3-Chloro,4-methoxyfendiline is a potent GABA(B) receptor potentiator in rat neocortical slices.

Using grease-gap recording from rat neocortical slices, the GABA(B) receptor agonist baclofen elicited reversible and concentration-dependent hyperpolarizing responses (EC50=18+/-2.3 microM). The hyperpolarizations were antagonised by the GABA(B) receptor antagonist Sch 50911 [(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid). (+)-N-1-(3-chloro-4-methoxyphenyl)ethyl-3,3-diphenylpropylamine (3-chloro,4-methoxyfendiline; 3-Cl,4-MeO-fendiline) reversibly potentiated baclofen-induced hyperpolarizing responses, which were reduced by Sch 50911, producing leftward shifts of the baclofen concentration-response curves, with a marked increase in the maximal hyperpolarization (EC50=2+/-0.5 microM). In slices preincubated with either [3H]GABA or [3H]glutamic acid, 3-Cl,4-MeO-fendiline (1 microM) potentiated the inhibitory effect of baclofen (2 microM) on the electrically evoked release of [3H]GABA and had a similar effect on the release of [3H]glutamic acid at a concentration of 0.5 microM, without affecting the basal release. These effects were blocked by Sch 50911 (10 microM). Our findings suggest that 3-Cl,4-MeO-fendiline is a potent potentiator of pre- and postsynaptic GABA(B) receptor-mediated functions.

Clinical potential of GABAB receptor modulators.

Metabotropic gamma-aminobutyric acid(B) (GABAB) receptors for the major inhibitory transmitter GABA, together with metabotropic glutamate (mGLuRs) receptors, the extracellular calcium-sensing receptors (CaSRs), some V2R pheromone receptors and T1R taste receptors, belong to the family of 3 G-protein-coupled receptors (GPCRs). GABAB receptors are known to control neuronal excitability and modulate synaptic neurotransmission, playing a very important role in many physiological activities. These receptors are widely expressed and distributed in the nervous system and have been implicated in a variety of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, depression, schizophrenia and drug addiction. To form a functional receptor entity, GABAB receptors must exist as a heterodimer consisting of GABAB1 and GABAB2 receptor subtypes with two 7-transmembrane proteins, and these subunits arise from distinct genes. The GABAB1 subunit binds the endogenous ligand within its extracellular N-terminus, whilst the GABAB2 subunit is not only essential for the correct trafficking of the GABAB1 subunit to the cell surface, but is also responsible for the interaction of the receptor with its cognate G-protein. Allosteric modulation has recently been recognized as an alternative pharmacological approach to gain selectivity in drug action. It is now generally accepted that modulators acting at the allosteric sites provide a novel perspective for the development of subtype-selective agents acting at GPCRs. These agents interact with allosteric binding sites quite separate from the highly conserved agonist binding region. In this review, we present a new class of phenylalkylamines, based on the lead compound fendiline, that are potent positive potentiators of GABAB receptor-mediated function and discuss their putative clinical applications. It is proposed that these new modulators may have therapeutic value in GABAB receptor pharmacology and are capable of selectively modifying GABAB receptor function. The allosteric modulators are offering an attractive and novel means to identify new leads, that are devoid of side effects associated with GABAB receptor agonists, and may, therefore, represent a major advance in the drug discovery process.

Gabapentin activates presynaptic GABAB heteroreceptors in rat cortical slices.

In electrically stimulated rat neocortical brain slices preloaded with [3H]gamma-aminobutyric acid (GABA) or [3H]glutamic acid, the pharmacological actions of 1-(aminomethyl)-cyclohexaneacetic acid (gabapentin, Gp) were compared with the GABAB receptor agonists baclofen (Bac) and (3-amino-2-(S)-hydroxypropyl)-methylphosphinic acid (CGP 44532). Gabapentin, baclofen and CGP 44532 all reduced the electrically stimulated release of [3H]glutamic acid (IC50=20 microM, 0.8 microM and 2 microM, respectively). These effects were sensitive to the GABAB receptor antagonists (+)-(S)-5,5 dimethylmorpholinyl-2-acetic acid (Sch 50911) or N-3-[[1-(S)-(3,4-dichlorophenyl)ethyl]amino]-2-(S)-hydroxypropyl-P-(cyclo-hexylmethyl)-phosphinic acid (CGP 54626). By contrast, gabapentin was without effect on the release of [3H]GABA, whilst baclofen (IC50=8 microM) and CGP 44532 (IC50=1 microM) inhibited [3H]GABA release. It is concluded that gabapentin selectively activates presynaptic GABAB heteroreceptors, but not GABAB autoreceptors, and may be a useful ligand to discriminate between presynaptic GABAB receptor subtypes.

Potentiation of metabotropic GABAB receptors by L-amino acids and dipeptides in rat neocortex.

Selected neutral L-alpha-amino acids, and their dipeptides, were reversible, stereospecific, potentiators of GABA(B) receptor-mediated hyperpolarizing responses to baclofen (3-100 microM) in rat neocortical slices. These responses were sensitive to the GABA(B) receptor antagonist (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch50911) (30 microM). Most potent were L-Leu, L-Ile and L-Phe, as were the dipeptides L-Phe-Phe and L-Phe-Leu, and less potent were L-Met, L-Val, L-Cys, L-Cystine, L-Tyr, L-Thr, L-Arg and L-Ser. Inactive were L-Trp, L-His, L-Lys and L-Pro. These potentiators gave leftward shifts of the baclofen concentration-response curves with a Hill slope of 2, and a marked increase in the maximal hyperpolarizing responses. Selected L-amino acids and dipeptides are a class of naturally occurring GABA(B) potentiators, which may be allosteric modulators.

Arylalkylamines are a novel class of positive allosteric modulators at GABA(B) receptors in rat neocortex.

Using grease-gap recording from rat neocortical slices, the gamma-aminobutyric acid(B) (GABA(B)) receptor agonists baclofen (3-100 microM) and SKF 97541 (3-aminopropyl-methylphosphinic acid) (1-30 microM) elicited reversible and concentration-dependent hyperpolarizing responses, with EC(50) values of 10 and 3 microM, respectively. The hyperpolarizations were antagonised by the GABA(B) receptor antagonist Sch 50911 ((+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid) (1, 5 and 10 microM). Fendiline (N-[3,3-diphenylpropyl)-alpha-methylbenzylamine) (5-50 microM) and its congeners, prenylamine (N-[3,3-diphenylpropyl)-alpha-methylphenylethylamine) (10-100 microM) and F551 (N-[3,3-diphenylpropyl)-alpha-methyl-3-methoxybenzylamine) (1-30 microM) reversibly enhanced hyperpolarizing responses to the agonists; such effects were reduced by Sch 50911. These arylalkylamines produced leftward shifts of the concentration-response curves, with a marked increase in the maximal hyperpolarization obtained, compared with the agonists alone, F551 being the most potent. These findings suggest that these arylalkylamines represent a new class of positive modulators of GABA(B) receptor-mediated function.

Redo cardiac surgery in a patient with severe peripheral vascular disease and pericardial adhesions using subclavian arterial cannulation and port-access technology.

Patients viewed as conventionally inoperative candidates are now given alternative surgical choices. The ability to provide new technology such as the port-access minimally invasive approach, kinetic venous assist, and specialized cannulae have made this possible. This case report discusses the ability to apply and modify this new technology to provide a successful surgical outcome in a patient with severe peripheral vascular disease and dense mediastinal adhesions.

Cost and length of hospital stay: comparisons between nonthoracotomy and epicardial techniques in patients receiving implantable cardioverter defibrillators.

Twenty-five patients with implantable cardioverter defibrillators (ICDs) implanted intrathoracically (group I) were compared with 25 patients who underwent implant using the nonthoracotomy approach (group II). All systems were implanted by the same medical team, in the same high volume implanting center. Indications for implantation were comparable in both groups. Patient characteristics were not statistically different with the exception of age (66-group I vs 71-group II; P < 0.05). Although left ventricular ejection fractions appeared to differ (32% vs 37%, respectively), this difference was not statistically significant (P = 0.06). ICD models used in group I were: Ventritex Cadence (16), Telectronics Guardian 4211 (2), Medtronic PCD (7); in group II they were: Ventritex Cadence (15), Guardian 4211 (2), and CPI 1600 (1). Total length of hospital stay was 16 +/- 6 days for group I versus 12 +/- 5 for group II (P < 0.05). Number of postoperative days in an intensive care unit was 3.2 +/- 2.8 for group I versus 0.5 +/- 0.6 for group II (P < 0.0001). Postoperative length of stay was 8.2 +/- 3.1 for group I versus 5.7 +/- 4.4 for group II (P < 0.001). Mean total hospital charges for the entire length of stay were $72,918 +/- $26,770 in group I versus $55,031 +/- $42,870 in group II, representing a mean reduction of 21% in global costs for group II patients. These data confirm that nonthoracotomy ICD implantation in an experienced center is associated with significantly shorter hospital stays, a virtual elimination of the need for postoperative intensive care, and globally lower total hospital costs. In addition, the presence of a statistically older population in group II does not negate these beneficial effects.

Simplified subxiphoid placement of implantable cardioverter defibrillators using a posterior rectus pocket.

A simplified subxiphoid procedure using a single longitudinal epigastric incision and posterior rectus pocket for implantable cardioverter defibrillators was used in 100 patients. Through a single incision, ventricular patches are placed via a transverse pericardiotomy, and a pouch is created behind the rectus abdominis muscle in the left upper quadrant for placement of the implantable cardioverter defibrillator. Patients have minimal discomfort soon after operation, and the implantable cardioverter defibrillator generator is imperceptible to most.

Changing trends in therapy delivery with a third generation noncommitted implantable defibrillator: results of a large single center clinical trial.

Thirty-four patients underwent implantation of a third generation ICD, the 4210 ATP, for sudden cardiac death or ventricular tachycardia. This device incorporates significant telemetry logs as well as a detailed analysis of each arrhythmia episode detected. During the period of clinical follow-up, a mean of 12.2 months, a total of 26,569 VT or VF detections were made. The vast majority of these were either due to atrial fibrillation, nonsustained VT, or "noise" detection, and only 6% led to device therapy. ATP was successful in 86.3% of episodes, with 3.5% accelerations and 2.4% failure of ATP trains. The majority of inappropriate therapy episodes were clustered in seven patients, and all were easily diagnosed with the aid of the extensive telemetry logs and sense histories. Of five late deaths, three were from congestive heart failure, one from cerebrovascular accident, and one unknown. These data reveal that this "tiered" therapy noncommitted ICD performs to expectations; the stored data is of significant value in diagnosing the cause of ICD therapy. In addition, ATP is an effective modality for termination of VT.

Improved patient surveillance and data acquisition with a third generation implantable cardioverter defibrillator.

Thirteen patients were implanted with the Telectronics 4210 ATP implantable cardioverter defibrillator (ICD) for ventricular tachycardia or ventricular fibrillation. This device has multiprogrammable antitachycardia pacing, bradycardia pacing, and shock therapies. In addition, there is extensive data logging and ECG snapshot capability for arrhythmia confirmation and response to therapy. These features permit easy retrieval of all detected and treated events, whatever the eventual outcome. In this study, the data logged at predischarge electrophysiological testing was compared to the data recorded in a standard manner. The bulk of the data, however, was derived from long-term follow-up of spontaneous events over a mean period of 203 days (range 154-257). During this period, a total of 6,193 arrhythmia detections were made: 20 were classified as ventricular fibrillation, and 6,173 as ventricular tachycardia. The vast majority of these (93%) terminated spontaneously without ICD intervention (5,738), underscoring the benefit of a standard second confirmation prior to therapy delivery (noncommitted system). There were 394 arrhythmia episodes treated with antitachycardia pacing; of these a total of 8.3% accelerated to either more rapid ventricular tachycardia or ventricular fibrillation (4.3% and 4.0%, respectively). Events were reported in an "episode log" format, listing all arrhythmia detections with time/date annotation; or in a "sense history" format, detailing each episode from start to conclusion. These data demonstrate that this advanced, "tiered" ICD with data recall contributes to better patient management, and permits a more tailored termination prescription for the individual patient.

Rational use of antibiotics for perforated appendicitis in childhood.

Gangrenous and perforated appendicitis was reviewed in 300 pediatric patients. Those with only gangrene generally had a benign course regardless of whether antibiotic therapy was used. However, patients with local perforation or generalized peritonitis had a high incidence of infective complications if they were not treated with antibiotics. Children treated with ampicillin, gentamicin, and clindamycin had markedly fewer wound infections and abscesses and were able to tolerate a diet and go home sooner than those receiving ampicillin and/or gentamicin.