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.

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.

Tissue and cellular basis for impaired bone formation in aluminum-related osteomalacia in the pig.

Bone formation is impaired in aluminum-associated bone disease. Reductions in the number of osteoblasts or in the function of individual osteoblasts could account for this finding. Thus, quantitative bone histology and measurements of bone formation were done at three skeletal sites in piglets given aluminum (Al) parenterally, 1.5 mg/kg per d, for 8 wk (Al, n = 4) and in control animals (C, n = 4). Bone Al was 241 +/- 40 mg/kg per dry weight in Al and 1.6 +/- 0.9 in C, P less than 0.001. All Al-treated animals developed osteomalacia with increases in osteoid seam width, osteoid volume, and mineralization lag time at each skeletal site, P less than 0.05 vs. C for all values. Mineralized bone formation at the tissue level was lower in Al than in C, P less than 0.05 for each skeletal site, due to reductions in active bone forming surface. Bone formation at the cellular level was similar in each group, however, and total osteoid production by osteoblasts did not differ in C and Al. Aluminum impairs the formation of mineralized bone in vivo by decreasing the number of active osteoblasts, and this change can be distinguished from the effect of aluminum to inhibit, either directly or indirectly, the calcification of osteoid.

Effect of CI-988 on cholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers.

A randomized, placebo-controlled, double-blind, three-way crossover design was used to evaluate the effectiveness of single oral 100 mg doses of CI-988, a cholecystokinin B (CCKB) antagonist, in attenuating panic symptoms induced by intravenous injection of cholecystokinin-tetrapeptide (CCK-4). Thirty healthy men received the following treatments on three separate occasions: placebo capsules/placebo, placebo capsules/CCK-4, or CI-988 capsules/CCK-4. There was no marked difference in the number, time to onset, or duration of panic symptoms between CI-988/CCK-4 and placebo/CCK-4. There was, however, a 14% difference in sum intensity scores between these treatments that was statistically significant (p = 0.039). The symptoms most affected by CI-988 were cold chills/hot flushes, chest pain/discomfort, and anxiety/fear/apprehension. Panic attack frequency also decreased following CI-988 treatment (8/30 vs. 16/30; p = 0.035). This decrease, amid otherwise modest effects, could be explained by a preferential effect of CI-988 on the subjective experience of anxiety/fear/apprehension. Possible reasons for the relatively modest effects of CI-988 on CCK-4-induced panic symptoms are discussed.

Inhibition of tacrine oral clearance by cimetidine.

Plasma tacrine, 1-hydroxytacrine, 2-hydroxytacrine, and 4-hydroxytacrine concentrations were measured in 12 healthy elderly subjects in this nonblinded two-period study to assess the effect of multiple doses of cimetidine on single-dose tacrine pharmacokinetics. Subjects received 40 mg tacrine (Cognex) alone and during multiple-dose cimetidine (300 mg four times a day) administration. Overall, tacrine and cimetidine were well tolerated by healthy elderly subjects. After coadministration of cimetidine with tacrine, plasma tacrine concentrations were approximately one-third higher than values after administration of tacrine alone; metabolite concentrations were also higher. Mean tacrine oral clearance was reduced by 30%; however, mean absorption rate and elimination half-life values were not affected by cimetidine. It was concluded that cimetidine inhibits first-pass hepatic extraction of tacrine by cytochrome P450 enzymes but has little effect on systemic drug clearance. Clinical considerations may dictate a reduction in tacrine dosage when tacrine is coadministered with cimetidine.

Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects.

This study examined the pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an investigational inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, in 50 healthy subjects by means of a randomized, double-blind parallel-group design. Volunteers received rising single and multiple doses of 0.5 to 80 mg/day atorvastatin (40 subjects) or placebo (10 subjects). The drug was administered once or twice daily for 14 days. Atorvastatin was well tolerated by healthy subjects. The most common adverse events reported after atorvastatin-headache and nausea-occurred as frequently after placebo. Atorvastatin peak concentration and area under the plasma concentration-time curve (AUC) values increased more than proportionally with atorvastatin dose after both single and multiple drug doses. The extent of atorvastatin absorption (AUC) was similar after once- or twice-daily drug administration. Steady-state drug concentrations were achieved by the third day of drug dosing. Mean elimination half-life values ranged from 11 to 24 hours. Atorvastatin accumulation was approximately 1.5- and 3.0-fold after once- and twice-daily administration, respectively. Atorvastatin produced dose-related reductions in total cholesterol and low-density lipoprotein cholesterol that were similar after once- and twice-daily drug administration. Reductions in mean total cholesterol and low-density lipoprotein cholesterol values ranged from 13% and 22% (2.5 mg/day) to 45% and 58% (80 mg/day), respectively (p < or = 0.0013 in comparison with placebo and with baseline over this dose range). In summary, atorvastatin doses of up to 80 mg/day were well tolerated and had significant cholesterol-lowering effects.

Enoxacin-warfarin interaction: pharmacokinetic and stereochemical aspects.

The interaction between the new quinoline-azaquinoline antibiotic enoxacin and the oral anticoagulant warfarin was investigated in six healthy male volunteers. Enoxacin was found not to affect the hypoprothrombinemic response produced by warfarin but did produce a decrease in the clearance of the less pharmacologically potent enantiomer of warfarin, (R)-warfarin. The decreased clearance of (R)-warfarin produced by concomitant enoxacin administration was found to be a consequence of inhibition by enoxacin of the (R)-6-hydroxywarfarin metabolic pathway.

Blood ethanol concentrations during and following constant-rate intravenous infusion of alcohol.

Blood ethanol concentrations were determined in 7 subjects during and subsequent to a 2-hr constant-rate intravenous infusion of ethyl alcohol (8% v/v). Eight to 10 capillary blood samples were collected during the infusion and 10 to 21 samples were obtained after the infusion ceased. Thus, the total time course of blood ethanol concentrations in man was defined, both during and postinfusion. Blood ethanol concentration data from each of 6 subjects were fitted simultaneously to the two equations for the one-compartment open model with zero order input and Michaelis-Menten elimination kinetics. The average Vm[0.232 mg/(ml x hr)] and Km[0.0821 mg/ml] obtained fron these fittings correspond very closely with corresponding values estimated by the fitting of all the mean concentration-time data obtained following oral administration of 4 different doses of ethanol to 8 other fasting subjects in another study. A disproportionate increase in area under the concentration-time curve with increase in dose (gm/kg) was observed in a single subject who was infused with equal volumes of a 4% and an 8% (v/v) ethanol solution at the same constant rate.

The theophylline-enoxacin interaction: I. Effect of enoxacin dose size on theophylline disposition.

Theophylline interacts pharmacokinetically with a variety of other drugs. Recently enoxacin was found to change theophylline's disposition. In a four-subject, four-way crossover study enoxacin was administered every 12 hours at four levels (0, 25, 100, and 400 mg) for 14 doses. With the ninth dose of enoxacin, 200 mg theophylline was coadministered. Blood and urine samples were assayed by sensitive and specific assays for the parent drugs and their metabolites. Significant reduction in the formation of theophylline's three major metabolites occurred on coadministration of enoxacin. At the 400 mg dose level, enoxacin caused a threefold decrease in theophylline's plasma clearance, a fourfold decrease in the urinary recovery of 3-methylxanthine and 1,3-dimethylurate, and a threefold decrease in the recovery of 1-methylurate.

The theophylline-enoxacin interaction: II. Changes in the disposition of theophylline and its metabolites during intermittent administration of enoxacin.

The pharmacokinetics of theophylline and its three major metabolites, 3-methylxanthine, 1-methylurate, and 1,3-dimethylurate, were studied during intermittent administration of enoxacin. The addition of enoxacin (400 mg, twice daily) to a theophylline dosing regimen (150 mg, twice daily) resulted in an immediate fall in plasma theophylline metabolite concentrations. Mean steady-state theophylline concentration in plasma during the dosing interval increased from 3.17 to 8.23 micrograms/ml. The mean 12-hour recovery of total theophylline metabolite decrease from 76.3 to 38.6 mg. After the discontinuation of enoxacin, but not theophylline, the plasma theophylline metabolite levels immediately increased to near or above the concentrations observed before enoxacin coadministration. Concurrently, theophylline concentrations decreased to levels equivalent to those observed before enoxacin coadministration. In general, the changes in plasma theophylline concentrations observed after the addition of discontinuation of enoxacin were complete within 3 days.

Effect of gastric acidity on enoxacin absorption.

The effect of gastric acidity on the oral absorption of the quinolone antibiotic enoxacin was evaluated in 12 healthy volunteers. In a randomized, crossover design, single 400 mg oral enoxacin doses were administered on four occasions: alone, after 50 mg intravenous ranitidine, after 2 micrograms/kg subcutaneous pentagastrin, and after combined ranitidine and pentagastrin treatment. Gastric pH was monitored by radiotelemetry capsule for 4 hours after enoxacin administration. Ranitidine pretreatment reduced enoxacin oral bioavailability by an average of 26%. This effect was abolished when pentagastrin was used to maintain low gastric pH. Thus the ranitidine-induced decrease in enoxacin oral bioavailability probably results from a decrease in gastric acidity rather than from an interaction with ranitidine itself.

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.

Cimetidine-drug interactions.

The use of cimetidine, the histamine H2 receptor antagonist, is associated with a relatively low incidence of adverse reactions. However, its liberal use has led to the identification of several clinically significant cimetidine-drug interactions that can lead to drug accumulation, toxicity, and life-threatening sequelae. A review of the literature and the clinical significance and physiologic basis of these interactions are presented. Recommended management of cimetidine-drug interactions is discussed.

Aluminum intoxication in a child: treatment with intraperitoneal desferrioxamine.

We report the successful chelation of aluminum and the clinical resolution of severe aluminum intoxication in an infant receiving chronic peritoneal dialysis through the use of intraperitoneal desferrioxamine. Following the introduction of desferrioxamine, urine and dialysate fluid aluminum levels exceeded those noted without the chelating agent, thus demonstrating enhanced removal of aluminum. As a result of therapy, plasma and bone aluminum levels decreased markedly, and previously noted histomorphometric abnormalities on bone biopsy resolved. Clinically, the aluminum-associated osteomalacia and microcytic hypochromic anemia completely reversed. Moderate developmental delay has also improved slightly but persists. Our experience suggests that intraperitoneal chelation therapy with desferrioxamine may be helpful to reverse aluminum intoxication in children with chronic renal failure. However, limited exposure to aluminum should remain a primary goal.

Pediatric renal transplantation with an emphasis on the prognosis of patients with chronic renal insufficiency since infancy.

In this report recent experience with renal transplantation in 43 children who were 17 days to 16 years old was reviewed. One-year patient survival rate was 98%, and overall one-year graft survival rate was 68%. One-year graft survival rate was 73% for cyclosporine-treated patients and 78% for recipients of related donor kidneys. A subpopulation of patients affected with renal insufficiency since infancy was analyzed separately to evaluate the prognosis of these patients, who have previously been reported to be a high risk for permanent neurologic, developmental, and growth retardation. All 16 such patients underwent transplantation. Gross motor delay that was noted in 31% of patients before surgery resolved in all patients after transplantation. No evidence of severe developmental delay was noted after transplant and seven of 11 patients with successful transplants had evidence of catch-up growth. Overall renal transplantation is a safe and effective procedure for children with renal failure, and even the patients at highest risk for growth and developmental failure caused by renal insufficiency show potential for rehabilitation after transplantation.

Effects of oral cimetidine or ranitidine on the pharmacokinetics of intravenous enoxacin.

Enoxacin is a quinolone antibacterial agent currently being developed for oral and intravenous treatment of bacterial infections. Ten healthy subjects received a single 400-mg intravenous dose of enoxacin alone, with 300 mg (four times daily) oral cimetidine and with 150 mg (twice daily) oral ranitidine. Serial blood and urine samples were collected over a 48-hour period. Plasma and urine enoxacin concentrations were determined using a validated high-performance liquid chromatographic method. Mean enoxacin plasma concentrations were higher after administration of enoxacin with cimetidine than those measured after enoxacin alone or enoxacin with ranitidine. Cimetidine coadministration reduced enoxacin renal clearance by 26% and systemic clearance by 20%, and resulted in a 30% increase in elimination half-life. In contrast, concurrent ranitidine therapy did not significantly alter the pharmacokinetics of intravenous enoxacin.

Diuretic effects, pharmacokinetics, and safety of a new centrally acting kappa-opioid agonist (CI-977) in humans.

The diuretic effects, pharmacokinetics, and safety of CI-977, a new centrally acting selective kappa-opioid agonist, were determined in 16 healthy subjects. Subjects received single intramuscular doses of CI-977 (5, 15, or 25 micrograms) or placebo 1 week apart according to a randomized, double-blind, placebo-controlled, four-period, crossover design. Serial blood and urine specimens were collected after each dose. Significant dose-related decreases in negative free water clearance and urine osmolality and increases in urine volume were observed after administration of 15- and 25-micrograms doses of CI-977. CI-977 had no effect on urine electrolyte excretion or serum antidiuretic hormone. Absorption of CI-977 was rapid with individual tmax values ranging from 0.17 to 1.5 hours. Cmax and AUC(0-infinity) increased proportionally with dose. Individual elimination half-life values ranged from 0.6 to 3.3 hours and were independent of dose. Changes in free water clearance were related to CI-977 Cmax (r2 = 0.29, P = 0.0001) and AUC(0-4 hr) (r2 = 0.32, P = 0.0001) values. The most frequently reported adverse events after CI-977 administration were dizziness, fatigue, paresthesia, headache, vasodilatation (facial flushing), emotional lability, high feeling, and abnormal thinking. The frequency and intensity of adverse events increased with increasing CI-977 dose. In conclusion, CI-977 Cmax and AUC(0-infinity) increased in proportion to dose over the range of 5 to 25 micrograms; decreases in negative free water clearance were related to CI-977 dose and Cmax and AUC(0-4 hr) values; and the frequency and intensity of adverse events increased with increasing CI-977 dose.

The effect of pirmenol administration on the anti-coagulant activity of warfarin.

The effect of administration of pirmenol, an extensively metabolized and plasma protein-bound antiarrhythmic agent, was evaluated in ten patients on chronic warfarin therapy. After a 3-week baseline period and 7 days of placebo administration, patients received 150 mg of oral pirmenol every 12 hours for 14 days. Prothrombin time was determined during the baseline and placebo periods, during pirmenol administration, and 14 days after the last pirmenol dose (washout). There was no significant difference between mean baseline, placebo, pirmenol, and washout prothrombin times. Coadministration of pirmenol does not appear to affect the anticoagulant activity of warfarin.

Effect of food on the bioavailability of atorvastatin, an HMG-CoA reductase inhibitor.

To determine whether atorvastatin, a new HMG-CoA reductase inhibitor, could be administered with food in Phase II and III clinical trials, a nonblind, randomized, two-way crossover study was conducted to assess the effect of food on rate and extent of atorvastatin absorption. Sixteen healthy volunteers received single 80-mg atorvastatin capsule doses on two occasions one week apart: once after an 8-hour overnight fast and once with a medium-fat breakfast. The single 80-mg atorvastatin capsule doses were well-tolerated. Mean maximum plasma atorvastatin equivalent concentration (Cmax) and area under the concentration-time curve (AUC) values with food were 47.9% and 12.7% lower, respectively, than without food. Mean time of maximum observed concentration (tmax) and elimination half-life (t1/2) values were 5.9 and 32.0 hours, respectively, with food and 2.6 and 35.7 hours, respectively, without food. A medium-fat breakfast decreased the rate of atorvastatin absorption significantly, but had little impact on extent of drug absorption. Changes in rate of atorvastatin absorption are not expected to have a clinically significant effect, as subsequent multiple-dose clinical studies have shown that dose but not plasma atorvastatin concentration profiles correlates with lipid-lowering effects.

The temporal effect of food on tacrine bioavailability.

A four-way cross-over study was performed to assess the temporal effect of food on the rate and extent of tacrine (Cognex, THA) absorption after drug administration to healthy, older volunteers. Each volunteer received four single 40-mg THA doses at 1-week intervals. Doses were administered after an 8-hour overnight fast, 1 hour before a standard breakfast, 15 minutes after beginning a standard breakfast, and 2 hours after completion of a standard breakfast. Gastrointestinal side effects were most frequently reported after drug administration to fasted subjects. Mean Cmax and AUC(0-infinity) values after THA administration during breakfast (9.9 ng/mL and 70.2 ng.hr/mL) and 2 hours after breakfast (11.6 ng/mL and 74.2 ng.hour-1.mL-1) were significantly lower than values determined after administration of THA to fasting subjects (15.8 ng/mL, and 91.8 ng.hour-1.mL-1). Little effect was evident when THA was administered 1 hour before breakfast.