Ethanol inhibits dopamine uptake via organic cation transporter 3: Implications for ethanol and cocaine co-abuse.

Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases extracellular monoamines by blocking dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transporters (DAT, NET and SERT, respectively). Likewise, ethanol also increases extracellular monoamines, however evidence suggests that ethanol does so independently of DAT, NET and SERT. Organic cation transporter 3 (OCT3) is an emergent key player in the regulation of monoamine signaling. Using a battery of in vitro, in vivo electrochemical, and behavioral approaches, as well as wild-type and constitutive OCT3 knockout mice, we show that ethanol's actions to inhibit monoamine uptake are dependent on OCT3. These findings provide a novel mechanistic basis whereby ethanol enhances the neurochemical and behavioral effects of cocaine and encourage further research into OCT3 as a target for therapeutic intervention in the treatment of ethanol and ethanol/cocaine use disorders.

Cohorts for the study of HIV­1-exposed but uninfected individuals: benefits and limitations.

Since the late 1980s, with the first identification of individuals who were exposed to human immunodeficiency virus type 1 (HIV-1) yet remained uninfected, or "HIV-1-resistant" individuals, a large number of cohorts that include HIV-exposed seronegative (HESN) subjects have been identified globally for the purpose of investigating the genetic, immunologic, and environmental factors that may help alter susceptibility to HIV-1. In this article, in light of the recent International Symposium on Natural Immunity to HIV, we review the characteristics of different groups with respect to their relative risks and briefly summarize the known cohorts that include exposed uninfected subjects worldwide.

IgA1 antibodies specific for outer membrane protein PorA modulate the interaction between Neisseria meningitidis and the epithelium.

Despite high carriage rates of Neisseria meningitidis, incidence of meningococcal disease remains low, partially due to development of natural immunity. We have previously demonstrated an inverse relationship between salivary anti-meningococcal IgA and disease incidence, but little is known about the contribution of IgA to immunity at mucosal surfaces. Here we show strong immunoreactivity by human salivary IgA against the meningococcal outer membrane porin, PorA. Monomeric anti-PorA IgA1 (humanized chimeric antibodies) but not IgG increased the association of unencapsulated serogroup B N. meningitidis (H44/76) with Chang (conjunctival) but not with either Detroit (pharyngeal) cells or with A549 (alveolar) epithelial cells. Association of encapsulated N. meningitidis was not increased. Epithelial binding of IgA was Fc fragment dependent and not inhibited by IgM. Together these data suggest the presence of a specific epithelial IgA receptor that could influence the effect of both naturally acquired and vaccine induced IgA antibodies at the epithelial surface.

Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and 'schizophrenia-related' behaviors.

There is growing evidence implicating dysfunctional glutamatergic neurotransmission and abnormal interactions between the glutamate and dopamine (DA) systems in the pathophysiology of various neuropsychiatric disorders including schizophrenia. The present study evaluated knockout (KO) mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) GluR1 receptor subunit for a range of behaviors considered relevant to certain symptoms of schizophrenia. KO showed locomotor hyperactivity during exposure to open field and in response to a novel object, but normal activity in a familiar home cage. Open field locomotor hyperactivity in KO was effectively normalized to WT levels by treatment with the DA antagonist and neuroleptic haloperidol, while locomotor stimulant effects of the NMDA receptor antagonist MK-801 were absent in KO. Social behaviors during a dyadic conspecific encounter were disorganized in KO. KO showed deficits in prepulse inhibition of the acoustic startle response. In vivo chronoamperometric measurement of extracellular DA clearance in striatum demonstrated retarded clearance in KO. These data demonstrate behavioral abnormalities potentially pertinent to schizophrenia in GluR1 KO, together with evidence of dysregulated DA function. Present findings provide novel insight into the potential role of GluR1, AMPA receptors and glutamate x DA interactions in the pathophysiology of schizophrenia and other neuropsychiatric conditions.

Influence of age and carriage status on salivary IgA to Neisseria meningitidis.

Asymptomatic carriage of Neisseria meningitidis is common (5-35% of individuals) while the incidence of invasive meningococcal disease is fairly low (<1-5 per 100,000 per annum in Europe). Naturally acquired protective immunity may account for this difference. In this study, we investigated the relationship between anti-meningococcal salivary IgA and age and carriage. We showed that salivary IgA to a range of meningococcal antigens increased successively with age with some specificity for commonly circulating serosubtypes. In a group of 258 students 37 (14%) of whom were carriers of N. meningitidis serogroup B, higher levels of specific IgA were associated with carriage. Stratified analysis revealed a positive relationship between smoking and specific anti- N. meningitidis IgA independent of current carriage, weighted odds ratio (OR) 4.1 (95% CI 1.1-18) and OR 3.8 (95% CI 0.96-16) for reference strains B:1:P1.14 and B:4:P1.5,4 respectively. These data implicate IgA as a factor in host defence from meningococcal invasion, although the precise mechanisms remain uncertain.

Escherichia coli CreBC is a global regulator of gene expression that responds to growth in minimal media.

We have identified nine genes, the expression of which are regulated by the CreBC two-component system: the first members of the cre regulon. They are divided into eight transcriptional units, each having a promoter-proximal TTCACnnnnnnTTCAC "cre-tag" motif. The cre regulon genes are: the ackA/pta operon, the products of which collectively catalyze the conversion of acetyl-CoA into acetate and ATP; talA, which encodes an enzyme involved in the mobilization of glyceraldehyde-3-phosphate into the pentose phosphate pathway; radC, which encodes a RecG-like DNA recombination/repair function; malE, which is the first gene in the malEFG maltose transporter operon; trgB, which encodes an ADP-ribose pyrophosphorylase; and three other genes, creD, yidS and yieI, the products of which have not been assigned a function. Expression of each of these cre regulon genes is induced via CreBC during growth in minimal media, with the exception of malE, which is more tightly repressed. The diverse functions encoded by the cre regulon suggest that CreBC is a global regulator that sits right at the heart of metabolic control in Escherichia coli.

A review of the pharmacoeconomics of pharmaceutical care.

Numerous studies have demonstrated that the therapeutic use of drugs results in adverse outcomes and contributes to high rates of morbidity and mortality. The causes of drug-related problems are multifactorial and their assessment has been based on factors such as inappropriate prescribing, inappropriate delivery, inappropriate patient behaviour, patient idiosyncrasy and inappropriate monitoring. The cost in the ambulatory setting has been estimated to exceed total prescription pharmaceutical use. Pharmaceutical care is defined as the responsible provision of drug therapy for the purpose of achieving definite outcomes that improve a patient's quality of life. It describes the process through which a pharmacist cooperates with a patient and other healthcare professionals in designing, implementing and monitoring a therapeutic plan that will produce specific therapeutic outcomes for the patient. This article evaluates published studies related to the economic analysis of pharmaceutical care in enhancing the value of pharmaceuticals. While numerous descriptive articles exist, our review found no studies which met accepted pharmacoeconomic criteria. A small number of studies measured process variables and/or quality of life, but only one considered costs. Barriers to optimising the economic value of pharmaceutical care were also explored. Common methodological shortcomings indicated a need for improvement in future studies. There is little published research to date which demonstrates the pharmacoeconomic benefits of pharmaceutical care. Evidence does exist that clinical pharmacy services have positive economic benefits, and it is this evidence that, at present, supports the assertion that pharmaceutical care has potential to increase the value of pharmaceuticals in society by minimising drug-related morbidity and mortality. Thus, well conducted research is required to determine the economic impact of pharmaceutical care.

Postoperative nausea and vomiting: development of a management protocol.

Postoperative nausea and vomiting (PONV) is still an important and common problem. Despite the introduction of new antiemetic drugs, the management of PONV remains difficult. In this article we describe the development and evaluation of a management protocol for PONV, which consists of a treatment algorithm accompanied by a nursing education program. Implementation of this management protocol has been well-accepted by staff, appears to have reduced delay in patient treatment and improved patient care, and has significantly reduced staff workload. It is planned to use continuous quality improvement techniques to further refine the algorithm and continue assessment of its efficacy and of patient satisfaction.

Distribution and excretion of sertraline and N-desmethylsertraline in human milk.

AIMS: To characterise milk/plasma (M/P) ratio and infant exposure, for sertraline and N-desmethylsertraline, in breast-feeding women taking sertraline for the treatment of depression. METHODS: Eight women (mean age 28 years) taking sertraline (1.05 mg kg(-1) day(-1)) and their infants (mean age 5.7 months) were studied. Sertraline and N-desmethylsertraline in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval at steady-state. M/P values were estimated from area under the plasma and milk concentration-time curves. All milk produced was collected over the dose interval. Infant exposure was estimated as the product of actual or estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean milk production was 321 ml day(-1) (range 34-974 ml). Mean M/P values of 1.93 and 1.64 were calculated for sertraline and N-desmethylsertraline respectively. Infant exposure estimated from actual milk produced was 0.2% and 0.3% of the weight-adjusted maternal dose for sertraline and N-desmethylsertraline (as sertraline equivalents) respectively. When calculated from estimated milk production (0.15 l kg(-1) day(-1)), infant exposure was significantly greater (P<0.0001) at 0.90% and 1.32% for sertraline and N-desmethylsertraline respectively. Neither sertraline nor its N-desmethyl metabolite could be detected in plasma samples from the four infants tested. No adverse effects were observed in any of the eight infants and all had achieved normal developmental milestones. CONCLUSIONS: Irrespective of the method of calculation of infant exposure, the mean total dose of sertraline and its N-desmethyl metabolite transmitted to infants via breast-feeding is low and unlikely to cause any significant adverse effects.

Methadone distribution and excretion into breast milk of clients in a methadone maintenance programme.

AIMS: Methadone is widely used in maintenance programs for opioid-dependent subjects. The aims of the study were to quantify the distribution and excretion of methadone in human milk during the early postnatal period and to investigate exposure of breast fed infants to the drug. METHODS: Blood and milk samples were obtained from 12 breast feeding women who were taking methadone in daily doses ranging from 20-80 mg (0.3-1.14 mg kg-1). Blood was also obtained from eight of their infants. Methadone concentration in these samples was quantified by h.p.l.c. The infants were observed for withdrawal symptoms. RESULTS: The mean (95% CI) milk/plasma ratio was 0.44 (0.24-0.64). Exposure of the infants, calculated assuming an average milk intake of 0.15 l kg-1 day-1 and a bioavailability of 100% was 17.4 (10.8-24) microg kg-1 day-1. The mean infant dose expressed as a percentage of the maternal dose was 2.79 (2.07-3.51)%. Methadone concentrations in seven infants were below the limit of detection for the h.p.l.c. assay procedure, while one infant had a plasma methadone concentration of 6.5 microg l-1. Infant exposure to methadone via human milk was insufficient to prevent the development of a neonatal abstinence syndrome which was seen in seven (64%) infants. No adverse effects attributable to methadone in milk were seen. CONCLUSIONS: We conclude that exposure of breast fed infants to methadone taken by their mothers is minimal and that women in methadone maintenance programs should not be discouraged from breast feeding because of this exposure.

Distribution and excretion of sumatriptan in human milk.

1. The excretion of a 6 mg subcutaneous dose of sumatriptan in breast milk was studied in five lactating volunteer subjects with a mean age of 27.6 years and a mean body weight of 75 kg. Drug concentrations in milk and plasma over the ensuing 8 h were measured by high-performance liquid chromatography. 2. The mean milk:plasma ratio estimated from the areas under the milk and plasma concentration-time curves (AUC) was 4.9 (95% CI 4.1-5.7), indicating a significant transfer of sumatriptan into the milk compartment. 3. The mean total recovery of drug in milk was estimated to be only 14.4 micrograms (95% CI 6.1-22.7 micrograms), or 0.24% of the 6 mg administered dose. On a weight-adjusted basis this corresponded to a mean infant exposure of 3.5% of the maternal dose (95% CI 0.3-6.7%). 4. If oral bioavailability in the infant is similar to that in adults (14%), the weight-adjusted infant dose is reduced to 0.49%. Furthermore, allowance for reduced clearance in the infant predicts an infant exposure varying from 4.9% in a very premature neonate to 0.7% in a 30 week old infant. 5. Since sumatriptan is usually administered as a single dose at infrequent intervals, the low level of excretion in breast milk suggests that continued breast feeding following its use will not pose a significant risk to the suckling infant. Even this minor exposure could be largely avoided by expressing and discarding all milk for 8 h after the dose.

Excretion of lignocaine and its metabolite monoethylglycinexylidide in breast milk following its use in a dental procedure. A case report.

The excretion of lignocaine in breast milk has been documented in a 34-year-old woman following the injection of 20 mg lignocaine for a dental alloy restoration in the right upper quadrant. Lignocaine and its primary metabolite monoethylglycinexylidide in milk and plasma were quantified by high-performance liquid chromatography. The concentration of lignocaine in milk ranged from 44-66 micrograms l-1 while that for monoethylglycinexylidide ranged from 35-41 micrograms l-1. The milk: plasma ratios for lignocaine and monoethylglycinexylidide were 1.1 and 1.8, respectively. The calculated daily infant doses for the parent drug and metabolite were both less than 0.01 mg kg-1 day-1. With the exception of very rare allergic reactions, these levels of infant exposure are extremely low and of no toxicological significance. Nursing mothers receiving lignocaine for standard dental procedures can be advised that continuation of breast feeding is safe.

The excretion of dothiepin and its primary metabolites in breast milk.

1. The excretion of dothiepin, nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide into breast milk was studied in eight women. Exposure to drug was measured in five of their infants, and possible drug-related effects were assessed in all eight infants. 2. Using pre-feed milk samples mean (+/- s.e. mean) milk:plasma (M:P) ratios were 0.78 +/- 0.12, 0.85 +/- 0.16, 1.18 +/- 0.29 and 1.86 +/- 0.29 for dothiepin, nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide, respectively. In post-feed milk samples, the mean M:P ratio for dothiepin (1.59 +/- 0.32) was significantly greater (P less than 0.05) but M:P ratios for the metabolites were similar. 3. Mean total calculated infant daily doses, (in dothiepin equivalents and as a percent of the maternal dose) were 0.58% for dothiepin, 0.23% for nordothiepin, 2.47% for dothiepin-S-oxide, and 1.17% for nordothiepin-S-oxide. 4. Plasma samples were obtained from five infants. In one, both dothiepin and nordothiepin were below their minimum quantifiable levels (2 micrograms l-1) while in four others both dothiepin-S-oxide and nordothiepin-S-oxide were below their minimum quantifiable levels (10 micrograms l-1). No adverse effects were found in any of the eight infants. 5. Use of dothiepin by depressed mothers is unlikely to be a significant hazard to their breast-feeding infants.

Excretion of indomethacin in breast milk.

1. The excretion of indomethacin into breast milk and subsequent exposure of infants was studied in 16 women and seven of their infants. The median milk:plasma ratio in seven patients where there were measurable drug concentrations in both milk and plasma was 0.37. 2. Total infant dose, assuming a daily milk intake of 150 ml kg-1 and 100% absorption, ranged from 0.07% to 0.98% (median = 0.18%) of the weight adjusted maternal dose. 3. Plasma samples were obtained in seven infants. In six of these, indomethacin concentrations were below the sensitivity of the assay (less than 20 micrograms l-1), while one infant had a plasma indomethacin concentration of 47 micrograms l-1. 4. No adverse effects due to indomethacin were reported in the infants.

From the National Institute of Allergy and Infectious Diseases. Summary of the National Institutes of Health workshop on group B streptococcal infection.

Group B streptococci remain a serious cause of morbidity and mortality in neonates. GBS vaccine or immunoglobulin administered iv may enhance neonatal GBS immunity. Likewise, intrapartum antibiotic therapy of colonized mothers appears to reduce vertical transmission of group B streptococci and to prevent both maternal and neonatal GBS disease. However, the safety and effectiveness of routine penicillin prophylaxis less than or equal to 1 hr after birth remain in question. For example, penicillin prophylaxis appears to be of little value in infants with low birth weights (less than 2,000 g) who become symptomatic shortly after birth; however, it may reduce the incidence of disease in larger, full-term infants who acquire the group B streptococci at delivery or in the few hours immediately thereafter. The potential harm of administering penicillin to all neonates must also be considered, since routine antibiotic therapy may alter the incidence of both neonatal infections due to penicillin-resistant pathogens and possible later penicillin allergy. Theoretically, a single injection of penicillin at birth may suppress GBS disease in some neonates but not effectively treat it, allowing the disease to progress prior to diagnosis and therapy. The decision to use penicillin routinely in neonates to prevent GBS disease must therefore be made with caution. Presently, this decision must be made on a situational basis, with institutions having a high incidence of early-onset GBS disease electing to use penicillin only if the potential benefits outweigh the risks.

A randomised controlled trial to compare local with general anaesthesia for short-stay inguinal hernia repair.

A series of 117 consecutive unselected patients with clinically reducible unilateral inguinal herniae were admitted for short-stay repair. Seven expressed a strong preference for one form of anaesthesia (6 general (GA)) local (LA) and 7 were unfit for GA; these were excluded from the trial. The remaining 103 patients were allocated at random to receive either LA or GA in order to compare the two methods of anaesthesia. The resulting groups (53 LA, 50 GA) were well matched for age and obesity. Perand postoperative symptoms were assessed with linear analogues self-assessment questionnaires. Statistically significant differences were demonstrated between the groups; those patients having LA were able to walk, eat, and pass urine earlier than those having GA, who experienced more nausea, vomiting, sore throat, and headache. The postoperative course and additional symptoms were otherwise similar. Forty-five LA patients experienced mild pain during the operation, but nevertheless 85% of the total group said they would consent to its use again. Ninety-three patients (90%) were discharged at 24 h. LA was applicable to all types of clinically reducible inguinal hernia and was an acceptable, safe, and satisfactory alternative to GA.

Long grafts in the treatment of critical ischaemia.

Forty-two woven 10-mm Dacron grafts were implanted from the common iliac artery to the distal popliteal artery in 38 patients with rest pain or gangrene. The long-term patency at 5 years was 50%, using life-table analysis. These results show that iliopopliteal Dacron grafts are effective in preventing major amputations of severely ischaemic limbs.