Characterization of succinic semialdehyde dehydrogenase from Aspergillus niger.

The catabolism of fungal 4-aminobutyrate (GABA) occurs via succinic semialdehyde (SSA). Succinic semialdehyde dehydrogenase (SSADH) from the acidogenic fungus Aspergillus niger was purified from GABA grown mycelia to the highest specific activity of 277 nmol min-1 mg-1, using phenyl Sepharose and DEAE Sephacel chromatography. The purified enzyme was specific for its substrates SSA and NAD+. The substrate inhibition observed with SSA was uncompetitive with respect to NAD+. While product inhibition by succinate was not observed, NADH inhibited the enzyme competitively with respect to NAD+ and noncompetitively with respect to SSA. Dead-end inhibition by AMP and p-hydroxybenzaldehyde (pHB) was analyzed. The pHB inhibition was competitive with SSA and uncompetitive with NAD+; AMP competed with NAD+. Consistent with the kinetic data, a sequential, ordered Bi Bi mechanism is proposed for this enzyme.

Efectividad y seguridad de gabapentina y pregabalina como monoterapia de primera línea en adultos con dolor neuropático / Effectiveness and safety of gabapentin and pregabalin as first-line monotherapy in adults with neuropathic pain

Antecedentes: Descripción de la condición de salud de interés: La Asociación Internacional del Estudio del Dolor en el año 2011 definió el dolor neuropático como una afección neurológica crónica causado por una lesión o enfermedad del sistema nervioso. Se debe a una lesión o mal funcionamiento del sistema nervioso, a un daño del nervio en sí (u otra parte del sistema sensorial) y no a una activación anormal de las vías nociceptoras. El mecanismo generador del dolor neuropático se halla en cualquier sitio a lo largo del recorrido de las vías nociceptivas (las vías que conducen la información de tipo doloroso), sin estimular inicialmente a los nociceptores (los receptores de dolor), a diferencia de lo que sucede con el dolor nociceptivo o fisiológico. Descripción de las tecnologías: Gabapentina y pregabalina son medicamentos anticonvulsivantes empleados en el tratamiento del dolor neuropático; a ctúan disminuyendo la liberación de neurotransmisores excitadores, lo que reduce la entrada de calcio en las terminaciones nerviosas. Las dos tecnologías tienen registro sanitario INVIMA para la indicación de interés. Evaluación de efectividad y seguridad: Pregunta de evaluación: En adultos con dolor neuropático, ¿cuál es la efectividad y seguridad de gabapentina y pregabalina comparadas con amitriptilina, oxcarbazepina, duloxetina, tramadol (sólo o en combinaciones) o lidocaína en parches, como monoterapia de primera línea para el alivio del dolor? La pregunta de evaluación fue refinada y validada con base en: autorización de mercadeo de \r\nlas tecnologías para la indicación de interés (registro sanitario INVIMA), listado de medicamentos vitales no disponibles, cobertura de las tecnologías en el Plan Obligatorio de Salud (POS) (Acuerdo 029 de 2011), revisión de grupos terapéuticos (clasificación ATC: Anatomical, Therapeutic, Chemical classification system), recomendaciones de guías de práctica clínica actualizadas, disponibilidad de evidencia sobre efectividad y seguridad (reportes de evaluación de tecnologías y revisiones sistemáticas de la literatura), uso de las tecnologías (listas nacionales de recobro, estadísticas de prescripción, etc), \r\nestudios de carga de enfermedad y consulta con un experto temático (especialista clínico). No se dentificaron otros comparadores relevantes para la evaluación. Población: Adultos con dolor neuropático tipo: Neuropatía diabética periférica; Neuralgia posherpética; Dolor neuropático asociado con lesión de la médula espinal. \r\nLa población se refinó después de revisar la evidencia disponible, considerando además, que los efectos de las tecnologías bajo evaluación podrían diferir entre pacientes con distintos tipos de dolor neuropático. Metodología: Búsqueda de literatura, Búsqueda en bases de datos electrónicas. Conclusiones: En pacientes con neuropatía diabética periférica, gabapentina es una opción con ventajas en efectividad, sin ventajas en seguridad y tolerabilidad. En la misma población, pregabalina sin discriminar por dosis no tiene ventajas en efectividad; en dosis ≥ 300 mg es una opción con ventajas en efectividad, no es segura y no presenta ventajas en tolerabilidad; para dosis ≤ 150 mg la evidencia sobre su efectividad no es concluyente, no presenta ventajas en cuanto a seguridad y tolerabilidad. En pacientes con neuralgia posherpética, la evidencia sobre la efectividad de gabapentina no es concluyente, para el mismo tipo de dolor, pregabalina es una opción desfavorable en términos de efectividad y de seguridad a altas dosis. En pacientes con dolor neuropático asociado con lesión de la médula espinal no se identificó evidencia sobre la efectividad de gabapentina o pregabalina. En la misma población, gabapentina no tiene ventajas en tolerabilidad, por su parte, pregabalina no es segura y no presenta ventajas en tolerabilidad. La calidad de la evidencia para las comparaciones de interés y desenlaces descritos es alta.

Optimization of Gabapentin Release and Targeting Absorption, Through Incorporation into Alginate Beads.

Aims: 1) To study the effect of some formulation variables on drug load, encapsulation efficiency, swelling ratio, mucoadhesion and drug release. 2) Optimize the mucoadhesion capabilities for targeting drug absorption and release-controlling capabilities of alginate beads. Methodology: Alginate beads were prepared by dripping sodium alginate gel into calcium chloride solution and then dried overnight at ambient temperature. The effects of alginate concentration, cross linker concentration, cross linking time, volume of cross linking solution and drug/polymer ratio on drug load, encapsulation efficiency, swelling ratio, mucoadhesion and drug release were investigated. Formulae containing sodium lauryl sulfate (SLS), gabapentin-ethylcellulose solid dispersion, mixture of free drug and solid dispersion were prepared for modifying the drug release rate. Results: Mucoadhesion of alginate beads was shown to be decreased upon adding SLS (30% after 8 hrs). Drug release was so fast (92.46% after 2 hrs). The incorporation of solid dispersion has led to well accepted mucoadhesion (74.44% after 8 hrs) as well as release properties (93.35% after 10 hrs) Beads containing mixtures of drug and ethylcellulose-drug solid dispersion showed acceptable mucoadhesion (74.44% after 8 hrs) and control of gabapentin release (93.35% after 10 hrs). Statistical analysis of variance between groups was performed using the one-way layout ANOVA with duplication. Significant differences in mean values were evaluated by Student's unpaired t test (P < 0.05). Conclusion: A finally optimized formula was suggested by incorporating a combination of solid dispersion and free gabapentin in alginate system to achieve burst release of gabapentin and hence fast effect (33.417% was released during the first 30 minutes in fasting-simulated conditions) and controlled release (91.217% after 6 hrs).

Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: A randomized, double-blind placebo controlled trial.

Aims and Objectives: We evaluated the efficacy of perioperative pregabalin on acute and chronic post-operative pain after off-pump coronary artery bypass (OPCAB) surgery. Materials and Methods: Forty patients undergoing elective OPCAB surgery were randomized to pregabalin and control groups. Pregabalin group received 150 mg pregabalin 2 h prior to induction of anesthesia and 75 mg twice daily for 2 post-operative days whereas the control group received placebo at similar timings; pregabalin and placebo were administered by an anesthesiologist blinded to the drugs. Pain scores (visual analogue scale [VAS]) and sedation scores were observed at 0, 4, 6, 12, 24, 36 and 48 h after extubation. Time to extubation, tramadol consumption and side-effects were noted. VAS score was analyzed by Mann-Whitney U test. The analysis of variance test for repeated measures was used for comparison of the means of continuous variables. Group comparisons were made using the Chi-square-test. Results: Pain-scores at 6, 12, 24 and 36 h from extubation at rest and at deep breath were less in pregabalin treated patients ( P < 0.05). Tramadol consumption was reduced by 60% in pregabalin group ( P < 0.001). Extent of sedation, extubation times and incidence of nausea were comparable. The effect on chronic post-operative pain was not significant. Conclusions: Perioperative pregabalin reduced pain scores at rest and deep breath and reduced consumption of tramadol in the post-operative period without delaying extubation and causing excessive sedation.

Role of pregablin in neuropathic pain

To evaluate the role of pregablin in neuropathic pain. Prospective descriptive study. This study was conducted in the department of medicine of Al-Tibri Medical College and Hospital from Jan. 2011 to Jan 2012. A prospective study conducted in a private hospital of Karachi from Jan 2011 to Jan 2012. A total 107 cases were enrolled. All patients are adult above 18 years of age. The neuropathic pain was analyzed by Leeds Assessment of Neuropathic symptoms and sign [LANSS]. The pain was assessed by numeric pain rating scale. The data was recorded on a preset performa. Primary disease was also controlled and all the patients were given pregablin 50-150mg/day for two-six weeks. The symptoms were re assess by numeric pain scale. The SPSS 16 used to analysed. Total number of patients were 107. Male were 52 while female were 55. The patients were grouped according to pathology. The most common pathology was Diabetes in 49 cases [45.79%] followed by hypertension in 35 cases [32.71%] and herpes zoster in 27 cases [25.23%]. The age ranges from 42-72 years with mean age is 56.66 +/- 16. The dose ranges from 50-150 mg per day and the duration of treatment were two- six weeks. The pregablin was superior in relieving pain and sleep in patient with diabetic neuropathy and post herpetic neuralgias. The adverse effects noted were somnolence, lethargy and ataxia. Two of the cases were stopped treatment due to somnolence. The result of adding pregablin in the treatment of a patient with neuropathic pain was very successful and it is improving the quality of life and sleep

Comparison of analgesic effects of oral carbamezapine with pregablin in idiopathic trigeminal neuralgia

Idiopathic trigeminal neuralgia, a form of neuropathic pain, caused by not well defined etiology, is a formidable therapeutic challenge to clinicians because it does not respond well to traditional drug therapies. Anticonvulsant drugs are regarded as useful treatment for neuropathic pain. Carbamazepine, the first anticonvulsant studied in clinical trials, probably alleviates pain by decreasing conductance in Na[+] channels and inhibiting ectopic discharges. Pregabalin has the most clearly demonstrated analgesic effect for the treatment of neuropathic pain. The role of anticonvulsant drugs in the treatment of Idiopathic trigeminal neuralgia is evolving and has been clearly demonstrated with Pregabalin and carbamazepine. The aim of this study was to investigate comparison of analgesic effects of oral carbamezapine with pregablin in idiopathic trigeminal neuralgia. Interventional study. Oral and Maxillofacial surgery department, LUMHS. Jan 2012 to DEC 2012 . 30 patients with well defined history and diagnostic clinical symptoms of idiopathic trigeminal neuralgia were selected, divided into two groups of 15 individuals with similar gender and age difference. Clinical trial were conducted with group 1 with carbamazepine and group 2 with Pregabalin for 4 weeks. Subjective pain level of both groups was recorded before intervention [pre treatment recording] and after intervention [1[st], 2[nd], 3[rd] and 4[th]] on weekly basis by using 0-10 visual analogue scale [zero represent no pain 10 represent pain that could not be worse]. Following intervention, both groups were evaluated for pain score in 1[st] and 2[nd] week, there was no significant difference observed between the two groups. [P value 0.44 and 0.456], but after 3[rd] and 4[th] weeks it was observed that, there is significant difference, [p value 0.000 and 0.009] on visual analogue scale. It was observed that there was a significant difference between pretreatment and fourth week mean pain score in group 2, [8.9 and 1.07]. Similarly marginally significant difference with [r = .640] was seen in 1[st] week of group 2 receiving Pregablin, the mean value was [2.53, 1.60] respectively. Based on these results that are in line with the recommendations made by other studies, the 1[st] line medical therapy is Carbamazepine but this should be changed to other drug therapy if there is no pain relief or adverse effect

Pregabalin in muscular cramps [charely hoarse] a new application

Pregabalin is a newly introduced medicine which is an analogue to Gaba pentin and similar to its structure, it was approved by the FDA in 2004 and marketed by Pfizer company under the name of LARYICA. It has been described in various medical disorders among which are: neuropathic pain as that of diabetes [1,2], post herpetic neuralgia [3], seizure disorders [4] and anxiety state [5]. Pregabalin the first medicine approved for treatment of fibromyalgia by the FDA [6,7] Pharmacologically Pregabalin bind to alpha 2 delta subunit of the voltage-dependent calcium channels in the central nervous system, it also decrease the releases neurotransmitters such as glutamate, noradrenalin and the substance P [8,9]. Though FDA label indications are; diabetic peripheral neuropathy, fibromyalgia, Post herpetic neuralgia and as an adjunct in seizure, yet Pregabalin have been Used in many other conditions on empirical bases as a treatment of a single case Or more as in post operative Pain [10] or hot flash [11] beside other diseases. Herewith I am reporting an unusual clinical observation never been described before, the Night Muscular cramps in the Legs collegially known as "Charley hoarse" known by Iraqis as "ABU SLSHERGATE"

The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid- sparing effect in patients undergoing off-pump coronary artery bypass grafting.

The clinical study was designed to evaluate and compare single preoperative dose of pregabalin to a placebo regarding hemodynamic responses to laryngoscopy and endotracheal intubation, to assess perioperative fentanyl requirement and any side-effects. It was a randomized, double-blind, placebo-controlled, parallel assignment, efficacy study. The study was done at a tertiary university hospital. This study was a comparison between two groups of 30 adult patients scheduled for elective off pump coronary artery bypass surgery. In the control group, the patients were given placebo capsules, and in the pregabalin group, the patients were given pregabalin 150 mg capsule orally 1 h before surgery. The patients were compared for hemodynamic changes before the start of the surgery, after induction, 1, 3, and 5 min after intubation. Additionally, fentanyl requirement during surgery and the first postoperative day was also compared. The present study shows that a single oral dose of 150 mg pregabalin given 1 h before surgery attenuated the pressor response to tracheal intubation in adults, but the drug did not show any effect on perioperative opioid consumption and was devoid of side-effects in the given dose.

Eye-related visual hallucinations: Consider ‘Charles Bonnet syndrome’.

The Charles Bonnet Syndrome (CBS) is typically characterized by visual hallucinations in elderly people without cognitive defects. This article presents the case of an 80-year-old male patient with a one-year history of visual hallucinations, secondary to glaucoma, in both eyes. Neither a dopamine agonist nor cholinesterase inhibitor therapy improved his symptoms. In this case, the hallucinations were gradually improved after administration of a GABAergic drug, pregabalin, for diabetic polyneuropathy. Placebo-controlled clinical trials would be needed to support this effect of pregabalin, as suggested by this association.

Pregabalin as a Neuroprotector after Spinal Cord Injury in Rats: Biochemical Analysis and Effect on Glial Cells

As one of trials on neuroprotection after spinal cord injury, we used pregabalin. After spinal cord injury (SCI) in rats using contusion model, we observed the effect of pregabalin compared to that of the control and the methylprednisolone treated rats. We observed locomotor improvement of paralyzed hindlimb and body weight changes for clinical evaluation and caspase-3, bcl-2, and p38 MAPK expressions using western blotting. On histopathological analysis, we also evaluated reactive proliferation of glial cells. We were able to observe pregabalin's effectiveness as a neuroprotector after SCI in terms of the clinical indicators and the laboratory findings. The caspase-3 and phosphorylated p38 MAPK expressions of the pregabalin group were lower than those of the control group (statistically significant with caspase-3). Bcl-2 showed no significant difference between the control group and the treated groups. On the histopathological analysis, pregabalin treatment demonstrated less proliferation of the microglia and astrocytes. With this animal study, we were able to demonstrate reproducible results of pregabalin's neuroprotection effect. Diminished production of caspase-3 and phosphorylated p38 MAPK and as well as decreased proliferation of astrocytes were seen with the administration of pregabalin. This influence on spinal cord injury might be a possible approach for achieving neuroprotection following central nervous system trauma including spinal cord injury.

Fast tracking possibility after outpatient anorectal surgery using "pregabalin" within multimodal analgesic regimen and monitored anaesthesia care technique

Pregabalin is a gabapentinoid compound, which has been alleged to possess anxiolytic, analgesic and anticonvulsant properties. Therefore, we designed a study to evaluate if the routine use of oral Pregabalin 150 mg within multimodal analgesic regimen [Dexamethasone-ketorolac-surgical field infiltration with local anesthetic mixture] would facilitate the early recovery process after anorectal surgery. Sixty adult outpatients undergoing anorectal surgery with standardized monitored anesthesia care technique were studied with one half of them receiving oral Pregabalin 150 mg. The other half of the Sixty patients is control group. All patients were received dexamethasone 4 mg IV and ketoraic 30 mg IV before induction. All patients were premedicated with midazolam 2 mg IV. A propofol infusion, 50 micro g kg[-1]. Min[-1] IV, was initiated and subsequently titrated to maintain an observer's assessment of alertness/sedation score 2 or 3 [with 5 awake/alert to 1=a sleep]. Fentanyl 25 micro g IV was administered 3-5 mm before infiltrating the surgical field with 30 ml local anesthetic mixture containing 15 ml of lidocaine 1% and 15 ml of bupivacaine 0.25% [with epinephrine 1:200.000]. All patients were fast-tracked directly from the operating room to the step-down recovery area. Even thought the incidences of postoperative pain and postoperative nausea and vomiting were small in both treatment groups, the time to "home readiness" was significantly shorter in the Pregabalin group. Pregabalin 150 mg PO within multimodal analgesic regimen. Shortened the time to home readiness after outpatient anorectal surgery

Anti-spasticity medications

Spasticity is common in patients with a variety of central nervous system disorders. It can lead to significant disability or cause complications that may result in severe morbidity. In such patients, treatment of spasticity is warranted. Several oral and parenteral medications are available for use in the treatment of spasticity. This article reviews the pharmacological properties and therapeutic effectiveness of these medications to provide a practical objective guide for physicians who may be involved in the management of spasticity

N-Phthaloyl gamma-aminobutyric acid affects biochemical circadian rhythms in Wistar rats.

N-Phthaloyl gamma-aminobutyric acid (P-GABA) was administered to Wistar rats and 24 hr rhythms of glucose, cholesterol, total protein and lactic acid levels in blood were studied under semi-natural light dark conditions. P-GABA administration caused desynchronisation of the rhythms; while glucose and lactic acid rhythms were advanced, cholesterol and total protein rhythms were delayed. Since GABA is being involved in conveying dark information to the clock, exogenous administration of P-GABA may reduce the photic information received by the clock. The results could be explained by slightly less than 1 hr daily delays (or) advances respectively which would bring the peak times to the points 21 days after the start of administration.

Temporal oscillations of phosphatases in N-phthaloyl gamma-aminobutyric acid treated rats.

N-pathaloyl gamma-aminobutyric acid (P-GABA) was administered to Wistar and 24 hr rhythms of acid and alkaline phosphatases were studied under light-dark conditions. P-GABA administration advanced the peak times of phosphatases. Since GABA is being involved in conveying dark information to the clock, exogenous administration of P-GABA might reduce the photic information received by the clock. The results could be explained by slight daily advances which would bring the peak times to the points 21 days after the start of administration.

Antistress activity of P-GABA in experimental animals.

A new gamma-aminobutyric acid derivative N-phthloyl GABA (P-GABA) was found to possess anticonvulsant, antiepileptic, antiulcer and antinociceptive activities. Effect of cold restrain stress (CRS) and its modulation by P-GABA were evaluated on some biochemical and biophysical parameters in rats. CRS induced elevations in blood sugar level were unaffected by P-GABA treatment. CRS also caused an increase of Na+K+ ATPase activities, and decrease of lipid peroxidation in RBC membrane. CRS also induced (a) membrane protein clusterization, (b) increased membrane fluidity and (c) reduced thickness. CRS induced RBC membrane dynamics were reversed by P-GABA in a differential manner. However, these parameters in synaptosomal membrane were unaffected by P-GABA.

Anti-stress activity of N-phthaloyl gamma-aminobutyric acid in rats.

The effect of immobilization restraint stress (RS) on some biochemical and biophysical parameters in rats and their modulation by N-phthaloyl gamma-aminobutyric acid (P.GABA) was studied. RS did not affect the levels of serum Ca2+, inorganic phosphate, bilirubin, total protein, but caused insignificant increase of albumin level and significantly decreased the cholesterol level. This RS induced decrease of serum cholesterol level was reversed by prior treatment with P.GABA, while the albumin content showed a decrease. RS-induced a generalised increase in serum enzyme activity of lactate dehydrogenase (LDH), alkaline phsophatase (AIP), serum glutamate pyruvate transaminase (SGPT) and serum glutamate-oxaloacetate transaminase (SGOT). P.GABA normalised RS-induced increase of LDH and AlP activity, but it further enhanced SGOT and SGPT activities. In synaptosomal membranes, RS caused a decrease in clusterization and fluidity, but the thickness of the membrane increased as studied by fluorescence probes. Prior administration of P.GABA normalised the changes observed in the synaptic membrane.

La epilepsia refractaria del adulto y los antiepilépticos nóveles: el rol de la gabapentina / Refractary epilepsy in adults and new antiepileptic drugs: role of gabapentin

The features of refractory epilepsies and the role of functional surgery and new antiepileptic drugs is reviewed. Among the latter, gabapentin, a drug with peculiar pharmacokinetic properties, is highlighted as a therapeutic alternative in refractory epilepsies and eventually for epileptic patients without previous treatment. A new type of relationship between the pharmaceutical industry and physicians, that privileges clinical research is discussed