Modelling the blast environment and relating this to clinical injury: experience from the 7/7 inquest.

This paper addresses the computational modelling of a series of specific blast-related incidents and the relationships of clinical and engineering interpretations. The Royal Centre for Defence Medicine and the Defence Science and Technology Laboratory were tasked in 2010 by the UK Ministry of Defence to assist the Coroner's inquests into the 7 July 2005 London bombings. A three phase approach was taken. The first phase included an engineering expert in blast effects on structures reviewing photographs of the damaged carriages and bus to give a view on the likely physical effects on people close to the explosions. The second phase was a clinical review of the evidence by military clinicians to assess blast injury in the casualties. The third phase was to model the blast environment by structural dynamics experts to assess likely blast loading on victims to evaluate the potential blast loading on individuals. This loading information was then assessed by physiology experts. Once all teams (engineering, clinical and modelling/physiological) had separately arrived at their conclusions, the information streams were integrated to arrive at a consensus. The aim of this paper is to describe the methodology used as a potential model for others to consider if faced with a similar investigation, and to show the benefit of the transition of military knowledge to a civilian environment.

Determining the wounding effects of ballistic projectiles to inform future injury models: a systematic review.

INTRODUCTION: Penetrating wounds from explosively propelled fragments and bullets are the most common causes of combat injury experienced by UK service personnel on current operations. There is a requirement for injury models capable of simulating such a threat in order to optimise body armour design. METHOD: A systematic review of the open literature was undertaken using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Original papers describing the injurious effects of projectiles on skin, bone, muscle, large vessels and nerves were identified. RESULTS: Projectiles injure these tissues by producing a permanent wound tract (PWT), comprised of a central permanent wound cavity, in conjunction with a zone of irreversible macroscopic tissue damage laterally. The primary mechanism of injury was the crushing and cutting effect of the presented surface of the projectile, with an additional smaller component due to macroscopic damage produced by the radial tissue displacement from the temporary tissue cavity (TTC). No conclusive evidence could be found for permanent pathological effects produced by the pressure wave or that any microscopic tissue changes due to the TTC (in the absence of visible macroscopic damage) led to permanent injury. DISCUSSION: Injury models should use the PWT to delineate the area of damage to tissues from penetrating ballistic projectiles. The PWT, or its individual components, will require quantification in terms of the amount of damage produced by different projectiles penetrating these tissues. There is a lack of information qualifying the injurious effect of the temporary cavity, particularly in relation to that caused by explosive fragments, and future models should introduce modularity to potentially enable incorporation of these mechanisms at a later date were they found to be significant.

Clinafloxacin pharmacokinetics in subjects with various degrees of renal function.

As the primary route for elimination of clinafloxacin is renal clearance (CL(R)) of unchanged drug, studies were conducted to determine the pharmacokinetic profile of clinafloxacin following administration to young and elderly subjects, subjects with various degrees of renal function, and subjects requiring dialysis. These were open-label studies in which subjects received single oral clinafloxacin doses. Sixteen young subjects (18 to 35 years old) and 16 elderly subjects (>65 years old) were enrolled in a study comparing pharmacokinetic profiles of clinafloxacin in young and elderly subjects. Twenty subjects having various degrees of renal function were enrolled into one of three groups based on degree of renal function as measured by creatinine clearance (CL(CR)). Twelve subjects with severe renal impairment requiring dialysis enrolled in a third study. Clinafloxacin was generally well tolerated by all subjects. Clinafloxacin pharmacokinetic profiles in elderly subjects were dependent only on age-related decreases in renal function. Clinafloxacin maximum concentrations in plasma, areas under the concentration-time curves, and terminal elimination half-life values increased with decreasing CL(CR) values. Total apparent body clearance of clinafloxacin from the plasma after oral administration (CL(oral)) and CL(R) were dependent on CL(CR) according to the following relationships: CL(oral) = 2.3. CL(CR) + 77 and CL(R) = 1.74. CL(CR). Hemodialysis had no significant effect on clinafloxacin clearance. Based on the relationship between CL(CR) and clinafloxacin CL(oral) and CL(R) values, the clinafloxacin dose should be halved in patients having a CL(CR) of <40 ml/min. Further dose adjustment is not warranted in patients requiring hemodialysis.

Drug interactions with clinafloxacin.

Many fluoroquinolone antibiotics are inhibitors of cytochrome P450 enzyme systems and may produce potentially important drug interactions when administered with other drugs. Studies were conducted to determine the effect of clinafloxacin on the pharmacokinetics of theophylline, caffeine, warfarin, and phenytoin, as well as the effect of phenytoin on the pharmacokinetics of clinafloxacin. Concomitant administration of 200 or 400 mg of clinafloxacin reduces mean theophylline clearance by approximately 50 and 70%, respectively, and reduces mean caffeine clearance by 84%. (R)-Warfarin concentrations in plasma during clinafloxacin administration are 32% higher and (S)-warfarin concentrations do not change during clinafloxacin treatment. An observed late pharmacodynamic effect was most likely due to gut flora changes. Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration.

Quinapril and its metabolite quinaprilat in human milk.

AIMS: To measure the milk to plasma ratio (M/P) of quinapril and its active metabolite quinaprilat in lactating mothers and to assess likely infant exposure. METHODS: A single dose of quinapril 20 mg was administered to six healthy mothers who had been breastfeeding their infants for at least 2 weeks. Blood was sampled for the measurement of quinapril and quinaprilat at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h. Milk was collected for measurement of quinapril and quinaprilat concentrations over the periods -4-0, 0-4, 4-8, 8-12, 12-18, 18-24 h. The areas under the plasma and milk concentration-time curves were estimated and an M/P ratio derived for both quinapril and quinaprilat. RESULTS: The M/P ratio for quinapril was 0.12 (95% CI 0.09,0.14). No quinapril was detected in milk after 4 h. No quinaprilat was detected in any of the milk samples. The estimated 'dose' of quinapril that would be received by the infant was 1.6% (95% CI 1.0,2.2) of the maternal dose, adjusted for respective weights. CONCLUSIONS: Quinapril appears to be 'safe' during breastfeeding according to conventional criteria, although as always, the risk:benefit ratio should be considered when it is to be given to a nursing mother.

Treatment of Henoch-Schönlein Purpura glomerulonephritis in children with high-dose corticosteroids plus oral cyclophosphamide.

BACKGROUND: Henoch-Schönlein Purpura (HSP) is a common childhood vasculitis with manifestations in numerous organ systems, including glomerulonephritis. Patients with more severe HSP-associated glomerulonephritis may develop chronic renal failure. Currently, no widely accepted treatment protocols exist for patients with significant renal involvement. METHODS: We retrospectively reviewed the clinical courses of 12 children (mean age 9 years) with HSP glomerulonephritis treated with high-dose corticosteroids plus oral cyclophosphamide. All patients had nephrotic-range proteinuria, and all had significant histopathologic changes on biopsy, including crescentic nephritis in 10 patients. Treatment consisted of either intravenous pulse methylprednisolone or oral prednisone followed by oral cyclophosphamide (2 mg/kg/day) for 12 weeks, along with either daily or alternate-day oral prednisone. Prednisone was tapered following completion of cyclophsophamide. RESULTS: Serum albumin rose significantly after treatment from 2.8 +/- (SD) 0.5 to 3.7 +/- 0.4 g/dl (p < 0.001), and there was a concurrent reduction in proteinuria, as reflected by decreasing serial protein-to-creatinine ratios: from 6.3 +/- 4.4 to 0.8 +/- 0.8 (p = 0.002). Renal function remained normal in all patients. Hypertension developed during treatment in 10 patients, all but 1 of whom were normotensive at last follow-up, 35 +/- 17 months following biopsy. CONCLUSIONS: We conclude that treatment of children with HSP nephritis with high-dose corticosteroids plus oral cyclophosphamide is safe and, as in nephrotic syndrome, appears to significantly reduce proteinuria which is a known risk factor for the development of renal insufficiency in HSP. Further studies with larger numbers of patients should be conducted to confirm this finding.

Effect of food on the pharmacodynamics and pharmacokinetics of atorvastatin, an inhibitor of HMG-CoA reductase.

The pharmacodynamics and pharmacokinetics of atorvastatin, an HMG-CoA reductase inhibitor, were characterized in 16 healthy subjects following administration of 10 mg atorvastatin tablets with, or 3 h after, evening meals for 15 days in an open-label, randomized, 2-way crossover study. Atorvastatin was well tolerated. Atorvastatin administration with evening meals resulted in 25.2% lower mean Cmax and 29.8% longer mean tmax values relative to administration after meals. The mean AUC(0-24) value was 8.6% lower for atorvastatin administration with meals compared to after meals. In contrast to the effect of food on pharmacokinetics, LDL-C reductions were similar after atorvastatin administration with or after evening meals. Average reductions from baseline were 24.4% for total cholesterol, 39.6% for LDL-C and 10% for triglycerides. Therefore, atorvastatin may be administered with or without food.

Steady-state pharmacokinetics and dose proportionality of troglitazone and its metabolites.

This study evaluated the steady-state pharmacokinetics and dose proportionality of troglitazone, metabolite 1 (sulfate conjugate), and metabolite 3 (quinone metabolite) following administration of daily oral doses of 200, 400, and 600 mg troglitazone for 7 days (per dosing period) to 21 subjects. During each dosing period, plasma samples were collected predose on days 1, 5, 6 and 7 and serially for 24 hours on day 7. Steady-state plasma concentrations for troglitazone, metabolite 1, and metabolite 3 were achieved by day 7. Troglitazone was rapidly absorbed with mean tmax values of 2.7 to 2.9 hours. Mean Cmax and AUC(0-24) values for troglitazone, metabolite 1, and metabolite 3 increased proportionally with increasing troglitazone doses over the clinical dose range of 200 mg to 600 mg administered once daily. Mean troglitazone CL/F, percent fluctuation, and AUC ratios of metabolite 1 and metabolite 3 to troglitazone were similar across dose groups. These data suggest that the pharmacokinetics and disposition of troglitazone and its metabolites are independent of dose over the dose range studied. Thus, troglitazone, metabolite 1, and metabolite 3 displayed linear pharmacokinetics at steady-state.

Gabapentin does not affect antipyrine clearance.

The effect of gabapentin on antipyrine clearance was assessed in 12 healthy male volunteers, using a known enzyme inducer, phenytoin, as control. Subjects received gabapentin 400 mg or phenytoin 100 mg three times daily for 2 weeks. Antipyrine tests were performed before, during, and after treatment with gabapentin or phenytoin. In contrast to phenytoin, chronic administration of gabapentin did not affect antipyrine clearance. Gabapentin appears to have little potential for drug interactions.

Effects of age and gender on single-dose pharmacokinetics of gabapentin.

PURPOSE: This study was conducted to evaluate the effect of age, age-related changes in renal function, and gender on the single-dose pharmacokinetics of orally administered gabapentin (GBP). METHODS: The pharmacokinetics of a single 400-mg oral dose of GBP were studied in 36 healthy subjects (18 men and 18 women) aged 20-78 years. Serial blood samples and total urine output were collected for 48 h after the dose. GBP concentrations in plasma and urine were measured by high-performance liquid chromatography, and pharmacokinetic parameters were calculated by noncompartmental methods. RESULTS: All subjects tolerated the drug well, with only mild symptoms reported. No change in maximal GBP plasma concentration (Cmax), time at which Cmax occurred (tmax), or apparent volume of distribution (V/F) with age was noted. A significant linear decline in apparent oral clearance (CL/F), elimination-rate constant (lambda z), and renal clearance (CLR) with increasing age was observed (p < 0.005). Because total urinary recovery of unchanged drug (an estimate of F for GBP) did not change with age, the decline in CL/F and lambda z can be explained by the decline in CLR. The only pharmacokinetic parameter that was significantly different between genders was Cmax, which was approximately 25% higher for women than for men (p = 0.016), consistent with gender differences in body size. CONCLUSIONS: The results of this study suggest that changes in renal function are responsible for age-related changes in GBP pharmacokinetics. Reduction of GBP dosage may be required in elderly patients with reduced renal function. The pharmacokinetics of GBP are similar in men and women.

Effect of troglitazone on the pharmacokinetics of an oral contraceptive agent.

Fifteen healthy women participated in a study to determine the effect of multiple doses of troglitazone on the pharmacokinetics of Ortho-Novum 1/35 (35 micrograms ethinyl estradiol [EE] and 1 mg norethindrone [NE]). Participants received three cycles (21 days each of active drug followed by 7 days without medication) of Ortho-Novum. During the third cycle, participants also received troglitazone 600 mg qd for 22 days. Pharmacokinetic profiles of EE and NE were determined on day 21 of the second and third cycles. Progesterone and sex hormone binding globulin (SHBG) levels were also measured. Troglitazone decreased EE Cmax and AUC(0-24) by 32% and 29%, respectively. Likewise, troglitazone decreased NE Cmax and AUC(0-24) by 31% and 30%, respectively. Plasma SHBG concentrations increased from 113 nmol/L during cycle 2 to 220 nmol/L during cycle 3. Troglitazone reduced plasma unbound AUC for NE by 49%. Serum progesterone levels were lower than 1.5 ng/mL on all occasions. Thus, coadministration of troglitazone and Ortho-Novum decreases the systemic exposure to EE and NE. A higher dose of oral contraceptive or an alternate method of contraception should be considered for patients treated with troglitazone.

Response to early measles-mumps-rubella vaccination in infants with chronic renal failure and/or receiving peritoneal dialysis.

Achieving immunity to childhood viral infections before renal transplantation is crucial. However, children with chronic renal failure (CRF) may respond poorly to vaccination, making it difficult to achieve immunity before transplantation, particularly if they will require transplantation at a young age. To address this problem, we developed a protocol of early measles-mumps-rubella (MMR) vaccination in infants with CRF. Nine infants received MMR vaccine at a mean age of 11.6 +/- 2.5 months. When vaccinated, 6 of the children (67%) were on peritoneal dialysis, and 3 (33%) had CRF [glomerular filtration rate (GFR) < 30 mL/min/1.73 m2]. Eight patients were later transplanted at a mean age of 16.8 +/- 4.8 months. Titers were measured before transplantation in all patients. Response to vaccination was excellent, with 89% developing immunity to measles, 88% developing immunity to mumps, 100% developing immunity to rubella, and 88% developing immunity to all three components of the vaccine. These response rates were equivalent to, or slightly better than, those previously reported by Schulman for older children (19 +/- 6 months) on dialysis: 80% for measles, 50% for mumps, 100% for rubella, and 30% for all three components. We conclude that early MMR vaccination induces immunity in most infants with CRF, even those on peritoneal dialysis. Response rates are similar to those previously reported in older children. This approach may help to facilitate transplantation in young infants by achieving immunity earlier than traditional vaccination schedules.

Renal tubular dysgenesis in twins.

In a fetal autopsy series, we have explored the occurrence of renal tubular dysgenesis in twins. Renal tubular dysgenesis was found exclusively among those monozygotic twins with evidence of twin transfusion syndrome, particularly in those donor twins with oligohydramnios and growth restriction. We infer that hypotension in the donor twin of the twin transfusion syndrome pair is responsible for the failure of proximal convoluted tubule differentiation, and the disturbance of renal function is manifested as oligohydramnios prenatally, and either oliguria or tubular dysfunction postnatally.

Initial safety, tolerability pharmacodynamics, and pharmacokinetics of CI-1007 in patients with schizophrenia.

CI-1007 is a novel dopamine autoreceptor agonist and partial dopamine D2/D3 agonist that is currently under development for the treatment of schizophrenia. This single-blind, rising, multiple-dose, inpatient bridging study was designed to evaluate the safety and tolerability of CI-1007 in consecutive panels of patients with schizophrenia. Following a 4-day placebo washout period, 16 patients (4 per panel) were assigned to receive one of four fixed-dosage regimens of CI-1007 (5, 10, 15, or 20 mg q12h for 9 doses). CI-1007 was generally well tolerated over the dose range evaluated. Adverse events, including mild to moderate sporadic orthostatic hypotension and/or nausea and vomiting, were most commonly observed after the initial drug dose and decreased after repeated dosing. Serum concentrations of growth hormone (GH) increased following the administration of CI-1007, confirming its central dopamine agonist activity. Changes in serum prolactin were not related to dose. The pharmacokinetics of CI-1007 and its active metabolite appear linearly related to dose. The results of this study suggest that patients with schizophrenia tolerate slightly higher initial doses of CI-1007 than do healthy subjects.

Gabapentin does not interact with a contraceptive regimen of norethindrone acetate and ethinyl estradiol.

Anticonvulsants that induce hepatic metabolism increase clearance of oral contraceptive hormones and thereby cause contraceptive failure. Gabapentin is not metabolized in humans and has little liability for causing metabolic-based drug-drug interactions. In healthy women receiving 2.5 mg norethindrone acetate and 50 microg ethinyl estradiol daily for three consecutive menstrual cycles, concurrent gabapentin administration did not alter the steady-state pharmacokinetics of either hormone. Thus, gabapentin is unlikely to cause contraceptive failure.

PIP: Anticonvulsants that induce hepatic metabolism increase the clearance of synthetic estrogens and progestogens used in oral contraceptives (OCs), thereby potentiating contraceptive failure. In contrast, the anticonvulsant drug gabapentin is not metabolized in humans and has little liability for metabolic-based drug interactions. The present study sought to confirm whether concurrent administration of gabapentin would alter the pharmacokinetics of norethindrone acetate (2.5 mg) and ethinyl estradiol (50 mcg) in healthy US women. A total of 13 women were enrolled for three menstrual cycles each. Pharmacokinetic values did not change appreciably as a result of the addition of gabapentin. The rate and extent of absorption of both hormones were unaffected by the anticonvulsant. Gabapentin plasma concentration time profiles and pharmacokinetic values from this study were similar to historical values after administration of gabapentin alone. The observed lack of interaction between gabapentin and norethindrone acetate or ethinyl estradiol is consistent with the fact that gabapentin is not metabolized, is not an inducer or inhibitor of hepatic drug metabolizing enzymes, is absorbed via a specific transport system for amino acids, and is not bound to plasma proteins. Anticonvulsant drugs that do not interact with OCs should be considered for the treatment of epileptic women of childbearing age who are using this method of fertility control.

Effect of troglitazone on steady-state pharmacokinetics of digoxin.

Twelve healthy subjects participated in a study to determine the effect of multiple doses of troglitazone on the steady-state pharmacokinetics of digoxin. Subjects received digoxin 0.25 mg orally once daily on days 1 through 20 and 400 mg of troglitazone orally once daily on days 11 through 20. Serial plasma samples and 24-hour urine samples collected before and after the doses on days 10 and 20 were analyzed for digoxin using a radioimmunoassay method. Eleven subjects completed the study. Administration of multiple oral doses of digoxin and troglitazone was well tolerated. Mean values for maximum concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve from 0 to 24 hours (AUC0-24) of digoxin on day 10 were similar to those on day 20. Mean day 10 digoxin values for minimum concentration (Cmin), apparent oral clearance (Cl/F), total urinary excretion from 0 to 24 hours (Ae0-24), and renal clearance (Clr) were also similar to corresponding values on day 20. Thus, concomitant administration of multiple-dose troglitazone does not alter the steady-state pharmacokinetics of digoxin.

Neoral induction in pediatric renal transplantation.

Neoral was instituted in pediatric renal transplant patients with the hypothesis it would have more predictable kinetics than Sandimmun. However, significant questions have arisen concerning potential toxicity and dosing interval related to its rapid absorption with subsequent high initial peak. This is compounded by the fact that children appear to metabolize cyclosporine at a greater rate than adults. This combination of a rapid peak and rapid absorption may then result in lower trough levels at 12 h. We compared the trough cyclosporine levels of nine children who received Neoral with nine who received Sandimmun at the time of initial transplantation. More frequent dosing (every 8 h) was required in the Neoral population compared with the Sandimmun population for the 1st month in order to obtain comparable trough levels. Beyond the initial 4-6 weeks, trough levels were similar for Neoral and Sandimmun. Whereas 1-month creatinine levels and blood pressures were similar, the number of blood pressure medications was significantly higher in the Neoral group. At 5.5 +/- 1.1 months' followup, a single patient in the current Neoral group and in the retrospective Sandimmun group each experienced a single OKT3 allograft-treated rejection. We suggest that the area under the curve is different in Neoral than Sandimmun, and the initial dosing frequency may need to be adjusted accordingly.

Outcome of antineutrophil cytoplasmic autoantibodies-positive glomerulonephritis and vasculitis in children: a single-center experience.

Vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCA) can be accompanied by a focal and necrotizing glomerulonephritis that carries a high morbidity. As many as 60% of reported children with ANCA-associated glomerulonephritis progress to end-stage renal disease. Seven children (13.0+/-0.89 years, mean age +/- SEM) with both a focal and necrotizing glomerulonephritis and a positive ANCA titer are described. Presenting symptoms were constitutional (100%) and sinopulmonary (71%); additional renal features included microscopic hematuria (100%), proteinuria (71%), and renal insufficiency (71%). Acute therapy (0 to 2 weeks from diagnosis) included intravenous corticosteroids and intravenous cyclophosphamide for all patients. Induction therapy (2 weeks to 6 months from diagnosis) consisted of cyclophosphamide (100%) and daily corticosteroids (86%) for a minimum of 6 months. Maintenance therapy that followed 6 months of induction therapy consisted of alternate day steroids (100%) combined with either oral azathioprine (50%) or oral cyclophosphamide (50%). Long-term follow-up for 48+/-12 months in all seven patients revealed that only one (14%) patient had end-stage renal disease, whereas the remaining patients had microscopic hematuria (100%), proteinuria (50%), and renal insufficiency (33%). These findings suggest that early recognition and aggressive treatment of children with ANCA-associated glomerulonephritis and vasculitis may result in an improved renal outcome compared with previous reports.

Improvement of glycemic control by CAPD with intraperitoneal insulin in a child with IDDM and ESRD.

Use of intraperitoneal insulin in diabetic end-stage renal disease (ESRD) patients receiving continuous ambulatory peritoneal dialysis (CAPD) is known to result in improved glycemic control. This route of insulin administration, although standard in adult diabetic CAPD patients, has not previously been reported in children. A 12-year old boy with ESRD from renal dysplasia who also had insulin-dependent diabetes mellitus (IDDM) was treated with CAPD and intraperitoneal insulin prior to renal transplantation. Diabetes and renal dysplasia were both diagnosed at 11 weeks of age. When he reached end-stage he was initially started on hemodialysis via a central line but was switched to CAPD because of recurrent line sepsis. His IDDM had been poorly controlled up to that time. CAPD was performed using 4 exchanges per day of 1.5% dialysate with a fixed dose of insulin added to each bag and with adjustments made based on blood glucose. His glycemic control markedly improved, with a fall in his glycosylated hemoglobin from 13.6% to 6%. CAPD was continued for 7 months until a living-related renal transplant was performed. Two episodes of peritonitis occurred while the patient received CAPD (1 episode/3.5 patient-months). We conclude that the use of intraperitoneal insulin in children with IDDM and ESRD leads to improved glycemic control. The rate of peritonitis, however, may be increased in these children.

Beneficial effect of Sandoglobulin upon allograft survival in the pediatric renal transplant recipient.

The use of pooled immunoglobulin (IgG) has been shown to decrease panel reactive antibodies (PRA) in highly sensitized patients awaiting transplantation. IgG infusions have also been found effective for CMV prophylaxis. Analysis of 52 non-highly sensitized children (ages 1-18) who received kidney transplants from May 1991 through January 1995 was undertaken to determine if the immunoglobulin administered for CMV prophylaxis effected allograft survival. Comparison of the "Sando Pos" group (those who received Sandoglobulin for CMV prophylaxis) to the "Sando Neg" group demonstrates a significantly improved allograft survival at 1, 2, and 3 yr post-transplantation. Despite the Sando Pos group being younger [7.3 +/- 1.3 yr vs. 10.7 +/- 0.9 yr; (mean +/- SEM) p < 0.05] allograft survival was 95%, 95% and 88% in the Sando Pos group vs. 88%, 79% and 79% in the Sando Neg group at 1, 2 and 3 yr, respectively (p < 0.01 at all three time points). It is concluded that the potential mechanism of the immunosuppressive benefit of Sandoglobulin is speculative but presumed to be upon inhibition of anti-HLA class I antibodies. We conclude that Sandoglobulin may not only be useful for CMV prophylaxis but also as an adjunct to routine immunosuppression.