Sociodemographic factors associated with patients hospitalised for coccidioidomycosis in California and Arizona, State Inpatient Database 2005-2011.

Coccidioidomycosis is endemic in the Southwestern United States. Disseminated infection can be life-threatening and is responsible for hospitalisation and significant healthcare resource utilisation. There are limited data evaluating factors associated with hospitalisation for coccidioidomycosis. We conducted a cross-sectional study to assess incidence and factors associated with coccidioidomycosis-associated hospitalisation in California and Arizona. We analysed hospital discharge data obtained from the State Inpatient Dataset for California and Arizona between 2005 and 2011 and performed multivariable logistic regression examining factors associated with coccidioidomycosis-associated hospitalisation. During our time frame, we found 23 758 coccidioidomycosis-associated hospitalisations. Coccidioidomycosis incidence was over sixfold higher in Arizona compared to California (198.9 vs. 29.6/100 000 person-years). In our multivariable model, coccidioidomycosis-associated hospitalisation was associated with age group 40-49 years (referent group: age 18-29 years, adjusted odds ratio (aOR) = 1.50 (95% confidence interval (CI) 1.43-1.59)), African American race (referent group: Caucasian, aOR = 1.98 (95% CI 1.89-2.06)), residing in a large rural town (referent group: urban area, aOR = 2.28 (95% CI 2.19-2.39)), uncomplicated diabetes (aOR = 1.47 (95% CI 1.41-1.52)) chronic obstructive pulmonary disease (aOR = 1.59 (95% CI 1.54-1.65)) and higher number of comorbidities (aOR = 1.02 (95% CI 1.02-1.03) for each point in the Elixhauser score). Identifying persons at highest risk for hospitalisation with coccidioidomycosis may be helpful for future prevention efforts.

Bayesian evidence and epidemiological implications of environmental contamination from acute respiratory infection in long-term care facilities.

Skilled nursing home facilities (SNFs) house a vulnerable population frequently exposed to respiratory pathogens. Our study aims to gain a better understanding of the transmission of nursing home-acquired viral respiratory infections in non-epidemic settings. Symptomatic surveillance was performed in three SNFs for residents exhibiting acute respiratory symptoms. Environmental surveillance of five high-touch areas was performed to assess possible transmission. All resident and environmental samples were screened using a commercial multiplex polymerase chain reaction platform. Bayesian methods were used to evaluate environmental contamination. Among nursing home residents with respiratory symptoms, 19% had a detectable viral pathogen (parainfluenza-3, rhinovirus/enterovirus, RSV, or influenza B). Environmental contamination was found in 20% of total room surface swabs of symptomatic residents. Environmental and resident results were all concordant. Target period prevalence among symptomatic residents ranged from 5.5 to 13.3% depending on target. Bayesian analysis quantifies the probability of environmental shedding due to parainfluenza-3 as 92.4% (95% CI: 86.8-95.8%) and due to rhinovirus/enterovirus as 65.6% (95% CI: 57.9-72.5%). Our findings confirm that non-epidemic viral infections are common among SNF residents exhibiting acute respiratory symptoms and that environmental contamination may facilitate further spread with considerable epidemiological implications. Findings further emphasise the importance of environmental infection control for viral respiratory pathogens in long-term care facilities.

Incidence and factors associated with emergency department visits for recurrent skin and soft tissue infections in patients in California, 2005-2011.

More than 2 million visits for skin and soft tissue infections (SSTIs) are seen in US emergency departments (EDs) yearly. Up to 50% of patients with SSTIs, suffer from recurrences, but associated factors remain poorly understood. We performed a retrospective study of patients with primary diagnosis of SSTI between 2005 and 2011 using California ED discharge data from the State Emergency Department Databases and State Inpatient Databases. Using a multivariable logistic regression, we examined factors associated with a repeat SSTI ED visits up to 6 months after the initial SSTI. Among 197 371 SSTIs, 16·3% were associated with a recurrent ED visit. We found no trend in recurrent visits over time (χ 2 trend = 0·68, P = 0·4). Race/ethnicity, age, geographical location, household income, and comorbidities were all associated with recurrent visits. Recurrent ED visits were associated with drug/alcohol abuse or liver disease [odds ratio (OR) 1·4, 95% confidence interval (CI) 1·3-1·4], obesity (OR 1·3, 95% CI 1·2-1·4), and in infections that were drained (OR 1·1, 95% CI 1·1-1·1) and inversely associated with hospitalization after initial ED visit (OR 0·4, 95% CI 0·3-0·4). In conclusion, we found several patient-level factors associated with recurrent ED visits. Identification of these high-risk groups is critical for future ED-based interventions.

Discontinuation of contact precautions with the introduction of universal daily chlorhexidine bathing.

Contact precautions are a traditional strategy to prevent transmission of methicillin-resistant Staphylococcus aureus (MRSA). Chlorhexidine bathing is increasingly used to decrease MRSA burden and transmission in intensive care units (ICUs). We sought to evaluate a hospital policy change from routine contact precautions for MRSA compared with universal chlorhexidine bathing, without contact precautions. We measured new MRSA acquisition in ICU patients and surveyed for MRSA environmental contamination in common areas and non-MRSA patient rooms before and after the policy change. During the baseline and chlorhexidine bathing periods, the number of patients (453 vs. 417), ICU days (1999 vs. 1703) and MRSA days/1000 ICU days (109 vs. 102) were similar. MRSA acquisition (2/453 vs. 2/457, P = 0·93) and environmental MRSA contamination (9/474 vs. 7/500, P = 0·53) were not significantly different between time periods. There were 58% fewer contact precaution days in the ICU during the chlorhexidine period (241/1993 vs. 102/1730, P < 0·01). We found no evidence that discontinuation of contact precautions for patients with MRSA in conjunction with adoption of daily chlorhexidine bathing in ICUs is associated with increased MRSA acquisition among ICU patients or increased MRSA contamination of ICU fomites. Although underpowered, our findings suggest this strategy, which has the potential to reduce costs and improve patient safety, should be assessed in similar but larger studies.

Patient-level analysis of incident vancomycin-resistant enterococci colonization and antibiotic days of therapy.

Vancomycin-resistant enterococci (VRE) infections are a public health threat associated with increased patient mortality and healthcare costs. Antibiotic usage, particularly cephalosporins, has been associated with VRE colonization and VRE bloodstream infections (VRE BSI). We examined the relationship between antimicrobial usage and incident VRE colonization at the individual patient level. Prospective, weekly surveillance was undertaken for incident VRE colonization defined by negative admission but positive surveillance swab in a medical intensive care unit over a 17-month period. Antimicrobial exposure was quantified as days of therapy (DOT)/1000 patient-days. Multiple logistic regression was used to analyse incident VRE colonization and antibiotic DOT, controlling for demographic and clinical covariates. Ninety-six percent (1398/1454) of admissions were swabbed within 24 h of intensive care unit (ICU) arrival and of the 380 patients in the ICU long enough for weekly surveillance, 83 (22%) developed incident VRE colonization. Incident colonization was associated in bivariate analysis with male gender, more previous hospital admissions, longer previous hospital stay, and use of cefepime/ceftazidime, fluconazole, azithromycin, and metronidazole (P < 0·05). After controlling for demographic and clinical covariates, metronidazole was the only antibiotic independently associated with incident VRE colonization (odds ratio 2·0, 95% confidence interval 1·2-3·3, P < 0·009). Our findings suggest that risk of incident VRE colonization differs between individual antibiotic agents and support the possibility that antimicrobial stewardship may impact VRE colonization and infection.

A comparison of clinical outcomes between healthcare-associated infections due to community-associated methicillin-resistant Staphylococcus aureus strains and healthcare-associated methicillin-resistant S. aureus strains.

There are limited data examining whether outcomes of methicillin-resistant Staphylococcus aureus (MRSA) healthcare-associated infections (HAIs) are worse when caused by community-associated (CA) strains compared to HA strains. We reviewed all patients' charts at our institution from 1999 to 2009 that had MRSA first isolated only after 72 h of hospitalization (n=724). Of these, 384 patients had a MRSA-HAI according to CDC criteria. Treatment failure was similar in those infected with a phenotypically CA-MRSA strain compared to a phenotypically HA-MRSA strain (23% vs. 15%, P=0.10) as was 30-day mortality (16% vs. 19%, P=0.57). Independent risk factors associated with (P<0.05) treatment failure were higher Charlson Comorbidity Index, higher APACHE II score, and no anti-MRSA treatment. These factors were also associated with 30-day mortality, as were female gender, older age, MRSA bloodstream infection, MRSA pneumonia, and HIV. Our findings suggest that clinical and host factors, not MRSA strain type, predict treatment failure and death in hospitalized patients with MRSA-HAIs.

Pneumocystis pneumonia in hospitalized patients: a detailed examination of symptoms, management, and outcomes in human immunodeficiency virus (HIV)-infected and HIV-uninfected persons.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is a life-threatening infection for immunocompromised individuals. Robust data and clear guidelines are available for prophylaxis and treatment of human immunodeficiency virus (HIV)-related PCP (HIV-PCP), yet few data and no guidelines are available for non-HIV-related PCP (NH-PCP). We postulated that prevention and inpatient management of HIV-PCP differed from NH-PCP. METHODS: We performed a retrospective case review of all pathologically confirmed cases of PCP seen at the University of Alabama Medical Center from 1996 to 2008. Data on clinical presentation, hospital course, and outcome were collected using a standardized data collection instrument. Bivariate analysis compared prophylaxis, adjunctive corticosteroids, and clinical outcomes between patients with HIV-PCP and NH-PCP. RESULTS: Our analysis of the cohort included 97 cases of PCP; 65 HIV and 32 non-HIV cases. Non-HIV cases rarely received primary prophylaxis (4% vs. 38%, P = 0.01) and received appropriate antibiotics later in the course of hospitalization (5.2 days vs. 1.1 days, P < 0.005). Among transplant patients, NH-PCP was diagnosed a mean of 1066 days after transplantation and most patients were on low-dose corticosteroids (87%) at the time of disease onset. No significant differences in adjunctive corticosteroid use (69% vs. 77%, P = 0.39) and 90-day mortality (41% vs. 28%, P = 0.20) were detected. CONCLUSIONS: Patients who have undergone organ or stem cell transplant remain at risk for PCP for many years after transplantation. In our cohort, patients who developed NH-PCP were rarely given prophylaxis, and initiation of appropriate antibiotics was significantly delayed compared to cases of HIV-PCP. Medical providers should be aware of the ongoing risk for NH-PCP, even late after transplantation, and consider more aggressive approaches to both prophylaxis and earlier empirical therapy for PCP.

Non-suppurative cellulitis: risk factors and its association with Staphylococcus aureus colonization in an area of endemic community-associated methicillin-resistant S. aureus infections.

Suppurative methicillin-resistant Staphylococcus aureus (MRSA) skin infections are common and associated with MRSA colonization, but little is known about non-suppurative cellulitis and its relationship with MRSA colonization in areas endemic for community-associated MRSA. We prospectively enrolled patients hospitalized for non-suppurative cellulitis (n=50) and matched controls (n=100) and found S. aureus colonization was similar in cases and controls (30% vs. 25%, P=0·95). MRSA was uncommon in cases (6%) and controls (3%) (P=0·39). All MRSA isolates were USA300 by pulsed-field gel electrophoresis. Independent risk factors for non-suppurative cellulitis were diabetes (OR 3·5, 95% CI 1·4-8·9, P=0·01) and homelessness in the previous year (OR 6·4, 95% CI 1·9-20·9, P=0·002). These findings suggest that MRSA may only rarely be causative of non-suppurative cellulitis.

Risk factors for transmission of carbapenem-resistant Enterobacterales to healthcare personnel gloves and gowns in the USA.

BACKGROUND: Hospitals are sources for acquisition of carbapenem-resistant Entero-bacterales (CRE), and it is believed that the contamination of healthcare personnel (HCP) hands and clothing play a major role in patient-to-patient transmission of antibiotic-resistant bacteria. AIM: The aim of this study was to determine which HCP types, HCP-patient interactions, and patient characteristics are associated with greater transmission of CRE to HCP gloves and gowns in the hospital. METHODS: This was a prospective observational cohort study that enrolled patients with recent surveillance or clinical cultures positive for CRE at five hospitals in four states in the USA. HCP gloves and gown were cultured after patient care. Samples were also obtained from patients' stool, perianal area, and skin of the chest and arm to assess bacterial burden. FINDINGS: Among 313 CRE-colonized patients and 3070 glove and gown cultures obtained after patient care, HCP gloves and gowns were found to be contaminated with CRE 7.9% and 4.3% of the time, respectively. Contamination of either gloves or gowns occurred in 10.0% of interactions. Contamination was highest (15.3%) among respiratory therapists (odds ratio: 3.79; 95% confidence interval: 1.61-8.94) and when any HCP touched the patient (1.52; 1.10-2.12). Associations were also found between CRE transmission to HCP gloves or gown and: being in the intensive care unit, having a positive clinical culture, and increasing bacterial burden on the patient. CONCLUSION: CRE transmission to HCP gloves and gown occurred frequently. These findings may inform evidence-based policies about what situations and for which patients contact precautions are most important.

Staphylococcus aureus is the most common identified cause of cellulitis: a systematic review.

We utilized Medline to perform a systematic review of the literature to quantify the aetiology of cellulitis with intact skin. Of 808 patients with cellulitis, 127-129 (15.7-16.0%) patients had positive needle aspiration and/or punch biopsy cultures from intact skin. Of the patients with positive cultures, 65 (50.4-51.2%) had cultures positive for Staphylococcus aureus, 35 (27.1-27.6%) for group A streptococcus, and 35-37 (27.1-29.1%) for other pathogens. The most common aetiology of cellulitis with intact skin, when it can be determined, is S. aureus, outnumbering group A streptococcus by a ratio of nearly 2:1. Given the increasing incidence of community-associated methicillin-resistant S. aureus infections, our findings may have critical therapeutic implications.

Potential economic burden of carbapenem-resistant Enterobacteriaceae (CRE) in the United States.

OBJECTIVES: The Centers for Disease Control and Prevention considers carbapenem-resistant Enterobacteriaceae (CRE) an urgent public health threat; however, its economic burden is unknown. METHODS: We developed a CRE clinical and economics outcomes model to determine the cost of CRE infection from the hospital, third-party payer, and societal, perspectives and to evaluate the health and economic burden of CRE to the USA. RESULTS: Depending on the infection type, the median cost of a single CRE infection can range from $22 484 to $66 031 for hospitals, $10 440 to $31 621 for third-party payers, and $37 778 to $83 512 for society. An infection incidence of 2.93 per 100 000 population in the USA (9418 infections) would cost hospitals $275 million (95% CR $217-334 million), third-party payers $147 million (95% CR $129-172 million), and society $553 million (95% CR $303-1593 million) with a 25% attributable mortality, and would result in the loss of 8841 (95% CR 5805-12 420) quality-adjusted life years. An incidence of 15 per 100 000 (48 213 infections) would cost hospitals $1.4 billion (95% CR $1.1-1.7 billion), third-party payers $0.8 billion (95% CR $0.6-0.8 billion), and society $2.8 billion (95% CR $1.6-8.2 billion), and result in the loss of 45 261 quality-adjusted life years. CONCLUSIONS: The cost of CRE is higher than the annual cost of many chronic diseases and of many acute diseases. Costs rise proportionally with the incidence of CRE, increasing by 2.0 times, 3.4 times, and 5.1 times for incidence rates of 6, 10, and 15 per 100 000 persons.

Effect of exogenous carnitine on carnitine homeostasis in the rat.

The interaction of exogenous carnitine with whole body carnitine homeostasis was characterized in the rat. Carnitine was administered in pharmacologic doses (0-33.3 mumols/100 g body weight) by bolus, intravenous injection, and plasma, urine, liver, skeletal muscle and heart content of carnitine and acylcarnitines quantitated over a 48 h period. Pre-injection urinary carnitine excretion was circadian as excretion rates were increased 2-fold during the lights-off cycle as compared with the lights-on cycle. Following carnitine administration, there was an increase in urinary total carnitine excretion which accounted for approx. 60% of the administered carnitine at doses above 8.3 mumols/100 g body weight. Urinary acylcarnitine excretion was increased following carnitine administration in a dose-dependent fashion. During the 24 h following administration of 16.7 mumols [14C]carnitine/100 g body weight, urinary carnitine specific activity averaged only 72 +/- 4% of the injection solution specific activity. This dilution of the [14C]carnitine specific activity suggests that endogenous carnitine contributed to the increased net urinary carnitine excretion following carnitine administration. 5 min after administration of 16.7 mumol carnitine/100 g body weight approx. 80% of the injected carnitine was in the extracellular fluid compartment and 5% in the liver. Plasma, liver and soleus total carnitine contents were increased 6 h after administration of 16.7 mumols carnitine/100 g body weight. 6 h post-administration, 37% of the dose was recovered in the urine, 12% remained in the extracellular compartment, 9% was in the liver and 22% was distributed in the skeletal muscle. In liver and plasma, short chain acylcarnitine content was increased 5 min and 6 h post injection as compared with controls. Plasma, liver, skeletal muscle and heart carnitine contents were not different from control levels 48 h after carnitine administration. The results demonstrate that single, bolus administration of carnitine is effective in increasing urinary acylcarnitine elimination. While liver carnitine content is doubled for at least 6 h following carnitine administration, skeletal muscle and heart carnitine pools are only modestly perturbed following a single intravenous carnitine dose. The dilution of [14C]carnitine specific activity in the urine of treated animals suggests that tissue-blood carnitine or acylcarnitine exchange systems contribute to overall carnitine homeostasis following carnitine administration.

Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions.

Herbal medicinals are being used by an increasing number of patients who typically do not advise their clinicians of concomitant use. Known or potential drug-herb interactions exist and should be screened for. If used beyond 8 weeks, Echinacea could cause hepatotoxicity and therefore should not be used with other known hepatoxic drugs, such as anabolic steroids, amiodarone, methotrexate, and ketoconazole. However, Echinacea lacks the 1,2 saturated necrine ring associated with hepatoxicity of pyrrolizidine alkaloids. Nonsteroidal anti-inflammatory drugs may negate the usefulness of feverfew in the treatment of migraine headaches. Feverfew, garlic, Ginkgo, ginger, and ginseng may alter bleeding time and should not be used concomitantly with warfarin sodium. Additionally, ginseng may cause headache, tremulousness, and manic episodes in patients treated with phenelzine sulfate. Ginseng should also not be used with estrogens or corticosteroids because of possible additive effects. Since the mechanism of action of St John wort is uncertain, concomitant use with monoamine oxidase inhibitors and selective serotonin reuptake inhibitors is ill advised. Valerian should not be used concomitantly with barbiturates because excessive sedation may occur. Kyushin, licorice, plantain, uzara root, hawthorn, and ginseng may interfere with either digoxin pharmacodynamically or with digoxin monitoring. Evening primrose oil and borage should not be used with anticonvulsants because they may lower the seizure threshold. Shankapulshpi, an Ayurvedic preparation, may decrease phenytoin levels as well as diminish drug efficacy. Kava when used with alprazolam has resulted in coma. Immunostimulants (eg, Echinacea and zinc) should not be given with immunosuppressants (eg, corticosteroids and cyclosporine). Tannic acids present in some herbs (eg, St John wort and saw palmetto) may inhibit the absorption of iron. Kelp as a source of iodine may interfere with thyroid replacement therapies. Licorice can offset the pharmacological effect of spironolactone. Numerous herbs (eg, karela and ginseng) may affect blood glucose levels and should not be used in patients with diabetes mellitus.

Metoclopramide-induced movement disorders. Clinical findings with a review of the literature.

Metoclopramide, a dopamine-2 receptor antagonist used for various gastrointestinal disorders, may cause or exacerbate a variety of extrapyramidal movement disorders. To draw attention to the frequent occurrence of metoclopramide-induced movement disorders, we identified and studied 16 patients who had been exposed to this neuroleptic. The average age at onset was 63 years (range, 24 to 85 years), and women outnumbered men 3 to 1. Tardive dyskinesia was the most common movement disorder (n = 10 [63%]). Five patients had metoclopramide-induced parkinsonism, 1 patient had tardive dystonia, and 1 patient had akathisia. The average duration of exposure prior to onset of movement disorders was 12 months (range, 1 day to 4 years). Therapy was continued for an average of 6 months (range, 1 day to 2 years) after the onset of symptoms, reflecting clinical nonrecognition of the movement disorder and its relationship to metoclopramide. To prevent persistent and disabling movement disorders, long-term use of metoclopramide should be avoided, and patients should be carefully observed for potential neurologic reactions.

Trazodone kinetics: effect of age, gender, and obesity.

Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P less than 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P less than 0.05), thereby increasing elimination half-life (t1/2) in elderly men (8.2 vs. 4.7 hours; P less than 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P less than 0.02), causing increased t1/2 (7.6 vs. 5.9 hours; P less than 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P less than 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t1/2 in obese subjects (13.3 vs. 5.9 hours; P less than 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.

A case of fluoxetine-induced serum sickness.

After 3-4 weeks of taking fluoxetine for depression, a 27-year-old man developed fever, skin eruptions, arthralgia, and lymphadenopathy. His clinical symptoms and results of laboratory assessment were consistent with a diagnosis of serum sickness reaction to the fluoxetine.

Chronic benzodiazepine administration. XI. Concurrent administration of PK11195 attenuates lorazepam discontinuation effects.

Benzodiazepine discontinuation is associated with alterations in motor activity and gamma-aminobutyric acid-A receptor upregulation in a mouse model. Prior studies indicate that concurrent administration of the compound N-methyl-N-(methyl-1-propyl)chloro-2-phenyl-1-isoquinoline-3- carboxamide (PK1195), a "peripheral" site benzodiazepine antagonist, can attenuate the effects of lorazepam on tolerance and receptor alterations. To evaluate the effects of PK11195 administration on benzodiazepine discontinuation, we administered lorazepam (2 mg/kg per day), PK 11195 (1 to 10 mg/kg per day) or the combination to mice for 7 days, and then evaluated pentylenetetrazole-induced seizure threshold and benzodiazepine binding at days 1, 4, and 7 after discontinuation. Seizure threshold was reduced at 4 days after lorazepam discontinuation; this effect was attenuated by coadministration of PK11195 at 5 mg/kg per day. Lorazepam discontinuation effects were not altered by PK11195 at 1 mg/kg per day, whereas the 10-mg/kg dose was not different from 5 mg/kg per day. The competitive ligand Ro5-4864 at 10 mg/kg per day, blocked the effects of PK11195 on lorazepam discontinuation. Benzodiazepine receptor binding in vivo was increased in the cortex and hippocampus at 4 days postlorazepam discontinuation. This effect was attenuated in the hippocampus but not in the cortex by concurrent administration of PK1195. These data indicate that concurrent administration of PK11195 may attenuate discontinuation effects of lorazepam.

Neurochemical and pharmacokinetic correlates of the clinical action of benzodiazepine hypnotic drugs.

Benzodiazepine derivatives are presumed to exert their pharmacologic activity via interaction with specific molecular recognition sites, termed benzodiazepine receptors, within the brain. The various benzodiazepines used in clinical practice differ considerably in their intrinsic receptor affinity, but the qualitative character of the drug-receptor interaction is similar or identical among this class of drugs. All benzodiazepines are lipophilic (lipid-soluble) substances that relatively rapidly cross the blood-brain barrier and equilibrate with brain tissue. After equilibrium is attained, a constant brain:plasma ratio is maintained, such that plasma concentrations proportionately reflect concentrations of drug in brain. Brain concentrations are proportional to the extent of receptor occupancy, which in turn determines the acute behavioral effect. Clinical differences among benzodiazepines largely reflect differences in pharmacokinetic properties. The onset of action after single oral doses reflects the rate of absorption from the gastrointestinal tract, whereas the duration of action is determined by the rate and extent of drug distribution to peripheral tissues, as well as by the rate of elimination and clearance. During multiple dosage, long half-life drugs accumulate, with the concurrent possibility of daytime sedation. However, a benefit of long half-life drugs is that rebound insomnia on abrupt termination is unlikely. Short half-life drugs accumulate minimally and have a lower likelihood of producing daytime sedation. However, they may be more likely to produce rebound insomnia on abrupt discontinuation.

Prenatal cocaine exposure: decreased sensitization to cocaine and decreased striatal dopamine transporter binding in offspring.

Pregnant mice were treated with cocaine, 10 mg/kg/day, during days 13 to 20 of gestation. Cocaine sensitization and dopamine transporter binding were evaluated in offspring at 6 weeks of age. Sensitization, defined as the increase in activity after 5 injections of cocaine compared to 1 injection, was reduced in cocaine-exposed mice. Dopamine transporter binding in striatum was also significantly reduced in cocaine-exposed mice compared to controls.

Chronic administration of benzodiazepines--V. Rapid onset of behavioral and neurochemical alterations after discontinuation of alprazolam.

Discontinuation of chronic treatment with alprazolam may cause a characteristic clinical syndrome. To assess the basis of this syndrome, mice were treated with alprazolam, 2 mg/kg, for 7 days, a regimen associated with the development of tolerance and downregulation of receptors. Effects on motor activity and the binding and function of GABA receptors were evaluated 1, 2, 4 and 7 days after discontinuation. Motor activity was similar to controls 1 day after cessation of alprazolam, increased from days 2 to 4 after-alprazolam, and returned to control values by 7 days. The binding of benzodiazepines in vivo and in vitro was increased in the cortex 2 and 4 days after alprazolam and in the hypothalamus at 4 days after alprazolam. Binding returned to control values in all areas by 7 days. Binding at the chloride channel, using [35S]t-butylbicyclophosphorothionate, was not significantly altered after discontinuation. Muscimol-stimulated uptake of [36Cl-] in cortical synaptoneurosomes was increased at 4 days after alprazolam, compared to days 1, 2 and 7. Thus, behavioral and neurochemical alterations was associated with the discontinuation of alprazolam. These alterations were qualitatively similar to those observed following discontinuation of lorazepam but occurred more rapidly and with differing regional specificity.