Current concepts in treating mild cognitive impairment in Parkinson's disease.

Impairment in various aspects of cognition is recognized as an important non-motor symptom of Parkinson's disease (PD). Mild cognitive impairment in PD (PD-MCI) is common in non-demented PD patients and is often associated with severity of motor symptoms, disease duration and increasing age. Further, PD-MCI can have a significant negative effect on performance of daily life activities and may be a harbinger of development of PD dementia. Thus, there is significant interest in developing therapeutic strategies to ameliorate cognitive deficits in PD and improve cognitive functioning of PD patients. However, due to significant questions that remain regarding the pathophysiology of cognitive dysfunction in PD, remediation of cognitive dysfunction in PD has proven difficult. In this paper, we will focus on PD-MCI and will review some of the current therapeutic approaches being taken to try to improve cognitive functioning in patients with PD-MCI.

Bioequivalence study of two perindopril tert-butylamine tablet formulations in healthy Chinese subjects under fasting and fed conditions: A randomized, open-label, single-dose, crossover trial.

BACKGROUND: To evaluate the bioequivalence between test and reference formulations of perindopril tert-butylamine under fasting and fed conditions and to assess their pharmacokinetic (PK) and safety profiles. METHOD: A randomized, open-label, single-dose, crossover trial was conducted in healthy Chinese subjects. Test or reference perindopril tert-butylamine tablets (4 mg) were randomly given to subjects under fasting (2-period crossover, with an administration sequence of test tablet (T), reference tablet (R) or RT) and fed (4-period crossover, with an administration sequence of TRTR or RTRT) conditions, while each single administration was followed by a 14-day washout period. The plasma concentrations and corresponding non-compartmental PK parameters of perindopril and perindoprilat were determined. The two formulations were considered to be bioequivalent if the 90 % confidence intervals (CIs) of the geometric mean (GM) ratio (test/reference) for Cmax, AUC0-t, and AUC0-∞ (perindopril) was both within the range of 80-125 %. Safety assessments including vital signs, physical examination, laboratory examination, 12-lead ECG and reports of treatment emergent adverse events (TEAEs) were carefully documented. RESULTS: A total of 64 subjects (32 in each trial) were randomized and all completed the trials. Regardless of fasting or fed trials, the PK characteristics of perindopril and perindoprilat for the test formulation were similar to those of the reference formulation (all P > 0.05). The 90 % CIs of the geometric mean (GM) ratio for Cmax, AUC0-t, and AUC0-∞, respectively, were 92.86-106.81 %, 98.44-102.88 % and 98.48-103.02 % under the fasting condition and 90.64-110.04 %, 96.95-101.90 % and 96.83-101.78 % under the fed condition, which were both within the pre-specified range of 80-125 %. A total of 10 (31.3 %) fasted subjects and 11 (34.4 %) fed subjects experienced 11 and 24 TEAEs, respectively, all of which were within the severity of grade 1. The incidence of TEAEs and drug-related TEAEs were similar between test and reference formulations (all P > 0.05) and no serious TEAEs or deaths occurred during the trials. CONCLUSIONS: The test and reference formulations of perindopril tert-butylamine tablets (4 mg) were bioequivalent and well tolerated in healthy Chinese subjects under fasting and fed conditions.

A phase 1b trial of the CXCR4 inhibitor mavorixafor and nivolumab in advanced renal cell carcinoma patients with no prior response to nivolumab monotherapy.

Background The CXCR4 chemokine receptor promotes tumor survival through mechanisms that include suppressing antitumor immune responses. Mavorixafor (X4P-001) is an oral, selective, allosteric CXCR4 inhibitor that decreases the recruitment of immunosuppressive cells into the tumor microenvironment and increases activated cytotoxic Tcell infiltration. Methods Patients with metastatic clear cell renal cell carcinoma (ccRCC) unresponsive to nivolumab monotherapy received oral mavorixafor 400 mg daily plus 240 mg intravenous nivolumab every 2 weeks. Results Nine patients were enrolled, median age 65 years. At baseline 4 had progressive disease (PD) and 5 had stable disease (SD). One of 5 patients with SD at study entry on prior nivolumab monotherapy had a partial response (PR) on combination treatment; all 4 patients with PD at study entry had a best response of SD with the combination treatment (median duration: 6.7 months; range: 3.7-14.7). Four patients discontinued therapy due to treatment-related adverse events (AEs). Grade ≥ 3 drug-related AEs were elevated alanine and aspartate aminotransferase (2 patients each); and autoimmune hepatitis, chronic kidney disease, increased lipase, maculopapular rash, and mucosal inflammation (1 patient each). A robust increase in levels of chemokine (C-X-C motif) ligand 9 CXCL9 on mavorixafor appeared to correlate with clinical benefit. Conclusions The CXCR4 inhibition mediated by mavorixafor, in combination with PD-1 blockade to enhance antitumor immune responses in patients unresponsive to checkpoint inhibitor monotherapy, is worthy of further study. Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile.Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016.

Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mavorixafor from a phase 2 open-label dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. Mavorixafor is an oral small molecule selective antagonist of the CXCR4 receptor that increases mobilization and trafficking of white blood cells from the bone marrow. Patients received escalating doses of mavorixafor, up to 400 mg once daily. Five patients continued on the extension study for up to 28.6 months. Mavorixafor was well tolerated with no treatment-related serious adverse events. At a median follow-up of 16.5 months, we observed dose-dependent increases in absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). At doses ≥300 mg/d, ANC was maintained at >500 cells per microliter for a median of 12.6 hours, and ALC was maintained at >1000 cells per microliter for up to 16.9 hours. Continued follow-up on the extension study resulted in a yearly infection rate that decreased from 4.63 events (95% confidence interval, 3.3-6.3) in the 12 months prior to the trial to 2.27 events (95% confidence interval, 1.4-3.5) for patients on effective doses. We observed an average 75% reduction in the number of cutaneous warts. This study demonstrates that mavorixafor, 400 mg once daily, mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. The trial was registered at www.clinicaltrials.gov as #NCT03005327.

Stellate Ganglion Blockade repairs Intestinal Mucosal Barrier through suppression of Endoplasmic Reticulum Stress following Hemorrhagic Shock.

Background: Hemorrhagic shock-induced ischemia and hypoxia elicit endoplasmic reticulum stress (ERS) that leads to cell apoptosis, tissue structural damage and organ dysfunction and failure. Stellate ganglion blockade (SGB) has been demonstrated to improve intestinal barrier dysfunction induced by hemorrhagic shock. The present study sought to investigate whether the beneficial effect of SGB on the intestinal mucosal barrier function is via suppression of ERS. Materials and methods: A conscious rat model of hemorrhagic shock (40 ±2 mmHg for 1 hour, followed by resuscitation) was established. The parameters reflecting intestinal morphology and intestinal mucosal barrier function including wet-dry ratio (W/D), intestinal permeability, D-lactic acid (D-LA) and intestinal fatty acid binding protein (I-FABP) in plasma, and expressions of ATF6α, PERK, and IRE1α in intestinal tissues were then observed. Furthermore, the effects of either SGB or ERS inhibitor, 4-phenylbutyric acid (4-PBA), on these parameters in rats with hemorrhagic shock were assessed. The effect of ERS agonist tunicamycin (TM) on the rats subjected with both SGB and hemorrhagic shock was also determined. Results: Either SGB or administration of ERS inhibitor, 4-PBA, alleviated hemorrhagic shock-induced adverse effects such as intestinal mucosal barrier dysfunction and excessive autophagy, which were characterized by damaged intestinal tissue, enhanced intestinal permeability and D-LA and I-FABP levels in plasma, and increased expressions of ATF6α, PERK, IRE1α in intestinal tissue. In contrast, administration of ERS agonist, TM, suppressed the beneficial effects of SGB on intestinal tissue and function during hemorrhagic shock. Conclusion: The SGB repairs intestinal mucosal barrier through suppression of ERS following hemorrhagic shock.

Decontamination efficacy of soapy water and water washing following exposure of toxic chemicals on human skin.

Aim of the study: Following exposure to toxic chemicals, skin uptake is a potential route of intoxication. Therefore, efficient methods for rapid skin decontamination to mitigate systemic effects are of utmost importance. In operational guidelines, skin decontamination is recommended to be performed by dry absorption and washing with water or soapy water. In the present study, evaluation of decontamination efficacy using water or soapy water was performed for five chemicals, three toxic industrial chemicals and two simulants for chemical warfare agents.Materials and methods: Decontamination was initiated at time points 5, 15, 45 and 120 min after exposure in order to evaluate the time window for efficient decontamination. Experiments were conducted utilizing an in vitro skin penetration model to allow exposure of toxic chemicals on human skin. Results: For all test substances, it was clearly demonstrated that decontamination had greater efficacy when initiated at the earliest time-point while decontamination after 120 min was less efficient. Adding soap to the water showed no significant improvement for any of the tested substances.Conclusion: These results are of reledvance for the development of efficient operational decontamination procedures.

Effect of butafosfan supplementation during oocyte maturation on bovine embryo development.

Around 60-80% of oocytes maturated in vivo reached competence, while the proportion of maturation in vitro is rarely higher than 40%. In this sense, butafosfan has been used in vivo to improve metabolic condition of postpartum cows, and can represent an alternative to increase reproductive efficiency in cows. The aim of this study was to evaluate the addition of increasing doses of butafosfan during oocyte maturation in vitro on the initial embryo development in cattle. In total, 1400 cumulus-oocyte complexes (COCs) were distributed in four groups and maturated according to supplementation with increasing concentrations of butafosfan (0 mg/ml, 0.05 mg/ml, 0.1 mg/ml and 0.2 mg/ml). Then, 20 oocytes per group were collected to evaluate nuclear maturation and gene expression on cumulus cells and oocytes and the remaining oocytes were inseminated and cultured until day 7, when blastocysts were collected for gene expression analysis. A dose-dependent effect of butafosfan was observed, with decrease of cleavage rate and embryo development with higher doses. No difference between groups was observed in maturation rate and expression of genes related to oocyte quality. Our results suggest that butafosfan is prejudicial for oocytes, compromising cleavage and embryo development.

Simultaneous determination of N-ethylpentylone, dopamine, 5-hydroxytryptamine and their metabolites in rat brain microdialysis by liquid chromatography tandem mass spectrometry.

N-Ethylpentylone (NEP) is a popular synthetic cathinone abused worldwide. To obtain more information about its pharmacokinetics and pharmacodynamics, a rapid, simple and sensitive liquid chromatography-tandem mass spectrometry method was developed for the determination of NEP, two important neurotransmitters, dopamine and serotonin, and their metabolites, including 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine and 5-hydroxyindole-3-acetic acid, in rat brain microdialysate. The analytes were separated on a Phnomenex Polar C18 column, with a mobile phase of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B) under gradient elution to shorten the total chromatographic run time. A triple quadruple mass spectrometer coupled with an electrospray ionization source in both positive and negative ion mode was used to detect the analytes. This method showed excellent accuracy (87.4-113.5%) and precision (relative standard deviation <15%) at three quality control levels. The limits of detection were 0.2 ng/mL for NEP and 0.2-50 nm for the others and good linearity was obtained. This study pioneered a method to integrate exogenous drugs and endogenous neurotransmitters as the drugs act on the same determination system, which means that this innovation can provide support for further study of the addictive effects of NEP or other synthetic cathinones on extracellular levels of dopamine and 5-hydroxytryptamine.

Determination of benzonatate and its metabolite in human plasma by HPLC-MS/MS: A preliminary pharmacokinetic study in healthy Chinese volunteers after oral administration of benzonatate soft capsule.

Benzonatate has been used as a non-narcotic oral antitussive drug for many years. Its pharmacokinetics has never been reported due to the technical difficulties in detecting benzonatate by mass spectrometry. However, its concentration can be extrapolated based on the concentration of its metabolite, 4-(butylamino)benzoic acid (BBA). In this study, two sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods were developed and fully validated for the determination of the original 4-(butylamino)benzoic acid (method B) and total 4-(butylamino)benzoic acid (containing the original 4-(butylamino)benzoic acid and 4-(butylamino)benzoic acid converted from benzonatate after collection, method A). For both methods, one-step protein precipitation by methanol was performed to extract analytes from the plasma samples. Chromatographic separation was done on an InfinityLab Poroshell 120 Phenyl Hexyl column (2.1 mm × 50 mm, 2.7 µm, Agilent) with initial mobile phase consisting of 5 mM ammonium acetate containing 0.3% formic acid and acetonitrile (60:40, v/v) at a flow rate of 0.3 mL/min. Quantification was achieved by multiple reaction monitoring (MRM) in electron spray ionization (ESI) positive mode with the transitions of m/z 194.2 → 138.1 and 515.3 → 497.3 for 4-(butylamino)benzoic acid and telmisartan (the internal standard), respectively. The two methods exhibited good linearity over the concentration range of 10-10000 ng/mL. Both of the methods were successfully applied to the preliminary pharmacokinetic study in healthy Chinese volunteers after oral administration of benzonatate soft capsule at a single dose of 100 mg. The results showed that 4-(butylamino)benzoic acid and benzonatate were rapidly absorbed and reached a maximum concentration (Cmax) of 1708 ±â€¯457 ng/mL and 1063 ±â€¯460 ng/mL, respectively. The half-life (t1/2) were 1.32 ±â€¯0.29 h for 4-(butylamino)benzoic acid and 1.01 ±â€¯0.41 h for benzonatate. The area under the curve from 0 h to 10 h (AUC0-10) for 4-(butylamino)benzoic acid and benzonatate were 2103 ±â€¯918 ng/mL·h and 1097 ±â€¯559 ng/mL·h, respectively. And the data was valuable for further clinical study.

4-PBA reverses autophagic dysfunction and improves insulin sensitivity in adipose tissue of obese mice via Akt/mTOR signaling.

BACKGROUND: 4-phenyl butyric acid (4-PBA) has been considered as a key regulator of insulin resistance in obesity. However the mechanism of 4-PBA involved in insulin resistance remains elusive. METHODS: We evaluated the effect of 4-PBA on abnormal autophagy and endoplasmic reticulum (ER) stress in obese mice. 4-PBA was administered in obese mice and adipocyte models, and metabolic parameters, autophagy markers, ER stress indicators, Akt/mTOR signaling and insulin signaling molecular were assessed. RESULTS: 4-PBA treatment not only reversed autophagic dysfunction and ER stress, but also improved impaired insulin signaling in tunicamycin-induced adipocytes, and 4-PBA also inhibited activated ER stress and elevated insulin sensitivity in adipocytes with Atg7 siRNA. Additionally, administration of 4-PBA improves glucose tolerance and insulin sensitivity in obese mice via regulating abnormal autophagy and ER stress in adipose tissue. The protective effects of 4-PBA were nullified by suppression of Akt and mTOR in adipocytes, suggesting that 4-PBA inhibits autophagy and restores insulin sensitivity via Akt/mTOR signaling partially. CONCLUSIONS: 4-PBA reverses autophagic dysfunction and improves insulin sensitivity in adipose tissue of obese mice via Akt/mTOR signaling partly, which could be regarded as novel opportunities for treatment of insulin resistance.

Pharmacokinetics of butafosfan after intravenous and intramuscular administration in piglets.

The pharmacokinetics and bioavailability of butafosfan in piglets were investigated following intravenous and intramuscular administration at a single dose of 10 mg/kg body weight. Plasma concentration-time data and relevant parameters were best described by noncompartmental analysis after intravenous and intramuscular injection. The data were analyzed through WinNolin 6.3 software. After intravenous administration, the mean pharmacokinetic parameters were determined as T1/2λz of 3.30 h, Cl of 0.16 L kg/h, AUC of 64.49 ± 15.07 µg h/mL, Vss of 0.81 ± 0.44/kg, and MRT of 1.51 ± 0.27 h. Following intramuscular administration, the Cmax (28.11 µg/mL) was achieved at Tmax (0.31 h) with an absolute availability of 74.69%. Other major parameters including AUC and MRT were 48.29 ± 21.67 µg h/mL and 1.74 ± 0.29 h, respectively.

In vivo characterization of a novel dopamine D3 receptor agonist to treat motor symptoms of Parkinson's disease.

Synthetic dopaminergic agents have found utility in treating neurological and neuropsychiatric disorders since the beginning of 19th century. The discovery of Levodopa (l-dopa) to effectively treat motor symptoms of Parkinson's disease (PD) revolutionized the therapy and remains a gold standard for treating PD. However, l-dopa therapy has been implicated in worsening of the non-motor symptoms including cognition and long-term therapy leads to plasticity and development of abnormal involuntary movements (AIMs) that are collectively called l-dopa induced dyskinesias (LID). Studies in rodents and non-human primates with PD have supported a role for dopamine D3 receptors in the etiology of both the motor symptoms and LID. We have recently developed SK609, a selective dopamine D3 receptor agonist with atypical signaling properties. In this study, we further characterized this novel small molecule using the unilateral lesioned rodent model of PD. In the forepaw stepping test paradigm, SK609 significantly improved the performance of the impaired paw and also normalized the bilateral asymmetry associated with the hemiparkinson rat. In addition, a chronic treatment of SK609 did not induce any AIMs and when used adjuvantly with l-dopa significantly reduced AIMs induced by l-dopa. Further, an optimal dose combination of SK609 with l-dopa was determined by dose dependent titrations of both SK609 and l-dopa that produced minimal AIMs and maximized the effect on improving motor symptoms. Results from this study suggest that SK609 is a novel dopaminergic agent that has the therapeutic potential to treat PD and LID. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.

Determination of designer doping agent--2-ethylamino-1-phenylbutane--in dietary supplements and excretion study following single oral supplement dose.

The quantitative analysis of a new designer doping agent, 2-ethylamino-1-phenylbutane (EAPB) and its metabolite, 2-amino-1-phenylbutane (APB) in urine samples, and the determination of EAPB in dietary supplement samples, have been presented. The main purpose of the present study was to develop simple and reliable gas chromatography-mass spectrometry method (GC-MS) for excretion study following a single oral administration of dietary supplements containing EAPB. Three analytical methods for the determination of EAPB in urine and supplement samples, and APB in urine samples using the GC-MS system, have been validated. The method of the determination of EAPB in supplement samples was applied to analyze seventeen dietary supplements, CRAZE and DETONATE. Two other methods were used to determine the urinary excretion profile of EAPB and APB in the case of three healthy volunteers and, on further investigation, it was applied to the anti-doping control in sport. Quantification was obtained on the basis of the ions at m/z 86, 58 and 169, monitored for EAPB, APB and diphenylamine (used as an internal standard), respectively. The limits of detection and quantification were 2.4 and 7.3µg/g for EAPB in the case of supplement analysis, 2.9 and 8.8ng/mL for EAPB in the case of urine analysis, and 3.2 and 9.7ng/mL for APB. The other validation parameters as linearity, precision and trueness have been also investigated with the acceptable results. The extraction yield of all presented methods was above 69%. EAPB was detected in fourteen analyzed supplements (not included EAPB in their labels) and its content varied between 1.8 and 16.1mg/g. Following oral administration of three supplements with EAPB to one male and two female volunteers, the parent compound of EAPB and its metabolite were monitored and the excretion parameters as the maximum concentration of the analyte in urine (2.2-4.2µg/mL for EAPB; 1.1-5.1µg/mL for APB) and the time for the maximum height of the excretion peak (2-8h and 22h in one case for EAPB; 20-22h and 4h in one case for APB) have been indicated. EAPB and APB were detected at the level above 50ng/mL (50% of the minimum required performance level for stimulants in the anti-doping control in-competition in sport) in the urine up to 46-106h and 58-120h, respectively. Additionally, the result of the anti-doping control during swimming competition of one athlete, whose urine sample was analyzed for stimulants and narcotics, has been presented. The qualitative and quantitative analyses of new designer agents in urine samples and the excretion studies of these substances are of a great importance in the anti-doping control in sport. Moreover, the presentation of detection examples of these agents in supplements that haven't got included an information about them in the labeling, make athletes (and other supplement customers) more and more aware of the risk of the supplement use and possible health and doping consequences.

Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor κB activation.

BACKGROUND: Despite many studies on endoplasmic reticulum (ER) stress in patients with various inflammatory diseases, there is scarce information on ER stress in patients with bronchial asthma. OBJECTIVE: In this study we aimed to elucidate the role of ER stress in the pathogenesis of bronchial asthma. METHODS: Using mice sensitized with ovalbumin (OVA) and LPS and challenged with OVA (OVA(LPS)-OVA mice), as well as mice sensitized and challenged with OVA (OVA-OVA mice), we investigated whether ER stress is involved in the pathogenesis of bronchial asthma. Moreover, we also determined the levels of ER stress markers in blood and bronchoalveolar lavage fluid from asthmatic patients. RESULTS: The OVA(LPS)-OVA mice showed that the expression of ER stress markers and the protein levels of unfolded protein response-related markers in lung tissue were significantly increased after OVA challenge. Moreover, we found that ER stress markers in PBMCs and bronchoalveolar lavage fluid from human asthmatic patients were dramatically increased compared with those from healthy control subjects. In OVA(LPS)-OVA mice 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced the increases in ER stress, nuclear translocation of nuclear factor κB, inflammatory cytokine levels, dendritic cell infiltration, Toll-like receptor 4 expression, airway inflammation, and bronchial hyperresponsiveness, whereas it further enhanced the increase in IL-10 levels. Additionally, the established asthmatic features of OVA-OVA mice were substantially attenuated by 4-PBA administered after completion of OVA challenge. CONCLUSION: These results indicate that ER stress might be implicated in the pathogenesis of bronchial asthma at least in part through modulation of nuclear factor κB activation.

Indolebutylamines as selective 5-HT(1A) agonists.

A series of new 1-[4-(indol-3-yl)butyl]-4-arylpiperazines was prepared to identify highly selective and potent 5-HT(1A) agonists as potential pharmacological tools in studies of mood disorders. The combination of structural elements (indole-alkyl-amine and aryl-piperazine) known to introduce 5-HT(1A) receptor affinity and the proper selection of substituents (R on the indole moiety and R' on the aryl moiety) led to compounds with high receptor specificity and affinity. In particular, the introduction of the methyl ether or the unsubstituted carboxamide as substituents in position 5 of the indole (R) guaranteed serotonergic 5-HT(1A) affinity compared to the unsubstituted analogue. Para-substituted arylpiperazines (R') decreased dopaminergic D(2) binding and increased selectivity for the 5-HT(1A) receptor. Agonistic 5-HT(1A) receptor activity was confirmed in vivo in the ultrasonic vocalization test, and the results suggest that the introduction of the carboxamide residue leads to better bioavailability than the corresponding methyl ether. 3-[4-[4-(4-Carbamoylphenyl)piperazin-1-yl]butyl]-1H-indole-5-carboxamide 54 was identified as a highly selective 5-HT(1A) receptor agonist [GTPgammaS, ED(50) = 4.7 nM] with nanomolar 5-HT(1A) affinity [IC(50) = 0.9 nM] and selectivity [D(2), IC(50) > 850 nM]. 3-[4-[4-(4-Methoxyphenyl)piperazin-1-yl]butyl]-1H-indole-5-carboxamide 45 is one of the most potent and selective 5-HT(1A) agonists known [5-HT(1A), IC(50) = 0.09 nM; D(2), IC(50) = 140 nM].

Management of cough in advanced cancer.

Cough is a common symptom in cancer, with causes that can be benign or malignant. When severe, it affects patients' quality of life and well being. Treatment begins with a detailed history and careful physical examination, followed by chest imaging. Managing cough is directed at correcting the reversible causes. Empiric treatment of cough is valuable in both reversible and irreversible causes. We prefer hydrocodone as first-line empiric treatment, but when the cough is resistant to this, our second-line therapy would be the addition or substitution of benzonatate. Bronchodilators, as well as corticosteroids, are commonly employed in our practice and can be useful in unsuspected bronchospasm.

Effects of di-n-butylamine on the respiratory system of Wistar (WU) rats after subchronic inhalation.

Aim of the study was to investigate the potential toxic effects of di-n-butylamine (DBA), a known skin and eye irritating compound, on the respiratory tract after inhalation exposure for up to 91 days in male and female rats [Crl:(WI)WU BR]. To check whether and to what degree the no-observed-(adverse)-effect level (NO(A)EL) decreases with increasing study duration, serial sacrifices were performed after 3 and 28 days, respectively. Based on two dose range-finding studies, the concentrations for this study were determined with 0 (clean air), 50, 150, and 450 mg/m(3). Animals were exposed for 3 days (6 h/day) 28, and 91 days (5 days/wk, 6 h/day), respectively, and immediately sacrificed thereafter. The results show clear irritating effects only in the upper part of the respiratory tract, that is, the nasal cavities. While after 3 and 28 days effects were found only in the high-dose group, slight adaptive effects, expressed as mucous (goblet) cell hyperplasia, could be diagnosed in the medium- and low-dose groups after 91 days of exposure. Pathological changes were most prominent after 3 days of exposure. In the lung, only marginal effects could be observed (increased relative lung weight only in females of the high concentration after 28 days, slight, not statistically significant histopathological effects in the high concentration after 3 days, no effects on parameters of bronchoalveolar lavage fluid), while no effects were found in the remaining groups.

Effects of acute and chronic administration of selective monoamine re-uptake inhibitors in the rat forced swim test.

The rat forced swim test (FST) is a model that is used extensively as a screening test for antidepressant activity. It has previously been reported that thorough analysis of behaviour in this model reveals two distinct types of active response - climbing and swimming - and that these are separately evoked by re-uptake inhibitors selective for noradrenaline (NA) and serotonin (5-HT), respectively. In the present study, utilising re-uptake inhibitors selective for NA, talsupram, and 5-HT, 5-chloro-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)- phthalan (Lu 10-134-C), we examined if this scoring technique could detect the antidepressant potential of a selective serotonin re-uptake inhibitor (SSRI), and whether re-uptake inhibitors selective for distinct monoamine systems induce exclusive behavioural responses. We also analysed if chronic antidepressant administration for three weeks was more effective than acute treatment. We found Lu 10-134-C (40 mg/kg; PO) to be behaviourally active in this paradigm. Although treatment with talsupram (40 mg/kg; PO) resulted solely in climbing behaviour, Lu 10-134-C induced both climbing and swimming behaviour. However, chronic pre-treatment with either re-uptake inhibitor (20 mg/kg; twice daily; PO) failed to augment the response observed with acute treatment. Similarly, chronic administration of either compound was without effect on the basal, or stress-induced, serum corticosterone concentrations or anterior pituitary (AP) preproopiomelanocorticotropin (POMC) mRNA expression. These results suggest that selective monoamine re-uptake inhibition produces distinct, but not necessarily exclusive, behavioural responses in the forced swim test.

Developmental toxicity of oral n-butylamine hydrochloride and inhaled n-butylamine in rats.

Pregnant Wistar rats were administered 0, 100, 400 or 1000 mg mono-n-butylamine hydrochloride/kg body weight/day by gavage on days 6 through 15 post coitum (sperm-positive=day 0), or inhaled mono-n-butylamine 0, 17, 50 or 152 ppm (whole-body exposure), 6 h/day on days 6 through 19 post coitum. Oral n-butylamine HCl 1000 mg/kg reduced maternal feed consumption, increased early post-implantation losses (embryonic resorptions), reduced fetal and placental weight, and retarded skeletal development (incomplete skull and sternebral ossification), and produced malformations (filiform/kinked tail, enlarged cardiac ventricular chamber(s), malpositioned heart, aortic arch atresia, diaphragmatic hernia); 100 mg/kg was the no-observed-adverse effect level (NOAEL) for prenatal developmental toxicity; 400 mg/kg, the maternal no-effect level, produced only malformations (aortic arch atresia, malpositioned heart, diaphragmatic hernia). Inhaled n-butylamine produced concentration-dependent nasal epithelial hyperplasia and squamous metaplasia, inflammation and necrosis; the maternal NOAEL was less than 17 ppm. There were no treatment-related signs of embryo/fetotoxicity, particularly, no effects on fetal morphology. The developmental NOAEL was 152 ppm. The neutralization of n-butylamine by hydrochloride converts it from a strong alkali causing tissue burns into a weak acid/base which is fetotoxic. Possible mechanisms of fetotoxicity are free radical production, metabolic acidosis, and lysosomotrophy.