Made available in DSpace on 2016-01-26T18:55:39Z (GMT). No. of bitstreams: 1 Giulianne.pdf: 642952 bytes, checksum: b1065f2a240f35cc8466ace402a0ed40 (MD5) Previous issue date: 2014-03-31 / The aim of this study was to evaluate the analgesic effects of gabapentin as an adjunct in the control of postoperative pain in dogs undergoing mastectomy. In a blinded study, 20 female dogs (10.5±5 kg body weight) were randomly assigned to 2 groups of 10 animals each and received 60 min prior of the surgery, by oral route: 10mg kg-1 of gabapentin (Gabapentin) or placebo (Control). Pre-anesthetic medication was intramuscular (IM) acepromazine (0.03mg kg-1) in combination with morphine (0.3mg kg-1). Anesthesia was induced with intravenously (IV) propofol (dose effect) and maintained with isoflurane. Meloxicam (0.2 mg kg-1, IV) was administered five minutes before the surgical incision. The analgesic intra-operative support was provided by IV continuous rate morphine (0.1mg kg-1h-1). Heart rate, respiratory rate, systolic arterial blood pressure, oxycapnography and end-tidal concentration of isoflurane were evaluated during the surgery. Postoperative analgesia was assessed during the first 72 hours after the tracheal extubation using a Dinamic and Interative Visual Analog Scale (DIVAS) and modified Glasgow Composite Measure Pain Scale (modified-GCMPS). Rescue analgesia with morphine (0.5mg kg-1 IM) was performed if the evaluation score exceeded 50% of DIVAS and/or 33% of GCMPS during the postoperative period. The cardiopulmonary variables, pain and sedation scores did not differ between groups. However, rescue analgesia was 40% less frequently for Gabapentin (6 of 10 dogs needs rescue analgesic, total of 9 rescued doses in the Gabapentin group) than in the Control group (8 of 10 dogs, total of 15 rescued doses in the Control group). It was concluded that the adjuvant gabapentin administration reduce the requirement for rescue opioid in dogs undergoing mastectomy / Objetivou-se avaliar a ação da gabapentina como adjuvante do controle da dor pós-operatória em cadelas encaminhadas à mastectomia. Foram avaliadas 20 cadelas, com peso médio de 10,5±5, distribuídas em dois grupos de dez animais cada: Gabapentina: tratamento com gabapentina (10mg kg-1) por via oral, 60 minutos antes da cirurgia, seguindo-se a administração da mesma dose a cada 24 horas, durante três dias subsequentes à cirurgia; Controle: tratamento placebo, administrado conforme descrito para o tratamento Gabapentina. Todos os animais foram tranquilizados com acepromazina (0,03mg kg-1), em associação à morfina (0,5mg kg-1), por via intramuscular. Vinte minutos após, foi iniciada a infusão contínua intravenosa (IV) de morfina (0,1mg kg-1 h-1), que foi mantida até o término do procedimento cirúrgico. A indução e manutenção anestésicas foram realizadas com propofol (dose efeito, IV) e isofluorano, respectivamente. Meloxicam (0,2mg kg-1, IV), foi administrado cinco minutos antes da incisão cirúrgica. Durante o procedimento anestésico foram avaliados: frequência cardíaca e respiratória, pressão arterial sistólica, oxicapnografia, temperatura retal, concentração final inspirada e expirada de isofluorano. No período pós-operatório o grau de analgesia foi mensurado 30 minutos, 1, 2, 4, 8, 12, 18, 24, 32, 40, 48, 56, 64 e 72 horas após extubação traqueal utilizando-se a Escala Analógica Visual Interativa e Dinâmica (EAVID) e a Escala Composta de Glasgow Modificada (ECGM). Analgesia de resgate foi feita com morfina (0,5mg kg-1 IM) em casos do escore de dor ser superior a 50% do EAVID e/ou 33% do ECGM. O grau de sedação foi avaliado por sistema de escore. As variáveis cardiorrespiratórias e os escores de dor e de sedação não diferiram entre os tratamentos. Porém, no período pós-operatório, analgesia de resgate foi 40% menos frequente no grupo Gabapentina (6 de 10 cães necessitaram de resgate analgésico, totalizando 9 resgates no grupo Gabapentina) em relação ao Controle (8 de 10 cães necessitaram de resgate analgésico, totalizando 15 resgates no grupo Controle). Conclui-se que a administração adjuvante da gabapentina reduziu o requerimento de morfina para controle da dor no período pós-operatório em cadelas pós-mastectomia

Made available in DSpace on 2016-07-18T17:53:12Z (GMT). No. of bitstreams: 1 Giulianne.pdf: 642952 bytes, checksum: b1065f2a240f35cc8466ace402a0ed40 (MD5) Previous issue date: 2014-03-31 / The aim of this study was to evaluate the analgesic effects of gabapentin as an adjunct in the control of postoperative pain in dogs undergoing mastectomy. In a blinded study, 20 female dogs (10.5±5 kg body weight) were randomly assigned to 2 groups of 10 animals each and received 60 min prior of the surgery, by oral route: 10mg kg-1 of gabapentin (Gabapentin) or placebo (Control). Pre-anesthetic medication was intramuscular (IM) acepromazine (0.03mg kg-1) in combination with morphine (0.3mg kg-1). Anesthesia was induced with intravenously (IV) propofol (dose effect) and maintained with isoflurane. Meloxicam (0.2 mg kg-1, IV) was administered five minutes before the surgical incision. The analgesic intra-operative support was provided by IV continuous rate morphine (0.1mg kg-1h-1). Heart rate, respiratory rate, systolic arterial blood pressure, oxycapnography and end-tidal concentration of isoflurane were evaluated during the surgery. Postoperative analgesia was assessed during the first 72 hours after the tracheal extubation using a Dinamic and Interative Visual Analog Scale (DIVAS) and modified Glasgow Composite Measure Pain Scale (modified-GCMPS). Rescue analgesia with morphine (0.5mg kg-1 IM) was performed if the evaluation score exceeded 50% of DIVAS and/or 33% of GCMPS during the postoperative period. The cardiopulmonary variables, pain and sedation scores did not differ between groups. However, rescue analgesia was 40% less frequently for Gabapentin (6 of 10 dogs needs rescue analgesic, total of 9 rescued doses in the Gabapentin group) than in the Control group (8 of 10 dogs, total of 15 rescued doses in the Control group). It was concluded that the adjuvant gabapentin administration reduce the requirement for rescue opioid in dogs undergoing mastectomy / Objetivou-se avaliar a ação da gabapentina como adjuvante do controle da dor pós-operatória em cadelas encaminhadas à mastectomia. Foram avaliadas 20 cadelas, com peso médio de 10,5±5, distribuídas em dois grupos de dez animais cada: Gabapentina: tratamento com gabapentina (10mg kg-1) por via oral, 60 minutos antes da cirurgia, seguindo-se a administração da mesma dose a cada 24 horas, durante três dias subsequentes à cirurgia; Controle: tratamento placebo, administrado conforme descrito para o tratamento Gabapentina. Todos os animais foram tranquilizados com acepromazina (0,03mg kg-1), em associação à morfina (0,5mg kg-1), por via intramuscular. Vinte minutos após, foi iniciada a infusão contínua intravenosa (IV) de morfina (0,1mg kg-1 h-1), que foi mantida até o término do procedimento cirúrgico. A indução e manutenção anestésicas foram realizadas com propofol (dose efeito, IV) e isofluorano, respectivamente. Meloxicam (0,2mg kg-1, IV), foi administrado cinco minutos antes da incisão cirúrgica. Durante o procedimento anestésico foram avaliados: frequência cardíaca e respiratória, pressão arterial sistólica, oxicapnografia, temperatura retal, concentração final inspirada e expirada de isofluorano. No período pós-operatório o grau de analgesia foi mensurado 30 minutos, 1, 2, 4, 8, 12, 18, 24, 32, 40, 48, 56, 64 e 72 horas após extubação traqueal utilizando-se a Escala Analógica Visual Interativa e Dinâmica (EAVID) e a Escala Composta de Glasgow Modificada (ECGM). Analgesia de resgate foi feita com morfina (0,5mg kg-1 IM) em casos do escore de dor ser superior a 50% do EAVID e/ou 33% do ECGM. O grau de sedação foi avaliado por sistema de escore. As variáveis cardiorrespiratórias e os escores de dor e de sedação não diferiram entre os tratamentos. Porém, no período pós-operatório, analgesia de resgate foi 40% menos frequente no grupo Gabapentina (6 de 10 cães necessitaram de resgate analgésico, totalizando 9 resgates no grupo Gabapentina) em relação ao Controle (8 de 10 cães necessitaram de resgate analgésico, totalizando 15 resgates no grupo Controle). Conclui-se que a administração adjuvante da gabapentina reduziu o requerimento de morfina para controle da dor no período pós-operatório em cadelas pós-mastectomia

The overarching objective of this thesis is to demonstrate a systematic approach for addressing the instability issues associated with low limit degradants by developing quantitative degradation models that incorporate key instability determinants into predictive equations. Chlorhexidine was used as model compound in aqueous solution to demonstrate the application of the predictive models to issues of formulation design and manufacturing. Chorhexidine degrades to p-chloroaniline, a well-established toxicant, by various pH-dependent pathways. In acidic conditions, the direct formation of p-chloroaniline from chlorhexidine is the major pathway whereas the indirect formation of p-chloroaniline via p-chlorophenylurea is the main alkaline pathway. Rate laws and mechanisms for each pathway were presented. Shelf life predictions equations for chlorhexidine formulations were derived based on the kinetics of p-chloroaniline appearance as a function of formulation strength, solution pH, bulk chlorhexidine purity and storage temperature. The pH range for optimal shelf-life was 5.0 to 5.5. Simple extraction procedures used during formulation preparation were identified to improve bulk chlorhexidine purity and thereby extend product shelf-life. Gabapentin degrades directly to gabapentin-lactam in the solid-state. The established limit on gabapentin-lactam in gabapentin pharmaceutical formulations is <0.5% w/w thus gabapentin instability was studied as a model compound for solid state formulation applications. Mechanical stress associated with drug product manufacturing in unit operations such as milling increased the subsequent lactamization rate upon storage due to increased gabapentin crystal disorder. The effect of environment moisture was to decrease the rate of gabapentin-lactam formation due to competitive recovery of gabapentin crystallinity which was accelerated by humidity. A degradation model that combined both physical and chemical instability pathways including autocatalytic branching, spontaneous intra-molecular cyclization and moisture-induced physical transformation steps was shown to be consistent with lactamization kinetics as a function of both environmental (temperature and humidity) and manufacturing-related effects. This kinetic model was used to predict the shelf-life of gabapentin tablets prepared under various exemplary manufacturing conditions thereby demonstrating the ability of the model to link manufacturing variation and shelf-life stability in for solid-state drug formulations.

The objective of the study is to analyze the factors associated with the severity of pruritus in patients with terminal chronic kidney disease undergoing hemodialysis. The methodology used is based on a cross-sectional study in patients receiving hemodialysis at the Centro Nacional de Salud Renal. Severe pruritus was defined as a score on the visual analogue scale greater than or equal to 7, and the strength of association with the possible risk factors was assessed by calculating prevalence ratios. Regarding the results, 264 patients were included, 59.9% were male, with a mean time on hemodialysis of 10.26 ± 7.14 years. 75% experienced pruritus, of this group, 1 in 3 presented severe pruritus. Hyperphosphatemia and the use of antihistamines were associated with a higher prevalence of severe pruritus (RP 1.71, 95% CI 1.09-267 and RP 2.39, 95% CI 1.51-3.75, respectively). The positive serology for Hepatitis C Virus was described as a protective factor for presenting severe pruritus (RP 0.55, 95% CI 0.33 - 0.89). In conclusion, severe uremic pruritus is a frequent problem in patients with chronic terminal kidney disease who have hyperphosphatemia and treatment with antihistamines independently of the time they have been on hemodialysis. / Revisión por pares

Acute and chronic pain conditions cause significant patient distress, interference with daily activities, and increased health care costs. It is important to evaluate analgesic interventions to improve pain relief, function, quality of life, and also to prevent persisting pain after surgery. This thesis is a combination of studies evaluating analgesic interventions in the setting of acute surgical pain; prevention of persistent post-surgical pain; and chronic low back pain. In part 1, we report our comparison of morphine and hydromorphone in 402 ambulatory surgery patients, for their ability to achieve satisfactory analgesia with minimal emesis using a design of multicentre randomized controlled trial. We observed no differences in their analgesic potential and common side effects and note that appearance of side effects is likely to be idiosyncratic. In part 2, we report our 2×2 factorial feasibility trial to prevent persistent post-surgical pain in patients having elective video-assisted thoracic surgery lobectomies, comparing N-methyl-D-aspartate antagonists versus placebo, and intravenous steroids versus placebo. As our feasibility outcomes were not met, we suggest appropriate considerations for protocol changes before embarking on a definitive larger trial. In part 3, we report on our systematic review and meta-analysis assessing the effectiveness and safety of gabapentinoids (gabapentin and pregabalin) in adult patients with chronic low back pain. We observed that the existing evidence is small and there is minimal improvement in pain and other outcomes with potential for adverse events. We suggest that the use of gabapentinoids for chronic low back pain merits caution and there is need for large high-quality trials. / Thesis / Doctor of Philosophy (PhD) / It is important to evaluate analgesic interventions to decrease pain, improve function, and lessen health care costs. In a randomized controlled trial of day surgery patients, we demonstrate that there are no differences between morphine and hydromorphone in achieving pain relief and common side effects. To prevent persistent post-surgical pain in patients having elective video-assisted thoracic surgery lobectomies, we performed a 2×2 factorial, feasibility randomized controlled trial, to compare N-methyl-D-aspartate antagonists versus placebo, and intravenous steroids versus placebo. We observe that appropriate protocol changes must be made before embarking on a larger trial. Finally, we report our systematic review and meta-analysis on the use of gabapentinoids in adult patients with chronic low back pain and observe that the existing evidence is small and not supportive, and the use of gabapentinoids for chronic low back pain merits caution.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal. / Le gabapentin est une molécule lipophile dérivée de l'acide y-aminobutyrique (GABA). Ce médicament traverse la barrière hémato-encéphalique, se lie à la sous-unité α2β des canaux calciques voltage-dépendents de type Let réduit l'influx de Ca2+ dans les neurones de rat. Le gabapentin diminue la libération de la sérotonine dans le système nerveux central. Par contre, il n'affecte pas directement les récepteurs sérotoninergiques et ne modifie pas la recapture du neurotransmetteur. Des études animales et cliniques ont démontré que le gabapentin possède des propriétés anticonvulsivantes, anxiolytiques et analgésiques. Si l'activité anticonvulsivante du gabapentin peut être, du moins, en partie, expliquée par son effet inhibiteur sur les canaux calciques de type L, son mécanisme d'action anxiolytique est encore inconnu. A l'encontre des benzodiazépines qui influencent la neurotransmission GABAergique, le gabapentin n'affecte pas directement les cibles moléculaires de cette neurotransmission. L'implication de la neurotransmission sérotoninergique dans l'anxiété est supportée par l'efficacité thérapeutique des agonistes 5-HTIA et des inhibiteurs spécifiques de la recapture sérotoninergique, ainsi que par les propriétés anxiogéniques des agonistes 5-HTrn. Considérant ces observations, nous avons émis l'hypothèse que le gabapentin, en diminuant la libération de la sérotonine centrale, induirait des modifications de la densité des récepteurs 5-HT 1A et 5-HT rn, sans affecter pour autant les transporteurs. Pour évaluer cette hypothèse, nous avons étudié les effets de l'administration chronique du gabapentin sur la radio liaison de ligands spécifiques aux récepteurs 5-HT1A, aux récepteurs 5-HTrn et aux transporteurs sérotoninergiques du rat. Le gabapentin fut administré i.p. pendant 21 jours à 30 mg/kg et à 100 g/kg et comparé au salin. Les études topologiques ont été effectuées par autoradiographie quantitative en utilisant le [3H]citalopram pour la radioliaison aux transporteurs sérotoninergiques, le [3H]8-0HDPAT pour marquer les récepteurs 5-HTIA et le [3H]GR 125743 pour la radioliaison aux récepteurs 5-HTrn. La densité des récepteurs et des sites de recapture de la sérotonine a été évaluée par un analyseur d'images informatisé (MCID™) qui permet une haute résolution dans la quantification des densités optiques de films autoradiographiques. Les régions cérébrales analysées ont été les suivantes : le cortex ( cingulaire, frontal, parietal, enthorinal), le septum (latérodorsal et latérointermédiaire), les noyaux raphé (dorsal et médian), l'hippocampe (CAl,2,3 et DG), la substance noire, le globus pallidus, le noyau accumbens et caudéputamen (rostral et caudal). Nous avons trouvé que le traitement au gabapentin diminue la radioliaison du 8-0HDPAT tritié aux récepteurs 5-HT1A de l'hippocampe (le CAl et DG), du cortex frontal et du septum et réduit aussi la radioliaison du GR 125743 tritié aux 5-HTrn du DG hippocampique. Par contre, ce traitement n'affecte pas la radioliaison aux sites de recapture de la sérotonine. Une interprétation possible de nos résultats est que le gabapentin affecte les récepteurs sérotoninergiques de façon indirecte. En diminuant l'influx calcique dans les canaux calciques centraux, au niveau du cortex frontal, de l'hippocampe (CAl et DG) et du septum, le gabapentin pourrait entraîner une réduction de la libération de la 5-HT. La diminution de ce neurotransmetteur induirait alors une régulation à la baisse des autorécepteurs 5-HTrn dans le DG. Par ailleurs, la diminution de l'entrée du calcium provoquée par le gabapentin pourrait induire une baisse d'affinité des récepteurs 5-HT1A postsynaptiques pour leur ligand spécifique.

La douleur neuropathique centrale post accident vasculaire cérébral est une condition débilitante dont le traitement s’avère souvent délicat et infructueux. Le but de ce projet était de reproduire cette condition chez le rat en injectant par stéréotaxie une solution de collagènase produisant une hémorragie localisée dans le noyau ventropostérolatéral du thalamus. Des tests comportementaux évaluant la coordination motrice, la sensibilité mécanique, au chaud et au froid étaient réalisés régulièrement afin d’établir la présence de douleur neuropathique puis les effets de l’administration de kétamine, d’amitriptyline, de gabapentine, et de carbamazepine étaient évalués. L’induction d’une hémorragie intrathalamique conduit à l’apparition d’allodynie mécanique bilatérale persistante ainsi que d’allodynie au froid transitoire chez certains sujets et ce sans modification de la coordination motrice. L’administration de kétamine à forte dose renverse l’allodynie mécanique mais est associée à une altération de la motricité. L’administration de gabapentine renverse également cette allodynie mécanique sans effet notable sur la coordination motrice. Les autres médicaments n’ont pas démontré d’effet significatif. L’évaluation histopathologique des cerveaux montre une lésion bien localisée dans la zone d’intérêt. Ces résultats montrent que l’injection intrathalamique de collagénase peut être utilisée comme un modèle fiable de douleur neuropathique centrale. Si la kétamine semble capable de soulager ce type de douleur, elle est associée à des effets indésirables. En revanche, la gabapentine serait une molécule prometteuse pour le traitement de cette condition. Le rôle des récepteurs NMDA et des canaux calciques voltage dépendants, cibles respectives de la kétamine et de la gabapentine dans le maintien de cette douleur mérite d’être précisé. / Central post stroke pain is a debilitating condition for which treatment is often difficult and unsuccessful. The goal of this project was to reproduce an animal model of this condition by performing a stereotaxic injection of collagenase solution inducing a localized hemorrhage within the ventroposterolateral thalamic nuclei of rats. Behavioral tests to evaluate motor coordination, sentivity to mechanical, hot and cold stimuli were performed regurlarly to establish if neuropathic pain was present. Then, the effects of ketamine, amitriptyline, gabapentin and carbamazepine on such pain were evaluated. Induction of an intrathalamic hemorrhage produced bilateral persistent mechanical allodynia as well as transient cold allodynia in some animals without notable changes in motor coordination. High doses of ketamine did reverse mechanical allodynia but with significant impairment in motor coordination. Similarly gabapentin also reversed mechanical allodynia without undesirable effect on coordination. The others two drugs failed to show any significant effect. Histopathological evaluation of the brain revealed a well localized lesion in the area of interest. These results show that an intrathalamic collagenase injection produced a reliable model of central neuropathic pain. Ketamine was able to reverse mechanical allodynia but with significant side effects. Gabapentin appeared to be a promising drug for the treatment of this condition. The role of NMDA receptors and voltage dependant calcium channels, that target ketamine and gabapentin respectively in the maintenance of this pain, needs to be further defined.

No description available.

Structural studies of peptides are of great importance in developing novel and effective biomaterials ranging from drugs and vaccines to nano materials with industrial applications. In addition, they provide model systems to study and mimic the protein conformations. The ability to generate folded intramolecularly hydrogen bonded structures in short peptides is essential for peptide design strategies, which rely on the use of folding nuclei in the construction of secondary structure modules like helices and β-hairpins. In these approaches, conformational choices at selected positions are biased, using local stereochemical constraints, that limit the range of accessible backbone torsion angles. X-ray crystallographic studies of designed peptides provide definitive proof of the success of a design strategy, and provide essential structural information that can be utilized in the future design of biologically and structurally important polypeptides. Recent trends in peptide research focus on the incorporation of β-, γ- and higher homologs of the α-amino acid residues in designed peptides as they confer more proteolytic stability to the polypeptides. X-ray crystallographic studies of such modified peptides containing non-protein residues are essential, since information on the geometric and stereochemical properties of modified amino acids can only be gathered from the systematic structural studies of synthetic peptides incorporating them. This thesis reports a systematic study of the structures and conformations of amino acid derivatives and designed peptides containing stereochemically constrained α-, β- and γ-amino acid residues and the structural studies of polymorphic peptide helices. The structures described in thesis contain the Cα,α-dialkyalted α-residues α-aminoisobutyric acid (Aib) and 1-aminocyclohexane-1-carboxylic acid (Ac6c), the β-amino acid residue 1-aminocyclohexane acetic acid (β3,3Ac6c) and the γ-amino acid residue 1-aminomethylcyclohexaneacetic acid (gabapentin, Gpn). The crystal structure determination of peptides incorporating conformationally constrained α-, β- and γ- amino acid residues permitted the characterization of new types of hydrogen bonded turns and polymorphs. The studies enabled the precise determination of conformational and geometric parameters of two ω-amino acid residues, gabapentin and β 3,3Ac6c and provided detailed information about the conformational excursions possible for peptide molecules. This thesis is divided into 10 chapters. Chapter 1 gives a general introduction to the stereochemistry of the polypeptide chain, description of backbone torsion angles of α- and ω- amino acid residues and the major secondary structures of α-peptides, β-peptides, γ-peptides and hybrid peptides. A brief introduction to polymorphism and weak interactions, in particular aromatic interactions, is also provided, followed by a discussion on X-ray diffraction and solution to the phase problem. Chapter 2 describes the crystal structures of gabapentin zwitterion and its eight derivatives (Ananda, Aravinda, Vasudev et al., 2003). The crystal structure of the gabapentin zwitterions determined in this study is identical to that previously reported (Ibers, J. A. Acta Crystallogr. 2001, C57, 641-643). Eight of the nine achiral compounds crystallized in centrosymmetric space groups P21/c, C2/c or Pbca, while one derivative (Tos-Gpn-OH) crystallized in non-centrosymmetric space group Pna21 with four independent molecules in the asymmetric unit.The structural studies presented in this chapter reveal that the geminal substituents on the Cβ atom limits the values of dihedral angles θ1 and θ2 to ±60°, resulting in folded backbone conformations in all the examples. Intramolecular hydrogen bonds with 7-atoms in the hydrogen bond turn (C7) are observed in three derivatives, gabapentin hydrochloride (GPNCL), Boc-Gpn-OH (BGPNH) and Piv-Gpn-OH (PIVGPN), while a 9-atom hydrogen bonded turn (C9) is observed in Ac-Gpn-OH (ACGPH). Unique structural features, such as an unusual anti conformation of the COOH group (in ACGPH) and positional disorder of the cyclohexane ring (in BGPNN), indicating the co-existence of both the interconvertible chair conformations, are revealed by the crystal structure analyses. Chapter 3 describes the structural characterization of novel hydrogen bonded conformations of homo oligomers of Gpn. The crystal structures of three peptides, Boc-Gpn-Gpn-NHMe (GPN2), Boc-Gpn-Gpn-Leu-OMe (GPN2L) and Boc-Gpn-Gpn-Gpn-Gpn-NHMe (GPN4) provide the first crystallographic characterization of two new families of polypeptide structures, the C9 helices and C9 ribbons (Vasudev et al., 2005, 2007), in which the molecular conformations are stabilized by contiguous C9 turns formed by the hydrogen bonding between the CO group of residue (i) and the NH group of residue (i+2). The C9 hydrogen bond is characterized by a specific combination of the four torsion angles for the Gpn backbone, with the torsion angles θ1 and θ2 adopting g+/g+ or g /g- conformations. The structural analysis also permits precise determination of hydrogen bond geometry for the C9 structures, which is highly linear in contrast to the analogous γ-turn hydrogen bonds in α-peptides. A comparison of the backbone conformations in the three peptides reveals two classes of C9 hydrogen bonded secondary structures, namely C9 helices and C9 ribbons. The packing arrangement in these γ-peptides follows the same patterns as the helix packing in crystals of α-peptides. Chapter 4 describes ten crystal structures of short hybrid peptides containing the Gpn residue (Vasudev et al., 2007). In addition to the C7 and C9 hydrogen bonded turns which are defined by the backbone conformations at the Gpn residue, hybrid turns defined by a combination of backbone conformations at the α and γ-residues or at the β and γ-residues have been determined. Peptides Boc-Ac6c-Gpn-OH (ACGPH), Piv-Pro-Gpn-Val-OMe (PPGPV) and Boc-Val-Pro-Gpn-OH (VPGPH) reveal molecular conformation stabilized by intramolecular C9 hydrogen bonds, while Boc-Ac6c-Gpn-OMe (ACGPO) and Boc-Gpn-Aib-OH (GPUH) are stabilized by a C7 hydrogen bonded turn at the Gpn residue. An αγ hybrid turn with 12 atoms in the intramolecular hydrogen bonded rings (C12 turns) has been observed in the tripeptide Boc-Ac6c-Gpn-Ac6c-OMe (ACGP3), while βγ hybrid turns with 13 atoms in the hydrogen bonded ring (C13 turns) have been characterized in the tripeptides Boc-βLeu-Gpn-Val-OMe (BLGPV) and Boc- βPhe-Gpn-Phe-OMe (BFGPF). The two βγ C13 turns belong to two different categories and are characterized by different sets of backbone torsion angles for the β and γ residues. A γα C10 hydrogen bond, which is formed in the N→C direction (NHi ••• COi+2), as opposed to the regular hydrogen bonded helices of α-peptides, has also been observed in BFGPF. The Chapter provides a comparison of the backbone torsion angles of the Gpn residue in various hydrogen bonded turns and a brief comparison of the observed hydrogen bonded turns with those of the α-peptides. Chapter 5 describes the crystal structures of three αγ hybrid peptides which show C12/C10 mixed hydrogen bond patterns (Vasudev et al., 2007, 2008a; Chatterjee, Vasudev et al.,2008a). The insertion of gabapentin in the predominantly α-amino acid sequences in Boc-Ala-Aib-Gpn-Aib-Ala-OMe (AUGP5) and Boc-Leu-Gpn-Aib-Leu-Gpn-Aib-OMe results in the observation of helices stabilized by αα C10 (310-turn) and αγ C12 turns. The tetrapeptide Boc-Leu-Gpn-Leu-Aib-OMe reveals a novel conformation, stabilized by C12 (αγ) and C10 (γα) hydrogen bonds of opposite hydrogen bond directionalities. The conformations observed in crystals have been extended to generate C12 helix and C12/C10 helix with alternating hydrogen bond polarities in ( αγ)n sequences. The structure determination of three crystals, providing five molecular conformations, presented in this chapter provides the first crystallographic characterization of two types of helices predicted for the regular αγ hybrid peptides from theoretical calculations. The crystal structure of Boc-Ala-Aib-Gpn-Aib-Ala-OMe also provides an example for the co-existence of left-handed and right-handed helix in the asymmetric unit. Chapter 6 describes the structural studies of αγ hybrid peptides containing Aib and Gpn residues, and is divided into two parts. The first part presents the crystal structure analysis of peptides of sequence length 2 to 4, with alternating Aib and Gpn residues, and illustrates the conformational variability in αγ hybrid sequences as evidenced by the observation of conformational polymorphs (Chatterjee, Vasudev et al., 2008b; Vasudev et al., 2007; Ananda, Vasudev et al., 2005). The peptide Boc-Gpn-Aib-NHMe (GUN), Boc-Aib-Gpn-Aib-OMe (UGU), Boc-Gpn-Aib-Gpn-Aib-OMe (GU4O), Boc-Aib-Gpn-Aib-Gpn-OMe (UG4O) and Boc-Aib-Gpn-Aib-Gpn-NHMe (UG4N), all of which are potential candidates for exhibiting αγ C12 hydrogen bonds, reveal molecular conformations stabilized by diverse hydrogen bonded turns such as C7, C9, C12 and C17 in crystals. The conformational heterogeneity in this class of hybrid peptides is further evidenced by the observation of three polymorphs in the monoclinic space group P21/c for the tetrapeptide Boc-Aib-Gpn-Aib-Gpn-NHMe (UG4N), providing four independent peptide molecules adopting two distinct backbone conformations. In one polymorph, C12 helices terminated with an unusual three residue ( γαγ) C17 turn is observed, while the unfolding of helical conformation by solvent insertion into the backbone is observed in the other two polymorphs. The studies indicate the possible utility of Gpn residue in stabilizing locally folded conformations in the folding pathway, thus permitting their crystallographic characterization in multiple crystal forms. A discussion of the structural and conformational features of Gpn residues determined from all the crystal structures is presented in the Chapter, along with a φ-ψ plot for the Gpn residue. Part 2 of Chapter 6 describes the crystal structures of two octapeptides, Boc-Gpn-Aib-Gpn-Aib-Gpn-Aib-Gpn-Aib-OMe (GU8) and Boc-Leu-Phe-Val-Aib-Gpn-Leu-Phe-Val-OMe (LFVUG8), featuring C12 turns at the Aib-Gpn segments (Chatterjee, Vasudev et al., 2009). GU8 folds into a C12 helix flanked by C9 hydrogen bonds at both the termini, while LFVUG8 adopts β-hairpin conformation with a chain-reversing C12 turn at the central Aib-Gpn segment. A remarkable feature of the Aib-Gpn turn in the β-hairpin structure is the anti conformation about the Cβ-Cα (θ2) bond, which is the only example of a Gpn residue not adopting gauche conformation for both θ1 and θ2. The crystal structures of the two peptides, mimicking the two major secondary structural elements of α-peptides in hybrid polypeptides, permits a comparative study of the mode of molecular packing in crystals of α-peptides and hybrid peptides. The chapter also discusses theoretical calculations on αγ hybrid sequences, which reveal new types of C12 hydrogen bonded turns. Chapter 7 describes the crystal structures of conformationally biased tert-butyl derivatives of Gpn. The crystallographic characterization of the E (trans) and Z (cis) isomers of the residue,three protected derivatives and a tripeptide provides examples of C7 and C9 hydrogen bonded conformations, suggesting that the C7 and C9 hydrogen bonds can be formed by Gpn residues with both the chair conformations of the cyclohexane ring. Chapter 8 describes the systematic structural studies of the derivatives and peptides of the stereochemically constrained β- amino acid residue, β3,3Ac6c (Vasudev et al., 2008c). The backbone torsion angles φ and θ adopt gauche conformation in majority of the examples, owing to the presence of a cyclohexane ring on the Cβ atom. In contrast to Gpn, β3,3Ac6c does not show strong preference for adopting intramolecularly hydrogen bonded conformations. Of the 16 crystal structures determined, intramolecular hydrogen bonds involving the β-residue are observed only in 4 cases. The amino acid zwitterion (BAC6C), the hydrochloride (BACHCL) and the dipeptide Boc-β3,3Ac6c-β3,3Ac6c-NHMe (BAC62N) form N-H•••O hydrogen bonds with 6-atoms in the hydrogen bond ring (C6 turns). An αβ hybrid C11 hydrogen bonded turn is characterized in the dipeptide Piv-Pro-β3,3Ac6c-NHMe, which is distinctly different from the C11 hydrogen bonds observed in αβ hybrid peptide helices. Several unique structural features such as a dynamic disorder of the hydrogen atom of the carboxylic acid group (in BBAC) and cis geometry of the urethane bond (in BBAC, BAC62N and BPBAC) have been observed in this study. A comparison of the backbone conformations of β3,3Ac6c with other β- amino acid residues is also provided. Chapter 9 describes the crystallographic characterization of a new polymorph of gabapentin monohydrate and crystal structures of the zwitterions of E and Z isomers of tert-butylgabapentin and its hydrochloride and hydrobromide (Vasudev et al., 2009). A comparison of the crystal structures of the monoclinic form (Ibers, J. A. Acta Crystallogr. 2001, C57, 641-643) of gabapentin monohydrate and the newly characterized orthorhombic form reveals identical molecular conformations and intermolecular hydrogen bond patterns in both the polymorphs. The two polymorphs show differences in the orientation of molecules constituting a layer of hydrophobic interactions between the cyclohexyl side chains. A comparison of the packing arrangements of the zwitterionic amino acid molecules in the crystal structures of gabapentin monohydrate, the tert-butyl derivatives and other co-crystals of gabapentin that had been characterized so far, is provided which would facilitate prediction of new polymorphs of the widely used drug molecule, Gpn. Chapter 10 describes the crystallization of α-peptide helices in multiple crystal forms (Vasudev et al., 2008b). Crystal structures of two peptides, Boc-Leu-Aib-Phe-Phe-Leu-Aib-Ala-Ala-Leu-Aib-OMe (LFF), Boc-Leu-Aib-Phe-Ala-Leu-Ala-Leu-Aib-OMe (D1) in two crystal forms and the crystal structure of a related sequence, Boc-Leu-Aib-Phe-Ala-Phe-Aib-Leu-Ala-Leu-Aib-OMe (D10) permit an analysis of the molecular conformation and packing patterns of peptide helices in crystals. The two polymorphs of LFF, crystallized in the space groups P21 and P22121, reveal very similar molecular conformation (α/310-helix) in both the polymorphic crystals; the two forms differ significantly in the pattern of solvation. The crystal structure determination of a monoclinic (P21) and an orthorhombic polymorph (P21212) of D1 provides five different peptide conformations, four of which are α-helical and one is a mixed 310/α-helix. The crystal structure determination of the three peptides provide an opportunity to compare the nature and role of aromatic interactions in stabilizing molecular conformation and packing and its significance in the observation of polymorphism. An analysis of the Cambridge Structural Database and a model for nucleation of crystals in hydrophobic peptide helices are also discussed.

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