Acute kidney failure after intra-articular use of gentamicin sponge.

An 83-year-old man developed acute kidney failure after intra-articular use of gentamicin sponges for a periprosthetic hip infection. Haemodialysis was necessary for clearance of gentamicin, and for kidney function replacement. It is important to be aware that there is a risk of renal toxicity due to gentamicin when using a locally applied sponge.

Strategy for implementation and first results of advanced clinical decision support in hospital pharmacy practice.

Clinical decision support systems (CDSS) are the new generation clinical support tools that 'make it easy to do it right'. Despite promising results, these systems are not common practice, although experts agree that the necessary revolution in health care will depend on its implementation. To accelerate adoption a strategy is handed for structured development and validation of CDSS' content (clinical rules). The first results show that the proposed strategy is easily applicable for creating specific and reliable rules, generating relevant recommendations.

Intra-thoracic blood volume measurement by contrast magnetic resonance imaging.

The intra-thoracic blood volume (ITBV) is a cardiovascular parameter related to the cardiac preload and left ventricular function. Its assessment is, therefore, important for diagnosis and follow-up of several cardiovascular dysfunctions. Nowadays, the ITBV can be accurately measured only by invasive indicator dilution techniques, which require a double catheterization of the patient. In this study, a novel technique is presented for ITBV assessment by dynamic magnetic resonance imaging after intravenous injection of a small bolus of gadolinium chelate. The dose was chosen on the basis of in vitro calibration. The bolus first pass is detected from a simultaneous dynamic image series of the right and left ventricles. Two indicator dilution curves are derived and used to inspect the transpulmonary dilution system. Various mathematical models for the interpretation of the measured indicator dilution curves are compared. The ITBV is assessed as the product of the transpulmonary mean transit time of the indicator and the cardiac output, obtained by phase contrast magnetic resonance angiography. In vitro measurements showed a correlation coefficient larger than 0.99 and preliminary tests with volunteers proved the feasibility of the method, opening new possibilities for noninvasive quantitative cardiovascular diagnostics.

[Schizophrenia and antipsychotics associated with the metabolic syndrome. An overview]. / Schizofrenie en antipsychotica: samenhang met het metabool syndroom.

BACKGROUND: Cardiovascular morbidity and mortality are higher in patients with schizophrenia than in the general population because the metabolic side-effects of antipsychotics and schizophrenia increase the risk of cardiovascular disease (cvd) and diabetes mellitus type 2 (DM2). The metabolic syndrome is defined in order to discover which patients have a high risk of developing cvd and DM2. AIM: To survey the current knowledge about the relationship between schizophrenia and the metabolic syndrome, the influence of the use of antipsychotics on the development of the metabolic syndrome, and the possible differences in the effects that first and second generation antipsychotics have on the syndrome. METHOD: The PubMed and Medscape databases were searched for relevant articles published between 2000 and July 2008. results Schizophrenia and the use of antipsychotics increase the prevalence of abdominal obesity, dyslipidemia and DM2 (i.e. the metabole syndrome). Second generation antipsychotics tend to cause a marked increase in the prevalence of abdominal obesity and dyslipidemia, whereas first generation antipsychotics hardly have any of these effects. Both first and second generation antipsychotics increase the risk of DM2. CONCLUSION: The metabolic syndrome has a significant effect on the morbidity and mortality of patients with schizophrenia because it increases the risk they will develop cvd and DM2. The risk increases still further if patients are taking antipsychotics. The risk of cvd can be decreased if patients with schizophrenia are screened in time and are monitored regularly.

Development of a stable solution of 5-aminolaevulinic acid for intracutaneous injection in photodynamic therapy.

Photodynamic therapy using 5-aminolaevulinic acid (ALA) as a photosensitiser is a new treatment modality for basal cell carcinomas. Until now ALA has been used topically as a cream. As this administration route leads sometimes to insufficient penetration in the skin, an intracutaneously injectable solution of ALA was developed. The influence of pH, concentration and temperature on the degradation of ALA in aqueous solution was investigated in order to optimise the formulation of the injection. In 0.1% ALA solutions with pH values between 4 and 8 a pH dependency of ALA degradation was shown, comprising fast decomposition at pH values higher than 7, whereas at a pH value of 6 or lower the solutions remained within the range of 90-110% of the initial concentration for at least 128 days. An increase of degradation rate with increasing concentrations became evident which is consistent with the supposed second-order degradation kinetics. After accelerated stability research at 63 degrees C and 85 degrees C a shelf life of 281 days for a 0.1% ALA solution pH 5 was calculated from an Arrhenius plot. A 2% ALA solution was proven to be isotonic. From our results a 0.1-2% ALA solution with pH 5 and an appropriate amount of sodium chloride to obtain isotonicity is recommended as an injectable solution.

In vivo pharmacokinetics of protoporphyrin IX accumulation following intracutaneous injection of 5-aminolevulinic acid.

Photodynamic therapy with 5-aminolevulinic acid (ALA) derived protoporphyrin IX (PpIX) as photosensitizer is a promising treatment for basal cell carcinomas. Until now ALA has been administered topically as an oil-in-water cream in most investigations. The disadvantage of this administration route is insufficiënt penetration in deeper, nodular tumours. Therefore we investigated intracutaneous injection of ALA as an alternative administration route. ALA was administered in 6-fold in the normal skin of three 6-week-old female Dutch pigs by intracutaneous injection of an aqueous solution of ALA (pH 5.0) in volumes of 0.1-0.5 ml and concentrations of 0.5-2% and by topical administration of a 20% ALA cream. During 8 h fluorescence of ALA derived PpIX was measured under 405 nm excitation. For the injection the measured fluorescence was shown to be dose dependent. All injected doses of 3 mg ALA or more lead to a faster initial increase rate of PpIX synthesis and significantly greater fluorescence than that measured after topical administration of ALA. Irradiation (60 Jcm(-2) for 10 min) of the spots was performed at 3.5 h after ALA administration. After 48 and 96 h visual damage scores were evaluated and biopsies were taken for histopathological examination. After injection of 2 mg ALA or more the PDT damage after illumination was shown to be significantly greater than after topical application of 20% ALA. An injected dose of 10 mg ALA (0.5 ml of a 2% solution) resulted in significantly more tissue damage after illumination than all other injected doses.

Partition coefficients (n-octanol/water) of N-butyl-p-aminobenzoate and other local anesthetics measured by reversed-phase high-performance liquid chromatography.

For the determination of the logarithmic partition coefficients between n-octanol and water (log P(o/w)) of local anesthetics, the pH of the aqueous phase needs to be adjusted to high values to ensure that the local anesthetics are in the unionized form. Using the shake-flask or the stir-flask method, this high pH may catalyze hydrolysis, leading to increasing amounts of impurities in time. These impurities exclude non-selective quantification methods like UV spectrometry and require repetitive quantitative analysis of both liquid phases resulting in a tedious and time-consuming method. A rapid reversed-phase HPLC method was developed to measure log P(o/w) of the local anesthetics N-butyl-p-aminobenzoate, methyl-p-aminobenzoate, benzocaine, procaine, mepivacaine, prilocaine, lidocaine, bupivacaine, etidocaine, tetracaine and oxubuprocaine.

Epidural and intrathecal n-butyl-p-aminobenzoate solution in the rat. Comparison with bupivacaine.

BACKGROUND: Epidural administration of an aqueous suspension of n-butyl-p-aminobenzoate (BAB) to humans results in long-lasting sensory blockade without motor block. The dose-response of BAB administered epidurally and intrathecally as a solution was studied in rats to define the local anesthetic properties in an established animal model. METHODS: The time course of changes in tail withdrawal latency and motor function were determined in rats after epidural or intrathecal administration of solutions of BAB or bupivacaine. The dose-response relation was determined and median effective dose values were calculated. RESULTS: After epidural and intrathecal administration of BAB solutions, the onset and duration of the antinociceptive action were comparable to bupivacaine. Median effective dose values for tail-withdrawal latency of 6 s or more were significantly greater for BAB. After both routes of administration, BAB clearly affected motor function. CONCLUSIONS: When administered epidurally and intrathecally as a solution, BAB is a local anesthetic of relative low potency with onset and duration of action comparable to those of bupivacaine. These findings suggest that the long-lasting action obtained after applying BAB suspension results from the slow dissolution (continuous release) of the solid BAB deposited in the epidural space.

The local anesthetic, n-butyl-p-aminobenzoate, reduces rat sensory neuron excitability by differential actions on fast and slow Na+ current components.

Effects of the local anesthetic, n-butyl-p-aminobenzoate, at a concentration of 100 microM, were investigated using the whole-cell voltage clamp on dorsal root ganglion neurons cultured from neonatal rat in a serum-enriched medium. During current clamp conditions, the drug either increased the firing threshold or blocked tetrodotoxin-sensitive and tetrodotoxin-resistant Na+ action potentials. These actions were reversible. Under voltage clamp conditions, inactivation of the Na+ current revealed the existence of 3 fast Na+ current components, termed F1, F2 and F3 (tetrodotoxin-sensitive) and 2 slow ones, termed S1 and S2 (tetrodotoxin-resistant). The local anesthetic shifted the midpoint potentials of Na+ inactivation curves for F1, F2 and F3 currents by 7, 21 and 6 mV, respectively, towards hyperpolarizing membrane voltages whereas it did not influence these potentials for the slow currents. The amplitudes of only F3 and S2 currents were reduced by n-butyl-p-aminobenzoate to 24 and 11%, respectively, of their control values. These results show that the local anesthetic has a differential mode of action on the 5 types of Na+ currents, which are apparently present in cultured sensory neurons. This differential action can play an important role in the selective analgesic effect observed after epidural administration of a 10% n-butyl-p-amino-benzoate suspension.

Haemodynamic responses to incision and sternotomy in relation to the auditory evoked potential and spontaneous EEG.

We investigated the effect of incision and sternotomy on the auditory evoked potential (AEP) and EEG, to try to predict a haemodynamic response to incision or sternotomy using the AEP and EEG in 41 patients undergoing cardiac surgery during propofol and alfentanil anaesthesia. The AEP and EEG were recorded before incision, between incision and sternotomy, and after sternotomy. Peak latencies and amplitudes of AEP peaks V, Na, Pa, Nb, Pb and Nc were determined. From the EEG the median, spectral edge and peak power frequencies, and percentages of delta, theta, alpha and beta power were calculated. Each patient was classified as responsive, equivocally responsive or unresponsive to incision or sternotomy based on increase in arterial pressure and heart rate on incision and sternotomy. Before incision, Nb and Pb latency and propofol concentration were higher for unresponsive patients but heart rate and median frequency before incision were lower. After sternotomy, Pa and Nb amplitude, peak power frequency and percentage alpha power were higher, and percentage theta power lower for responsive patients. Pa latency was higher after sternotomy for unresponsive patients. Using a combination of heart rate, arterial pressures and features derived from the AEP (all recorded before incision), the occurrence of a response to incision could be predicted in individual patients with a sensitivity of 85%, positive predictive accuracy of 63% and total accuracy of 72%. We conclude that AEP are more sensitive to pain stimuli than spectral features of the spontaneous EEG. In addition, the AEP may help in predicting inadequate anaesthesia.

Spinal anesthesia. Volume or concentration--what matters?

BACKGROUND AND OBJECTIVES: An investigation was made of the effects of volume and concentration of a constant dose of subarachnoid lidocaine on the extent and duration of sensory and motor anesthesia produced, as well as of the lidocaine concentration of the cerebrospinal fluid (CSF) as a function of time. METHODS: In a prospective study, 40 American Society of Anesthesiologists (ASA) status 2 or 3 patients were assigned to one of five groups, who received a 70-mg subarachnoid dose of lidocaine hydrochloride as a 0.5, 1, 2, 5, or 10% solution. Dural puncture was performed at the L3-L4 interspace with a 19.5-gauge Periquick needle (Pajunk, Germany), and a 24-gauge catheter was inserted 3-4 cm into the subarachnoid space. The patient remained in the lateral position during injection of the local anesthetic and was then turned to the supine horizontal position. The level of anesthesia and the motor block were measured at 5, 10, 15, 20, 30, 40, 50, and 60 minutes and then at 15-minute intervals until the effect of the anesthesia had ceased. Samples of CSF were collected at the same times that the pinprick and motor block measurements were made. RESULTS: Five minutes after injection, a median sensory block height of T4 or T5 was observed in all groups. The range of mean total times to complete recovery of the sensory blocks was 139-152 minutes, while that for the motor blocks of the lower extremities was 100-122 minutes. The values were similar in all groups (P > .05). The motor block was complete in all patients 10 minutes after the lidocaine injection. Five minutes after injection, the mean CSF lidocaine concentration was highest in the 10% group (P < .001 vs. the other four groups). At 15 minutes, the only statistical difference was found between the 0.5% and the 10% group (P = .026). At 20 minutes, the CSF lidocaine concentrations were similar in all groups (P > .05). CONCLUSIONS: A constant 70-mg dose of subarachnoid lidocaine produced the same pinprick level of analgesia, degree of motor block, and duration of spinal anesthesia in spite of being injected over an extremely broad range of concentrations and volumes. Despite the fact that all patients received the same dose of lidocaine, the CSF concentrations at 5, 10, and 15 minutes were different and directly related to the concentration of the solution injected. at 20 minutes, the CSF concentrations were similar in all groups. These results indicate a relatively uniform distribution of lidocaine in the CSF for all solutions tested.

Capillary gas chromatographic method for the determination of n-butyl-p-aminobenzoate and lidocaine in plasma samples.

A fast capillary gas chromatographic method with nitrogen-selective detection is described that allows selective and reproducible quantification of n-butyl-p-aminobenzoate (BAB) and lidocaine in plasma. The sampling and sample storage conditions are critical for the quantification of BAB. Diisopropyl fluorophosphate, an organo-phosphorus pesticide, has to be added during sampling to prevent the rapid decomposition of BAB by cholinesterases.

The local anesthetic n-butyl-p-aminobenzoate selectively affects inactivation of fast sodium currents in cultured rat sensory neurons.

BACKGROUND: Aqueous suspensions of the local anesthetic n-butyl-p-aminobenzoate (BAB), epidurally applied in terminal cancer patients, resulted in a sensory blockade, lasting up to several months. To investigate the mechanism of action on the cellular level, the effect of 100 microM BAB on Na+ action potentials and on Na+ currents in dorsal root ganglion neurons from neonatal rats was studied. METHODS: Small neurons grown in cell culture were selected for patch-clamp measurements. Both Na+ action potentials, evoked by current pulses of increasing amplitude (current clamp) and Na+ currents, activated at different membrane potentials (voltage clamp), were investigated in the absence and presence of 100 microM BAB. The local anesthetic was applied by external perfusion for 2 or 10 min. RESULTS: In the presence of 100 microM BAB, either the firing threshold was raised or the action potential was abolished. The maximal peak conductances, underlying the fast sodium current INa,F and the slow sodium current INa,5, were not changed. However, the inactivation of INa,F was increased by BAB. The sigmoid inactivation curve shifted 12 mV toward hyperpolarizing membrane voltages, whereas no changes were found for the inactivation of the slow Na+ current. Only at short exposure times of 2 min, the effects of BAB could be reversed during a 10-min wash-out. CONCLUSIONS: BAB dramatically increased the firing threshold, and in part of the sensory neurons, it blocked the action potential. The inactivation of the fast Na+ channels, but not of the slow Na+ channels, was increased by BAB. Thus, the block of fast Na+ channels by BAB may contribute to epidural analgesia. At exposure times of 10 min, the effect of BAB was not reversible. This probably originates from its high lipid-solubility, which may be an important factor in determining the duration of the block in vivo.

Long-lasting epidural sensory blockade by n-butyl-p-aminobenzoate in the terminally ill intractable cancer pain patient.

An aqueous suspension of n-butyl-p-aminobenzoate (BAB), a highly lipid-soluble congener of benzocaine, was applied epidurally in terminally ill cancer patients with intractable pain. The suspension consisted of 10% BAB and 0.025% of the nonionic surfactant polysorbate 80 in 0.9% sodium chloride. Twelve consecutive patients received epidural BAB because pain was uncontrollable either by palliative radiotherapy or oral or epidural administrations of analgesics. The catheter or injecting needle was positioned at the segmental level of the pain. Repeated epidural injections were administered. In all patients, long-lasting sensory blockade (segmental analgesia) occurred, accompanied by a marked reduction or even absence of pain. In all patients, treatment with epidural opioids, alone or combined with local anesthetics, was no longer necessary. Five of the 12 patients did not require further administration of oral opioids. Motor, bowel, and bladder function were well preserved. In 6 patients, extensive necropsy of the spinal cord and spinal nerves did not reveal pathomorphologic changes. The outer aspect of the dura showed signs of focal necrosis on microscopy, yet its collagen structure and thickness were unchanged. Epidurally, focal infiltrative reactions were seen. The epidural use of an extremely lipid-soluble--hence hydrophobic--local anesthetic, with an exceptionally low pKa (2.3), formulated in suspension of the base, is conceptually innovative and needs further investigation. The authors conclude that the epidural administration of a BAB suspension may be an effective alternative to the neurolytic agents alcohol and phenol and may replace procedures such as cordotomy. Further investigation to determine the safety of BAB in this patient group appears warranted.

Butyl-p-aminobenzoate. Preparation, characterization and quality control of a suspension injection for epidural analgesia.

The conditions for the preparation of a 10% butyl-p-aminobenzoate suspension for epidural administration were investigated. Pharmaceutically acceptable suspensions are composed of butyl-p-aminobenzoate particles dispersed in a solvent consisting of the surfactant polysorbate 80 added to normal saline in a concentration of 0.25 mg/ml. pH Correction is not necessary. The suspensions are sterilized at 120 degrees C followed by special milling procedures to accomplish acceptable particle size. Butyl-p-aminobenzoate suspensions are stable at 4 degrees C during a period of at least four weeks.

Long-lasting epidural sensory blockade by n-butyl p-aminobenzoate in the dog: neurotoxic or local anesthetic effect?

An aqueous suspension of n-butyl p-aminobenzoate (BAB), a highly lipid-soluble congener of benzocaine, was applied epidurally and around ulnar nerves in dogs. The suspension consisted of 10% BAB and 0.025% polysorbate in 0.9% NaCl. Sensory effects were tested by electrical stimulation. Three epidural injections were given, and the dogs were killed after 21 days. The increase in stimulation threshold was comparable to the effect of lidocaine in a concentration between 0.5% and 1%. Increased sensory threshold lasted for days, whereas no long-lasting motor effects were observed. Pathomorphologic changes were found primarily in the dorsal spinal nerve roots, although slight changes were also found in the ventral spinal roots. White matter degeneration was found only in the lumbar dorsal columns. This result suggested Wallerian degeneration in the dorsal spinal nerves and was at variance with recently published data on epidural BAB. No changes were observed in the ulnar nerves. The authors demonstrated that the pathomorphologic changes were induced by the BAB suspension and not by the suspending additive polysorbate 80. It was postulated that the suspension of BAB, which contains particles of a median size of 15 microns, was mainly confined to the dorsal epidural space where neurolytic changes in axons of the dorsal spinal nerve roots and dorsal columns are induced. This may explain the long-lasting sensory effects seen in intractable cancer pain patients after epidural BAB administration. More research is necessary to define the distribution of BAB in nervous tissue after its epidural administration and to better characterize toxicity, neurolytic effects, and regeneration of nervous tissue after BAB administrations.

Binding of 99mTc(113Sn)-MDP to human serum albumin. The influence of various technetium, tin, and MDP concentrations.

The HSA-binding of 99mTc incubated as 99mTc(113Sn)-MDP depends in vitro on the presence of competing anions normally present in plasma and on the MDP and Tc concentration, but is independent of the Sn concentration. The HSA-binding of 113Sn depends on the MDP and Sn concentration; not on the Tc concentration. 99mTc(Sn)-MDP binds to HSA as a unit. The binding of 99mTc(Sn)-MDP to plasma proteins in vivo is much lower as calculated from in vitro experiments because of competition between 99mTc(Sn)-MDP and endogenous anions for the same binding-sites.

Protein-binding and urinary excretion of 99mTc(Sn)-MDP and 99mTc-MDP.

In an incubation experiment the Human Serum Albumin (HSA) binding of 99mTc-MDP (electrolytically labeled) and 99mTc(Sn)-MDP is established. During the incubation some pertechnetate is formed and in the case of 99mTc(Sn)-MDP also some hydrolyzed 99mTc. The HSA binding of 99mTc-MDP is less than the HSA binding of 99mTc(Sn)-MDP as established with gel chromatography, TCA-precipitation, ammonium sulfate precipitation and ultrafiltration. TCA-precipitation seems to be an insufficient method for determining the protein binding of 99mTc(Sn)-MDP. The urinary excretion in rats shows only one 99mTc-compound in both cases. The bone seeking properties of the urine-excreted 99mTc-compound were confirmed in another rat.