Scope and limitations of the co-drug approach to topical drug delivery.

Many currently available drugs show unfavourable physicochemical properties for delivery into or across the skin and temporary chemical modulation of the penetrant is one option to achieve improved delivery properties. Pro-drugs are chemical derivatives of an active drug which is covalently bonded to an inactive pro-moiety in order to overcome pharmaceutical and pharmacokinetic barriers. A pro-drug relies upon conversion within the body to release the parent active drug (and pro-moiety) to elicit its pharmacological effect. The main drawback of this approach is that the pro-moiety is essentially an unwanted ballast which, when released, can lead to adverse effects. The term 'co-drug' refers to two or more therapeutic compounds active against the same disease bonded via a covalent chemical linkage and it is this approach which is reviewed for the first time in the current article. For topically applied co-drugs, each moiety is liberated in situ, either chemically or enzymatically, once the stratum corneum barrier has been overcome by the co-drug. Advantages include synergistic modulation of the disease process, enhancement of drug delivery and pharmacokinetic properties and the potential to enhance stability by masking of labile functional groups. The amount of published work on co-drugs is limited but the available data suggest the co-drug concept could provide a significant therapeutic improvement in dermatological diseases. However, the applicability of the co-drug approach is subject to strict limitations pertaining mainly to the availability of compatible moieties and physicochemical properties of the overall molecule.

Improving documentation of head injured patients admitted to the emergency department ward.

OBJECTIVE: Well-written and factually accurate medical records are one of the cornerstones of Emergency Medicine. This audit aimed to assess whether documentation could be improved for head injured patients admitted to the Emergency Department observation ward using a pre-printed proforma. METHODS: In the first phase the notes of a consecutive series of forty patients admitted for observation to an Emergency Department ward after sustaining a head injury were prospectively audited. A data collection instrument was designed to measure the presence or absence of documentation of mechanism of injury, specific symptoms, signs, medications, investigations and treatment considered essential for gold standard head injury management. In the second phase a specially designed proforma was introduced for all patients being admitted for observation. The notes of a second consecutive series of forty patients were then audited using the same data collection instrument. RESULTS: The first phase of the audit revealed inadequate documentation with regard to many of the measured variables. Significant Improvements were noted in all measured variables after the introduction of the proforma. CONCLUSIONS: Documentation of all important positive and negative signs in head injured patients can be time consuming and often a challenge for doctors working in busy Emergency Departments. Accurate documentation is however important from both a clinical and a medico-legal position and this audit have shown that the introduction of a customized proforma can improve the quality of documentation. In addition clinical management of head injured patients may improve as the proforma also acts as a prompt for their subsequent investigation and treatment.

Inter- and intralaboratory variation of in vitro diffusion cell measurements: an international multicenter study using quasi-standardized methods and materials.

In vitro measurements of skin absorption are an increasingly important aspect of regulatory studies, product support claims, and formulation screening. However, such measurements are significantly affected by skin variability. The purpose of this study was to determine inter- and intralaboratory variation in diffusion cell measurements caused by factors other than skin. This was attained through the use of an artificial (silicone rubber) rate-limiting membrane and the provision of materials including a standard penetrant, methyl paraben (MP), and a minimally prescriptive protocol to each of the 18 participating laboratories. "Standardized" calculations of MP flux were determined from the data submitted by each laboratory by applying a predefined mathematical model. This was deemed necessary to eliminate any interlaboratory variation caused by different methods of flux calculations. Average fluxes of MP calculated and reported by each laboratory (60 +/- 27 microg cm(-2) h(-1), n = 25, range 27-101) were in agreement with the standardized calculations of MP flux (60 +/- 21 microg cm(-2) h(-1), range 19-120). The coefficient of variation between laboratories was approximately 35% and was manifest as a fourfold difference between the lowest and highest average flux values and a sixfold difference between the lowest and highest individual flux values. Intralaboratory variation was lower, averaging 10% for five individuals using the same equipment within a single laboratory. Further studies should be performed to clarify the exact components responsible for nonskin-related variability in diffusion cell measurements. It is clear that further developments of in vitro methodologies for measuring skin absorption are required.

The use of prophylactic flucloxacillin in treatment of open fractures of the distal phalanx within an accident and emergency department: a double-blind randomized placebo-controlled trial.

Open fractures of the distal phalanx commonly present to the Accident and Emergency Department. Controversy surrounds the use of prophylactic antibiotics in treating this injury. A double-blind, prospective, randomized placebo-controlled study was undertaken comparing the use of prophylactic flucloxacillin to placebo in addition to meticulous wound toilet. One hundred and ninety-three adult patients with an open fracture of the distal phalanx were studied. Seven patients developed superficial infections, an overall infection rate of 4%. No patient developed osteitis or a deep wound infection. There were three cases of infection in the 98 patients (3%) in the antibiotic group and four cases of infection in the 95 patients (4%) in the placebo group. A difference of proportion test confirmed no significant difference. It is concluded that the addition of prophylactic flucloxacillin to thorough wound toilet and careful soft-tissue repair of open fracture of the distal phalanx confers no benefit.

Emergency airway management in a case of lingual haematoma.

A previously unreported cause of acute tongue swelling is presented and the airway issues discussed. Cases with different aetiology have been sporadically published however the consequent, and sometimes fatal, airway obstructions have been dealt with somewhat variably. The aetiogy of acute tongue swelling and modern emergency airway algorithms are discussed with reference to the literature.

The electrocardiogram in hypothermia.

OBJECTIVE: Hypothermia is known to adversely affect the electrocardiogram (ECG) in many cases. This study set out to determine the incidence of defined cardiac dysrhythmias, J waves, and conduction abnormalities in urban hypothermia. METHODS: A prospective, multicenter study was carried out to determine the incidence of defined cardiac rhythms in patients suffering from accidental urban hypothermia. The ECGs were independently analyzed by 2 of the authors and placed into 1 of 6 rhythm categories. RESULTS: Seventy-three ECGs were analyzed. Normal sinus rhythm was the most common rhythm (41%). Overall mortality was 36% (26/73). J waves occurred in 36% of survivors and 38% of non-survivors and were, therefore, not prognostic. Shivering artifact was present in 66% of survivors and 38% of nonsurvivors. Although there was no statistically significant association between J waves and survival (P = .21), the presence of shivering artifact was associated with survival in severe hypothermia (P = .047). Atrial fibrillation and junctional bradycardia were both associated with high mortality. CONCLUSIONS: This study confirms that the ECG is abnormal in the majority of patients suffering from accidental hypothermia. J waves do not appear to be independently prognostic in hypothermia. The results suggest that the inability to mount a shivering response may be associated with a poorer outcome; this finding requires further study.

The management of elderly blunt trauma victims in Scotland: evidence of ageism?

Health services are challenged with providing trauma care to an increasingly elderly population. The objectives of this study were to determine the in-hospital mortality for injured elderly patients, and by analysing key features of their management, to ascertain whether these trauma patients were managed less aggressively than their younger counterparts. Main outcome measures included; use of resuscitation room facilities, senior medical staff involvement, admission to intensive care units, transfers to regional neurosurgical centres and mortality. Three thousand seven hundred patients initially managed in a resuscitation room were significantly younger (mean age 43) than those not treated in this area (mean age 54, 95% CI 10.7-12.4). Considering seriously injured patients with a significant head injury (who did not present in coma) those transferred to neurosurgical care were younger (mean age 44) than patients who were not transferred (mean age 49, 95% CI 1. 6-8.6). Logistic regression analysis showed that age did not have a significant independent effect on the seniority of medical response from key specialties. For the severely injured, the odds of being admitted to an intensive care unit when aged 70 in comparison to age 30 were 0.7436 (95% CI 0.5787-0.9559). Overall in-hospital mortality of the 290 elderly patients who had sustained major trauma was 42.1%. Significantly more of the elderly died than would be predicted. Age appears to be an independent factor in the process of trauma care in Scottish hospitals. We consider that outcomes for the injured elderly could be improved by a more dynamic approach to their management.

'Popping': a cause of soft tissue sepsis in chronic drug abusers.

Septic complications arising from drug misuse are well documented. It is likely that most complications occur as a result of attempted intravenous (i.v.) injection. We report four cases of soft tissue infections where the patients were unable to obtain i.v. access and gave injections of drugs using a technique known as 'popping'. 'Popping' is the deliberate injection of drugs subcutaneously or intramuscularly when i.v. access is not possible. This practice is further discussed and the literature associated with soft tissue infections from drug misuse is reviewed.

Inadvertent subclavian artery puncture in an intravenous drug abuser.

Arterial complications from inadvertent arterial puncture in intravenous drug abusers are well recognised. Most reports describe injury to the femoral artery with occasional reports of brachial and radial artery injury. A case of subclavian artery injury is described in this paper, and the pathophysiology and treatment of intraarterial drug injection discussed.

A prospective study of rock climbing injuries.

OBJECTIVES: To study the rate, causes, and nature of rock climbing injuries presenting to an accident and emergency (A&E) department. METHODS: Patients presenting with rock climbing injuries to an urban A&E department were studied prospectively for one year. RESULTS: 19 rock climbers presented during the year, at a rate of one per 2774 A&E attendances. Fourteen climbers were injured on outdoor cliffs and five on the local indoor climbing wall, where the safety mats were noted to be in poor condition. Eighteen climbers had been injured during falls, 17 hitting the ground. Twelve of these climbers sustained fractures, four of which were missed on initial attendance. The remaining climber sustained the characteristic A2 pulley finger injury, which was treated conservatively with a good result. CONCLUSIONS: The risks of rock climbing in Britain would be reduced if lead climbers arranged protection at earlier stages of climbs. Sports centres with climbing walls should regularly inspect and repair their safety equipment. It is important for staff in A&E departments to appreciate the large forces involved in any climbing fall, in order that significant injuries are not missed. Those treating injured climbers should also be aware of the specific injuries to which elite climbers are predisposed.

Defibrillation--a burning issue in coronary care units!

Skin burns are accepted to be a complication of defibrillation, however there is no published data on their frequency, cause and treatment. A postal questionnaire survey was designed to assess the relative frequency of defibrillation burns in coronary care units and identify the possible factors contributing to their occurrence. Treatments prescribed in coronary care units were also noted. The questionnaire was sent to the Senior Sister/Charge Nurse in all 263 coronary care units in the United Kingdom. 232 Replies were received (88.2%). Defibrillation burns were seen in 98.7% of CCU's. Ten contributory factors were proposed. The commonest implicated cause was recurrent defibrillation. The most frequently prescribed topical treatment was 1% silver sulphadiazine cream (Flamazine). Defibrillation burns are relatively common in coronary care units. Many result from recurrent defibrillation and may be unavoidable in the patient undergoing prolonged resuscitation. However there are other identifiable factors which, if avoided, may lead to a reduction in the number of burns seen.

The collapse of toilets in Glasgow.

Three cases are presented of porcelain lavatory pans collapsing under body weight, producing wounds which required hospital treatment. Excessive age of the toilets was implicated as a causative factor. As many toilets get older episodes of collapse may become more common, resulting in further injuries.

Irregular discharge against medical advice from the accident and emergency department--a cause for concern.

An irregular discharge (ID) from the A&E department is an undesirable, but relatively common occurrence. A prospective study was undertaken to quantify the size of the problem and by arranging a subsequent review of the patient, to determine the clinical outcome. Over a 3-month period, 139 patients (0.73%) of attendances) took their own discharge against medical advice. A further 566 patients (3.03% of attendances) left prematurely prior to any medical assessment (DNW). Attenders irregularly discharged, often with serious untreated conditions. A high proportion were intoxicated with alcohol (65.5%). Attempted follow up proved difficult and incomplete. Patients with serious conditions appeared to return spontaneously for further care. Methods of minimizing the numbers of patients who take an ID or DNW are discussed. Taken together, the numbers of these attenders leaving prematurely, can be used as a valid performance indicator of the delivery of health care in the A/E department.

Illumination increases the phosphorylation state of maize leaf phosphoenolpyruvate carboxylase by causing an increase in the activity of a protein kinase.

Illumination of maize leaves increases the phosphorylation state of phosphoenolpyruvate carboxylase and reduces the sensitivity of the enzyme to feedback inhibition by malate. Red, white and blue light were each found to be equally potent, and the effect of light was blocked by 3(3,4-dichlorophenyl)-1,1-dimethylurea. A phosphoenolpyruvate carboxylase kinase was partially purified from illuminated maize leaves by a three-step procedure. Phosphorylation of phosphoenolpyruvate carboxylase by this protein kinase reached 0.7-0.8 molecules/subunit and correlated with a 3- to 4-fold increase in Ki for malate. The protein kinase was inhibited by L-malate, but was insensitive to a number of other potential regulators. Freshly prepared and desalted extracts of darkened maize leaves contained very little kinase activity, but the activity appeared when leaves were illuminated for 30-60 min before extraction. The catalytic subunit of protein phosphatase 2A from rabbit skeletal muscle, but not that of protein phosphatase 1, could dephosphorylate phosphoenolpyruvate carboxylase. The protein phosphatases 1 and 2A activities of maize leaves were not affected by illumination. It is suggested that the major means by which light stimulates the phosphorylation of phosphoenolpyruvate carboxylase is by an increase in the activity of the protein kinase.

Ammonium assimilation by Candida albicans and other yeasts: a 13N isotope study.

Nuclear magnetic resonance spectra of cultures of Candida albicans incubated in the presence of 15N-labelled ammonium demonstrated that glutamine and glutamate were the only initial products of ammonium assimilation. The nature of the route of assimilation in the yeasts Candida albicans, Saccharomyces cerevisiae, and Candida tropicalis was further examined by the use of the short-lived isotope 13N. [13N]ammonium was generated in the reaction 16O(p,alpha)13N, induced by proton bombardment of water in tandem accelerator. High-pressure liquid chromatography was used to separate and identify the products of assimilation, and radioactivity was detected and corrected for decay, using a computer-linked NaI scintillation detector. In the three yeasts studied, the labelled ammonium was assimilated into the acid-extractable fraction of cell suspensions within 1 min, and over 75% was converted to glutamine and glutamate. Subsequent to exhaustion of the labelled ammonium, the stoichiometry of the distribution of radiolabel was consistent with a net transfer of radiolabel from glutamine to glutamate, confirming the operation of glutamate synthase (EC 1.4.1.14) in these yeasts. Initial assimilation of label was mostly into glutamine (at a maximal rate within 10 s in C. albicans), whereas accumulation in glutamate did not occur at maximal rate until more than 70% of the labelled ammonium had been assimilated (between 30 and 60 s in C. albicans). We conclude that the glutamine synthetase-glutamate synthase pathway is the major route of ammonium assimilation in C. albicans and also in nitrogen-starved cultures of S. cerevisiae and C. tropicalis.

Regulation of phosphoenolpyruvate carboxylase: an example of signal transduction via protein phosphorylation in higher plants.

There is now good evidence that the malate sensitivity of PEPc is regulated by phosphorylation/dephosphorylation in the leaf tissue of C4 and CAM plants. This statement is based on the assessment of the phosphorylation state of PEPc in [32P]-labeled intact tissue by immunoprecipitation and the correlation between phosphorylation state and malate sensitivity that has been observed during incubation of purified PEPc in vitro with protein kinases or protein phosphatases. The phosphorylation of PEPc in the CAM plant B. fedtschenkoi is controlled by an endogenous rhythm whereas that of PEPc in the C4 plant maize is triggered directly by light. In neither case has the mechanism of signal transduction been identified. It is hoped that further work on the protein kinases and protein phosphatases involved will reveal the nature of the signalling systems. Preliminary work suggests that plant protein phosphatases are very similar to their mammalian counterparts. It is also noteworthy that higher plant genes very similar to the genes encoding the cyclic nucleotide-dependent protein kinases and the protein kinase C family have recently been identified. It is interesting to speculate that the protein kinases and phosphatases involved in signal transduction systems in plants may prove to be closely related to well-studied mammalian enzymes.

Purification, oligomerization state and malate sensitivity of maize leaf phosphoenolpyruvate carboxylase.

A method was developed for the purification of phosphoenolpyruvate carboxylase from darkened maize leaves so that the enzyme retained its sensitivity to inhibition by malate. The procedure depended on the prevention of proteolysis by the inclusion of chymostatin in the buffers used during the purification. The purified enzyme was indistinguishable from that in crude extracts as judged by native polyacrylamide-gel electrophoresis. SDS/polyacrylamide-gel electrophoresis followed by immunoblotting, and Superose 6 gel filtration. Gel-filtration studies showed that the purified enzyme and the enzyme in extracts of darkened or illuminated leaves showed a concentration-dependent dissociation of tetrameric into dimeric forms. Purified phosphoenolpyruvate carboxylase and enzyme in crude extracts from darkened leaves were equally sensitive to inhibition by malate (Ki approx. 0.30 mM) under conditions where it existed in the tetrameric or dimeric forms, but the enzyme in crude extracts from illuminated leaves was less sensitive to malate inhibition (Ki approx. 0.95 mM) whether it was present as a tetramer or as a dimer. It is concluded that changes in the oligomerization state of phosphoenolpyruvate carboxylase are not directly involved in its regulation by light.