An uncommon, unilateral motor variation of the intercostobrachial nerve.

The intercostobrachial nerve (ICBN) is commonly defined as a purely sensory nerve supplying the skin of the lateral chest wall, axilla, and medial arm. However, numerous branching patterns and distributions, including motor, have been reported. This report describes an uncommon variant of the right ICBN observed in both an 86-year-old white female cadaver and a 77-year-old white male cadaver. In both cases the ICBN presented with an additional muscular branch, termed the "medial pectoral branch", piercing and therefore innervating the pectoralis major and minor muscles. Clinically, the ICBN is relevant during surgical access to the axilla and can result in sensory deficits (persistent pain/loss of sensory function) to this region following injury. However, damage to the variation observed in these cadavers may result in additional partial motor loss to pectoralis major and minor.

Vinum resinatum: Scientists and unintended consequences.

The art of winemaking has a long history. The methods and techniques changed over millennia as did the consumers taste and habits. Improving the taste of the wine and preventing conversion to vinegar required fantasy and creativity. The principal substances employed as conditurae were seawater, turpentine, either pure, or in the form of pitch (pix), tar (pix liquida), or resin (resina); lime, in the form of gypsum, burnt marble, or calcined shells; inspissated must, aromatic herbs, spices, and gums, and these were used either singly, or cooked up into a great variety of complicated confections. Turpentine exposure (oral. dermal. or respiratory) confers urine the scent of violets. It is generally assumed that turpentine's effect on urine was noticed subsequent to its use as medicine, as a component of various remedies popular in antiquity and thereafter. The high price of such elaborate concoctions would have made however such means available to only a privileged few. Furthermore, the high number of components would also have made association of a particular ingredient with a specific effect difficult if not impossible. We examined the possibility that the effect of turpentine on urine was noticed due to its presence in wines and therefore to the likely widespread exposure of the population to its effects. We review the literature supporting this possibility and provide biographic data on some of the pharmacists, chemists, and physicians involved.

Possible metabolic conversion of pinene to ionone.

The unintended consequence of the ingestion of certain foods to alter the scent or color of urine is well known. Less awareness exists regarding the practice of ingestion of natural products or drugs with the intended purpose of conferring urine the scent of violets. The resin of the terebinth tree and the derived turpentine were widely used in antiquity in wine-making, both as taste enhancer and conserving agent, so the effect on urine was possibly noticed due to the presence in wines. It is also possible that turpentine's effect on urine was noticed subsequent to its use as medicine, as a component of various remedies popular in those days. The scent altering effect requires metabolic conversion of pinene, the main turpentine component to ionone, the molecule mainly responsible for the scent of violets. The metabolic pathway (in humans or otherwise) was (to our knowledge) not yet described. We here propose a possible metabolic pathway for the conversion of pinene to ionone, explaining the scent altering effect of turpentine. We also provide calculated pharmacokinetic (pK) data for the mentioned substances.

Cleopatra: from turpentine and juniper to ionone and irone.

Cleopatra VII (69-30 BC), the last Ptolemaic ruler of Egypt, is probably best known for her love affairs with Julius Caesar (100-44 BC) and Marcus Antonius (83-30 BC). Rightly or wrongly she became the epitome of shrewd seduction, leading brave Roman commanders on a path to debauchery and destruction. Among the seductive strategies attributed to her is the ingestion of small amounts of turpentine [the resin of the terebinth tree (Pistacia terebinthus)] or of derived oil (Oleum terebinthinae) with the purpose of conferring to her urine a more pleasant scent reminding of violets. Turpentine components are metabolized among other compounds to ionones and irones, which - renally excreted - are responsible for the flowery scent. Having obviously worked with great generals, the strategy is said to have been embraced for everyday use by many affluent Roman women. Complicating the issue somewhat is the fact that juniper berries (Fructus juniperi) and derived oil (Oleum juniperi) containing many of the same terpenoids as turpentine have a similar effect on urine. The purpose of this contribution is to briefly review the pharmacology of turpentine and juniper derived compounds assumed to be responsible for altering the scent of urine and to examine the origin and veracity of the mentioned habit. While the effect of ingested turpentine on the scent of urine is well documented our attempts at identifying Greek or Latin authors mentioning its intentional use for this explicit purpose (by Cleopatra or anybody else) failed.

Inhibitory actions of bisabolol on α7-nicotinic acetylcholine receptors.

Bisabolol is a plant-derived monocyclic sesquiterpene alcohol with antinociceptive and antiinflammatory actions. However, molecular targets mediating these effects of bisabolol are poorly understood. In this study, using a two-electrode voltage-clamp and patch-clamp techniques and live cellular calcium imaging, we have investigated the effect of bisabolol on the function of human α7 subunit of nicotinic acetylcholine receptor (nAChR) in Xenopus oocytes, interneurons of rat hippocampal slices. We have found that bisabolol reversibly and concentration dependently (IC50 = 3.1 µM) inhibits acetylcholine (ACh)-induced α7 receptor-mediated currents. The effect of bisabolol was not dependent on the membrane potential. Bisabolol inhibition was not changed by intracellular injection of the Ca(2+) chelator BAPTA and perfusion with Ca(2+)-free solution containing Ba(2+), suggesting that endogenous Ca(2+)-dependent Cl(-) channels are not involved in bisabolol actions. Increasing the concentrations of ACh did not reverse bisabolol inhibition. Furthermore, the specific binding of [(125)I] α-bungarotoxin was not attenuated by bisabolol. Choline-induced currents in CA1 interneurons of rat hippocampal slices were also inhibited with IC50 of 4.6 µM. Collectively, our results suggest that bisabolol directly inhibits α7-nAChRs via a binding site on the receptor channel.

In an animal model nephrogenic systemic fibrosis cannot be induced by intraperitoneal injection of high-dose gadolinium based contrast agents.

AIM AND OBJECTIVE: Nephrogenic systemic fibrosis (NSF) has been reported in humans to be most likely induced by gadolinium based contrast agents (GBCA), namely by gadodiamide, gadopentetate dimeglumine, and gadoversetamide, rarely by other GBCA. The pathogenesis of NSF remains unclear; different hypotheses are under discussion. The objective of the study is to assess if in the animal model human-like NSF changes can be induced by high-dose, intraperitoneal GBCA injections over four weeks. MATERIALS AND METHODS: After approval by the institutional animal ethics committee, six rats each were randomly assigned to groups, and treated with seven different GBCA. Intraperitoneal (IP) injections - proven in the animal model to be effective - were chosen to prolong the animals' exposure to the respective GBCA. GBCA doses of previous intravenous (IV) animal studies were applied. After five weeks all rats were sacrificed. Sham controls were treated with IP saline injections, employing the same regimen. RESULTS: No findings comparable with human NSF were observed in all animals after IP treatment with all seven GBCA at daily doses of 2.5 and 5.0 mmol/kg body weight (BW). No histopathological abnormalities of all examined organs were noted. Weight loss was stated in weeks three and four with GBCA injections at doses of 5.0 mmol/kg BW, but rats regained weight after cessation of GBCA treatment. CONCLUSIONS: NSF-comparable pathological findings could not be induced by high dose intraperitoneal injection of seven GBCA.

Interventional management of intractable sympathetically mediated pain by computed tomography-guided catheter implantation for block and neuroablation of the thoracic sympathetic chain: technical approach and review of 322 procedures.

We retrospectively evaluated the safety and efficacy of computed tomography-guided placement of percutaneous catheters in close proximity to the thoracic sympathetic chain by rating pain intensity and systematically reviewing charts and computed tomography scans. Interventions were performed 322 times in 293 patients of mean (SD) age 59.4 (17.0) years, and male to female ratio 105:188, with postherpetic neuralgia (n = 103, 35.1%), various neuralgias (n = 88, 30.0%), complex regional pain syndrome (n = 69, 23.6%), facial pain (n = 17, 5.8%), ischaemic limb pain (n = 7, 2.4%), phantom limb pain (n = 4, 1.4%), pain following cerebrovascular accident (n = 2, 0.7%), syringomyelia (n = 2, 0.7%) and palmar hyperhidrosis (n = 1, 0.3%). The interventions were associated with a total of 23 adverse events (7.1% of all procedures): catheter dislocation (n = 9, 2.8%); increase in pain intensity (n = 8, 2.5%); pneumothorax (n = 3, 0.9%); local infection (n = 2, 0.6%); and puncture of the spinal cord (n = 1, 0.3%). Continuous infusion of 10 ml.h(-1) ropivacaine 0.2% through the catheters decreased median (IQR [range]) pain scores from 8 (6-9 [2-10]) to 2 (1-3 [0-10]) (p < 0.0001). Chemical neuroablation was necessary in 137 patients (46.8%). We conclude that this procedure leads to a significant reduction of pain intensity in otherwise obstinate burning or stabbing pain and is associated with few hazards.

TUNEL and growth factor expression in the prefrontal cortex of Alzheimer patients over 80 years old.

To elucidate factors underlying the increased risk of developing Alzheimers disease (AD) in older individuals, the prefrontal cortices of younger (58-79 years) and of older (over 80 years) AD patients were examined by silver impregnation, TUNEL assay and immunohistochemistry for hyperphosphorylated tau, LDH and two growth factors (BDNF, NGF). Quantitative data were compared with those of age-matched controls. TUNEL-positive cells were mainly located in superficial cortical layers of younger and in deeper layers of older AD patients. Their density was more than 5 times higher in older AD than in younger AD (p < or = 0.05), but apoptotic cell morphology was rarely seen. Significantly more neuronal somas were contacted by degenerating fibers both in younger and older AD cortices. Density of tau-immunoreactive cells, which were virtually absent in controls, was twice as high in older AD patients as in younger AD individuals (p < or = 0.05). In younger AD, TUNEL positive cells generally lacked tau immunoreaction, whereas in older AD, most cells were double-labeled for hyperphosphorylated tau and TUNEL (p < or = 0.05). Numerical density of BDNF-immunoreactive cells was significantly reduced by 20 percent in older AD patients, compared to both control individuals and younger AD patients, whereas density of NGF-positive cells was the same in all patient groups examined. The distinct differences between younger and older AD patients suggest a faster progression of AD in older patients.

In vitro assessment of the antibiotic efficacy of contrast media and antibiotics and their combinations at various dilutions.

Discography is a controversial diagnostic procedure involving the injection of radiographic contrast medium (RCM) into the intervertebral disc. Iatrogenic bacterial discitis is a rare but serious complication. The intervention has been increasingly performed in our patients here in the United Arab Emirates. Prophylactic intravenous antibiotic administration can reduce post-interventional discitis; however, this may favour the development of bacterial resistance. Direct intradiscal injection of an antibiotic together with the RCM is a potential alternative. To date, there has been only one study on the efficacy of antibiotics added to an RCM. Equally, there are only limited data regarding the potential direct effect of RCM on bacterial growth. The purpose of this study was to determine whether the efficacy of antibiotics is affected when RCM are added. In an in vitro study, the effect of non-ionic RCM on the growth of five laboratory bacterial strains, alone and in combination with three broad-spectrum antimicrobials, was tested. Bacterial growth was assessed in the absence and the presence of RCM, antibiotics and their combinations. All three RCM alone demonstrated some inhibition of bacterial growth at high concentrations. In the presence of the RCM, all three antibiotics retained their inhibitory effect on bacterial growth. In conclusion, our in vitro experiments did not reveal any changes in the antimicrobial efficacy of the three antibiotics in the presence of the three tested RCM. Subsequent clinical trials will need to assess whether intradiscal antibiotic administration may be a suitable substitute for, or a supplement to, prophylactic systemic antibiotics before discography.

Efficacy of two new asymmetric bispyridinium oximes (K-27 and K-48) in rats exposed to diisopropylfluorophosphate: comparison with pralidoxime, obidoxime, trimedoxime, methoxime, and HI-6.

Introduction. The new K-oximes, K-27 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridinium) propane dibromide] and K-48 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], show good in vitro efficacy in protecting acetylcholinesterase from inhibition by different organophosphorus compounds (OPCs), including nerve agents. To assess their efficacy in vivo, the extent of oxime-conferred protection from mortality induced by diisopropylfluorophosphate (DFP) was quantified and compared with that of five established oximes. Materials and Methods. Rats received DFP intraperitoneally in a dosage of 6, 8, or 10 micromol/rat and immediately thereafter intraperitoneal injections of K-27, K-48, pralidoxime, obidoxime, trimedoxime, methoxime, or HI-6. The relative risk (RR) of death over time (48 h) was estimated by Cox survival analysis, comparing results with the no-treatment group. Results. Best protection was observed when K-27 was used, reducing the RR of death to 19% of control RR (p < or = 0.005), whereas obidoxime (RR = 26%, p < or = 0.01), K-48 (RR = 29%, p < or = 0.005) and methoxime (RR = 26%, p < or = 0.005) were comparable. The RR of death was reduced only to about 35% of control by HI-6, to 45% by trimedoxime, and to 59% by 2-PAM (p < or = 0.005). Whereas the differences between the best oximes (K-27, obidoxime, methoxime, and K-48) were not statistically significant; these four oximes were significantly more effective than 2-PAM (p < or = 0.05). The efficacy of K-27 was also significantly higher than that of HI-6, trimedoxime, and 2-PAM (p < or = 0.05). Conclusion. Our data provide further evidence that K-27 is a very promising candidate for the treatment of intoxication with a broad spectrum of OPCs.

Minireview: does in-vitro testing of oximes help predict their in-vivo action after paraoxon exposure?

K-oximes have recently been developed in the search for efficacious broad-band reactivators of acetylcholinesterase (AChE) inhibited by organophosphorus compounds (OPC). Before clinical use, their toxicity and efficacy need to be assessed, and there is clear demand for simple in vitro tests that can predict in vivo performance. This article summarizes our in vitro data obtained for conventional and experimental oximes in human and rat blood exposed to the OPC paraoxon and correlates them with our in vivo results. The intrinsic AChE inhibitory activity of oximes, as reflected by their in vitro IC(50), is strongly correlated with their LD(50) (rat): oximes with a high IC(50) (K-27, K-48, pralidoxime and obidoxime) also show a high LD(50) and are thus relatively non-toxic, whereas oximes K-105, K-108 and K-113 have a low IC(50), a low LD(50) and are far more toxic. The IC(50) is also correlated with the in vivo capacity to protect from paraoxon-induced mortality: oximes with a higher IC(50) reduce the relative risk of death more. In contrast, the protective ability as assessed in vitro by the slope of the IC(50) shift (tanalpha), is not correlated with in vivo protection from paraoxon-induced mortality: the best in vivo protectors (K-27 and K-48) show a much lower tanalpha value (around 2) than K-110 and K-113 (tanalpha around 10), which hardly reduce the relative risk of death after paraoxon exposure. The partition coefficient logP of the individual oximes is inversely correlated with their IC(50) and with their LD(50) and is therefore an indicator of toxicity: strongly hydrophilic oximes tend to be less toxic than less hydrophilic ones. These data highlight the good predictive value of in vitro IC(50) testing for in vivo toxicity and the limited practical significance of in vitro assessment of protective potency.

Efficacy of eight experimental bispyridinium oximes against paraoxon-induced mortality: comparison with the conventional oximes pralidoxime and obidoxime.

Recently, several experimental K-oximes with two functional aldoxime groups have been synthesized that show excellent in vitro efficacy in protecting acetylcholinesterase (AChE) from inhibition by a broad variety of organophosphorus compounds (OPCs). However, oximes themselves are also AChE inhibitors, albeit at higher concentrations, which is a major cause of their toxicity and may be a dose-limiting factor in oxime therapy. To assess the efficacy of the experimental K-oximes in vivo, the extent of oxime-conferred protection from mortality induced by paraoxon was quantified. Rats received paraoxon in a dosage of 1, 5, or 10 mumol, and immediately thereafter intraperitoneal injections of the respective oxime at a dosage of half the LD(01). The relative risk of death (RR) over time was estimated by Cox survival analysis for treatment with experimental K-oximes (K-53, K-74, K-75, K-107, K-108, and K-113), with the clinically available oximes pralidoxime (2-PAM) and obidoxime, and with the well-characterized K-oximes K-27 and K-48, comparing results with the no-treatment group. Best protection was conferred by K-27, reducing the RR to 20% of controls (P

Pyridinium oxime reactivators of cholinesterase inhibited by diisopropyl-fluorophosphate (DFP): predictive value of in-vitro testing for in-vivo efficacy.

Poisoning with organophosphorus cholinesterase inhibitors (OPCs) poses a serious global threat. Therapy comprises the use of atropine and pyridinium oximes to reactivate acetylcholinesterase (AChE). Clinical experience with established oximes (pralidoxime and obidoxime) is disappointing and several experimental potential alternatives (K oximes) have been developed. This review summarizes data on these oximes, when used in exposure to the OPC diisopropylfluorophosphate (DFP). In vitro testing includes determination of IC(50) (intrinsic oxime AChE inhibitory activity), of tan alpha (reactivation capacity) and in silico estimation of LogP (lipophilicity/hydrophilicity) of the individual oximes. In vivo approaches encompass determination of toxicity (LD(50)) and of protective efficacy (reduction of relative risk of death after DFP exposure in rats). Correlations between the different in vitro and in vivo data available reveal that an oxime with a low in vitro AChE inhibitory activity (high IC(50)) is rather non-toxic and reduces DFP-induced mortality (low cumulative relative risk). Oximes with a high in vitro AChE reactivation potency (high tan alpha) also have a high in vitro AChE inhibitory activity (low IC(50)) and have a low LD(50) in vivo, implying high toxicity. Less hydrophilic oximes have strong in vitro AChE inhibitory activity, are better in vitro AChE reactivators, but are also more toxic in vivo and are associated with a high cumulative risk of death after DFP exposure in rats, implying low in vivo efficacy. In vitro reactivation capacity of human red blood cell (RBC)-AChE has no predictive value for in vivo (rat) efficacy, at least in the case of DFP exposure.

Eight new bispyridinium oximes in comparison with the conventional oximes pralidoxime and obidoxime: in vivo efficacy to protect from diisopropylfluorophosphate toxicity.

In search for more efficacious reactivators of acetylcholinesterase (AChE) inhibited by organophosphorus compounds, experimental K-oximes have been synthesized which show good in vitro efficacy. However, AChE inhibition by oximes themselves (as quantified by their intrinsic IC50) is the major cause of oxime toxicity and the dose-limiting factor. To assess K-oxime efficacy in vivo, the extent of protection from mortality induced by diisopropylfluorophosphate (DFP) was quantified by Cox survival analysis and compared with that of the clinically available oximes. Oximes were administered in an equitoxic dosage, i.e. half the LD01. Best protection was conferred by K-27, reducing the relative risk of death (RR) to 16% of control RR (P < or = 0.05), which was statistically significantly better (P < or = 0.05) than all other tested oximes, except obidoxime, K-53 and K-75. The efficacy of obidoxime (RR = 0.19), K-48 (RR = 0.28), K-53 (RR = 0.22), K-74 (RR = 0.38) and K-75 (RR = 0.29) was significantly (P < or = 0.05) better than that of 2-PAM (RR = 0.62) and K-113 (RR = 0.73). No significant protective effect was observed for K-107 and K-108. Our LD50 data show that K-107, K-108 and K-113 (which strongly inhibit AChE in vitro) are in vivo markedly more toxic than all other oximes tested and can therefore only be safely administered at a low dosage which is insufficient to protect from DFP-induced mortality. Dosage calculations based on in vitro IC50 measurements may therefore in future replace in vivo LD50 determinations, thereby reducing the number of animals required.

Effect of intrathecal pralidoxime administration upon survival of rats exposed to the organophosphate paraoxon.

The therapeutic results of systemic administration of pralidoxime (2-PAM) in the treatment of poisoning with organophosphate-type cholinesterase inhibitors are disappointing. It has been hypothesized that this is due to poor entry of 2-PAM into the brain. To test if survival rates can be improved by direct administration of 2-PAM into the cerebrospinal fluid (CSF), the effect of intrathecal 2-PAM injections upon mortality after paraoxon intoxication was examined. Eight groups of rats (n=30 each) were examined, all of which received paraoxon (1 micromol=272 microg, 3 micromol=816 microg, or 5 micromol=1.36 mg) intraperitoneally (i.p.). One group received no further treatment; the other groups were given 50 micromol (=8.63 mg) 2-PAM i.p., 5 micromol (=863 microg) 2-PAM intrathecally and pentobarbital/lidocaine in various combinations. Results were compared with the no treatment group and the control groups that did not receive any paraoxon injections, but were given intrathecal injections of saline or 2-PAM. The relative risk of death was estimated by Cox survival analysis. Mortality was lowest after treatment with a combination of both i.p. and intrathecal 2-PAM plus pentobarbital, and with 2-PAM i.p. alone plus pentobarbital. Both treatments were significantly better than 2-PAM i.p. alone (p

Entry of oximes into the brain: a review.

The passage of hydrophilic drugs, such as oxime acetylcholinesterase reactivators, into the central nervous system is restricted by the blood-brain and the blood-cerebrospinal fluid barriers. The present review summarizes morphological and functional properties of the blood-brain barrier, blood-cerebrospinal fluid barrier and cerebrospinal fluid-brain interface and reviews the existing data on brain entry of oximes. Due to the virtual absence of transcytosis, lack of fenestrations and unique properties of tight junctions in brain endothelial cells, the blood-brain barrier only allows free diffusion of small lipophilic molecules. Various carriers transport hydrophilic compounds and extrude potentially toxic xenobiotics. The blood-cerebrospinal fluid barrier is formed by the choroid plexus epithelium, whose tight junctions are more permeable than those of brain endothelial cells. The major function of plexus epithelium cells is active transport of ions for the production of the cerebrospinal fluid. The cerebrospinal fluid-brain interface is not a biological barrier and allows free diffusion. However, in contrast to passage via the blood-brain barrier or the blood-cerebrospinal fluid barrier, direct penetration from the cerebrospinal fluid into the brain is very slow, since much longer distances have to be covered. A bulk flow of brain interstitial fluid and cerebrospinal fluid speeds up exchange between these two fluid compartments. Oximes, by reactivating acetylcholinesterase, are important adjunct therapeutics in organophosphate poisoning. They are very hydrophilic and therefore cannot diffuse freely into the central nervous system. Changes in brain acetylcholinesterase activity, oxime concentration and some biological effects elicited by oxime administration in the periphery indicate, however, that oximes can gain access to the brain to a certain degree, probably by carrier-mediated transport, reaching in the brain about 4-10% of their respective plasma levels. The clinical relevance of this effect is hotly debated. Possible strategies to improve brain penetration of oximes are discussed.

In vitro oxime protection of human red blood cell acetylcholinesterase inhibited by diisopropyl-fluorophosphate.

Oximes are enzyme reactivators used in treating poisoning with organophosphorus cholinesterase (AChE) inhibitors. The oxime dose which can be safely administered is limited by the intrinsic toxicity of the substances such as their own AChE-inhibiting tendency. Clinical experience with the available oximes is disappointing. To meet this need, new AChE reactivators of potential clinical utility have been developed. The purpose of the study was to estimate in vitro both the intrinsic toxicity and the extent of possible protection conferred by established (pralidoxime, obidoxime, HI-6, methoxime, trimedoxime) and experimental (K-type) oximes, using diisopropyl-fluoro-phosphate (DFP) as an AChE inhibitor. The IC50 of DFP against human red blood cell AChE was determined ( approximately 120 nm). Measurements were then repeated in the presence of increasing oxime concentrations, leading to an apparent increase in DFP IC50. Calculated IC50 values were plotted against oxime concentrations to obtain an IC50 shift curve. The slope of this shift curve (tan alpha) was used to quantify the magnitude of the protective effect (nm IC50 increase per microm oxime). We show that, in the case of a linear relationship between oxime concentration and IC50, the binding constant K, determined using the Schild equation, equals IC50/DFP/tan alpha. Based on the values of tan alpha and of the binding constant K, some of the new K-oxime reactivators are far superior to pralidoxime (tan alpha = 0.8), obidoxime (1.5), HI-6 (0.8), trimedoxime (2.9) and methoxime (5.9), with K-107 (17), K-108 (20), and K-113 (16) being the outstanding compounds.

The organophosphate paraoxon has no demonstrable effect on the murine immune system following subchronic low dose exposure.

Paraoxon is the bioactive metabolite of the organophosphate pesticide parathion. Desulphuration of parathion by liver enzymes or sunlight results in the formation of paraoxon which inhibits acetylcholine esterase (AChE) activity. In the present study, we analyzed the effect of a 6-week, subchronic treatment with two different daily intraperitoneal doses (30 or 40 nmol) of paraoxon on the immune system of BALB/c mice. At a dose of 30 nmol/day, body weight of treated animals was unchanged compared to the controls. In contrast, the higher dose (40 nmol/day) induced a reduction in body growth, particularly in the first 3 weeks of treatment, peaking at week 2 when the saline group showed a 14.2-fold increase in body weight gain compared to paraoxon-treated animals. Moreover, mice treated with either dose of paraoxon had a >50% reduction in AChE activity during the first 3 weeks of treatment, but by the end of the treatment (week 6), AChE activity returned to normal. With regard to immunological parameters, there was no significant difference in either total spleen weight or in the ratios of various spleen cell populations between control and paraoxon-treated animals. Furthermore, no changes were observed in mitogen-induced cytokine secretion from splenocytes of paraoxon-treated mice. Finally, subchronic exposure to paraoxon did not alter mortality of mice exposed to a bacterial infection with Salmonella typhimurium. These data suggest that although subchronic exposure to paraoxon induced a transient inhibition in AChE activity, it had no demonstrable effect on the host immune system.

Recombinant hirudin for cardiopulmonary bypass anticoagulation: a randomized, prospective, and heparin-controlled pilot study.

BACKGROUND: Lepirudin, a recombinant hirudin, is a direct acting thrombin inhibitor that has been used as a heparin alternative in patients with heparin-induced thrombocytopenia requiring on-pump cardiac surgery. To evaluate the efficacy, safety, and clinical utility of lepirudin as a cardiopulmonary bypass (CPB) anticoagulant, we compared lepirudin with heparin in a routine CPB setting. METHODS: Twenty patients were randomly assigned to receive lepirudin (0.25 mg/kg b. w. bolus and 0.2 mg/kg b. w. added to the CPB priming) or heparin (400 U/kg b. w. bolus) with protamine reversal. Lepirudin and heparin anticoagulation during CPB was monitored using the ecarin clotting time or ACT, respectively and additional lepirudin (5 mg) or heparin (5000 U) boluses were administered. RESULTS: The CPB circuit was performed in both groups without thromboembolic complications. Median blood loss during the first 36 hours was statistically higher ( P = 0.007) in the lepirudin group (1.226 +/- 316 ml) compared to the heparin group (869 +/- 189 ml). One patient of the lepirudin group developed pulmonary embolism 24 hours after surgery. This patient was tested homozygous for the FV-Leiden mutation. CONCLUSION: Lepirudin provides effective CPB anticoagulation but induces a higher postoperative blood loss than heparin. Lepirudin should be restricted to patients undergoing CPB who cannot be exposed to heparin.

Entry of two new asymmetric bispyridinium oximes (K-27 and K-48) into the rat brain: comparison with obidoxime.

In the search for new oximes with higher reactivation potency and a broader spectrum, K-27 and K-48, have recently been synthesized. To test if their superior efficacy was related to better penetration across the blood-brain barrier, their brain entry was compared with that of obidoxime, when administered either alone or after the organophosphate paraoxon (POX). Rats received 50 micromol obidoxime, K-27 or K-48, either alone or in addition to 1 micromol POX. Oxime concentrations at various points in time in brain and plasma were measured using HPLC. The obidoxime C(max) in brain was 1.3% of the plasma C(max) when injected alone, and 1.5% when injected following POX. The ratio of the area under the curve (AUC) brain to plasma for obidoxime was around 6%, irrespective of whether it was administered alone or after POX. For K-27, C(max) (brain) was 0.6% of C(max) (plasma) when injected alone, and 0.7% when injected after POX (no significant difference). The AUC (brain) was 2% of AUC (plasma) for both K-27 groups. K-48, when injected alone reached 1.4% of C(max) (plasma) in the brain and 1.2% of C(max) (plasma), when injected following POX. The AUC (brain) was 5% of the AUC (plasma), both when K-48 was administered alone and in combination with POX. Entry of all three oximes into the brain is minimal and cannot explain the better therapeutic efficacy of K-27 and K-48. As already observed for pralidoxime, injection of POX before oxime administration had no influence upon penetration across the blood-brain barrier.