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Biomedical subjects

M A Russell

Publications and source records attributed to M A Russell.

At least 19 recordsLinked to original sources
PubMed2000

Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase.

Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.

Administration, Oral↗
PubMed1999

Prescription of transdermal nicotine patches for smoking cessation in general practice: evaluation of cost-effectiveness.

BACKGROUND: The 1998 UK government White Paper Smoking Kills emphasises that normal practice should be for general practitioners (GPs), practice nurses, and others to offer advice and support to smokers in their efforts to stop. However, GPs are not allowed to write NHS prescriptions for nicotine-replacement therapy, even though this is the only effective pharmaceutical treatment available in the UK. We estimated the cost-effectiveness, for the NHS, of allowing GPs to prescribe transdermal nicotine patches for up to 12 weeks. METHODS: We used data from a randomised, placebo-controlled efficacy trial of nicotine patches and a survey of associated resource use in 30 GP surgeries in 15 English counties. We calculated the health benefit of nicotine-patch treatment in number of life years that would be saved by stopping smoking at various ages, and used an abstinence-contingent treatment model to calculate the incremental cost per life year saved by GP counselling with nicotine-patch treatment over GP counselling alone. Cost effectiveness was assessed on the basis that GPs would provide repeat NHS prescriptions for up to 12 weeks if the treatment was proving successful. FINDINGS: If GPs were allowed to prescribe transdermal nicotine patches on the NHS, for up to 12 weeks, the incremental cost per life year saved would be: Pound Sterling 398 per person younger than 35 years; Pound Sterling 345 for those aged 35-44 years; Pound Sterling 432 for those aged 45-54 years; and Pound Sterling 785 for those aged 55-65 years. INTERPRETATION: The low cost per life year saved would make GP intervention against smoking a cost-effective life-saving treatment. The priniciples of the government White Paper could be cost-effectively extended into general practice to reduce smoking and smoking-related illnesses.

Administration, Cutaneous↗
PubMed1999

Higher dosage nicotine patches increase one-year smoking cessation rates: results from the European CEASE trial. Collaborative European Anti-Smoking Evaluation. European Respiratory Society.

The Collaborative European Anti-Smoking Evaluation (CEASE) was a European multicentre, randomized, double-blind placebo controlled smoking cessation study. The objectives were to determine whether higher dosage and longer duration of nicotine patch therapy would increase the success rate. Thirty-six chest clinics enrolled a total of 3,575 smokers. Subjects were allocated to one of five treatment arms: placebo and either standard or higher dose nicotine patches (15 mg and 25 mg daily) each given for 8 or 22 weeks with adjunctive moderately intensive support. The 12 month sustained success rates were: 25 mg patch for 22 weeks (L-25), 15.4%; 25 mg patch for 8 weeks (S-25), 15.9%; 15 mg patch for 22 weeks (L-15), 13.7%; 15 mg patch for 8 weeks (S-15), 11.7%; and placebo (P-0) 9.9% (placebo versus 15 mg, p<0.05; 25 mg versus 15 mg, p<0.03; 25 mg versus placebo, p<0.001, Chi-squared test). There was no significant difference in success rate between the two active treatment durations. Of the first week abstainers (n=1,698), 25.1% achieved success at 12 months as opposed to first week smokers, 2.7% of 1,877 subjects (p< 0.001). In summary, a higher than standard dose of nicotine patch was associated with an increase in the long-term success in smoking cessation but continuation of treatment beyond 8-12 weeks did not increase the success rates.

Administration, Cutaneous↗
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↗
PubMed1998

Nicotine availability from Eclipse tobacco-heating cigarette.

A cigarette which heats rather than burns tobacco (Premier) was introduced in 1988, but was unacceptable due to unpleasant taste and low nicotine intake. We examined availability of nicotine from a new version (Eclipse), in the same four subjects as our earlier Premier study. Average blood nicotine boosts of 23.7 and 17.8 ng/ml were obtained from smoking a first and second Eclipse. This substantially exceeds intake from Premier (boost 13 ng/ml) and that obtained by heavy smokers from conventional brands (boost 12-15 ng/ml). Eclipse (or similar product) may be the best option for averting Peto's dire warnings of rising millions of annual smoking deaths in the 2020s, and its potential for large-scale, long-term switching warrants further study.

Adult↗
PubMed1998

Cirrhosis and portal hypertension in pregnancy.

Cirrhosis and portal hypertension infrequently coincide with pregnancy but increase maternal and fetal morbidity and mortality when present. Chronic liver disease and portal hypertension are not contraindications to pregnancy but necessitate intensive monitoring throughout pregnancy. The complications of liver disease are numerous and pose additional risks. Management of complications arising during pregnancy is similar to management in the nonpregnant patient. Provision of optimal care for mother and fetus can require the skills of multiple specialties such as maternal fetal medicine, gastroenterology, nutrition, and surgery. This report provides guidelines for the management of cirrhosis and portal hypertension in pregnancy.

Counseling↗
PubMed1998

Nicotine absorption and dependence in unlicensed lozenges available over the counter.

AIM: To demonstrate the nicotine absorption and dependence potential from unlicensed nicotine containing lozenges. DESIGN: A single case report of dependence on nicotine lozenges, plus measurements of nicotine levels before and after consumption of eight nicotine lozenges over 2 hours in volunteers. SETTING: Hospital Smokers' Clinic. PARTICIPANTS: One male patient suffering from schizophrenia who had consumed 150 "Stoppers" lozenges per day for the previous 5 years, plus seven non-smoker volunteers. MEASUREMENTS: Blood nicotine concentration. FINDINGS: The patient's low expired carbon monoxide level (5 p.p.m.) and high plasma nicotine (32 ng/ml) and cotinine levels (947 ng/ml) were consistent with very heavy lozenge consumption. The non-smoker volunteers obtained nicotine concentrations of around 11 ng/ml by consuming eight Stoppers lozenges over 2 hours. Other brands of nicotine lozenges produced lower initial levels, but also produced delayed intestinal absorption and vomiting after food consumption. CONCLUSION: Nicotine lozenges are a potential aid to smoking cessation but their safety, efficacy and abuse potential remain to be properly evaluated.

Humans↗
PubMed1998

Clinical status of ulcerative colitis in patients who smoke.

OBJECTIVES: Ulcerative colitis (UC) is largely a disease of nonsmokers. There are few patients who are current smokers, but we have identified a group and reviewed their clinical status, disease activity, and nicotine exposure to examine whether they remain well controlled while smoking. METHODS: Fifty-one patients from three centers with verified UC were reviewed. RESULTS: Thirty of the group were men; mean age 50 yr, with a mean age of onset of 37 yr. Twenty-two patients had proctosigmoid disease, 12 involvement of left colon, and 17 total colitis. All were current smokers; 41 were cigarette smokers averaging 17 daily. At the onset of colitis 30 were nonsmokers, 25 of them were ex-smokers and 19 developed colitis within 2 yr of stopping smoking. Twenty-eight believed smoking improved disease activity and none felt smoking had a detrimental effect on their UC. Eleven were receiving no medication for UC, 40 were receiving 5-ASA (5-aminosalicylic acid) preparations, and only two took oral steroids. All were in clinical remission, with the exception of one patient; mean St. Marks score was 1.5, out of a possible total of 22. Sigmoidoscopic grades were inactive in all patients except three. Histological assessment showed significant activity in only five. Median serum nicotine was 8 ng/ml (range, 0.4-24.4), median serum cotinine 180 ng/ml (range, 20-453), with corresponding salivary cotinine of 255 ng/ml (range, 34-683). Median rise in nicotine 2 min after a cigarette in 35 patients was 12.1 ng/ml (range, 0.4-44). CONCLUSIONS: Because most current smokers with UC have inactive disease, smoking may contribute to the clinical remission in these patients.

Adult↗
PubMed1998

Lethal P-lacZ insertion lines expressed during pattern respecification in the imaginal discs of Drosophila.

The imaginal discs of Drosophila are a useful experimental system in which we can study the origin and genetic determination of spatial patterns in development. This involves the separation of the disc-cell population into distinct lineage compartments, based on clonally transmitted expression states of a number of known selector genes. However, these commitments can be abrogated and the compartment boundaries redeployed, when repatterning occurs in cultured disc fragments. This has so far only been explained using the idea of positional information. The genetic basis of this property of the imaginal disc system and its relationship to compartments have not been identified. Here we have screened over 470 recessive lethal P-lacZ enhancer-trap insertions from the Berkeley Drosophila Genome Project for expression after cell death, which initiates pattern respecification in the imaginal discs. The positive lines obtained identify essential genes that may be important for pattern formation. Most show patterned imaginal disc expression, and many have maternal or zygotic effects on embryonic development. One is an allele of schnurri, a gene that encodes a component of the decapentaplegic (dpp) signal transduction pathway used for positional signalling in the embryo and in imaginal discs.

Animals↗
PubMed1998

Spectroscopic studies of nitric oxide (NO) interactions with cobalamins: reaction of NO with superoxocobalamin(III) likely accounts for cobalamin reversal of the biological effects of NO.

Recent reports indicate that oxidized cobalamin, Cbl(III), can interfere with the biological effects of nitric oxide (NO) on vascular and visceral smooth muscle and in other systems. In attempting to elucidate the mechanism of these effects of Cbl(III), we reported that a Cbl(III)NO complex could be detected by electron paramagnetic resonance (EPR) spectroscopy, but not by ultraviolet/visible spectroscopy. Subsequently, others concluded that the alleged Cbl(III)NO complex is detectable by ultraviolet/visible, but not by EPR spectroscopy and provided ultraviolet/visible evidence for an alleged Cbl(III)NO complex. We report further investigation of the interaction of NO with Cbl, using both techniques, Fourier transform infrared (FTIR) spectroscopy and mass spectrometry. Our EPR results and the UV/VIS results of others appear to be experimental artifacts that can now, at least in part, be explained. Under conditions where FTIR measurements readily detect a N-O stretching frequency of NO bound to Fe(II), we do not detect a similar signal that can be ascribed to either Cbl(III)NO or Cbl(II)NO, indicating that neither Cbl(III) nor Cbl(II) form a stable complex with NO. Loss of the Cbl(II) EPR signal and mass spectral detection of N2O upon addition of NO to Cbl(II) solutions, demonstrates that Cbl(II), which is present in aerobic Cbl(III) solutions, reduces NO; however, this reaction does not appear to be fast enough to account for the observed biological effects in aerated media. Nitric oxide also reacts rapidly and irreversibly with the superoxo complex of Cbl(III), Cbl(III)O2-, which is always present in aerated solutions of Cbl(III). We believe that this latter reaction accounts for the observed inactivation of NO by Cbl(III) in biological systems. Because Cbl(III)O2- is spontaneously regenerated from Cbl(II) and O2 in aerated solutions, this may constitute a cyclic mechanism for the rapid elimination (oxidation) of NO. Thus, several physicochemical techniques fail to provide convincing evidence for the existence of stable Cbl(III)NO or Cbl(II)NO complexes but do provide evidence that Cbl species participate in redox reactions with NO under aerobic conditions, thereby inhibiting its physiological roles.

Electron Spin Resonance Spectroscopy↗
PubMed1998

Nicotine carbomer enemas--pharmacokinetics of a revised formulation.

AIMS: Ulcerative colitis is predominantly a disease of non-smokers, and transdermal nicotine has therapeutic benefit but causes frequent side-effects. We have previously developed a topical enema combining nicotine with a polyacrylic carbomer; pharmacokinetic parameters were similar in healthy volunteers and patients with active ulcerative colitis. This enema was reformulated to reduce and delay nicotine absorption, thereby improving tolerance. METHOD: Pharmacokinetic observations and side-effects with both formulations are compared in the same 8 healthy volunteers--all non-smokers, 3 male, mean age 33 years. Six milligrams of nicotine were complexed with 400 mg of carbomer in a 100 ml liquid enema. The original formulation was buffered with potassium/phosphate to pH 5.5, kinematic viscosity was 3 mNm; the revised preparation incorporated trometamol 1% solution to buffer to pH 4.2, viscosity 5 mNm. All subjects had the two formulations on separate occasions at least a month apart, with serial blood measurements and side-effect profile recorded for 8 hours. RESULTS: The revised enema formulation significantly reduced Cmax for nicotine from 8.3 +/- 2.7 to 6.6 +/- 2.1, p = 0.03 with some reduction in nicotine absorption and improved tolerance. Although there was considerable intersubject variation in profiles for nicotine and cotinine, they were similar for each subject on both occasions. CONCLUSIONS: The lower pH and greater viscosity reduced the amount of free nicotine in its unionised form available for absorption, but made it possible to expose colonic mucosa to the same nicotine dose. In other drug formulations where side-effects are a limiting factor these modifications may also be relevant.

Acrylic Resins↗
PubMed1997

Molecular genetic analysis of type-4 pilus biogenesis and twitching motility using Pseudomonas aeruginosa as a model system--a review.

Genetic analysis of Pseudomonas aeruginosa pilus biogenesis and twitching motility has revealed the requirement for several pil loci which have been localized to different regions of the chromosome. One pil locus, designated pilE, resides at approx. 71 min on the PAO genetic map, a region of the chromosome previously shown to harbor a number of genes required for pilus assembly (i.e., pilA, -B, -C, -D, -R and -S). The PilE protein shows significant sequence identity to the N-terminal domain of PilA as well as to the pilin precursors from a variety of type-4 pilus producers. Included within this homologous region is a short, positively charged leader sequence followed by a prepilin peptidase cleavage site and a largely hydrophobic region. Additionally, an unlinked set of pil genes, designated pilG, -H, -I, -J and -K, has been localized to the SpeI fragment H which corresponds to approx. 20 min on the PAO genetic map. This gene cluster encodes proteins that demonstrate remarkable similarity to the chemotaxis proteins of enterics and the gliding bacterium Myxococcus xanthus and are thought to be part of a signal transduction system that controls P. aeruginosa pilus biosynthesis and twitching motility.

Bacterial Outer Membrane Proteins↗
PubMed1997

Mood and physiological effects of subcutaneous nicotine in smokers and never-smokers.

This study compared the effect of subcutaneous nicotine injections (2 x 0.3 mg and 2 x 0.6 mg) with saline on subjective and physiological measures in 18 never-smokers and 18 smokers (24-h nicotine deprived), under conditions of rest and cognitive testing. Prior to the injections the mood of the smokers had deteriorated to a level significantly below that of the never-smokers as a result of tobacco withdrawal. Cognitive tests caused reductions in calmness and increased alertness but there was no evidence of nicotine improving mood in either group under either condition. The 0.6 mg dose worsened mood in never-smokers and caused unpleasant symptoms (e.g. dizziness and arm pain) in both groups. Compared with smokers, never-smokers experienced stronger symptoms of nicotine toxicity and a greater reduction in alertness in response to the 0.6 mg dose, suggesting chronic tolerance to some nicotine effects in smokers. Nicotine produced similar increases in heart rate and decreases in finger pulse volume in both groups. Our results imply that if nicotine has a mood enhancing effect it occurs only after tolerance has been acquired to its primary adverse effects, and that its ability to reverse the mood deterioration caused by tobacco withdrawal is susceptible to situational factors such as our experimental conditions.

Adult↗
PubMed1997

Pharmacokinetics of nicotine carbomer enemas: a new treatment modality for ulcerative colitis.

BACKGROUND: Ulcerative colitis is largely a disease of nonsmokers, and transdermal nicotine is of therapeutic value in the active disease. Because side effects are common, we developed a topical enema formulation of nicotine. OBJECTIVE: To study the pharmacokinetics of nicotine complexed with a polyacrylic carbomer and administered by enema to eight healthy volunteers and to eight patients with active ulcerative colitis, verified sigmoidoscopically. PATIENTS AND METHODS: All 16 subjects were nonsmokers. The mean age for normal subjects was 33 years; the mean for patients with ulcerative colitis was 60 years. Median stool frequency for patients with ulcerative colitis was four daily. Patients were taking 5-amino salicylic acid compounds and five were taking oral prednisolone (median dose, 12 mg daily). Nicotine, 6 mg, complexed with carbomer 974P, 400 mg, was administered in a 100 ml enema after an overnight fast, with serial blood measurements taken over 8 hours. Serum nicotine and cotinine were measured by gas liquid chromatography. Area under the concentration-time curves were calculated by the trapezoidal method, and the terminal elimination half-life was derived by extrapolation of the log-linear terminal phase. RESULTS: With the exception of nicotine time to reach peak concentration, which was longer in patients (median of 60 minutes compared with 45 minutes; p < 0.005), other comparisons between normal subjects and patients showed no statistically significant difference, although there was considerable inter-subject variation. Maximum concentration of nicotine, 8.1 +/- 3.5 ng/ml, in the 16 subjects occurred after a median of 60 minutes (range, 30 to 180 minutes); maximum cotinine concentrations of 60.4 +/- 11.5 ng/ml occurred after 4 hours. Side effects in five subjects were mild (four subjects) or moderate (one subject) and included lightheadedness, nausea, and headache; these five subjects were female lifelong nonsmokers of low body weight. CONCLUSION: Because most of the active ingredient of nicotine is converted to continine on the first pass through the liver, substantial concentrations can be achieved at the site of disease with only modest rises in serum nicotine, which are responsible for side effects; cotinine has low pharmacologic activity. Topical administration of nicotine may be useful treatment for distal ulcerative colitis.

Acrylic Resins↗
PubMed1997

Lichenoid dermatitis after consumption of gold-containing liquor.

Medicinal gold has a well-known side effect profile that includes mucocutaneous eruptions. We describe three patients with a pruritic dermatitis that began after consumption of a gold-containing alcoholic beverage. Blood and urine gold levels, chemistry panels, hepatitis screens, skin biopsies, and patch tests were performed. The gold-containing liquor was analyzed for the presence and quantity of gold. The liquor consumed by all of the patients was a cinnamon schnapps with free-floating gold-colored flakes. Gold is present in the liquid portion of this liquor and in the solid flakes. Elevated levels of gold in the urine and blood were present in one patient 3 months after last drinking this beverage. Another patient had a positive patch test to gold sodium thiosulfate. All patients experienced improvement of their dermatitis after they stopped drinking the gold-containing liquor.

Adult↗
PubMed1997

Sucrose as an aid to manual reduction of incarcerated rectal prolapse.

Incarcerated rectal prolapse is a potential surgical emergency. We report a case in which a simple but effective technique involving the desiccating effect of granulated sugar (sucrose) was used to aid the manual reduction of prolapsed but viable rectal tissue.

Administration, Rectal↗
PubMed1997

Law enforcement K-9 dog bites: injuries, complications, and trends.

STUDY OBJECTIVE: To quantify the number of individuals bitten, the number of bites per patient, and the types of injuries and complications caused by law enforcement K-9 dog bites treated in the Jail Ward Emergency Department of the Los Angeles County-University of Southern California Medical Center. These variables were compared before and after a change in K-9 police policy from the "bite-and-hold" to the "find-and-bark" technique or stricter controls were instituted over the K-9 teams. METHODS: A retrospective chart review of all patients in police custody with K-9 dog bites who presented to the Jail Ward ED between January 1, 1988, and December 31, 1995, was conducted. Demographic data of patients with K-9 dog bites, the number and location of bites, complications, procedures performed, and management of bites were recorded and compared between the periods 1988-1991 (before the policy changes) and 1992-1995 (after the changes). RESULTS: Between 1988 and 1995 790 in-custody patients were treated for K-9 dog bites in the Jail Ward ED; 705 charts were available for review. Nearly all the patients (98.6%) were male, with a mean age of 25; 85.0% were Hispanic or black. More than half (57.2%) sustained three or more bites, mainly to the extremities. Complications ensued in 19.3%: vascular in 7.0%, infection in 5.0%, fracture or cortical violation in 4.0%, nerve injury in 1.9%, and tendon injury in 1.1%. Half (49.9%) were hospitalized, with a median stay of 3 days. After the change in K-9 policy, the number of patients with K-9 dogs bites presenting to the Jail Ward ED decreased from 639 (1988-1991) to 66 (1992-1995). The proportion of patients who sustained three or more bites decreased from 58.4% to 45.5%. The rate of vascular complications decreased from 7.5% to 1.6%, the rate of fractures decreased from 2.4% to 0, and the rate of cortical violations increased from 1.4% to 6.3%. The proportion of patients hospitalized decreased from 52.0% to 33.8%. CONCLUSION: K-9 dog bites are associated with significant injuries and complications. In this study, changes in law enforcement K-9 policy contributed to a significant decrease in the overall number of individuals bitten, the number of injuries and complications, and the proportion of patients hospitalized.

Adolescent↗