Of the 55 patients listed but not transplanted, 45 (82%) died within a median of 7 days (range, 1-90 days). Multivariate analysis showed that adult LDLT (hazard ratio [HR] 0.10, P < 0.01) and DDLT (HR 0.12, P = 0.04) were associated with decreased mortality, whereas older age (HR 1.03, P = 0.01) and higher Model for End-stage Liver selleck chemicals Disease (MELD) (HR 1.03, P = 0.04) was associated with increased mortality of patients. There was no living donor mortality. Eight (17.8%) and three (6.7%) living donors experienced grade 1 and 2 complications, respectively. Conclusion: Emergency adult LDLT can be performed expeditiously and safely

for patients with ALF, and greatly improves the survival rate. As the window during which transplantation is possible is limited, emergency adult LDLT should be considered one of the first-line treatment options in patients with ALF, especially in regions in which ALFs are caused by etiologies associated with poor outcome and the supply of organs is severely limited. (HEPATOLOGY 2010.) Acute liver failure (ALF) is a condition in which rapid deterioration of liver function results in altered mentality

check details and coagulopathy in individuals without preexisting cirrhosis.1 The probability of spontaneous recovery is usually poor, with emergency liver transplantation (LT) often being the only effective treatment.1 The cause of ALF is the most important determinant of patient outcomes.2 For example, spontaneous recovery rates from ALF caused by hepatitis B virus (HBV) infection are significantly lower than from ALF attributable to acetaminophen (APAP) toxicity.3 The etiology of ALF varies markedly by geographical region.2 Because ALF progresses rapidly, the need for LT is urgent. In Western countries, not all patients listed for LT receive a liver graft from a deceased donor, and the death rate of patients awaiting LT ranges from

10% to 40%.3, O-methylated flavonoid 4 The donation rate from deceased donors is even much lower in Asian countries.5, 6 The high mortality rates from ALF and the limited number of organs available from deceased donors has led to the use of adult-to-adult living donor liver transplantation (adult LDLT) in many countries.7–9 Emergency adult LDLT is likely to be particularly effective for patients in regions where ALF is mainly caused by etiologies associated with a high mortality rate and a severely limited supply of organs. However, its use has been limited by ethical concerns and the time constraints needed to evaluate donors. In this prospective cohort study we evaluated the long-term effect and donor safety of emergency adult LDLT for ALF in Korea, an HBV-endemic area with a severe shortage of organs from deceased donors.

Concomitant prednisolone, azathioprine and 5-aminosalicylic acid was administered to 37, 61 and 68 subjects, respectively. Previous treatments included prednisolone in 40 subjects, granulocyte–monocyte adsorptive apheresis in 68 and calcineurin inhibitor (cyclosporin

selleck products or tacrolimus) treatment in 33. The 1-, 3-, and 5-year cumulative noncolectomy rates were 75%, 70%, and 65%, respectively. Multivariate Cox regression analysis revealed that previous treatment with calcineurin inhibitors was the background factor that significantly decreased the cumulative noncolectomy rate (hazards ratio, 5.406; 95% confidence interval, 1.732–16.871; P = 0.004). Conclusion: This retrospective study revealed satisfactory long-term outcomes

of IFX treatment in Japanese patients with refractory UC. Previous treatment with calcineurin find more inhibitors may be a poor prognostic factor for patients who undergo IFX treatment for refractory ulcerative colitis. Key Word(s): 1. ulcerative colitis; 2. infliximab; Presenting Author: SOPHIA ZAMORAMEJIA ZAMORA Additional Authors: EULENIA NOLASCORASCO NOLASCO Corresponding Author: SOPHIA ZAMORAMEJIA ZAMORA Affiliations: Manila Doctors Hospital Objective: The data in inflammatory bowel disease (IBD) in the Philippines is still lacking. This study aims to describe the cumulative incidence, clinicopathologic and endoscopic features of patients with IBD in Manila Doctors Hospital (MDH), a tertiary hospital in

the Philippines from 2007 to 2011. Methods: This is a descriptive study involving allpatients diagnosed with IBD in MDH based on clinical, endoscopic or pathologic features with negative TB-PCR results. Results: Sixteen patients were diagnosed with IBD. Nine patients, 56.25% had Ulcerative Colitis (UC),7 patients, 43.25% had Crohn’s Disease (CD) with a UC:CD ratio of 1.28:1. The cumulative incidence was 9.78 new cases per 100,000. IBD has equal male and female distribution. The peak incidence of both CD and UC was between 31 to 40 years old. The most common presentingsymptom was diarrhea, 57.14% in CD while LGIB, 67% in UC. The most common endoscopic findingswere ulcers and nodular/cobblestone mucosa, 71.4% in CD while erythematous Rutecarpine mucosa, 88.9%in UC. The localization of Crohn’s disease was mostly colonic, 57% followed by ileocolonic, 43%. All patients with CD had inflammatory or ulcerating pattern. UC commonly involves theleft side of the colon. The most frequent histopathology result was chronic activecolitis. Conclusion: There is an increasing trend in the incidenceof IBD in MDH from 2007 to 2011. The most common presenting symptom was diarrhea in CD while LGIB in UC. The most common endoscopic findings in CD were ulcers and nodular/cobblestone mucosa while erythematous mucosa in UC patients. Chronic active colitiswas the most frequent histopathology findings. Key Word(s): 1. IBD; 2. Ulcerative Colitis; 3. Crohn’s Disease; 4.

7%-81%,1, 14, 17 whereas for extrahepatic cholangiocarcinomas, the reported rates of ErbB1 expression are varied between <10% and 86%.14, 17, 18 This wide range in values for ErbB2 or ErbB1 expressed in cohorts of archival specimens of human intrahepatic or extrahepatic cholangiocarcinomas reflects

in large part a lack of standardized methodologies, as well as to other factors critically reviewed in Sirica.1 We recently reassessed several separate immunohistochemical studies Protease Inhibitor Library high throughput published between 1998 and 2005 on ErbB2 expression in archival human intrahepatic cholangiocarcinoma specimens,1 selecting those in which antigen unmasking was performed by heating of the tissue specimens in citric acid buffer (pH 6.0) and taking into account only those tumors which were scored as moderately-to-strongly Ku-0059436 mouse positive (≥2+) for plasma membrane ErbB2 immunoreactivity. From the published results of these studies, we calculated a mean frequency value of 25% ± 6% (n = 6) for intrahepatic cholangiocarcinomas exhibiting ≥ 2+ ErbB2 immunostaining.

This value is within the range of our previously published immunohistochemical findings,8 and is in line with those of more recently published studies in which the proportions of biliary tract cancers (intrahepatic, extrahepatic, and/or combined intrahepatic and extrahepatic) exhibiting moderate to strong positivity for ErbB2 immunoreactivity ranged between ∼20% and 33%.15, 17 In contrast, other recent immunohistochemical studies have yielded 2+ to 3+ ErbB2-positive immunostaining, ranging from 0.9%-4% of analyzed cases of human intrahepatic biliary tract cancers.16, 18 Reported incidences of c-erbB2 gene amplification in archival human cholangiocarcinoma specimens have also varied widely ranging from 0%-100%,1 but more recently ranged from 5%-20%, being higher in extrahepatic cholangiocarcinomas.15, 17 Our results shown in Supporting Table 2 indicate, as also reported by others15, 17 that c-erbB2 gene amplification

is relatively uncommon in human intrahepatic cholangiocarcinomas. However, as we have also now shown, cancerous epithelium of human intrahepatic Farnesyltransferase cholangiocarcinomas with high micro-optical density values for ErbB2 immunohistochemical staining intensity, can also exhibit strong immunoreactivity for phospho-ErbB2Tyr1248, regardless of whether they scored positive or negative for c-erbB2 amplification, and that constitutive phosphorylation of ErbB2 at Tyr1248, as detected by western blotting, in cultured rat (C611B) and human (HuCCT1 and TFK1) cholangiocarcinoma cell lines also occurred in the absence of c-erbB2 gene amplification. These data support the view that for most ErbB2-positive cholangiocarcinomas, ErbB2 protein overexpression when detected is more likely due to gene deregulation rather than to gene amplification.

7%-81%,1, 14, 17 whereas for extrahepatic cholangiocarcinomas, the reported rates of ErbB1 expression are varied between <10% and 86%.14, 17, 18 This wide range in values for ErbB2 or ErbB1 expressed in cohorts of archival specimens of human intrahepatic or extrahepatic cholangiocarcinomas reflects

in large part a lack of standardized methodologies, as well as to other factors critically reviewed in Sirica.1 We recently reassessed several separate immunohistochemical studies click here published between 1998 and 2005 on ErbB2 expression in archival human intrahepatic cholangiocarcinoma specimens,1 selecting those in which antigen unmasking was performed by heating of the tissue specimens in citric acid buffer (pH 6.0) and taking into account only those tumors which were scored as moderately-to-strongly KU-60019 positive (≥2+) for plasma membrane ErbB2 immunoreactivity. From the published results of these studies, we calculated a mean frequency value of 25% ± 6% (n = 6) for intrahepatic cholangiocarcinomas exhibiting ≥ 2+ ErbB2 immunostaining.

This value is within the range of our previously published immunohistochemical findings,8 and is in line with those of more recently published studies in which the proportions of biliary tract cancers (intrahepatic, extrahepatic, and/or combined intrahepatic and extrahepatic) exhibiting moderate to strong positivity for ErbB2 immunoreactivity ranged between ∼20% and 33%.15, 17 In contrast, other recent immunohistochemical studies have yielded 2+ to 3+ ErbB2-positive immunostaining, ranging from 0.9%-4% of analyzed cases of human intrahepatic biliary tract cancers.16, 18 Reported incidences of c-erbB2 gene amplification in archival human cholangiocarcinoma specimens have also varied widely ranging from 0%-100%,1 but more recently ranged from 5%-20%, being higher in extrahepatic cholangiocarcinomas.15, 17 Our results shown in Supporting Table 2 indicate, as also reported by others15, 17 that c-erbB2 gene amplification

is relatively uncommon in human intrahepatic cholangiocarcinomas. However, as we have also now shown, cancerous epithelium of human intrahepatic AMP deaminase cholangiocarcinomas with high micro-optical density values for ErbB2 immunohistochemical staining intensity, can also exhibit strong immunoreactivity for phospho-ErbB2Tyr1248, regardless of whether they scored positive or negative for c-erbB2 amplification, and that constitutive phosphorylation of ErbB2 at Tyr1248, as detected by western blotting, in cultured rat (C611B) and human (HuCCT1 and TFK1) cholangiocarcinoma cell lines also occurred in the absence of c-erbB2 gene amplification. These data support the view that for most ErbB2-positive cholangiocarcinomas, ErbB2 protein overexpression when detected is more likely due to gene deregulation rather than to gene amplification.

Because we did not know whether they were on the same chromosome, we cloned a promoter with these two mutations. The promoter activity was even lower when these two mutations were on the same haplotype. The mutations in the 5′ UTR were analyzed using the promoter analysis tool21 with International Union for Pure and Applied Chemistry consensus

strings of the transcription factor binding site. The −215AT and −133AC mutations abolished BTK inhibitor the activator protein 1 (AP1) and specificity protein 1 (SP1) transcription factor binding sites, respectively.21 These mutations may interfere with normal regulation of the ATP7B gene, leading to WD. Alternative splicing is important in medicine because it is the major source of proteome diversity. Selleck CCI-779 Alternatively spliced protein isoforms may have indistinguishable, related, diverse, or antagonistic functions.22, 23 The ATP7B gene exhibits a tissue-specific splicing pattern.9 Most ATP7B transcripts in the liver have all the exons found in the genomic DNA, whereas splice variants in the brain have several combinations of skipped exons. Skipping exons 6, 7, 8, 12, and 13 maintains the open reading frame

of the gene; however, the function of alternatively spliced variants of ATP7B is unknown. We have demonstrated that alternatively spliced variants of exon 12 retained 80% of wild-type function, which likely explained the mild symptoms observed in the patient with the 2810delT mutation. In mammalian cells, exons constitute only a small part of pre-mRNA transcripts. Accurate splicing requires correct NADPH-cytochrome-c2 reductase recognition

of shorter exonic sequences from longer intronic sequences by spliceosomal components that bind an array of intronic and exonic splicing sequence elements. These elements can either enhance (exonic splicing enhancers) or repress (exonic splicing silencers) splicing at a nearby splice site.24, 25 A higher density of exonic splicing enhancers in authentic exons than in pseudoexons may differentiate recognition of the correct exons, whereas the presence of exonic splicing silencers in pseudoexons may suppress their splicing.26, 27 Thus, both these types of elements may contribute to the specificity of pre-mRNA splicing. A web-based splicing regulatory element recognition program28 predicted that the 2810delT mutation increases the number of putative exonic splicing enhancer sites from 1 (TGGTGG) to 4 (GTTGGG, TTGGGG, TGGGGT, and GGGGTA), which may explain the increase in alternatively spliced variants of exon 12 and, consequently, the reduction in disease symptoms.28 Splice-correction therapy modifies or corrects RNA splicing. Most methods that have been reported use antisense oligonucleotide-based compounds that target key elements in pre-mRNA to control splicing in the nucleus.29, 30 For example, this method has been used to correct the alternative splicing of SMN2 pre-mRNA to compensate for a defective SMN1 gene has been used to reduce the severity of spinal muscular atrophy.

35 Bcl-2 was the first gene identified as a regulator of apoptosis,36 and subsequently, several bcl-2 homologues were discovered that act as either proapoptotic or antiapoptotic effectors. The present data are in agreement with previous BI 2536 cost observations demonstrating that the overexpression of bcl-2, mcl-1, and bcl-xL37, 38 prevents cells from undergoing apoptosis,

whereas bax, apaf-1, caspase-6, and p53 function to promote cell death.39 Ca buffering also shifted the Bax/Bcl-2 ratio toward the antiapoptotic profile, and this resulted in the accelerated restoration of liver mass after PH. This agrees with recent proteomic data showing that apoptosis pathways are inhibited during liver regeneration.40 Additionally, hepatocyte growth factor, an essential stimulus for liver regeneration, is known to have antiapoptotic activity in injured tissue.41 Similarly, TNF, another initiator of liver regeneration, also

modulates apoptosis in addition to stimulating hepatocyte proliferation.42 Although our results suggest that Ca buffering accelerates liver regeneration by inhibiting apoptosis, an effect on cell proliferation cannot be entirely excluded because Bax/Bcl-2 family proteins regulate liver regeneration independently of their role in modulating apoptosis in the liver.43, 44 Moreover, Ca buffering GS 1101 might also accelerate liver regeneration by modulating ATP production in the mitochondrial matrix because the activity of enzymes of the tricarboxylic acid cycle is regulated by Ca2+.13 Heterologous expression of the Ca2+ binding protein PV has been widely used to study the role of Ca2+ Clomifene signaling in the regulation of the cell cycle. PV was targeted to the nucleus or cytoplasm, and with this approach, the role of nuclear Ca2+ in regulating the cell cycle was established in a liver cell

line.9 More recently, PV expression in the cytosol of hepatocytes in vivo demonstrated that cytosolic Ca2+ affects progression through the cell cycle after PH.32 Using PV targeted to the mitochondria, we have now shown that Ca also regulates liver regeneration. Future advances in this field should lead to a better understanding of the ways in which these various Ca2+ compartments act in an integrated manner to regulate liver regeneration. The authors thank Gilson Nogueira for his technical support and Soraya Smaili for antibodies against Bax and Bcl-2 and useful discussions. The authors also thank Dawidson A. Gomes for assistance in the design of the parvalbumin construct. Confocal imaging was supported by CEMEL (Centro de Microscopia Eletrônica, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil). Additional Supporting Information may be found in the online version of this article. “
“Purpose: Allograft hepatitis C is accelerated following liver transplantation (LT). Factors associated with disease progression include viral, demographic, and genetic characteristics of recipients and donors.

The treatment with this formulation was proved effective overall in the three treatment modalities considered, and the majority of patients including patients with type 3 VWD achieved haemostatic responses rated as ‘good’ to ‘excellent’, with no significant differences between disease subtypes. These results confirmed those of a preplanned ad interim analysis of the study

[12]. The new formulation was therefore at least as effective as the previous one, also associated with clinical responses rated excellent/good in the majority of patients [9, 13-17]. Our efficacy findings were also in line with those of recently published studies with other commercially available VWF/FVIII ubiquitin-Proteasome degradation concentrates [18-20]. During the 24-month follow-up period, there was an increase in the number of patients receiving Haemate® P VR for long-term prophylaxis (n = 31) compared with those

on prophylaxis at baseline (n = 16). The role of prophylaxis with VWF/FVIII concentrates in VWD is still a matter of debate. So far, few studies Vadimezan molecular weight have evaluated the use of secondary prophylaxis in VWD. [21-27]. In the study by Berntorp et al. [23] in 35 patients with VWD, mostly with type 3 VWD, prophylaxis was associated with a substantial decrease in the annual number of bleeding events [23, 24]. Also, patients who started prophylaxis at a young age had no joint bleeds and no clinical signs of arthropathy. Similar results were obtained in a recently published cohort study in 32 patients with a median prophylaxis duration of 3 years leading to the resolution of recurrent bleeding in 31 of the 32 patients [21]. Our results show that prophylactic treatment with Haemate® P VR, both for short-term and long-term bleeding prevention, was effective across all disease subtypes. To our knowledge, the treatment of VWD has not been evaluated in pharmacoeconomic analysis

so far. This type of analysis is strongly needed and is likely to contribute also to establishing the role of long-term prophylaxis in the treatment of VWD. We thus collected data describing the impact check details of VWD on a set of pharmacoeconomic variables. During the 24-month follow-up almost half of the patients lost days of school or work and about one-third was hospitalized because of the disease, whereas another third underwent invasive procedures made necessary by the condition. As no previous studies have addressed this aspect it is difficult to make any comparison. However, these figures are in keeping with the presence of significant bleeding histories and morbidity, as shown by the high average BS observed at enrolment. Haemate® P VR was well-tolerated and the switch to this new formulation was not associated with any serious or unexpected adverse event, including thromboembolic events or inhibitor development, in agreement with previous findings [12].

Conclusion: Our study uncovers key roles for IL-17 and TNF-α as mediators of liver inflammation and activation of hepatic stellate cells in

NLRP3 inflammasome activated myeloid cells. These findings may lead to novel therapeutic strategies aimed at halting the progression of liver injury and fibrogenesis. Protease Inhibitor Library Disclosures: The following people have nothing to disclose: Alexander Wree, Matthew D. McGeough, Maria E. Inzaugarat, Carla A. Pena, Alejandra Chernavsky, Hal M. Hoffman, Ariel E. Feldstein Liver ischemia and reperfusion (I/R) injury can be a detrimental consequence encountered during major liver resection, transplant, massive trauma and hypovolemic shock. The initiation of liver sterile inflammation results in the release of damage associated molecular patterns (DAMPs) such as HMGB1 and histones, in addition to the rapid recruitment of neutrophils to the site of injury. Neutrophil infiltration and accumulation in the ischemic liver lobe after reperfusion contributes to the damage observed during liver I/R injury.

Upon activation, neutrophils have been shown to release fibers composed of chromatin and protein to form neutrophil extracellular p38 MAPK pathway traps (NETs). Whether NETs participate in liver I/R and the subsequent consequences remain unknown. Therefore, the purpose of our work is to elucidate whether NETs are formed during liver I/R and their role. In vitro, treatment of neutrophils isolated from the femur of mice with media from hypoxic hepatocytes, HMGB1 or histones resulted in significant NET formation by immunofluorescence. This was inhibited by adding peptidylarginine deiminases (PAD) 4 (a nucleoprotein that mediates NET formation by citrullinating histones) inhibitor or DNase1 to either inhibit or disrupt NET formation, Farnesyltransferase respectively. In vivo, mice were subjected to a non-lethal partial (70%) warm liver I/R model. We found abundant NET formation in ischemic liver lobes after I/R as evidenced by confocal immunofluorescence, increased

citrullinated histone in the liver tissue, and increased levels of serum free DNA and nucleosomes. Treatment with either PAD4 inhibitor or DNAse conferred significant protection compared to controls after liver I/R evidenced by decreased AST and ALT levels, significantly less hepatic necrosis by histology, and decreased levels of circulating inflammatory cytokines, free DNA, and nucleosomes. In summary, our study reveals that NETs are formed during liver I/R and subsequently increase the injury. Targeting NET formation may be a new therapeutic strategy to reduce ischemia-related liver damage. Disclosures: The following people have nothing to disclose: Samer Tohme, Hai Huang, Allan Tsung Expansion of the visceral adipose tissue (VAT) volume can lead to the hypoxic death of adipocytes.

Because productions of HBsAg and HBcrAg are regulated by different promoter and enhance systems of HBV genome, their clinical values vary. FOLLOW-UP AFTER DISCONTINUATION of NUC includes periodical measurement of HBV DNA levels (real-time PCR) and ALT levels. This study revealed that relapse after discontinuation occurs mostly within 1 year, gradually

decreases after 1 year and rarely occurs after the first 3 years of discontinuation.[6] Therefore, we determined it necessary to pay attention especially to relapse immediately after discontinuation. In particular, we determined that www.selleckchem.com/products/PF-2341066.html it is desirable to follow up patients by blood tests at every 2 weeks up to 16 weeks after discontinuation and every 4 weeks after 16 weeks. One of the important points is what the definition of hepatitis relapse is and how to follow up after discontinuation. Transient abnormalities in the

ALT level or the HBV DNA level may be observed in approximately two-thirds patients who would finally achieve the inactive carrier state. Therefore, even if the ALT or HBV DNA levels show mild elevations, it is possible to follow up without retreatment. However, no criteria have been identified about when to discontinue follow up and start retreatment. We assessed the transitions of ALT levels and HBV DNA levels after discontinuation of NUC by the mean and maximum values to identify the criteria. From this assessment, a strong correlation was shown between the mean and the maximum value in both (Fig. 5).[6] Results of the ROC analysis revealed that the mean ALT 3-deazaneplanocin A mouse of 30 IU/L corresponded to the maximum ALT of 79 IU/L and the mean HBV DNA of 4.0 log copies/mL corresponded to the maximum HBV DNA of 5.7 log copies/mL. Patients with ALT values of not less than 80 IU/L after discontinuation are highly likely to show a mean value of more than 30 IU/L and not assumed to finally meet the criteria

for successful discontinuation. Similarly, patients with HBV DNA value of not less than 5.8 log copies/mL after discontinuation are most likely to show a mean value of more than 4.0 log copies/mL and not assumed to meet the criteria for successful discontinuation. Based on these ID-8 results, we established the condition that patients with ALT value of not less than 80 IU/L or HBV DNA level of not less than 5.8 log copies/mL are less likely to finally achieve the inactive carrier state and should be considered for retreatment with NUC. It is considered that NUC can be discontinued more efficiently and specifically in this condition. Physicians can use more severe criteria at their own discretion in consideration of safety. Less strict criteria also can be used, but it is recommended that the treatment should be done under a certain policy and do not follow the treatment without any aims. THIS MAY BE the first guideline for discontinuation of NUC.

In general, three different agents/classes of agent are used—narcotics, benzodiazepines and propofol. In a recent survey of Australian anesthetists,45 propofol use was virtually universal for endoscopic sedation and a majority of respondents used both fentanyl and midazolam. Most of the anesthetists who were surveyed administered propofol sedation in private clinics and private hospitals, although there has been an increasing use of anesthetist-administered propofol in public hospitals. These findings were similar to those reported by Clarke et al.,46 also from Australia,

with each of these drugs being given by general practitioner sedationists in over 97% of cases. In Australia, fentanyl is the narcotic used most commonly,45,46 and there is also significant use of pethidine. A group from London has shown a shorter recovery period for patients undergoing endoscopy if fentanyl and midazolam are used compared with the use www.selleckchem.com/products/Trichostatin-A.html of pethidine and midazolam, and there was no difference in pain perception.47 Fentanyl is a synthetic opioid with a rapid onset and short duration of action. The half life is 2–7 h; this variation stems largely from differences in redistribution into adipose tissues and is independent of renal function. Fentanyl metabolites

are not active and true allergy to it is very rare. These properties make it suitable for use in procedures of short Metformin chemical structure duration. As with other opiates, it can lead to respiratory depression and hypotension. Hypovolemic patients and those

with reduced respiratory reserve are particularly at risk of developing these complications.48 In the elderly and frail and those with high ASA status, the dose of fentanyl should be reduced or opiate analgesia not used. Adult doses typically range from 25 µg to 100 µg (0.35–1.4 µg/kg). Naloxone, which Florfenicol competitively binds to µ-opioid receptors, is a reversal agent, the administration of which may be required to prevent or attenuate the above complications. Repeated administration may be necessary. Benzodiazepines are also used very frequently for endoscopy throughout the world. They have amnestic, sedative and anxiolytic properties in addition to their well-known anticonvulsant and muscle relaxant effects. These actions are thought to be mediated by attachment to gamma-amino butyric acid (GABA) receptors in the central nervous system. Its anxiolytic and muscle relaxant properties are not only mediated through GABA receptors but also through glycine receptors in the spinal cord.49,50 Respiratory depression, which is probably related to a direct effect on the respiratory centre in the brain stem, leading to hypoventilation is an important adverse effect. Cardiovascular compromise with diminished cardiac output and peripheral resistance leading to hypotension, usually does not occur unless administration occurs during deep sedation.