modelling and simulation in drug discovery and drug development.

The benefits of modelling and simulation at the pre-clinical stage of drug development can be realized through formal and realistic integration of data on physicochemical properties, pharmacokinetics, pharmacodynamics, formulation and safety. Such data integration and the powerful combination of physiologically based pharmacokinetic (PBPK) with pharmacokinetic-pharmacodynamic relationship (PK/PD) models provides the basis for quantitative outputs allowing comparisons across compounds and resulting in improved decision-making during the selection process. Such PBPK/PD evaluations provide crucial information on the potency and safety of drug candidates in vivo and the bridging of the PK/PD concept established during the pre-clinical phase to clinical studies. Modelling and simulation is required to address a number of key questions at the various stages of the drug-discovery and -development process. Such questions include the following. (1) What is the expected human PK profile for potential clinical candidate(s)? (2) Is this profile and its associated PD adequate for the given indication? (3) What is the optimal dosing schedule with respect to safety and efficacy? (4) Is a food effect expected? (5) How can formulation be improved and what is the potential benefit? (6) What is the expected variability and uncertainty in the predictions?

Impact of stents on urological complications and health care expenditure in renal transplant recipients: results of a prospective, randomized clinical trial.

PURPOSE: We performed a randomized, prospective trial to compare the incidence of early urological complications and health care expenditures in renal transplant recipients with or without ureteral stenting. MATERIALS AND METHODS: Patients receiving a renal transplant at a single center were randomized preoperatively to undergo Double-J stent or no-stent ureterovesical anastomosis from November 1998 to October 2001. Early urological mechanical complications were recorded, including urinary leakage or obstruction, or urinary tract infections within 3 months of transplantation. Direct health care costs associated with stenting, urological complications and urinary tract infection management were also collected. RESULTS: A total of 201 patients were randomized to a stent (112) and a no-stent (89) group. In the no-stent group 11 patients received a stent due to intraoperative findings and were excluded from study. At 3 months there were significantly more cases of urinary leakage (8.9% vs 0.9%, p <0.008) and ureteral obstruction (7.7 % vs 0%, p <0.004) in the no-stent than in the stent group. Mean time of stent removal was 74.3 days. A significant increase in urinary tract infections was observed when stent was left greater than 30 days after transplantation compared to the rate in the no-stent group (p <0.02). An additional cost of 151 UK pounds per patient was incurred in the no-stent group vs the stent group. CONCLUSIONS: Using a ureteral stent at renal transplantation significantly decreases the early urinary complications of urine leakage and obstruction. However, there is a significant increase in urinary tract infections, primarily beyond 30 days after transplantation. Stent removal within 4 weeks of insertion appears advisable.

Azathioprine-induced pure red cell aplasia: case report and review.

The major adverse effect of azathioprine is its myelotoxicity, with leukocytes being affected more commonly than the other bone marrow elements. Although megaloblastic change is frequent, reportedly seen in 16% to 82% of bone marrow aspirates, long-term use of azathioprine rarely causes severe anemia. We report a case of refractory pure red cell aplasia resulting from long-term use of azathioprine in a renal transplant recipient and examine the possible underlying mechanisms. There was no response to dose reduction or to erythropoietin administration. However, there was immediate recovery after complete drug withdrawal. A review of the literature revealed that only ten cases of azathioprine-induced red cell aplasia have so far been described, all in transplant recipients.

Kidney transplantation into an ileal conduit: a single center experience of 59 cases.

PURPOSE: Congenital and acquired conditions of the lower urinary tract can lead to renal failure requiring transplantation. Under these circumstances transplantation into a urinary diversion or an augmented bladder may be the only option. We report our experience with renal transplantation into ileal conduits in the last 22 years. MATERIALS AND METHODS: Between January 1980 and August 2002, 59 renal transplants were drained into an ileal conduit in 54 patients at our center, accounting for 2.3% of the total number of transplants during this period. Median patient age was 28 years (range 1 to 63) and 13 patients were children. There were 12 living related and 47 cadaveric kidneys transplanted. Spina bifida, the most common cause of end stage renal disease, was seen in 22 patients (41%). Patient and graft survival following transplantation into an ileal conduit were compared with that in the 2,579 other transplants done at this center between January 1980 and December 2001. RESULTS: Actuarial graft survival was 90% at 1 year, 63% at 5 years, 52% at 10 years and 52% at 15 years. Actuarial patient survival was 95% at 1 year, 83% at 5 years, 69% at 10 years and 69% at 15 years. Graft and patient survival was statistically similar to the outcome of the 2,579 other transplants done at our center between January 1980 and December 2001. At a mean followup of 4.6 years (range 0.1 to 20) mean serum creatinine in the 39 functioning grafts was 156 mmol/l. Of the surgical complications 21% were directly attributable to the ileal conduit and it could be considered a risk factor contributing to the complication in a further 39%. Symptomatic urinary tract infection was noted in 65% of the patients, although it did not lead to graft loss. At followup 7 patients had died with a functioning graft. Grafts were lost due to chronic allograft nephropathy in 3 cases, renal artery stenosis in 2, renal vein thrombosis in 2, and acute severe rejection, staghorn calculus and ureteroileal stricture in 1 each. CONCLUSIONS: Kidney transplant drainage into an ileal conduit for urinary diversion is an effective treatment for patients with end stage renal disease due to abnormal lower urinary tracts. Despite preexisting co-morbidity and the increased complication rate long-term graft and patient survival is comparable to that in the normal transplant population.

Small intestinal infarction: a fatal complication of systemic oxalosis.

Primary hyperoxaluria is a rare genetic disorder characterised by calcium oxalate nephrolithiasis and nephrocalcinosis leading to renal failure, often with extra-renal oxalate deposition (systemic oxalosis). Although ischaemic complications of crystal deposition in vessel walls are well recognised clinically, these usually take the form of peripheral limb or cutaneous ischaemia. This paper documents the first reported case of fatal intestinal infarction in a 49 year old woman with systemic oxalosis and advocates its consideration in the differential diagnosis of an acute abdomen in such patients.

Banff criteria as predictors of outcome following acute renal allograft rejection.

BACKGROUND: The Banff classification of renal allograft rejection grades acute tubulointerstitial rejection (AIR) by severity of tubulitis and acute vascular rejection (AVR) by severity of arteritis. The intensity of tubulitis has not, however, been demonstrated to be of prognostic value and other features such as glomerulitis and eosinophil infiltration are of uncertain significance. This study was performed in order to determine the clinical value of this pathological classification. METHODS: Banff criteria were correlated with outcome in 134 consecutive graft recipients transplanted in our unit over a 3-year period (1994 1996) who experienced at least one biopsy-confirmed acute rejection episode. Of 197 biopsies performed for the diagnosis of rejection, 177 contained at least one artery and were suitable for Banff grading. Tissue eosinophil counts were available for 101 biopsies. Clinical severity of rejection was classified as mild (fully responsive to pulse steroid therapy), moderate (partially steroid responsive) and severe (steroid unresponsive/requiring ATG therapy). RESULTS: Graft failure ensued in 18 of 58 patients with AVR compared with 10 of 65 patients with AIR (P= < 0.05). Clinical severity of rejection correlated with the presence of arteritis, but not severity of tubulitis; rejections graded I, IIA and IIB according to the Banff' 93 classification were clinically severe in 3/68 (4%), 2/28 (7%) and 15/67 (22%) respectively (P= <0.05). The presence of glomerulitis showed no correlation with clinical severity or graft loss. Tissue eosinophilia (>10 eosinophils/mm2) was present in 18 of 33 patients who had at least one episode of AVR (v1/2), compared with 11 of 45 patients who suffered only AIR (P= <0.02). CONCLUSIONS: We conclude that: arteritis, but not severe tubulitis or glomerulitis, is an adverse prognostic factor in acute rejection and that tissue eosinophilia is associated with vascular rejection. Our findings support the 1997 revision of the Banff classification, replacing grades with types of acute rejection.

Pre-emptive kidney transplantation: the attractive alternative.

BACKGROUND: Dialysis can be life-saving for patients with end-stage renal failure. However, not only is it associated with significant morbidity and a greater mortality than transplantation, but it is also expensive. Therefore renal transplantation is generally regarded as the treatment of choice for patients in whom this form of renal replacement therapy is appropriate. Transplantation usually takes place after a variable period of dialytic therapy, but pre-emptive kidney transplantation (PKT) has established itself as an attractive alternative. MATERIALS AND METHODS: 1463 consecutive first kidney transplants performed between January 1980 and December 1995 in a single centre were analysed. The 161 patients (11%) transplanted without prior dialysis were compared with the 1302 patients who had been dialysed prior to being transplanted. The pre-emptive group did not differ from the dialysis group in respect of donor age, donor and recipient gender, HLA mismatch, or cold ischaemic time, although there were more live donor transplants within the pre-emptive group. RESULTS: Delayed graft function occurred more frequently in the dialysis group (25% vs 16%) but more patients experienced an acute rejection episode in the pre-emptive group (67 vs 55%). The actuarial graft survival in the pre-emptive group at 1, 5, and 10 years (84, 76 and 67%) was significantly higher than the respective values in the dialysis group (83, 69, and 56%). Within the live donor recipient cohort the survival advantage for the pre-emptive group was even more striking. CONCLUSION: Pre-emptive kidney transplantation not only avoids the risks, cost, and inconvenience of dialysis, but is also associated with better graft survival than transplantation after a period of dialysis, particularly within the live donor cohort.

Clinical response and temporal patterns of acute cellular rejection: relationship to chronic transplant nephropathy.

The association between acute cellular rejection (ACR) and the development of chronic rejection has been the subject of much debate. Studies have suggested that the two phenomena may be linked, or, conversely that there may be no association at all. In order to clarify this relationship the outcome of 284 renal allografts were examined. The transplants were all performed at a single institution between April 1989 and December 1991, allowing a minimum follow up of 5 years. ACR was classified into three clinical response groups: (1) fully responsive to therapy (type 1 ACR), (2) partially responsive (type 2) and (3) ACR requiring treatment with ATG or OKT3 (type 3). Acute and chronic rejection were determined by histological (Banff) criteria. Chronic transplant nephropathy (CTN) occurred significantly more frequently in those with late ACR after day 60 than in those who had early rejection (53.5% versus 17.3%, respectively, P < 0.00001). Acute rejection that was fully responsive to therapy (type 1) had no association with CTN, but partially responsive rejection and rejection requiring second-line treatment were both significantly associated with CTN (P < 0.0001 and P < 0.001, respectively). This study suggests that it is the clinical behaviour and response to treatment of ACR that is paramount in determining the onset of chronic rejection, and not hte mere presence or absence of the clinical phenomenon.