High Safety Margin Research Articles

소 가죽 유래 Type I Collagen 생산 공정에서 바이러스 불활화

세포치료제 또는 조직공학제제에 사용되는 동물 유래 콜라겐은 원료물질 유래 바이러스가 오염될 가능성이 있기 때문에 생산과정 중 바이러스가 오염되지 않도록 하여야 한다. 이를 위해 콜라겐 생산공정은 오염될 가능성이 있는 바이러스들을 불활화 하거나 제거하는 과정을 포함하여야 하며, 바이러스 불활화/제거 능력은 제품의 안전성을 보증하는 중요한 지표로 사용된다. 본 연구의 목적은 소 가죽을 원료로 하여 type I 콜라겐을 생산하는 공정에서 소 유래 바이러스들의 불활화/제거 효능을 평가하는 데 있다. 이를 위해 70% 에탄올 처리 공정과 펩신 처리 공정(pH 2)에서 바이러스 불활화 효과를 평가하였다. 바이러스 불활화 효과 평가를 위해 bovine herpes virus (BHV), bovine viral diarrhoea virus (BVDV), bovine parainfluenza 3 virus (BPIV-3), bovine parvovirus (BPV)를 모델 바이러스로 선정하였다. 바이러스 불활화를 위해 24시간 동안 70% 에탄올을 처리하는 공정에서 BHV, BVDV, BPIV-3, BPV 모두 처리 1시간 안에 검출 한계 이하로 불활화되었으며, 바이러스 로그 감소 값은 각각 <TEX>${\geq}5.58$</TEX>, <TEX>${\geq}5.32$</TEX>, <TEX>${\geq}5.11$</TEX>, <TEX>${\geq}3.42$</TEX>이었다. 또한 소 조직으로부터 콜라겐을 추출하기 위한 14일간의 펩신 처리 공정에서 BHV, BVDV, BPIV-3, BPV 모두 처리 5일 안에 검출한계 이하로 불활화되었으며, 바이러스 로그 감소 값은 각각 <TEX>${\geq}7.08$</TEX>, <TEX>${\geq}6.60$</TEX>, <TEX>${\geq}5.60$</TEX>, <TEX>${\geq}3.59$</TEX>이었다. 두 공정에서 BHV, BVDV, BPIV-3, BPV의 누적 바이러스 로그 감소 값은 각각 <TEX>${\geq}12.66$</TEX>, <TEX>${\geq}11.92$</TEX>, <TEX>${\geq}10.71$</TEX>, <TEX>${\geq}7.01$</TEX>이었다. 이상의 결과에 의하면, 소 가죽 유래 type I 콜라겐제조공정은 바이러스 안전성 보증을 위한 충분한 바이러스 불활화 능력을 가지고 있는 것으로 판단된다. Most types of collagen used for biomedical applications, such as cell therapy and tissue engineering, are derived from animal tissues. Therefore, special precautions must be taken during the production of these proteins in order to assure against the possibility of the products transmitting infectious diseases to the recipients. The ability to remove and/or inactivate known and potential viral contaminants during the manufacturing process is an ever-increasingly important parameter in assessing the safety of biomedical products. The purpose of this study was to evaluate the efficacies of the 70% ethanol treatment and pepsin treatment at pH 2.0 for the inactivation of bovine viruses during the manufacture of collagen type I from bovine hides. A variety of experimental model viruses for bovine viruses including bovine herpes virus (BHV), bovine viral diarrhea virus (BVDV), bovine parainfluenza 3 virus (BPIV-3), and bovine parvovirus (BPV), were chosen for the evaluation of viral inactivation efficacy. BHV, BVDV, BPIV-3, and BPV were effectively inactivated to undetectable levels within 1 h of 70% ethanol treatment for 24 h, with log reduction factors of <TEX>${\geq}5.58$</TEX>, <TEX>${\geq}5.32$</TEX>, <TEX>${\geq}5.11$</TEX>, and <TEX>${\geq}3.42$</TEX>, respectively. BHV, BVDV, BPIV-3, and BPV were also effectively inactivated to undetectable levels within 5 days of pepsin treatment for 14 days, with the log reduction factors of <TEX>${\geq}7.08$</TEX>, <TEX>${\geq}6.60$</TEX>, <TEX>${\geq}5.60$</TEX>, and <TEX>${\geq}3.59$</TEX>, respectively. The cumulative virus reduction factors of BHV, BVDV, BPIV-3, and BPV were <TEX>${\geq}12.66$</TEX>, <TEX>${\geq}11.92$</TEX>, <TEX>${\geq}10.71$</TEX>, and <TEX>${\geq}7.01$</TEX>. These results indicate that the production process for collagen type I from bovine hides has a sufficient virus-reducing capacity to achieve a high margin of virus safety.

Synthesis and biological evaluation of thieno [2′,3′:4,5]pyrimido[1,2-b][1,2,4]triazines and thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines as anti-inflammatory and analgesic agents

A new series of thieno[2′,3′:4,5]pyrimido[1,2-b][1,2,4]triazines and thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was synthesized. The newly synthesized compounds were evaluated for their anti-inflammatory and analgesic activity using diclofenac Na as a reference standard. Additionally, the ulcerogenic effects and acute toxicity (ALD50) values of the active compounds were also determined. In general, the thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine derivatives exhibited better biological activities than the thieno[2′,3′:4,5]pyrimido[1,2-b][1,2,4]triazines. Collectively, the thienotriazolopyrimidine derivatives 9, 13 and 14a were proved to display distinctive anti-inflammatory activity at the acute and subacute models as well as good analgesic profile with a delayed onset of action. Moreover, they revealed good gastrointestinal safety profile and are well tolerated by experimental animals with high safety margin (ALD50 > 0.3 g/kg).

Zum Risiko der Ausbreitung von E. coli/EHEC O104:H4 stx 2 positiven Bakterien über Kläranlagen während der EHEC - Epidemie 2011 in Norddeutschland

During an EHEC outbreak with E. coli O104:H4 stx2-pos in northern Germany 2 sewage treatment plants (Cuxhaven and Stade) of highly affected areas were monitored for the presence of the outbreak strain. 7 efflux water samples were collected at 1 h and 6 h intervals. The overall E. coli content of the treated sewage water was approximately 35 000 CFU/100 mL in both treatment plants. Among these about 500 were ESBL-E. coli (1.4%). ESBL-Agar was used as selective medium as the outbreak strain is highly resistant to 3rd generation cephalosporins. From the ESBL-isolates 208 strains have been typed by molecular methods for markers specific to the outbreak strain (O104rfb -351 base pairs (bp), flic H4-201 bp, stx2-584 bp, Tellur D - 434 bp). No outbreak strain was detected. The number of E. coli O104:H4 stx2-pos was calculated to be less than 3 per 100 mL in the treated sewage at the time of the study. Therefore it can be concluded that there was no threat for bathers to fall sick with this highly pathogenic strain from possibly sewage-contaminated bathing waters during the outbreak. The national limit value of 1 800 E. coli in 100 mL offers a high safety margin.

Toxicological Safety Evaluation of Gadobutrol

Gadobutrol (Gadovist/Gadavist, Bayer Pharma AG, Berlin, Germany) is a nonionic, macrocyclic, gadolinium-based contrast agent for magnetic resonance imaging of the central nervous system as well as liver and kidneys and for contrast enhancement in magnetic resonance angiography. For risk assessment of the single diagnostic use in humans, the toxicity of this compound was evaluated with a series of preclinical studies. Preclinical studies into acute, repeated-dose, reproductive, and developmental toxicity as well as genotoxicity, local tolerance, contact-sensitizing potential, and antigenicity were performed. In rodents, lethality was observed after a single intravenous administration of 20 mmol/kg, representing doses at least 2 orders of magnitude higher than the standard single diagnostic dose in humans (0.1 mmol/kg). The no observed adverse effect levels after repeated (daily) administrations over the course of 4 weeks exceeded the single diagnostic dose in humans by a factor of 12 in rats and 10 in dogs (calculated on the basis of body weight), and no unexpected organ toxicity was observed. The most salient finding of repeated dosing in both rats and dogs was vacuolization of renal tubular epithelium without concomitant effect on kidney function, which represents a well-known finding for this class of compounds. Gadobutrol was not teratogenic in rats, rabbits, and monkeys even when given repeatedly during organogenesis at maximum dose levels tested, being 25 to 100 times (based on body weight) above the diagnostic dose in humans. No indications of potential genotoxic, contact allergenic, or immunotoxic effects were observed. In local tolerance testing, gadobutrol was well tolerated after intravenous administration. Gadobutrol was well tolerated with high safety margins between the single diagnostic dose of 0.1 mmol/kg in humans and the doses showing effects in animal studies.

Effect of Fatigue on Grip Force Control During Object Manipulation in Carpal Tunnel Syndrome

Eight subjects with carpal tunnel syndrome (CTS) (47.13 ± 7.83 years) and 8 matched controls (46.29 ± 7.27 years) manipulated a test object fitted with an accelerometer and force sensor, both before and after hand muscle fatigue. Grip force and object acceleration were recorded and used to calculate grip force control variables that included Grip Force Peak, Safety Margin, and Time to Grip Force Peak. Individuals with CTS exhibited a higher Safety Margin (p = .010) and longer Time to Peak of Grip Force (p = .012) than healthy controls during object manipulation. Once fatigued, both groups significantly decreased their grip force to perform the task (Grip Force Peak; p = .017 and Safety Margin; p < .001). Nevertheless, individuals with CTS maintained an unnecessarily high safety margin. Our results suggest that CTS can adversely affect how the central nervous system regulates grip force, which might aggravate the inflammatory process and exacerbate the symptoms of this disease.

Design and synthesis of novel 1,4-benzodiazepine derivatives and their biological evaluation as cholinesterase inhibitors

A new series of 1,4-benzodiazepine-2,5-dione structurally related to cyclopenin has been synthesized. The new compounds were assayed in vivo and in vitro for their ability to inhibit acetylcholinesterase enzyme and were found to have potent reversible anticholinesterase activity when tested in vitro for isolated frog rectus abdominis and guinea pig ileum in addition to increasing brain cholinesterase level in rats when percentage inhibition were tested in vivo, moreover compounds 5a, 5b, 5c and 5g were the most active. LD(50) was performed for these derivatives and they displayed high safety margin.

Low Cycle Fatigue Behavior and Seismic Assessment for Elbow Pipe Having Local Wall Thinning

One of the concerned technical issues in the nuclear piping under operation is pipe wall thinning caused by flow accelerated corrosion. Recently, it has been reported that the elbow section is more suspicious on pipe wall thinning by erosion–corrosion. Some researchers including authors have been studied static and fatigue strength of elbows with local wall thinning. However, still more experiment and analysis data are needed to clarify the technical issues. Accordingly, further experiments and their evaluations were carried out by the authors. This paper presents the influences of size and location on fatigue life. Also as one of the application of the test results, safety margin of elbows with wall thinning against seismic loading is discussed. Low cycle fatigue tests were conducted using elbow specimens made of STPT410 steel with local wall thinning. The local wall thinning was machined on the inside of elbow specimens in order to simulate erosion/corrosion metal loss. The local wall thinning areas were located at three different areas, called extrados, crown, and intrados. Eroded ratio (eroded depth/wall thickness) is 0.5 and 0.8 and eroded angle is 90 deg and 180 deg. The elbow specimens were subjected to cyclic in-plane bending under displacement control (±20 mm) without and with internal pressure of 3 MPa using a universal testing machine. Fatigue life was defined as fatigue crack penetration through the thickness and crack penetration was watched by naked eyes during the test through the protection window made of a transparent plastic plate. Obtained main conclusions are as follows: (1) Existence of local wall thinning in extrados does not have an important effect on fatigue life. Especially, fatigue crack does not initiate at the extrados where the extreme local wall thinning exists (eroded ratio = 0.8 and eroded angle = 180 deg). (2) Regardless of existence of internal pressure, fatigue crack initiates at the crown where local wall thinning does not exist for an elbow with local wall thinning at extrados. This conclusion should be confirmed using eroded elbow specimens under more high pressure. (3) Even if the eroded ratio and the eroded angle reached up to 0.8 and 180 deg, the elbows with local wall thinning have high safety margin against seismic loading, comparing to ASME Boiler and Pressure Vessel Code Section 3 allowable seismic stress criteria.

Re-assessment of resistance of cast iron pipes subjected to vertical loads and internal pressure

Longitudinal fracture is one predominant observed failure mode in large diameter cast iron pipes installed between 1850 and early 1960s. Some of these failures occur where there is evidence of some corrosion activity. This paper addresses three specific issues, namely, (1) review of expected loads, i.e., internal pressure, earth loads, traffic loads, (2) estimated pipe failure load (pipe resistance), and (3) estimated structural factor of safety. The second and third issues can be equally applicable to non-deteriorated and deteriorated pipes. The procedures described in this paper were motivated by the need to purposefully use the information derived from pipe inspection to assess the margin of safety of deteriorated large diameter cast iron pipes. A mechanistic model that accounts for cast iron material non-linearity is described. The model is validated using data obtained from experimental tests conducted in the mid 1930s on undamaged (new) pipes. The model is subsequently extended to permit the analysis of pipes with corrosion pits or corroded areas. Reliability analysis using Monte Carlo simulations is proposed to account for uncertainties in input data. Illustrative analyses of 16″ and 48″ diameter pipes subjected to vertical loads and internal pressure showed that significantly high margins of safety exist in cast iron pipes with no damage (due to corrosion and or casting voids) while this margin of safety is meaningfully reduced in the presence of corrosion pits or corroded areas. The methodology described should enable engineers to realistically assess the pipe resistance capacity and hence the corresponding margin of safety of undamaged or damaged cast iron pipes encountered in current operational conditions.

Tratamiento combinado con fenofibrato. Seguridad

In atherogenic dyslipidemia uncontrolled by statin monotherapy, the association of fenofibrate has been shown to be safe and effective in achieving overall lipid profile control. This combination has a high safety margin when appropriately used and particularly if avoided in patients with renal or liver failure and those under treatment with a third drug that could interact with fibrates or statins. In patients with atherogenic dyslipidemia and contraindications to statins, the association of fenofibrate and ezetimibe or resins is also safe, although the former combination has not yet been approved for clinical use, despite a considerable number of clinical trials. Resins can increase triglyceride concentrations and, consequently, should only be used in patients with normal triglyceride levels. In patients with hypertriglyceridemia uncontrolled with monotherapy, the combination of fenofibrate and omega-3 fatty acids is effective and has a high safety margin, even in polymedicated patients, such as those with HIV infection. The combination of fenofibrate and nicotinic acid-laropiprant is well tolerated by most patients and has a high safety margin.

1042 ABTL0812, a Dual Inhibitor of mTOR and Dihydrofolate Reductase With High Oral Efficacy and Safety Margin in Human Lung and Pancreatic Cancer Xenograft in Mice

1042 ABTL0812, a Dual Inhibitor of mTOR and Dihydrofolate Reductase With High Oral Efficacy and Safety Margin in Human Lung and Pancreatic Cancer Xenograft in Mice

Peracetic acid is effective for controlling fungus on channel catfish eggs

Peracetic acid (PAA) is a relatively new compound suggested for use to treat pathogens in aquaculture. It is approved for use in Europe, but not in the United States. This study determined the effectiveness of PAA for fungus control on channel catfish, Ictalurus punctatus (Rafinesque), eggs. The study consisted of five PAA concentrations (2.5, 5, 10, 15 and 20mgL(-1) ) and an untreated control in a flow-through system. A single spawn was used for each replication (N =4). Eggs were treated twice daily until the embryos developed eyes. When hatching was complete for all viable eggs, fry were counted to determine the percent survival in each treatment. Fungal growth was severe in the untreated controls resulting in 11% survival. Treatments of 2.5, 5 and 10mgL(-1) PAA were significantly different from the controls (P<0.05). The highest percent survival of hatched fry was with 5mgL(-1) PAA administered twice daily; the 2.5mgL(-1) PAA treatment had slightly less survival, but gives a higher margin of safety in case of treatment error. Very little fungus was present in treatments receiving 2.5mgL(-1) PAA or higher, and concentrations of 15 and 20mgL(-1) PAA were toxic to the eggs. The mean survivals in the 0, 2.5, 5, 10, 15 and 20mgL(-1) PAA treatments were 11%, 60%, 63%, 62%, 32% and 0%, respectively. Therefore, PAA may be a compound that merits further investigations regarding its use in U.S. aquaculture.

Virus reduction in an intravenous immunoglobulin by solvent/detergent treatment, ion-exchange chromatography and terminal low pH incubation

Virus reduction by several steps in the manufacturing process for the intravenous immunoglobulin Vigam®, has been investigated. The solvent/detergent step based on treatment with 0.3% tri-n-butyl phosphate and 1% polysorbate 80 at 37 °C, was confirmed to be effective for a range of enveloped viruses. Virus infectivity was undetectable i.e. >6 log inactivation within 30 min of the standard 6 h process. This was consistent over the range of conditions tested i.e. solvent/detergent and protein concentration, temperature and pH. The ion-exchange chromatography step in the process was also able to remove some viruses. Virus spiked followed by blank column runs confirmed the effectiveness of the sanitisation step for ensuring there was no virus cross contamination between column runs. The terminal low pH incubation step was also able to inactivate enveloped viruses, as well as some non-enveloped viruses. The combination of these three steps ensures a high margin of virus safety for this product.

Chinese Herbal Therapy for the Treatment of Food Allergy

Traditional Chinese medicine (TCM) has been widely used in China to treat various diseases for thousands of years. Given its reputed effectiveness, low cost, and favorable safety profile, TCM is attracting great interest in Western societies as a source of therapy for an array of illnesses, including allergies and asthma. Although food allergy has not been described in the TCM literature, a novel treatment for food allergy, named the food allergy herbal formula-2 (FAHF-2), was developed using TCM principles. Using a well-characterized murine model of peanut allergy, FAHF-2 has been shown to be highly effective in providing long-term protection against peanut-induced anaphylaxis, with a high safety margin. Phase 1 human trials have demonstrated the safety of FAHF-2 in food allergic individuals. Currently, a phase 2 trial examining efficacy of FAHF-2 is on-going. Other TCMs also show a potential for treating food allergies in preclinical studies.

Safety evaluation of MJ33 as a potential in vivo inhibitor of NADPH oxidase (NOX2) activation

Inhibition of NOX2 has been proposed for the treatment of acute lung injury (ALI) by preventing the generation of reactive O2 species (ROS). MJ33, a fluorinated phospholipid analogue, functions as a potential ALI therapeutic agent by inhibiting the phospholipase A2 (PLA2) activity that is required for NOX2 activation (J. Biol. Chem., 286:11696, 2011). Long‐term toxicity studies were performed to evaluate the feasibility for this use of MJ33. MJ33 incorporated into mixed unilamellar liposomes was injected either intra‐tracheally (IT) or intravenously (IV) in single or multiple doses, up to 25μmol for a 20g mouse. Mice treated with MJ33 up to 10μmol did not show any obvious changes in clinical score, general appearance, activity level, hair quality, body temperature or feces. At 5μmol by IT or IV route, weight loss was &lt;10% and mice recovered with a subsequent small weight gain. Hematocrit and lung wet to dry weight ratio were not altered by MJ33. Weight loss was greater with 10μmol (in multiple doses: 4× 2.5μmol) but was not progressive. Thus, the maximal tolerated dose (defined as causing &gt;15% reduction in body weight) was 0.42μmol/g body wt (~2000 times higher than the dose shown to inhibit PLA2 activity). LD50 was 1.3μmol/g body wt. These results indicate a high margin of safety for administration of MJ33 in the intact mouse.Supported by NHLBI R01 HL075587

BIOPHYSICS, BIOENERGETICS AND MECHANISTIC APPROACHES TO ECOLOGY

Biophysics – the study of how the structure of individual plants and animals contributes to their function – has rarely been considered on the ecological scale. However, Mark Denny from Stanford University, USA, has a broader vision. Because the mechanisms that underpin individual performance

Treatment of demodicosis in dogs: 2011 clinical practice guidelines

These guidelines were written by an international group of specialists with the aim to provide veterinarians with current recommendations for the diagnosis and treatment of canine demodicosis. Published studies of the various treatment options were reviewed and summarized. Where evidence in form of published studies was not available, expert consensus formed the base of the recommendations. Demodicosis can usually be diagnosed by deep skin scrapings or trichograms; in rare cases a skin biopsy may be needed for diagnosis. Immune suppression due to endoparasitism or malnutrition in young dogs and endocrine diseases, neoplasia and chemotherapy in older dogs are considered predisposing factors and should be diagnosed and treated to optimize the therapeutic outcome. Dogs with disease severity requiring parasiticidal therapy should not be bred. Secondary bacterial skin infections frequently complicate the disease and require topical and/or systemic antimicrobial therapy. There is good evidence for the efficacy of weekly amitraz rinses and daily oral macrocyclic lactones such as milbemycin oxime, ivermectin and moxidectin for the treatment of canine demodicosis. Weekly application of topical moxidectin can be useful in dogs with milder forms of the disease. There is some evidence for the efficacy of weekly or twice weekly subcutaneous or oral doramectin. Systemic macrocyclic lactones may cause neurological adverse effects in sensitive dogs, thus a gradual increase to the final therapeutic dose may be prudent (particularly in herding breeds). Treatment should be monitored with monthly skin scrapings and extended beyond clinical and microscopic cure to minimize recurrences.

Spontaneous CSF Rhinorrhea Our Experience

To analyse the possible factors contributing to spontaneous cerebrospinal fluid (CSF) rhinorrhea and to assess the outcome of Transnasal endoscopic repair at our centre. Retrospective case series of patients with spontaneous CSF rhinorrhea at our institution from Jan 2006 to May 2010. 7 patients were diagnosed with spontaneous CSF rhinorrhea. 5 of the 7 patients were obese, middle aged females managed with Transnasal endoscopic repair with fascia lata auto graft. Successful repair of CSF rhinorrhea was achieved in all the patients with a single endoscopic procedure; no patient required a revision procedure. Spontaneous CSF rhinorrhea is a rare condition seen mostly in middle aged obese females with the anterior part of the cribriform plate being the most common site of leak. HRCT paranasal sinus (1mm cuts) was an effective modality of investigation in our study with ancillary investigations been CT Cisternography, CSF analysis and MRI for inactive leaks. In the absence of a large breech of the skull base, endoscopic repair of CSF rhinorrhea carries a high success rate with a high safety margin and very low morbidity rate.

Age effects on rotational hand action

We investigated age-related differences in finger coordination during rotational hand actions. Two hypotheses based on earlier studies were tested: higher safety margins and lower synergy indices were expected in the elderly. Young and elderly subjects held a handle instrumented with five six-component force sensors and performed discrete accurate pronation and supination movements. The weight of the system was counterbalanced with another load. Indices of synergies stabilizing salient performance variables, such as total normal force, total tangential force, moments produced by these forces, and total moment of force were computed at two levels of a hypothetical control hierarchy, at the virtual finger-thumb level and at the individual finger level. At each level, synergy indices reflected the normalized difference between the sum of the variances of elemental variables and variance of their combined output, both computed at comparable phases over repetitive trials. The elderly group performed the task slower and showed lower safety margins for the thumb during the rotation phase. Overall, the synergy indices were not lower in the elderly group. In several cases, these indices were significantly higher in the elderly than in the younger participants. Hence, both main hypotheses have been falsified. We interpret the unexpectedly low safety margins in the elderly as resulting from several factors such as increased force variability, impaired feed-forward control, and the fact that there was no danger of dropping the object. Our results suggest that in some natural tasks, such as the one used in this study, healthy elderly persons show no impairment, as compared to younger persons, in their ability to organize digits into synergies stabilizing salient performance variables.

P-1110 - Aripiprazole add on therapy with ssri for depression: an alert for probable drug-drug adverse interaction

Although akathisia is not uncommon in patients receiving aripiprazole, other extrapyramidal side effects of this drug were equivalent to placebo in controlled trials. Induction of adverse extrapyramidal reaction by aripiprazole within the therapeutic dose range was first reported in 2006. That report, describing a patient aged 56 years with no relevant medical comorbidities who developed extrapyramidal side effects 5 weeks after initiating aripiprazole, emphasized the importance of slowly escalating the dose. Two other reports of extrapyramidal manifestations in childrenwith high dosage of aripiprazole have suggested the possibility of dose-dependent induction of extrapyramidal side effects. Although aripiprazole is known to have high affinity to D2 receptors in the striatum, this effect is partially agonistic, and clearly differs from the purely antagonistic effects of other conventional or atypical antipsychotics. This may account for its high margin of safety with regard to extrapyramidal side effects (other than akathisia) which have been comparable to placebo. The occurrence of extrapyramidal side effects of aripiprazole in the case reported here is likely attributable to multiple drug interaction. This may be explained by hepatic cytochrome P450-dependent metabolism of aripiprazole, in particular the enzyme subtypes 2D6 and 3A4, both of which have been shown to be inhibited by sertraline. Sertraline-inhibited metabolism of aripiprazole would cause serum aripiprazole levels to become elevated, resulting in greater occupancy of striatal D2 receptors and producing the observed extrapyramidal side effects.

Clinical Implications of the Transversus Abdominis Plane Block in Adults

The transversus abdominis plane (TAP) block is a relatively new regional anesthesia technique that provides analgesia to the parietal peritoneum as well as the skin and muscles of the anterior abdominal wall. It has a high margin of safety and is technically simple to perform, especially under ultrasound guidance. A growing body of evidence supports the use of TAP blocks for a variety of abdominal procedures, yet, widespread adoption of this therapeutic adjunct has been slow. In part, this may be related to the limited sources for anesthesiologists to develop an appreciation for its sound anatomical basis and the versatility of its clinical application. As such, we provide a brief historical perspective on the TAP block, describe relevant anatomy, review current techniques, discuss pharmacologic considerations, and summarize the existing literature regarding its clinical utility with an emphasis on recently published studies that have not been included in other systematic reviews or meta-analyses.