By J. Goran. Southwestern Oklahoma State University.

Transverse Abdominal Plexus Block | 43 The TAPB is also indicated for patients unsuitable for epidural analgesia (Niraj 2011) discount indocin 75mg. Iliohypogastric and Ilioinguinal Nerve Block Giovanni Vitale Blind Iliohypogastric and Ilioinguinal Nerve Block The block of iliohypogastric and ilioinguinal nerves (IIB) is performed by anesthesiologists and can be achieved blindly or under ultrasound visualization trusted indocin 25 mg. Aseptic technique and patient security procedures should be strictly observed. Before performing a block on an awake patient, sedation with a benzodiazepine or an opioid together with oxygen may be administered. Blocks can also be administered after general anesthesia induction; in this case the patient will not be able to communicate. Various injection landmarks have been suggested such as 1. Iliohypogastric and Ilioinguinal Nerve Block | 45 4. Single or multiple injections may be done and different puncture sites provide similar effectiveness (Lim 2002). The fascia between the EOM and the IOM offers a first resistance to the needle felt as a “pop” or “ting” or “ping”, whereas the fascia between the IOM and the TAM provides a second resistance. After the second resistance has been felt, the local anesthetic may be injected. A useful tip is to hold a skin fold between the thumb and index of one hand and puncture the skin to reach the subcutaneous tissue. Another way is to use a sharp introducer to puncture the skin. However, anatomic and ultrasound control studies on the classical landmarks show that only two muscle layers instead of three may be identified in 50% of the patients. This occurs because the EOM is limited to an aponeurosis in the medial area adjacent to the ASIS (Willschke 2005). There is also a high potential for complications such as peritoneal or visceral puncture (Weintraud 2008, van Schoor 2005). The reported failure rate remains high and variable, 6 to 43%, even in 4. Iliohypogastric and Ilioinguinal Nerve Block | 47 experienced hands or when multiple punctures are performed because of the high anatomical and landmark variability (Randhawa 2010). The failure rate may be as high as 6 to 40% especially in infants and children, even when the nerve is exposed at surgery (Weintraud 2008, Lim 2002). Correct administration of local anesthetic around the target nerves occurred in only 14% and 57% of cases in two studies when using a landmark method with a fascial click (Weintraud 2008, Randhawa 2010). The remainder of the injections were deposited in adjacent anatomical structures (iliac muscle 18%, TAM 26%, IOM 29%, EOM 9%, subcutaneous tissue 2%, and peritoneum 2%) (Weintraud 2008). Adults Absolute abdominal muscle size at the IIN to bone distance mid-axillary line at the ASIS Males 3. There is a weak correlation between weight and the depth of the IIN (Willschke 2005). These findings emphasize the usefulness of ultrasounds for this block technique and the fact that needle tip visualization is mandatory (Weintraud 2008). The ultrasound approach increases the safety of this block because the nerves, the surrounding anatomical structures and the needle are visualized. The site of injection is under direct control and the volume of the local anesthetic can be individualized so that it surrounds the nerve structures (Willschke 2006). Preoperative block administration is recommended as tissue visualization with ultrasounds may be impaired after surgery and tissue manipulation. Moreover, late persistence of elevated local anesthetic levels in the plasma after abdominal blocks have been shown. On long axis scans, the nerves have a fascicular pattern made of multiple hypo-echoic parallel and linear areas separated by hyper-echoic bands. The hypo-echoic structures correspond to the neuronal fascicles that run longitudinally within the nerve, and the hyper-echoic background relates to the inter-fascicular epineurium (Martinoli 2002). On short axis scans, nerves assume a honeycomb-like appearance with hypo-echoic rounded areas embedded in a hyper-echoic background (Martinoli 2002). Color Doppler can help differentiating the hypo-echoic nerve fascicles from adjacent hypo-echoic small vessels (Martinoli 2002). However the IIN and the IHN are small nerves that can generally be seen only as oval hypo-echoic structures embedded in a hyper-echoic border (Figure 4. The IHN and IIN visualization with ultrasounds may be possible in 100% of cases in children between 1 month and 8 years of age and in 95% of cases in adults (Hong 2010, Willschke 2005, Eichenberger 2006). The difficulties that arise because of the smaller anatomical structures in children and the altered anatomy of the abdominal wall in pregnancy, can be 4. Iliohypogastric and Ilioinguinal Nerve Block | 49 compensated by the greater aqueous consistency and the reduced calcification of tissues. Ultrasound-guided Iliohypogastric and Ilioinguinal Nerve Block The transducer is placed over the mid-axillary line and above the iliac crest (Figure 4. The best image is tracked by moving the transducer along the course of the iliac crest in the direction of the ASIS (Figure 4.

The beta(2)-adrenergic receptor dimerization and activation discount indocin 75 mg with mastercard. J Biol Chem 1996;271: receptor mediates extracellular signal-regulated kinase activation 16384–16392 order 75mg indocin mastercard. Coexpression studies with mutant growth factor receptor. Proc Natl of the Aequorea victoria green-fluorescent protein. Chemical structure quired for the formation of a functional GABA(B) receptor. A beta-arrestin/green function as a heteromeric assembly of the subunits GABA(B)R1 fluorescent protein biosensor for detecting G protein-coupled and GABA(B)R2. Visualization of agonist- zation modulates receptor function. Direct protein-protein coupling protein-tagged beta2-adrenergic receptor. J Biol Chem 1998;273: enables cross-talk between dopamine D5 and gamma-aminobu- 322–328. The sequencing of the human Genes are made of DNA, a nucleic acid polymer that genome and the genomes of a number of other species sub- has deoxyribose as its sugar backbone. Each sugar moiety ject to research (1–6) have paved the way for new sorts of in the chain has a base (adenine, A; cytosine, C; guanine, studies. Soon researchers will be able to look at the response G; or thymine, T) attached to it. DNA exists as a double- of every human gene to specific manipulations or develop- stranded helix. The two antiparallel strands are bound to mental events at multiple time points. This will require one another because their sequences are complemen- a new mindset. Researchers will not necessarily be testing tary—that is, the opposing bases are held together by hydro- specific hypotheses as they have done in the past. Similarly, messenger RNA they will rely on the emergence of patterns and systematic (mRNA), the transcription product of the coding region of features in their data sets (and those of others) to describe each gene, is complementary to the DNA strand from which the phenomena being examined. Such patterns may hint at it was copied and can bind to it. Northern blotting, the functions of collections of genes, the interactions of their first method developed for detecting single mRNA species products, and their importance in physiologic and patho- in a cellular extract, is based on this phenomenon. This chapter introduces array technology, technique, RNA samples are fractionated by agarose gel discusses the sorts of experiments that can now be done electrophoresis, and the RNA bands are transferred (blotted) with it, and suggests future advances. Single RNA species can already been published on this subject, and the reader then be detected by hybridizing a radiolabeled DNA to the should refer to them for additional information (7–15). In blot that is complementary to the RNA of interest. Initially, Northern blotting was used to exam- ine the abundance of specific mRNA species. Subsequently, other methods were chosen because they were simpler and EARLY STUDIES OF GENE EXPRESSION more sensitive, such as reverse-transcriptase polymerase chain reaction (RT-PCR) (34), or because they were more The human genome is composed of approximately 3 billion comprehensive, such as SAGE (serial analysis of gene expres- DNA nucleotides encoding more than 100,000 genes (16). These techniques provide useful information, Each of these genes must be turned on or off in the right but they are tedious, time-consuming, and expensive to em- cells at the right time for an individual to develop and pros- ploy. The genes that are ultimately expressed in a particular In the last 5 years, spurred by the availability of large tissue define it. That is, brain is brain and liver is liver volumes of genomic and cDNA (EST [expressed sequence because of the particular collections of transcripts found tag]) sequence data from a variety of organisms, investiga- in their respective cells. Brain, however, is extraordinarily tors have developed methods to study mRNA profiles in cells and tissues by means of large-scale, high-throughput, parallel methods. Brownstein: National Institutes of Health, National Institute of Men- protein and small molecule profiles as well, but the reagents tal Health, Bethesda, Maryland. Even though there is not a one-to-one date, the identity of the structures and biochemical altera- correspondence between the level of a particular transcript tions that are responsible for the antidepressant actions of in a cell and that of its translation products, a great deal SSRIs is still moot. Array experiments will allow investigators to explore the serotoninergic system in a way that is model independent and comprehensive, and the experiments should become GENE EXPRESSION ARRAYS easy and cheap enough to perform to permit varying many parameters and comparing many conditions. Expression profiling relies on large ordered collections of Initially, regional responses to a single dose of SSRI at cDNAs immobilized on glass (microarrays) or synthetic oli- a variety of times in one mouse strain might be examined.

In a double-blind buy indocin 50 mg otc, placebo-controlled study of buspirone in GAD patients (83) buy indocin 75 mg without a prescription, the drug was reported to be as effica- cious as lorazepam at the end of a 4-week treatment period. NEUROKININ RECEPTOR ANTAGONISTS After the drugs were discontinued, however, the lorazepam- Rationale treated patients worsened whereas the buspirone-treated subjects maintained clinical improvement. Thus, there con- There is an extensive literature demonstrating that the pep- tinues to be evidence that buspirone is effective in GAD. In addi- was discontinued, but these early clinical data will undoubt- tion, anatomic and physiologic evidence has also indicated edly lead to further clinical evaluation of NK-1 antagonists. Preclinical volved in the regulation of mood and affect, such as the studies have shown that NK-2 antagonists such as amygdala, hypothalamus, and periaqueductal gray (97). GR159897 and SR48968 have also demonstrated activity This notion is supported by early positive clinical findings in social interaction and exploration anxiolytic models, and using a selective neurokinin-1 (NK-1) antagonist for the activity has been reported in the marmoset monkey using treatment of depression and anxiety (98). Good therapeutic ratios were de- scribed for these agents. NK-3 antagonists described in the literature include os- Molecular Mechanism of Action netant (Sanofi-Synthelabo), talnetant, PD-161182, and Tachykinins collectively refer to small peptides that include PD-157672 (Parke-Davis). The latter two have been desig- substance P (SP), neurokinin A (NK-A), and neurokinin B nated for the treatment of anxiety disorders, though there (NK-B). These peptides showpreferential affinity for three have been no reports of clinical trials with any NK-3 antago- receptors, designated NK-1, NK-2, and NK-3, respectively, nist for this indication. It should be noted that preclinical which are members of the seven-transmembrane, G-pro- data described to date are sparse, and there is some sugges- tein–coupled family. Of these three receptors, NK-1 and tion that NK-3 agonism may produce an anxiolytic profile. NK-3 are found in the brain, whereas NK-2 is primarily Thus, intraventricular administration of the NK-3 agonist localized peripherally in smooth muscle of the respiratory, senktide produced anxiolytic effects in mice that could be urinary, and gastrointestinal tracts. Neurokinin receptors blocked by administration of the NK-3 antagonist SR are localized in a number of different brain areas that are 142801, and SR 142801 was found to have some anxiogenic implicated in anxiety, including the amygdala, hypothala- activity (100). Studies assessing the effects of direct administration of neurokinin agonists such as substance P into the nervous Future Drugs and Directions system are complicated by the findings that, depending on Further depression and anxiety clinical trials with centrally factors such as the site and dose, opposite effects on behavior active NK-1 antagonists are needed to provide further vali- may be achieved. In addition, further assessment of the Current Drugs in Development role of NK-2 and NK-3 subtypes is needed to determine the possible relevance, if any, of these receptor subtypes. Numerous NK-1 antagonists have been described in the literature, including MK-869 (Merck) and an analogue, L- 760,735 (Merck), SR140333 (Sanofi), CP-122,721 (Pfizer), RP67580 (Rhone-Poulenc), FK-888 (Fujisawa), GLUTAMATE RECEPTOR AGONISTS AND SDZ NKT 343 (Novartis), and PD 154075 (Parke-Davis). MODULATORS NK-1 antagonists have been reported to demonstrate anxio- Rationale lytic effects in animal models such as social interaction (99), though these effects are not consistently seen across all com- Glutamate is the major mediator of excitatory neurotrans- pounds (34). Researchers from Merck have reported that mission in the CNS. Despite this ubiquity, the elucidation vocalizations elicited by maternal separation in guinea pigs of numerous glutamate receptor subtypes with differential are robustly blocked by NK-1 antagonists such as MK-869, localizations in the brain, and the development of selective an effect that is shared by a range of antidepressant and pharmacologic agents, has led to the realization that gluta- anxiolytic agents (98). MK- 869, which progressed to phase III trials for emesis, has also Molecular Mechanism of Action been evaluated in a phase II depression trial in which it was reported that, in addition to showing a significant antide- The molecular biology of glutamate receptors has been the pressant effect, MK-869 also showed significant anxiolytic subject of numerous reviews (101,102). Glutamate recep- activity that emerged over the course of the 6-week study tors are classified as either ionotropic or metabotropic. The data supported the conclusion that NK-1 antago- tropic receptors, which mediate fast synaptic transmission, nists might be useful for the treatment of depression and are coupled to cation-specific ion channels and bind the anxiety. Further development of MK-869 for depression agonists N-methyl-D-aspartate (NMDA), -amino-3-hy- 1002 Neuropsychopharmacology: The Fifth Generation of Progress droxy-5-methyl-4-isoxazole propionic acid (AMPA), and LY354740 (group II), L-AP4 (group III), and L-CCG-I kainic acid (KA). Pharmacologic agents for antagonizing metabo- dent and voltage-independent currents carried by Na ,K , tropic glutamate receptors are currently limited. NMDA receptors, which are selectively activated by Genetically Altered Mouse Models NMDA, form a receptor/channel complex that is allosteri- Site-directed mutagenesis studies have indicated that point cally regulated by several sites. Receptor activation results mutations in the glycine binding site of the NR1 subunit in depolarization and Ca influx. Allosteric binding sites result in mice that have reduced glycine affinity and have include a strychnine-insensitive glycine site, a polyamine an anxiolytic profile as seen by decreased natural aversion site, a zinc site, and a channel site that binds agents such to an exposed environment (105). These data supported as MK-801 or phencyclidine to block channel opening. The other pharmacologic lines of evidence (see below), indicat- NMDA receptor has been cloned and has two families of ing that blockade of the glycine site can have anxiolytic subunits, the NR1, with seven splice variants (1A–1G), and actions. NR1 receptors possess the receptor/ion channel complex, whereas the NR2 Current Drugs in Development receptors lack the ion channel and appear to be modulatory. NR2 receptors, however, can form functional heteromeric LY354740 is an orally active group II metabotropic receptor channels by combining with NR1 subtypes. NMDA antag- agonist (106) currently in clinical development.