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J Rhodes

Publications and source records attributed to J Rhodes.

At least 37 records · Page 2Linked to original sources
PubMed2001

Anesthesia protocol for hyperpnea-induced airway obstruction in the guinea pig.

Guinea pigs (GP; Cavia porcellus) are used extensively as an experimental animal model in a wide range of disciplines including respiratory physiology. Guinea pigs are difficult to anesthetize, and many investigators use paralytic agents to eliminate spontaneous respiratory movements; however, strict federal regulations and institutional policies governing use of paralytic agents are few. We report an anesthesia protocol, using the injectable anesthetic agents sodium pentobarbital (SP) and xylazine (XYL) for the GP that induces consistent anesthesia while eliminating use of paralytic agents. Sixty percent of the calculated SP dose (45 mg/kg of body weight) was given for anesthesia induction, followed by 50% of the calculated XYL dose (7 mg/kg) 15 min later. Depth of anesthesia was monitored by response to toe pinch, ECG, and spontaneous respiratory movements. The animals were given additional boosts of SP (5 to 15% of the original dose, i.p. or i.v.) if a change in anesthesia depth was noted. Thirty-one animals completed the hyperpnea-induced bronchoconstriction (HIB) study with no fatalities. Using this protocol, we collected consistent, repeatable, and reliable data without use of propranolol or skeletal muscle paralytics. We believe that this protocol is not restricted to the GP and could be adapted for use in other terminal experiments.

Airway Obstruction↗
PubMed2000

In vitro immunomodulatory properties of tucaresol in HIV infection.

The immunomodulatory properties of tucaresol (compound 589C80) were tested on in vitro antigen- and mitogen-stimulated proliferation and cytokine production by peripheral blood mononuclear cells (PBMC) of HIV-infected individuals and healthy controls (HC). Results showed that tucaresol: (1) increases influenza A virus-, gp 160 peptide-, and HLA alloantigen-stimulated proliferation as well as interleukin (IL)-2 and interferon gamma (IFN gamma) production by PBMC of HIV-infected individuals with higher CD4 counts (>500/microl) but had only a marginal immunomodulatory effect on PBMC of patients with lower CD4 counts (<500/microl); (2) did not modify IL-10 production; (3) augmented CD25 expression on mitogen-stimulated T cells of HC but not of HIV-infected individuals; and (4) marginally increased CTL activity. The immunomodulatory properties of tucaresol were confirmed by PCR analyses; additional data showed that tucaresol costimulated CD3-dependent triggering of T cells and that this stimulation was independent of CD28 costimulation. The immunomodulatory effects of tucaresol on T cell functions are characterized by a bell-shaped dose response curve; the action of the compound is optimal in the 100 to 300 microM range. Analyses of mitogen-stimulated apoptosis demonstrated that the lack of effect of tucaresol at higher doses is not the result of increased cell death, suggesting a role of functional impairment. These data confirm that tucaresol can stimulate T helper cell function and enhance the production of type 1 cytokines, thus eliciting cell-mediated immunity, and warrant its potential utility in the therapy of HIV infection.

Adjuvants, Immunologic↗
PubMed2000

CrkL functions as a nuclear adaptor and transcriptional activator in Bcr-Abl-expressing cells.

OBJECTIVE: To identify tyrosine phosphorylated proteins that interact with CrkL in Bcr-Abl-expressing cells and analyze the function of that association. MATERIALS AND METHODS: Immunoprecipitation of CrkL was performed on lysates from parental cells (Rat-1, MO7e, or 32D) or Bcr-Abl-expressing cells (Rat-1p185, MO7p210, 32Dp210, K562) followed by immunoblotting for pTyr, Stat5, or CrkL. Interactions were confirmed in vitro using GST-CrkL fusion proteins. Electrophoretic mobility shift assays were performed on K562 nuclear extracts using a beta-casein promoter-derived probe. Supershift analysis was performed with CrkL, Stat5, Stat1, Grb2, and peptide-blocked CrkL and Stat5 antibodies. CrkL localization in Rat-1 and Rat-1p185 cells was detected with indirect immunofluorescence. Transcriptional activation was analyzed in COS7 cells transfected with a Stat-responsive luciferase reporter construct and Bcr-Abl, kinase-defective Bcr-Abl, CrkL, or Grb2. RESULTS: We show that, in Bcr-Abl-expressing cells, CrkL+ interacts with tyrosine phosphorylated Stat5. Additionally, in the presence of Bcr-Abl, CrkL is found in the nucleus, can be detected in a Stat5/DNA complex, and increases transcriptional activation from a Stat-responsive reporter construct. CONCLUSION: This suggests a novel role for CrkL, functioning as a nuclear adaptor protein that can associate with and activate Stat proteins in Bcr-Abl-expressing cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Early ECG abnormalities associated with transcatheter closure of atrial septal defects using the Amplatzer septal occluder.

UNLABELLED: Conduction abnormalities and arrhythmias may occur in patients following secundum atrial septal defect (ASD) closure using the Amplatzer septal occluder (ASO). Therefore, the aim of this study was to prospectively perform ambulatory ECG monitoring to assess the electrocardiographic effects of transcatheter closure (TCC) of ASD using the ASO device. From 5/97 to 3/99, 41 patients with secundum ASD, underwent TCC using the ASO device at a median age of 9.2[emsp4 ]y. (0.5-87[emsp4 ]y.) and median weight of 34[emsp4 ]kg (5. 6-88[emsp4 ]kg.). Ambulatory Holter monitoring was performed pre- and immediately post TCC. Holter analysis included heart rate (HR), ECG intervals, supraventricular ectopy (SVE), ventricular ectopy (VE), and AV block. No change in baseline rhythm was noted in 37 patients (90%). Changes in AV conduction occurred in 3 patients (7%), including intermittent second degree AV block type II, and complete AV dissociation post closure. SVE was noted in 26 patients (63%) post closure, ranging from 5-2207 supraventricular premature beats (SVPB), including 9 patients (23%) with non-sustained supraventricular tachycardia (SVT), 3 of whom had short runs of SVT prior to closure. A significant increase in post-closure number of SVPB per hour (p=0.047) was noted. No significant difference was noted in PR interval, ventricular premature beats per hour, or QRS duration. CONCLUSIONS: Based on ambulatory ECG analysis, TCC of ASD with the ASO device is associated with an acute increase in SVE and a small risk of AV conduction abnormalities, including complete heart block. Long term follow-up studies will be necessary to determine late arrhythmia prevalence and relative frequency compared with standard surgical ASD repair.

Adolescent↗
PubMed2000

Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis.

BACKGROUND: Ulcerative colitis is a condition of nonsmokers in which nicotine is of therapeutic benefit. AIMS: To examine the in vitro effect of nicotine on colonic smooth muscle activity and the role of nitric oxide (NO) as a mediator. METHODS: Nicotine, 1-10 microM, was administered to strips of circular muscle from the distal sigmoid colon of 9 patients with active ulcerative colitis and 18 with colorectal cancer. The effect of electrical field stimulation (EFS) was examined before nicotine was added. Finally L-NAME, a NO synthetase inhibitor, was added before nicotine was administered again. RESULTS: Muscle strips developed similar spontaneous resting tone. In response to EFS, ulcerative colitis tissue developed lower tensions than the controls. Nicotine significantly reduced the resting tone and peak tension after EFS, with a greater effect in controls. With L-NAME, peak tensions were increased more in ulcerative colitis than controls, and nicotine produced a much smaller reduction. CONCLUSIONS: Nicotine reduces circular muscle activity, predominantly through the release of nitric oxide-this appears to be 'up-regulated' in active ulcerative colitis. These findings may explain some of the therapeutic benefit from nicotine (and smoking) in ulcerative colitis and may account for the colonic motor dysfunction in active disease.

Adult↗
PubMed2000

Diurnal variation in the quantitative EEG in healthy adult volunteers.

AIMS: To define the change in power in standard waveband frequencies of quantitative cortical electroencephalogram (EEG) data over a 24 h period, in a drug free representative healthy volunteer population. METHODS: This was an open, non randomised study in which 18 volunteers (9 male and 9 female) were studied on 1 study day, over a 24 h period. Volunteers had a cortical EEG recording taken at 0, 2, 4, 6, 8, 10, 12, 16 and 24 h. Each recording lasted for 6 min (3 min eyes open, 3 min eyes closed). All EEG recordings were taken in a quietened ward environment with the curtains drawn round the bed and the volunteer supine. During the 3 min eyes open, volunteers were asked to look at a red circle on a screen at the foot of the bed, and refrain from talking. RESULTS: Plots produced of geometric mean power by time of the standard wave band frequencies gave some indication of a circadian rhythm over the 24 h period for theta (4. 75-6.75 Hz), alpha1 (7.0-9.5 Hz) and beta1 (12.75-18.50 Hz) wavebands. Mixed models were fitted to both the eyes open and eyes closed data which confirmed a change in mean waveband power with time with statistical significance at the conventional 5% level (P < 0.05). CONCLUSIONS: These data indicate the presence of a diurnal variation in the cortical quantitative EEG. They support the use of a placebo control group when designing clinical trials which utilize quantitative EEG to screen for central nervous system (CNS) activity of pharmaceutical agents, to control for the confounding variable of time of day at which the EEG recordings were made.

Adult↗
PubMed2000

Activity of the novel immunomodulatory compound tucaresol against experimental visceral leishmaniasis.

Tucaresol, a novel immunomodulator, was inactive against Leishmania donovani amastigotes in both peritoneal and bone marrow macrophages in vitro at concentrations between 100 and 1 microM, with toxicity to macrophages and parasites at 300 microM. However, against L. donovani in BALB/c mice at doses between 80 and 1.25 mg/kg of body weight administered once daily by the oral route during days 7 to 11 of infection, an optimal dose of 5 mg/kg produced a 43.8 to 62.4% suppression of liver amastigotes, with significantly reduced activity at the extremes of the dose range. This response was not related to levels of infection. No interaction with the standard pentavalent antimonial sodium stibogluconate (Pentostam) was observed during this period of infection. The optimum dose of 5 mg/kg was ineffective when administered during the first week of infection and was most effective against the liver infection when administered during weeks 2 to 3 of infection (42.3 to 46.8% inhibition) and against the splenic infection when administered during week 6 of infection (59.5% inhibition). The optimum dose of tucaresol against L. donovani in C57BL/6 mice was 5 mg/kg, which produced a 40.8 to 48.7% suppression of liver amastigotes when administered in a range of 80 to 1.25 mg/kg during days 7 to 11 of infection. The drug had no activity against L. donovani infections in C.B-17 scid mice when the same regimen was used.

Adjuvants, Immunologic↗
PubMed2000

Transcriptional regulation of beta-defensin gene expression in tracheal epithelial cells.

Innate immunity provides an ever-present or rapidly inducible initial defense against microbial infection. Among the effector molecules of this defense in many species are broad-spectrum antimicrobial peptides. Tracheal antimicrobial peptide (TAP) was the first discovered member of the beta-defensin family of mammalian antimicrobial peptides. TAP is expressed in the ciliated epithelium of the bovine trachea, and its mRNA levels are dramatically increased upon stimulation with bacteria or bacterial lipopolysaccharide (LPS). We report here that this induction by LPS is regulated at the level of transcription. Furthermore, the transfection of reporter gene constructs into tracheal epithelial cells indicates that DNA sequences in the 5' flanking region of the TAP gene, within 324 nucleotides of the transcription start site, are responsible in part for mediating gene induction. This region includes consensus binding sites for NF-kappaB and nuclear factor interleukin-6 (NF IL-6) transcription factors. Gel mobility shift assays indicate that LPS induces NF-kappaB binding activity in the nuclei of these cells, while NF IL-6 binding activity is constitutively present. The gene encoding human beta-defensin 2, a human homologue of TAP with similar inducible expression patterns in the airway, was cloned and found to have conserved NF-kappaB and NF IL-6 consensus binding sites in its 5' flanking region. Previous studies of antimicrobial peptides from insects indicated that their induction by infectious microbes and microbial products also occurs via activation of NF-kappaB-like and NF IL-6-like transcription factors. Together, these observations indicate that a strategy for the induction of peptide-based antimicrobial innate immunity is conserved among evolutionarily diverse organisms.

Animals↗
PubMed2000

Role of smoking in inflammatory bowel disease: implications for therapy.

The relationship between smoking and inflammatory bowel disease is now firmly established but remains a source of confusion among both patients and doctors. It is negatively associated with ulcerative colitis but positively associated with Crohn's disease. In addition, it has opposite influences on the clinical course of the two conditions with benefit in ulcerative colitis but a detrimental effect in Crohn's disease. These differences have been the subject of much interest and scrutiny with the hope that they may offer some insight into the pathogenesis of the two conditions and possibly lead to alternative therapeutic options. Nicotine is probably the principal active ingredient in smoking responsible for the association; trials have shown it to be of some benefit in ulcerative colitis, but further research is required to establish its therapeutic role, and the relevant mechanisms responsible for its action. In this article, we review the role of smoking in inflammatory bowel disease and its implication for therapy.

Colitis, Ulcerative↗
PubMed2000

Palliative balloon pulmonary valvuloplasty in tetralogy of fallot: echocardiographic predictors of successful outcome.

Although balloon pulmonary valvuloplasty (BPV) has been advocated as a means of palliating patients with tetralogy of Fallot (TOF), the results of this procedure were not uniformly good in this patient population. The purpose of this study was to review our institutionOs experience with BPV in patients with TOF, and to determine whether echocardiographic criteria exist that may be used to identify patients likely to derive prolonged benefit from this procedure. Between 1991 and 1999, nine patients with TOF, ages 0. 4Eth 26.1 weeks (mean, 7.4 +/- 7.6 weeks) underwent BPV due to cyanosis and other associated medical conditions (e.g., coronary artery anomalies, small size) that rendered immediate surgical intervention undesirable. Data from the catheterization and pre-BPV echocardiograms were analyzed. All patients had at least transient improvement in oxygen saturation. However, 4 patients (Group 1) required intervention (1 open-heart repair, 3 palliative shunts) within 5 weeks of BPV due to recurrent desaturation. In the remaining 5 patients (Group 2), open-heart repair was delayed 8Eth 36 weeks (mean, 23 +/- 13 weeks). Groups 1 and 2 did not differ regarding pulmonary valve annulus, main pulmonary artery or branch pulmonary artery diameter. However, the diastolic diameter of the right ventricular outflow tract (RVOT) was significantly smaller in Group 1 (18.3 +/- 3.5 mm/m2 versus 24.4 +/- 4.1 mm/m2 in Group 2; p < 0.05). Four out of five patients with a RVOT diameter < 23 mm/m2 were in Group 1, and all patients with RVOT diameter greater than 25 mm/m2 were in Group 2. We conclude that BPV can effectively palliate patients with TOF whose RVOT diastolic diameter is > 25 mm/m2. However, patients with a diastolic RVOT diameter < 23 mm/m2 are unlikely to have sustained improvement following BPV.

Cardiac Catheterization↗
PubMed1999

Histopathologic comparison of human coronary in-stent and post-balloon angioplasty restenotic tissue.

Histomorphometric studies for smooth muscle cells, macrophages, tissue factor, collagen, and cell proliferation were performed on 20 atherectomy specimens from patients with in-stent restenosis and 20 specimens from patients with post-balloon PTCA restenosis. Smooth muscle cell content was larger and proliferation index was higher in in-stent restenotic tissue; macrophage, tissue factor, and collagen content were larger in post-balloon percutaneous transluminal coronary angioplasty restenotic tissue, suggesting a more cellular and proliferative response with less thrombogenic potential in human tissue from in-stent restenosis than tissue from post-balloon percutaneous transluminal coronary angioplasty restenosis.

Aged↗
PubMed1999

Echocardiographic characteristics of successful deployment of the Das AngelWings atrial septal defect closure device: initial multicenter experience in the United States.

The AngelWings device is a newer transcatheter device used for closure of secundum atrial septal defects (ASD) and patent foramen ovale (PFO), which consists of a self-centering, 2-disk system. Transesophageal echocardiography (TEE) plays a pivotal role in the deployment of the 2 disks of this device, on the appropriate sides of the atrial septum. The objective of this study is to describe the echocardiographic findings associated with successful deployment of the AngelWings device for closure of ASD and PFO. We evaluated the TEE studies of 70 patients enrolled in 4 United States centers, for closure of ASD and PFO with the AngelWings device. The TEE characteristics of successful and unsuccessful deployments were analyzed. Residual shunts across the atrial septum were assessed by TEE at the end of the procedure, 24 hours later by transthoracic echocardiography, and at 6 months by TEE. The deployment of the device was successful in 65 patients (93%). In the unsuccessful group, ASD size by TEE was larger (13.4 +/- 3.1 vs 8.9 +/- 4.7 mm, p <0.05). TEE was successful in identifying snagging of the device by intracardiac structures and prolapse of corners of the left or right atrial disk through the ASD, features that were difficult to identify by fluoroscopy. The echocardiographic characteristics outlined here are important guidelines for successful deployment of the AngelWings device.

Adolescent↗
PubMed1999

Three-dimensional echocardiographic analysis of valve anatomy as a determinant of mitral regurgitation after surgery for atrioventricular septal defects.

Mitral regurgitation (MR) is a significant complication after atrioventricular septal defect (AVSD) surgery. The relation of the valve leaflet morphology and the MR mechanism remains a conundrum. Two-dimensional echocardiography depicts leaflet edges, whereas volume-rendered 3-dimensional echocardiography provides direct visualization of the surface areas of the mitral valve leaflets. This study examines the relation of mitral valve anatomy as determined by 3-dimensional echocardiography with MR origins in patients after AVSD repair. Twenty-seven patients with AVSD surgery and Doppler color MR were prospectively enrolled (median age was 5 years and 16 patients had Down syndrome). Doppler color flow imaging of the MR jet and 3-dimensional echocardiography of the mitral valve were performed with a probe in the transthoracic or transesophageal position. Enface 3-dimensional views of the mitral valve from the left atrium were reconstructed. Analysis of the 3-dimensional data was possible in 21 of the 27 patients. Mean area ratios of the 3 mitral leaflets were calculated (superior 40 +/- 7%, inferior 35 +/- 5%, mural 25 +/- 6%). Both intra and interobserver variability on the area measurements were <5%. In 12 patients (group 1) the jet appeared to emanate medially from the region of coaptation of the superior and inferior components of the anterior leaflet. In 9 patients (group 2) the jet emanated more laterally from the region toward the mural leaflet. The area ratios of the inferior leaflet were 32 +/- 4% in group 1 and 38 +/- 6% in group 2 (p = 0.02). The area ratios of the mural leaflet were 28 +/- 5% in group 1 and 21 +/- 5% in group 2 (p = 0.007). The superior leaflet area ratio was not different in groups 1 and 2, 40 +/- 9% and 41 +/- 6%, respectively. Three-dimensional echocardiography provides new insight into the anatomic determinants of MR following AVSD surgery.

Adolescent↗
PubMed1999

Long-term outcome of transcatheter coil closure of small to large patent ductus arteriosus.

Coil closure of patent ductus arteriosus (PDA) has become an accepted alternative to surgical closure in most pediatric cardiac centers. However, little is known about the mid-to long-term outcome of this procedure. Therefore, we evaluated the immediate, short-, and long-term outcome of transcatheter coil closure (TCC) of PDA using single or multiple Gianturco coils or the Gianturco-Grifka Vascular Occlusive Device (GGVOD). One hundred forty-nine patients underwent an attempt at TCC of their PDAs at a median age of 2.4 years (2 weeks to 55 years) and median weight of 13.5 kg (2.3-87 kg). There were 33 patients < 1 year of age. The median PDA minimal diameter was 2 mm (0.4-7 mm) with 26 patients whose PDA minimal diameter was > 4 mm. A 4 Fr catheter was used for coil deployment in 136 patients, a 3 Fr in 4, and an 8 Fr in 4 patients who received the GGVOD. A single coil was used in 77 patients and multiple coils (2-6) were used in 66 patients. One hundred forty-six patients had successful closure (142 had immediate complete closure and 4 had residual shunt), 3 patients failed the initial attempt (2 underwent surgical ligation and 1 had a successful second attempt a year later). Of the four patients with residual shunt, three underwent a second procedure with implantation of 1-3 coils resulting in complete closure in all and one patient had spontaneous resolution of the residual shunt. Complications were encountered in nine patients: six had coil migration with successful retrieval in four; two had left pulmonary artery stenosis (2.4 kg and 6.3 kg infants), and one patient had loss of femoral arterial pulse. The median fluoroscopy time was 16 min (2-152 min). One hundred forty-two patients had the procedure as an outpatient, five patients stayed greater than 24 hr, and two of these patients were in hospital for 1 month for noncardiac reasons. At a median follow-up interval of 3.0 years (1 month to 5.1 years), there were no episodes of delayed coil migration, delayed recanalization, thromboembolic episodes, or bacterial endocarditis. Lung perfusion scans performed at a median follow-up interval of 1.6 years in 31 patients who received multiple coils revealed 45% +/- 5% blood flow to the left lung. Long-term follow-up of coil closure of PDA indicates that the technique is safe and effective for most patients with PDA up to a diameter of 7 mm.

Adolescent↗
PubMed1999

The association of sexual and physical abuse with somatization: characteristics of patients presenting with irritable bowel syndrome and non-epileptic attack disorder.

BACKGROUND: Physical symptoms are commonly presented for treatment in the absence of physical pathology. This study tests predictions arising from the theory that childhood sexual abuse leads to emotional distress, illness orientation and social dysfunction as adults and that one or more of these effects, in turn, leads to presentation of functional (i.e. unexplained) symptoms. METHODS: Two groups of patients with physical symptoms in the absence of organic disease (non-epileptic attack disorder or irritable bowel syndrome) were contrasted with organically diseased groups with comparable symptoms (epilepsy and Crohn's disease, respectively). RESULTS: Despite their contrasting clinical presentation, irritable bowel and non-epileptic attack groups were similar in recalling more sexual and physical abuse, as both children and adults, than their comparison groups. They were also similar in being more emotionally and socially disturbed and illness-orientated, but these putative mediating variables could not account for the relationship of abuse with presentation of functional symptoms. CONCLUSIONS: Adults presenting functional neurological and abdominal symptoms are characterized by history of abuse. The current focus on childhood sexual abuse should be broadened to include sexual, and particularly physical, abuse in adulthood as well as childhood. The intervening processes that link abuse to somatization remain to be identified but are unlikely to include adult emotional and social disturbance or general illness-orientation.

Adult↗
PubMed1999

Electroencephalographic and psychomotor effects of chlorpromazine and risperidone relative to placebo in normal healthy volunteers.

AIMS: To investigate the effects of single oral doses of chlorpromazine (50 mg) and risperidone (2 mg) relative to placebo on topographical electroencephalometry (CATEEMTM ) and psychomotor tests in 12 healthy male volunteers. METHODS: A double-blind, placebo-controlled, three-way crossover design using a double dummy blinding technique was utilized. Chlorpromazine was selected as representative of the 'typical' neuroleptics, being also highly sedative. Risperidone has been suggested as representative of the newer 'atypical' neuroleptics and is claimed to be only minimally sedative. Volunteers were dosed on 3 separate days with a minimum of 7 days interval between trial days. On each trial day volunteers were dosed twice. Dose 1 consisting of either chlorpromazine 50 mg or placebo to chlorpromazine, and dose 2 either risperidone 2 mg or placebo to risperidone. The volunteers were randomized so that each received either chlorpromazine or risperidone (or neither), but not both on an individual trial day. A 17 electrode quantitative topographical electroencephalograph (EEG) recording was taken for each volunteer before and after each dosing period. Seven psychomotor function tests were used to determine the effects of each treatment on psychomotor performance. RESULTS: The data confirm the cited reports of sedation following single oral doses of chlorpromazine 50 mg. However, 7 of the 12 volunteers dosed with risperidone 2 mg also reported drowsiness/lethargy which was of greater severity and duration than 5 of the 12 volunteers who reported somnolence following dosing with chlorpromazine 50 mg. Objective assessment of psychomotor impairment using a short battery of psychomotor function tests mirrored the subjective reports of somnolence in that the impairment in volunteers dosed with risperidone 2 mg was greater in extent and magnitude than in volunteers dosed with chlorpromazine 50 mg. With respect to the cortical quantitative electroencephalogram, both chlorpromazine (50 mg) and risperidone (2 mg) increased power (4.75-6.75 Hz) in keeping with cited effects of other neuroleptics on the quantitative EEG. In addition, there was a statistically significant increase (P<0.05) in alpha1 (7.0-9.5 Hz) and beta1 (12.75-18.5 Hz) wavebands in volunteers dosed with risperidone 2 mg. Furthermore, based on estimates of variability, we propose that a 3 min eyes open and 3 min eyes closed quantitative EEG recording is sufficient to maintain adequate power for this technique, whilst allowing its application to early volunteer trials of novel neuroleptic agents. CONCLUSIONS: This study demonstrates that quantitative EEG can be utilized in the profiling of neuroleptic agents, and could be readily applied to the early profiling of novel neuroleptics in limited numbers of volunteers, early in drug development. The chosen battery of psychomotor tests has clearly demonstrable sensitivity to the quantification of the subjective reports of somnolence secondary to both chlorpromazine and risperidone.

Adolescent↗
PubMed1999

An oral formulation of nicotine for release and absorption in the colon: its development and pharmacokinetics.

AIMS: Ulcerative colitis is predominantly a disease of nonsmokers and transdermal nicotine has therapeutic value in active disease; however side-effects are troublesome. The aim of this study was to develop an oral formulation of nicotine which would be slowly released in the colon over 6 h, and to examine its pharmacokinetic profile in 12 healthy volunteers, with measurements of serum nicotine and cotinine, its principal metabolite. METHODS: Nicotine was combined with a polyacrylic carbomer, Carbopol 974P which was incorporated into 13 different vehicles and their release profiles examined in vitro. The polyglycolized glyceride, Gelucire 50/13, was chosen for subsequent kinetic studies because it consistently produced a suitable release pattern which was linear. Capsules containing 3 mg nicotine, combined with carbomer in Gelucire 50/13, were coated with an acrylic resin Eudragit L; this ensured the capsule would remain intact until the ileum. On 2 separate days, 6 and 15 mg nicotine, contained in 2 and 5 capsules, respectively, were administered to 12 subjects, all nonsmokers, mean age 28 years. Serial blood measurements were taken for 36 h, serum nicotine and cotinine concentrations were measured by gas liquid chromatography. RESULTS: There was considerable intersubject variability in the nicotine and cotinine values. Plasma nicotine levels began to rise about 4 h after ingestion of the capsules, corresponding with the oro-caecal transit time. Cmax nicotine values were 2.2 and 5 ng ml-1, obtained 7 h after the ingestion of 6 and 15 mg, respectively, of the formulation. The corresponding Cmax values for cotinine were 37 and 94.4 ng ml-1, occurring after 9-10 h. The mean for elimination half-lives in the 24 studies, including the 6 and 15 mg doses, for nicotine were 4.3+/-2.7 h and for cotinine 16.8+/-7.5 h. With 6 mg nicotine-carbomer, only 1 of 12 volunteers had possible side-effects, but with the 15 mg dose 11 out of the 12 reported adverse effects which were systemic or gastrointestinal in nature-their timing corresponded with peak serum concentrations of nicotine. CONCLUSIONS: An oral formulation of nicotine has been developed; in the ileum and colon, this becomes available for slow linear release over 6 h and delivers high concentrations of nicotine for topical effect on the colon. 6 mg Nicotine was well tolerated, whilst 15 mg gave both systemic and gastrointestinal side-effects. High concentrations of topical nicotine in the colon are achieved with relatively low systemic bioavailablity-reflected by the Cmax and AUC values for nicotine. This, or comparable formulations, may be of therapeutic value in ulcerative colitis.

Absorption↗