The effects of topical doxepin on responses to histamine, substance P and prostaglandin E2 in human skin

The tricyclic antidepressant, doxepin, is known to have H1 and H2 antihistaminic effects. Recently, 5% doxepin cream has been marketed in the U.S.A. for treatment of eczematous dermatoses. We investigated the effects of topical doxepin treatment on histamine-, substance P- and prostaglandin E2- (PGE2) induced responses in the skin of normal and atopic subjects. We compared the effects of topical doxepin with those of the oral antihistamine terfenadine. The weal volume and flare area responses to histamine were significantly reduced by treatment with topical doxepin or oral terfenadine in both normal and atopic subjects (P < 0.05). The mean +/- SEM percentage reduction in flare area for 10 micrograms/site of histamine in non-atopics and atopics was 48 +/- 8% and 60 +/- 17% with terfenadine, and 54 +/- 12% and 81 +/- 4% with topical doxepin, respectively. The mean percentage reduction in weal volume for the same dose of histamine in non-atopics and atopics was 70 +/- 9% and 63 +/- 16% with terfenadine, and 96 +/- 2% and 89 +/- 6% with topical doxepin, respectively. The flare but not the weal response to substance P was inhibited by both treatments in all subjects (P < 0.05). The mean +/- SEM percentage reduction in flare area for 200 pmol/site of substance P in non-atopics and atopics was 53 +/- 10% and 73 +/- 4% with terfenadine, and 74 +/- 7% and 75 +/- 4% with topical doxepin, respectively. The cutaneous responses to PGE2 were not affected by either drug. The inhibitory effects of doxepin were as great as those of terfenadine, and doxepin had a significantly greater effect than terfenadine in inhibiting the weal response to histamine and flare response to substance P in normal volunteers (P < 0.05). There was no significant difference between atopics and non-atopics in the percentage reduction of cutaneous responses by oral terfenadine or topical doxepin. Marked sedation occurred in three of the first 10 subjects treated with topical doxepin, necessitating a reduction in dosage for the remaining six subjects. In summary, topical doxepin was as effective as, and sometimes more effective than, a standard dose of oral terfenadine in the inhibition of histamine-induced and axon-reflex-mediated cutaneous responses. The marked sedative effect may limit its clinical use in some patients.     

Stereoselective in vivo and in vitro studies on the metabolism of doxepin and N-desmethyldoxepin

1. Doxepin is marketed as an irrational mixture of geometric isomers such that the more active Z-isomer comprises only 15% of the total doxepin whereas the less active E-isomer makes up the remaining 85%. 2. The ratio of isomers of the doxepin remains approximately Z:E = 15:85 in the plasma of depressed patients whereas plasma levels of the active Z-N-desmethyl metabolite are similar to those of E-N-desmethyldoxepin. 3. After examination of four animal species (dog, rabbit, guinea pig, rat), rat was closest to human in terms of the Z:E ratio of the geometric isomers of N-desmethyldoxepin excreted in the 0-24-h urine. 4. Changes in the urinary Z:E ratio of the metabolite were observed after oral but not after intravenous or intraperitoneal administration of commercial doxepin to rat. 5. There was no evidence of Z/E interconversion after administration of the pure isomers to rat in vivo, or after incubation of rat or human liver homogenates with pure isomers. 6. In vitro data suggested that the distortion of the Z:E ratio of N-desmethyldoxepin was a consequence of faster metabolism of the E-isomer in comparison with Z-N-desmethyldoxepin rather than 'enrichment' of the Z-isomer at the expense of the E-isomer.     

Lag-screw fixation of anterior mandibular fractures using biodegradable polylactide screws: a preliminary report

Antidepressants and neuroleptic drugs are sometimes the reason for the occurrence of the polymorphic ventricular arrhythmia torsades de pointes in patients. Therefore, it was of interest to study the actions of some of these drugs such as imipramine, amitriptyline, doxepin, chlorpromazine, trifluoperazine and thioridazine in isolated, spontaneously beating Purkinje fibers of guinea-pig hearts using the intracellular microelectrode technique because experimentally induced early afterdepolarizations (EADs) may be associated with this special type of arrhythmia. If the extracellular K+ concentration was 2.7mM none of these drugs could elicit EADs. For that reason the K+ concentration was lowered to 1. 35mM and EADs were evoked by imipramine (2 and 5 microM). Amitriptyline (2 and 5 microM) and doxepin (2 microM) did not induce EADs. Only a concentration of 5 microM doxepin elicited EADs. Among the neuroleptic drugs, chlorpromazine at a concentration of 2 and 5 microM was responsible for the occurrence of EADs as well as thioridazine in the same concentrations. When trifluoperazine (2 and 5 microM) was applied no EADs could be observed. Tetrodotoxin (0. 2 microMl-1) abolished thioridazine-induced EADs. Several membrane depolarizing currents may participate in the initiation of these EADs. Our results demonstrate that in guinea-pig Purkinje fibers some tricyclic antidepressants and some neuroleptic drugs are responsible for the rare occurrence of EADs under hypokalemic conditions.     

Inhibition of neuronal Na+ channels by antidepressant drugs

Although tricyclic antidepressant (TCA) blockade of cardiac Na+ channels is appreciated, actions on neuronal Na+ channels are less clear. Therefore, the effects of TCAs (amitriptyline, doxepin and desipramine) as well as trazdone and fluoxetine on voltage-gated Na+ current (INa) were examined in bovine adrenal chromaffin cells using the whole-cell patch-clamp method. Amitriptyline produced concentration-dependent depression of peak INa evoked from a holding potential of -80 mV with KD value of 20.2 microM and a Hill coefficient of 1.2. Although 20 microM amitriptyline induced no change in the rate or voltage dependence of INa activation, steady-state inactivation demonstrated a 15-mV hyperpolarizing shift. Similar results were observed for doxepin and desipramine. This shift in steady-state inactivation was associated with a slowed rate of recovery from the inactivated state. Contrasting results were observed with the atypical antidepressants: while 20 microM fluoxetine depressed peak INa by 61% and caused a 7-mV hyperpolarizing shift in steady-state inactivation, 100 microM trazodone decreased peak INa by only 19% and caused only a 3-mV shift. Although the magnitude of fluoxetine effects was similar to those of the TCAs, the onset of fluoxetine effects was substantially slower than for amitriptyline. In voltage-clamp and current-clamp measurements from neonatal rat dorsal root ganglion neurons, 20 microM amitriptyline decreased INa by 52% and depressed action potential dynamics consistent with enhanced Na+ channel inactivation. The effects of the TCAs on INa are similar to local anesthetic behavior and could contribute to certain analgesic actions.     

The efficiency of alprazolam for seasonal affective disorder (SAD, autumn/winter type)]

Tricyclic antidepressants, or "tricyclics" as they are commonly called, are effective in reducing pain in chronic neurological and musculoskeletal disorders. Tricyclics appear to be effective in the control of chronic orofacial pain of non-inflammatory origin, and include amitriptyline, doxepin, nortriptyline and desipramine. Daily doses of the medications are smaller for the management of pain than doses typically used in the treatment of depression. Certain medical conditions may contraindicate tricyclic trials, while others may warrant starting at a lower dose with more conservative dose adjustments. Common side effects include dry mouth, sedation, constipation and orthostasis. Tricyclics are just one therapeutic modality which can be considered in the management and treatment of chronic refractory orofacial pain that is suspected to arise from neurogenic or myofascial etiologies.     

A clinical experience with a hierarchically controlled myoelectric hand prosthesis with vibro-tactile feedback

The decline of plasma fibronectin after surgery, trauma, and burn, as well as during severe sepsis after injury, appears to limit hepatic Kupffer cell phagocytic activity. Intravenous infusion of gelatin-coated particles to simulate blood-borne particulate collagenous tissue debris in the circulation after injury also depletes plasma fibronectin. We used soluble gelatin conjugated with 125I-labeled dilactitol tyramine (DLT-gelatin) as a model of soluble collagenous tissue debris. We studied its blood clearance as well as organ localization in normal and postburn rats. Fibronectin-deficient plasma harvested early after burn exhibited limited ability to support in vitro phagocytic uptake of the gelatinized microparticles by Kupffer cells in liver tissue from normal rats. However, Kupffer cells in liver tissue from normal and postburn rats phagocytized the test particles at a normal rate when incubated in normal plasma. The DLT-gelatin ligand bound to fibronectin in a dose-dependent manner as verified by its capture with anti-fibronectin coated plastic wells when coincubated with purified fibronectin. By gel filtration chromatography, the binding of fibronectin with the DLT-gelatin ligand was readily detected, resulting in the formation of a high-molecular-weight complex. In normal animals the plasma clearance and liver localization of 125I-DLT-gelatin was competitively inhibited by infusion of excess nonradioactive gelatin. The blood clearance and liver localization of the soluble gelatin ligand were also impaired after burn injury during periods of fibronectin deficiency similarly to the pattern observed with gelatin-coated microparticles. By autoradiography, the cellular site for the uptake of the 125I-DLT-gelatin was primarily but not exclusively hepatic Kupffer cells; 125I-DLT-asialofetuin and 125I-DLT-ovalbumin were removed by hepatocytes and sinusoidal endothelial cells, respectively. Thus, gelatin conjugated with 125I-DLT can be used to simulate blood-borne soluble collagenous tissue debris after burn. It rapidly binds to plasma fibronectin before its hepatic Kupffer cell removal, and its blood clearance is markedly delayed after burn injury during periods of plasma fibronectin deficiency.     

等离子体钢包炉传热物理数学模型

研究了等离子体钢包炉内自由空间辐射传热和等离子枪水冷强制对流传热，建立了等离子体钢包炉传热数学模型。该模型可用于模拟等离子体钢炉不同工艺参数时的热行为，为其工艺和设备的设计及操作参数优化提供了一重要的理论分析工具。     

Some effects of chronic tritium exposure during selected ages in the rat

The clotting of C. V. Helleri plasma is not accelerated by the factor X activator or thrombin-like enzymes from its own venom. Clotting of the plasma is accelerated by the factor Xactivator from Russell's viper venom, but not by the thrombin-like enzyme from Agkistrodon Rhodostoma venom ("Arvin"). The prothrombin activator from the Taipan venom clots C.V. Helleri plasma equally well as human plasma, but the thrombin which is produced has a marked specificity for its own fibrinogen, and clots bovine fibrinogen more slowly. C.V. Helleri plasma contains an inhibitor which progressively inactivates bovine factor Xa and thrombin, but the inhibitor is not potentiated by heparin. The slow, protracted clotting of the snake plasma either alone or when mixed with human plasma or bovine fibrinogen suggests that this inhibitor may interfere with the polymerisation of fibrin monomer.     

Nitrogen activity determination in plasmas

In many important materials processing operations, such as welding and plasma processing, a solid or a liquid metal is exposed to a plasma. In such systems, the activity of a species, such as nitrogen, in the plasma cannot be estimated from a straightforward application of the established thermochemical principles of gas-metal reactions. Currently, there is no established method for the determination of activity of a species in a plasma. In this article, a method for determination of nitrogen activity in plasmas is presented. High-purity tantalum and niobium samples were isothermally exposed to a well-characterized helium-nitrogen plasma, and the corresponding nitrogen solubility in each metal was determined by the vacuum fusion method. In each case, the activity of nitrogen in the plasma with respect to a standard state of 1 atm nitrogen pressure was calculated from the nitrogen solubility data and its value was demonstrated to be about an order of magnitude higher than the partial pressure of nitrogen in the source gas used to generate the plasma. The solubility of a species in a condensed phase exposed to a plasma can be used to determine its activity in the plasma.     

Improved liquid-chromatographic determination of caffeine in plasma

We describe a rapid, specific, and sensitive liquid-chromatographic micro-method for caffeine in plasma. Each plasma sample can be assayed within about 15 min of its receipt. Samples are denatured with acetonitrile, centrifuged, and the supernate is chromatographed on a reversed-phase column. Only 100 microL of plasma is required, and concentrations as low as 0.3 mg/L can be measured accurately. Other xanthines and their metabolites do not interfere. The small sample required makes the procedure ideally suited for measuring caffeine in the plasma of infants and small animals as well as adults.     

Determination of ivabradine and its N-demethylated metabolite in human plasma and urine, and in rat and dog plasma by a validated high-performance liquid chromatographic method with fluorescence detection

A sensitive and selective high-performance liquid chromatographic method with native detection of fluorescence was developed and validated for the quantitation of ivabradine and its N-demethylated metabolite in plasma (rat, dog, human) and human urine. The procedure involves the use of an analogue as internal standard, solid-phase extraction on cyano cartridges, separation on a Nova-Pak C8 column and fluorescence detection. Calibration curves are linear in the concentration ranges from 0.5 to 100 ng/ml in plasma and 2.0 to 500 ng/ml in urine with a limit of quantitation set at 0.5 and 2.0 ng/ml in plasma and urine, respectively. The analysis of plasma and urine samples (spiked with the analytes at low, medium and high concentrations of the calibration range) demonstrates that both analytes can be measured with precision and accuracy within acceptable limits. Quality controls spiked with analyte concentrations up to 10000 ng/ml can also be analysed with excellent precision and accuracy after dilution of the samples. The parent drug and its metabolite are stable in plasma and urine after short-term storage (24 h at room temperature and after three freeze-thaw cycles) as well as after long-term storage at -20 degrees C (at least 6 months in animal plasma and 12 months in human plasma and urine). The method has been used to quantify both compounds in plasma and urine samples from clinical and non-clinical studies with ivabradine.     

Simultaneous determination of dextromethorphan and its metabolites in human plasma by capillary electrophoresis

A sensitive capillary electrophoretic method was developed and validated for the simultaneous determination of dextromethorphan and its metabolites, dextrorphan, 3-hydroxymorphinan, and 3-methoxymorphinan, in human plasma. After cleavage of conjugates by enzymatic hydrolysis with beta-glucuronidase, dextromethorphan and its metabolites were extracted from 1.5 ml of plasma by a liquid liquid extraction procedure using heptane-ethylacetate (50:50, v/v) and re-extracted to aqueous phase. The compounds were separated within 8 min on a fused silica capillary, 75 microm internal diameter using sodium borate (pH 9.4; 50 mM) as running buffer, and measured by UV-detection at 195 nm using a detection cell with a path length of 1.2 mm. The method was accurate and precise. Linear relationships were observed between the peak response and the concentration in the range of 1-400 ng ml(-1) plasma with correlation coefficients above 0.998. The limit of detection was 0.5-1 ng ml(-1) plasma for all compounds. The method was used for determination of plasma levels of dextromethorphan and its metabolites after transdermal and oral administration of dextromethorphan.     

Studies on androgen transport into canine prostate in vitro

Significant rise of fructose in the blood plasma of cattle resulted from an application of sorbite solution (0.5 g sorbite per kg live weight), with its onset as early as during the infusion. The highest concentration was reached 15 minutes after completion of infusion. Rise in glucose (11 mg/100 ml plasma on average) failed to prove statistically significant and dropped temporarily (after 60 to 120 minutes) below the original value. The lactate level in the blood went up temporarily and reached its maximum 30 minutes from the end of infusion. Sorbite solution (1 g/kg live weight) was intravenously applied to sheep and tock fructose to its maximum after 30 minutes. Intraperitoneal application of sorbite solution (1 g/kg live weight) was tolerated well also by piglets and triggered an age-dependent decline of glucose in blood plasma.     

Prostasome-like particles in stallion semen

From undetectable basal levels, TNFalpha is produced in the hypothalamus of rats challenged with a systemic low profile endotoxin (LPS) at least 30 min before its release may be detected in the plasma. The cytotoxic activity of this hypothalamic TNFalpha correlates with its immunoreactivity. Injection of BB-1101, a matrix metalloprotease inhibitor, immediately after the LPS totally inhibits the plasma LPS-induced TNFalpha release without affecting the hypothalamic TNFalpha response. Likewise, L-NAME pretreatment, a nitric oxide inhibitor which reportedly crosses the blood-brain barrier, blunts the plasma TNFalpha response by almost 66%, but leaves the hypothalamic TNFalpha response unchanged. The present study thus describes the early occurrence of hypothalamic TNFalpha in response to systemic LPS injection, which is not subjected to the same regulations as plasma TNFalpha.     

Determination of clonazepam ("Rivotril" or "Ro 5-4023") in plasma by gas chromatography using an internal standard

A method has been developed for gas-chromatographic determination of clonazepam ("Rivotril" or "Ro 5-4023") in plasma, using methyl-clonazepam ("Ro 4082") as an internal standard. Following extraction of the benzodiazepines and hydrolysis, the benzophenones are analyzed by gas-chromatography, using a glass column filled with 3% OV 225 on Gas Chrom Q and a 63Ni electron-capture detector. The technique has good selectivity. The limit of sensitivity is less than 1 ng/ml of plasma. Using this method the plasma kinetics of clonazepam may be studied in man and the correlations between plasma levels and therapeutic activity investigated. It is also available for toxicological analysis, as well as pharmacovigilance purpose. The same internal standard and a similar method can also be used for the determination of flunitrazpem ("Rohypnol" or "Ro 5-4200") and its major metabolite (N-desmethyl-flunitrazepam) in plasma.     

电感耦合等离子体原子发射光谱仪故障与处理

电感耦合等离子体原子发射光谱仪具有稳定性高、检出限低、线性动态范围宽、分析速度快等特点,在金属材料、水质及环境、矿产资源等众多领域实验室的检测工作中被广泛应用。以MPX-VISTA电感耦合等离子体原子发射光谱仪为例,归纳了自激式等离子体发生器中火焰监测装置、振荡电路及附属电路、控制电路、气路系统等4个仪器方面的常见故障,通过系统地分析仪器等离子体发生器的结构及原理,找到了故障原因,并介绍了处理方法。对于从总体上把握等离子体发生器结构及快速处理等离子体发生器部分的故障提供了一种思路,降低等离子体发生器故障率,确保其能稳定有效地工作,为日常测试提供准确的分析数据。     

电感耦合等离子体原子发射光谱仪故障与处理

电感耦合等离子体原子发射光谱仪具有稳定性高、检出限低、线性动态范围宽、分析速度快等特点,在金属材料、水质及环境、矿产资源等众多领域实验室的检测工作中被广泛应用。以MPX-VISTA电感耦合等离子体原子发射光谱仪为例,归纳了自激式等离子体发生器中火焰监测装置、振荡电路及附属电路、控制电路、气路系统等4个仪器方面的常见故障,通过系统地分析仪器等离子体发生器的结构及原理,找到了故障原因,并介绍了处理方法。对于从总体上把握等离子体发生器结构及快速处理等离子体发生器部分的故障提供了一种思路,降低等离子体发生器故障率,确保其能稳定有效地工作,为日常测试提供准确的分析数据。     

Inhibitory activity in human marrow plasma directed against mouse marrow cell proliferation: reduced in subjects with decreased granulopoiesis

Human venous plasma is known to contain a lipoprotein-inhibitor of mouse marrow cell growth which we have found does not have cell type-specificity, in that it inhibits mouse lymphoma cell as well as marrow cell colony formation in vitro. Following its removal by CHCl3, we have identified residual inhibitory activity which reduces the growth of mouse marrow cells but not lymphoma cells. This inhibitory activity was found to be present in marrow and to much lesser extent in peripheral venous plasma obtained from subjects without disturbances in granulopoiesis. It was markedly reduced in subjects with disorders in which normal granulopoiesis was reduced, such as acute leukemia. The deficiency of this inhibitory activity in the marrow plasma of subjects with leukemia and related disorders may be due to a reduction in the cells from which it is derived (e.g. normal neutrophils or stromal cells), although further studies will be required to verify its presence and to determine its source and physiological role in granulopoiesis in man.     

Liposomes disposition in vivo. V. Liposome stability in plasma and implications for drug carrier function

The kinetics of [14C]sucrose release from multilamellar liposomes of fixed diameter (approx. 0.23 micron) incubated in human plasma (serum and blood) were quantified. Composition was various ratios of phosphatidylcholine, phosphatidic acid and cholesterol with alpha-tocopherol included as antioxidant. Considerable intra-individual variability was noted for liposome stability in blood and its derived fluids, yet reproducible results were obtained for pooled samples. The destabilizing effects of plasma decreased with increasing lipid concentrations. Results of fitting a kinetic model to the data showed that four of five model parameters were linearly related to liposome cholesterol content. Liposomes depleted plasma of its destabilizing factors, and when pre-incubated with plasma were partially stabilized to the effects of a subsequent plasma addition. Plasma caused a rapid rise in liposome membrane permeability which then declined non-linearly, presumably because of a rearrangement of membrane lipids and adsorbed proteins to form their most stable configuration. The therapeutic availability of drugs administered encapsulated in liposomes, which can be governed by the kinetics of their in vivo extracellular release, may be directly proportional to--and predictable from--the time-course and extent of release in plasma. The kinetic model was used in conjunction with simple pharmacokinetic assumptions to show that the effectiveness of a liposome drug carrier cannot be predicted based simply on its plasma stability; more stable liposomes may not be more effective drug carriers. Interestingly, plasma-induced solute release from liposomes serendipitously mimics an important facet of ideal carrier behavior.     

Absorption and metabolism of lanatoside C. II. Fate after oral administration

The absorption, metabolism, and excretion of lanatoside C were studied in hospitalized subjects following oral administration of the tritiated drug. Previous reports of an unusual double peak in plasma levels of radioactivity were confirmed. Fifty plasma samples taken from 31 patients showed that an average of 74% of the radioactive material was digoxin and its metabolites. There was little or no lanatoside C in 36 of the 50 samples of plasma. Similar results were obtained for urine radioactivity. The results confirm that lanatoside C is converted to "digoxin" in the gut prior to absorption as previously proposed by us. "Digoxin" refers to digoxin and its breakdown products, namely, digoxigenin and its mono- and didigitoxosides. According to these proposals, the conversion to "digoxin" takes place partly as a result of acid hydrolysis in the gut and partly by the action of bacteria in the intestine. The effects of concurrent administration of antacid therapy, anticholinergic therapy, and food on the fate of oral lanatoside C were separately studied. There were no significant differences between groups with respect to the amount of radioactive material absorbed or excreted, but there were marked qualitative differences in the plasma profiles. There was a statistically significant increase in the time to the first peak in plasma radioactivity in patients concurrently receiving either food or anticholinergic therapy and there was a significant decrease in the relative height of the first peak in patients treated concurrently with antacid.