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PubMed2005

Effect of L-menthol and 1,8-cineole on phase behavior and molecular organization of SC lipids and skin permeation of zidovudine.

The aim of this investigation was to study the effect of 1,8-cineole and L-menthol on phase behavior and molecular organization of Stratum corneum (SC) lipids and permeation of zidovudine (AZT) across human cadaver skin (HCS). Permeation studies were conducted across HCS using Franz diffusion cells at 37 degrees C. Differential scanning calorimetry (DSC) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were employed to understand the effect of terpenes on phase behavior and molecular organization of a model SC lipid system consisting of an equimolar mixture of ceramide, palmitic acid and cholesterol. Both 1,8-cineole and L-menthol applied at 5% w/v in 66.6% ethanol as a vehicle significantly enhanced the pseudosteady state flux of AZT across HCS. The vehicle reduced the number of endothermic transitions observed in the DSC thermogram of a hydrated model SC lipid system from three to two with a lowered midtransition temperature (Tm), while the inclusion of terpenes resulted in a single but very broad endothermic transition for the model SC lipid system. Correspondingly, ATR-FTIR studies revealed that both 1,8-cineole and L-menthol increased CH2 stretching frequencies on either side of lipid transition in addition to lowering the Tm of model SC lipid system by approximately 2-8 degrees C. The alterations observed in the amide-I frequencies of model SC lipid system after the inclusion of terpenes suggest that they disrupt the interlamellar hydrogen-bonding network at the polar head group region. Further, terpenes also increased the hydration levels of the lipid system probably by forming new aqueous channels. These results indicate that terpenes enhance transdermal permeation of AZT and other drugs by transforming SC lipids from a highly ordered orthorhombic perpendicular subcellular packing to a less ordered hexagonal subcell packing.

Animals↗
PubMed2005

Effect of physicochemical properties of cyclic terpenes on their ex vivo skin absorption and elimination kinetics.

BACKGROUND: The terpenes disturb lipid arrangement in the intercellular region of the stratum corneum (SC) that leads to the increased permeability of the skin. This effect is used in technology of transdermal drug forms and depends on physicochemical properties of terpenes and their amounts penetrated to the stratum corneum; however terpenes do not need penetrate into viable skin tissue and this event is not even desired. OBJECTIVE: To correlate skin absorption and elimination kinetics of four cyclic terpenes, namely alpha-pinene, beta-pinene, eucalyptol and terpinen-4-ol, applied as neat substance with their physicochemical properties. METHODS: The terpenes were applied onto the human skin in vitro, and after 1-4 h their content in the separated by a tape-stripping method stratum corneum layers and in the epidermis/dermis was determined using GC. Similarly, the amounts of terpenes in the skin were analysed during 4 h following 1 h absorption. RESULTS: The fastest and progressive penetration into all skin layers was observed for terpinen-4-ol. All studied terpenes are absorbed in the viable epidermis/dermis, however penetration into this layers is time-dependent process, constantly increasing during 4 h. Like for stratum corneum, the largest cumulation in epidermis/dermis was observed for terpinen-4-ol. The elimination of terpenes from the stratum corneum was fast, especially in deeper layers, and much faster if the initial cumulation was small. CONCLUSION: Investigated cyclic terpenes represent different penetration and elimination characteristics and do not permeate across the skin to the acceptor medium due to large cumulation in the skin tissue. The penetration of terpenes into stratum corneum is greater if their log P-value is close to 3.

Adult↗
PubMed2005

Synthesis, characterization and biological activity of oxovanadium (IV) complexes with cyclic polyalcohols.

Oxovanadium (IV) complexes of the cyclic polyols conduritol C (cond) and myo-inositol (inos) of stoichiometry Na(2)[VO(cond)(2)].2H(2)O and Na(2)[VO(inos)(2)].H(2)O were obtained in aqueous alkaline solutions. They were characterized by infrared and UV-Vis spectroscopies, thermoanalytical (thermogravimetric and differential thermal analysis) data and magnetic susceptibility measurements. The biological activities of the complexes on the proliferation, differentiation and glucose consumption were tested on osteoblast-like cells in culture. Conduritol C and myo-inositol did not produce any effect on these parameters. Normal and tumoral cell proliferation was inhibited about (ca.40-60%) by the two oxovanadium (IV) complexes in concentrations as low as 100microM. The complexes were also inhibitory on cell differentiation (ca. 70-80%) while they stimulate glucose consumption. Comparisons of these effects with those of the oxovanadium (IV) cation, under the same experimental conditions, were also performed.

Animals↗
PubMed2003

Cannabinoids and opioids share cAMP pathway in rat splenocytes.

In the present work we investigated on rat splenocytes long-term interactions between opioid and cannabinoid drugs in terms of a common regulation of cAMP intracellular pathway. Both morphine and the synthetic cannabinoid compound CP-55,940 inhibited in a concentration-dependent manner the intracellular cAMP level in splenocytes stimulated by forskolin. The in vitro combination of submaximal concentrations of the two drugs did not yield any additive effect on the inhibition induced by the two drugs. In splenocytes taken from rats chronically treated with CP-55,940 (0.2 mg/kg i.p., twice a day for 4.5 days) or morphine (5 mg/kg s.c., twice a day for 6.5 days) and in vitro exposed to either CP-55,940 or morphine, it was found a desensitisation and cross-desensitisation to the inhibitory effects on cAMP production induced by the two drugs. Binding experiments on the cannabinoid receptors level in spleen coronal sections after in vivo chronic administration of morphine, revealed that there was no changes in the binding of [H3]-CP-55,940. Thus, these results strengthen the hypothesis of cAMP as part of the common intracellular pathway shared by opiates and cannabinoids at immune cell level.

Animals↗
PubMed2006

Cost-effectiveness of duloxetine versus routine treatment for U.S. patients with diabetic peripheral neuropathic pain.

UNLABELLED: The purpose of this study was to compare the cost-effectiveness of duloxetine versus routine treatment in management of diabetic peripheral neuropathic pain (DPNP). Two hundred thirty-three patients with DPNP who completed a 12-week, double-blind, placebo-controlled, randomized, multicenter duloxetine trial were re-randomized into a 52-week, open-label trial of duloxetine 60 mg twice daily versus routine treatment. Routine treatment included pain management therapies. Effectiveness was measured by using the bodily pain domain (BP) of the Medical Outcomes Study Short Form 36 (SF-36). Costs were analyzed from 3 perspectives: third party payer (direct medical costs), employer (direct and indirect medical costs), and societal (patient's out-of-pocket costs and total medical costs). Costs of study medications were not included because of limited data. Bootstrap method was applied to calculate statistical inference of the incremental cost-effectiveness ratio (ICER). Routine treatment most frequently used included gabapentin (56%), venlafaxine (36%), and amitripytline (15%). From employer and societal perspectives, duloxetine was cost-effective (ICER= -342 dollars and -429 dollars, respectively, per unit of SF-36 BP; both P <or= .03) and the dominant therapy compared with routine DPNP treatment (both P < .05). From payer perspective, duloxetine trended toward cost-effectiveness (ICER= -249 dollars per unit of SF-36 BP; P <or= .06). These results, however, reflect the controlled environment of a clinical trial. An analysis of real-world data would be beneficial. PERSPECTIVE: Evaluation of the cost and benefit of new pharmacologic treatments is highly desired by decision makers. From both employer perspective and societal perspective (including patient's out-of-pocket costs), this study demonstrated that duloxetine was more cost-effective than routine treatment in management of DPNP.

Adrenergic Uptake Inhibitors↗
PubMed2004

Evaluation of efficacy of the perioperative administration of venlafaxine XR in the prevention of postmastectomy pain syndrome.

Postmastectomy pain syndrome (PMPS) is a neuropathic pain syndrome that may develop following breast surgery. Venlafaxine has been shown to be efficacious in the management of PMPS. The preemptive administration of venlafaxine has been shown to be efficacious in reducing the incidence of neuropathic pain in the rat model. We examined the efficacy of administering either venlafaxine or placebo for two weeks starting the night before surgery to 100 patients scheduled for either partial or radical mastectomy with axillary dissection. Patients were administered PCA morphine for the first 24 hours following surgery and then acetaminophen/oxycodone tablets. Pain scores were recorded at rest and movement on day 1, at 1 month, and at 6 months after surgery. At 6 months postoperatively, the presence of pain in the chest, arm, and axilla; edema; decreased sensation in the operative area; and phantom breast pain were recorded. There was no difference in postoperative opioid use. Pain scores with movement were lower in the venlafaxine group at 6 months. Pain scores at all other time intervals were similar. There was a significant decrease in the incidence of chest wall pain (55% vs. 19%, P = 0.0002), arm pain (45% vs. 17%, P = 0.003), and axilla pain (51% vs. 19%, P = 0.0009) between the control group and the venlafaxine group, respectively. No significant differences were noted between the two groups with regard to edema, phantom pain, or sensory changes. We conclude that the perioperative administration of venlafaxine beginning the night prior to surgery significantly reduces the incidence of PMPS following breast cancer surgery.

Analgesics↗
PubMed2006

Optimization of the separation of some psychotropic drugs and their respective metabolites by liquid chromatography.

A chemometric procedure is described to optimize the separation of some drugs used in the treatment of psychotic disorders: haloperidol, levomepromazine, risperidone, venlafaxine, carbamazepine and their main metabolites: reduced haloperidol, 9-hydroxy risperidone, desmethyl levomepromazine, desmethyl venlafaxine. The purpose of the procedure is the unambiguous identification and detection in biological fluids. Isocratic reversed-phase liquid chromatography with diode array detection was utilized. An experimental design methodology was carried out in which the experimental response is selectivity. In this way the designs for mixture compounds and for process variables (five variables) was performed which produced 36 experiments to carry out. The desirability function was used to select optimum separation conditions. The procedure provides a chromatogram of well separated solutes.

Acetonitriles↗
PubMed2004

Daily variation in cellular content of UV-absorbing compounds mycosporine-like amino acids in the marine dinoflagellate Scrippsiella sweeneyae.

Sudden exposure experiments to high PAR (photosynthetically available radiation) or high PAR+UVR (ultraviolet radiation) were conducted for the marine dinoflagellate Scrippsiella sweeneyae acclimated to either low PAR or high PAR to determine the induction of cellular mycosporine-like amino acid (MAA) in relation to photosynthesis status. When the exposure to high PAR (30.8 Wm(-2)) was provided at different time in the light period for S. sweeneyae acclimated to low PAR (7.7 Wm(-2)) which suppressed photosynthesis, S. sweeneyae could enhance the induction of MAA but it only occurred in the first half of the light period. When UVR exposure was provided for the culture acclimated to high PAR which enhanced photosynthesis, cellular MAA content did not increase during the entire light period, but displayed daily variation similar to the control for two and half days. Daily variation of cellular MAA content did not synchronized with that of cell volume and cellular chlorophyll a content. The individual MAAs also revealed similar daily variations with different phase, which increased for a few hours in the beginning of the light period, except for cellular palythine content. Thus the total cellular MAA content revealed daily variation with changing the relative composition within a few hours. As one of the biological protective strategies against harmful UVR in sunlight, the daily vertical migration in the bloom forming dinoflagellates might be accompanied by the daily variation of cellular MAA content for a photosynthesis at daytime.

Animals↗
PubMed2006

Biotransformation of mycosporine like amino acids (MAAs) in the toxic dinoflagellate Alexandrium tamarense.

Changes in mycosporine-like amino acids (MAAs) induced by the increase of photosynthetically active radiation (PAR) were studied in the toxic dinoflagellate Alexandrium tamarense. Cultures of A. tamarense were maintained at exponential growth under low (25 micromol quanta m(-2)s(-1)) PAR irradiance. The cultures were nutrient enriched and one day later exposed to higher irradiance (150 micromol quanta m(-2)s(-1)). The content of MAAs was determined by means of high performance liquid chromatography (HPLC). Eleven MAAs, including some partially characterized compounds, were identified. The MAAs synthesis induction can be described as a two-stage process. The first one involves the net synthesis of the MAAs bi-substituted by amino acids. In the second stage these compounds were transformed into other secondary MAAs. The two most prominent changes were observed in the concentration of porphyra-334 and palythene. The cellular concentration of porphyra-334 increased during the first 2h of exposure to higher irradiance and then decreased rapidly. In contrast, the cellular concentration of palythene showed a continuous accumulation since the beginning of the exposure. In A. tamarense the main route of MAAs transformation has porphyra-334 as a precursor of a sequential conversion resulting in the accumulation of palythene.

Amino Acids↗
PubMedDate not supplied

Extended-release venlafaxine in relapse prevention for patients with major depressive disorder.

Many studies have demonstrated that venlafaxine is an efficacious and safe treatment for major depressive disorder (MDD). This double-blind, placebo-controlled study was performed to evaluate the efficacy of venlafaxine extended-release (XR) (75-225 mg/day) in the prevention of relapse of depression. Patients with MDD who responded to an 8-week course of venlafaxine XR treatment, i.e., had a score < or = 3 on the Clinical Global Impressions scale-Severity of Illness item (CGI-S) and a 21-item Hamilton Rating Scale for Depression (HAM-D(21)) score < or = 10, were randomly assigned to receive continuation treatment (up to 6 months) with venlafaxine XR (n=161) or placebo (n=157). The main efficacy outcome measure was the number of patients who experienced a relapse of depression. Relapse was defined by either a combination of a patient meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for MDD and a CGI-S score > or = 4, two consecutive CGI-S scores > or = 4, or a final CGI-S score > or = 4 for a patient who withdrew from the study. The cumulative probability of relapse was calculated using the Kaplan-Meier method of survival analysis. During the 6-month evaluation period, significantly more patients in the placebo group had a relapse of MDD than did patients who continued treatment with venlafaxine XR. Cumulative relapse rates at 3 and 6 months were 19 and 28%, respectively, for venlafaxine XR, and 44 and 52%, respectively, for placebo. This study demonstrates that venlafaxine XR is an effective and safe continuation therapy.

Adult↗
PubMed2005

A double-blind, placebo-controlled comparison of venlafaxine and fluoxetine treatment in depressed outpatients.

This double-blind, placebo-controlled study compared venlafaxine (immediate release), the first modern serotonin-norepinephrine reuptake inhibitor, with the selective serotonin reuptake inhibitor fluoxetine. Outpatients were randomly assigned to 6 weeks of treatment with venlafaxine (75-225mg/day; n=102), fluoxetine (20-60mg/day; n=104), or placebo (n=102). Efficacy was assessed using the 21-item Hamilton Depression Rating Scale (HAM-D(21)), the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression-Severity of Illness (CGI-S) scale, response and remission rates, and several other measures. Intent-to-treat analyses utilized both the last observation carried forward and ETRANK methods to account for missing data. At week 6 or study endpoint, venlafaxine (mean dose: 142mg/day) was superior to placebo on most outcomes measures, whereas the differences between fluoxetine (mean dose: 41mg/day) and placebo were less consistent. Final remission (defined as HAM-D < or =7) rates were 32%, 28%, and 22% for venlafaxine, fluoxetine, and placebo, respectively. Few differences between the active treatments attained statistical significance. Both active therapies were generally well tolerated; however, attrition due to adverse events, incidence of selected side effects, and increases in pulse and blood pressure favored fluoxetine over venlafaxine. This study provides further evidence that venlafaxine is effective after 6 weeks of treatment compared with placebo. The efficacy profile of fluoxetine was somewhat less consistent. It is strongly recommended that future studies of comparative antidepressant efficacy be adequately powered to detect modest between-drug differences in efficacy.

Adult↗
PubMed2004

Cannabinoid receptor-independent suppression of the superoxide generation of human neutrophils (PMN) by CP55 940, but not by anandamide.

Cannabinoids have been shown to affect various immune functions. To date, almost no data exist on PMN, which provide the first line antimicrobial defense. The objective of the present study was to investigate the effects of the synthetic dibenzopyrane ligand CP55 940, the endogenous cannabinoid anandamide and methanandamide on the "respiratory burst" of isolated human PMN in vitro. After preincubation with high micromolar concentrations of CP55 940, fMLP-stimulated PMN showed a reduction in superoxide production, whereas the spontaneous burst activity of resting PMN remained unaffected. This inhibitory effect of CP55 940 was not CB-receptor-mediated. In contrast, anandamide and methanandamide did not alter the oxidative microbicidal PMN function.

Adult↗
PubMed2005

Different pharmacological profile of two closely related endocannabinoid ester analogs.

The pharmacological and neuroprotective properties of two ester analogs of the endocannabinoids, arachidonoylethyleneglycol (AA-EG) and alpha,alpha,-dimethyl arachidonoylethyleneglycol (DMA-EG), were investigated. We examined the interaction of both compounds with cannabinoid receptors (CB1 and CB2) and their efficacy in functional assays. In competition binding assays, AA-EG and DMA-EG had low potency to displace the CB1/CB2 agonist [3H]CP-55,940 in membrane preparations expressing rodent or human receptors. Binding data correlate with low efficacy of both compounds as regards to inhibition of adenylyl cyclase activity. It was also shown that DMA-EG resists hydrolysis by rat brain membranes while AA-EG undergo complete splitting under these conditions. In the cannabinoid tetrad, AA-EG induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating cannabimimetic activity. By contrast, DMA-EG was completely inactive in the same models. DMA-EG and AA-EG potently protected rat cortical neurons in culture against oxygen deprivation at nanomolar concentrations. In glutamate-induced damage, the compounds were less active protecting neurons at micromolar concentrations. The data obtained indicate that the ester endocannabinoid template can be used for the development of new compounds with potent biological activity lacking some of the undesirable behavioral side effects.

Animals↗
PubMed2005

Evaluation of low-dose venlafaxine hydrochloride for the therapy of hot flushes in breast cancer survivors.

OBJECTIVE: To evaluate the efficacy and tolerability of long-term treatment with venlafaxine at low dose for the reduction of vasomotor symptoms in breast cancer survivors. DESIGN: Forty consecutive breast cancer patients suffering troublesome hot flushes have been treated for 8 weeks with venlafaxine XR 37.5 mg/day in an open-label study. Vasomotor symptoms have been evaluated before starting treatment and every 4 weeks with a hot flushes diary pointing out the number and the severity of vasomotor symptoms. A Beck Depression Inventory (BDI) was completed at baseline and at the end of the treatment. RESULTS: Thirty patients had completed the first 4 weeks of treatment, reporting a reduction of hot flushes frequency of 39% as compared to baseline (p<0.001). After 8 weeks of treatment, a further significant reduction was observed both for the hot flushes frequency (-53%; p<0.001) and for the hot flushes score (-59%; p<0.001), a measure which reflects both the number and the severity of hot flushes. Very few side effects were reported, mostly nausea in the first 2 weeks of assumption and mouth dryness. Only 23 women had completed BDI at week 8; a reduction of 23% was observed (p=0.000). CONCLUSION: Venlafaxine is an effective treatment for the relief of vasomotor symptoms in patients previously treated for breast cancer. A favourable effect is maintained also in those patients using tamoxifen as adjuvant therapy. The use of the low dose (37.5 mg/day) is associated with minimal side effects and produces a good improvement in hot flushes if pursued over 8 weeks.

Adolescent↗
PubMed2005

Menopausal symptoms after cessation of hormone replacement therapy.

OBJECTIVES: To determine the prevalence of recurrent menopausal symptoms among post-menopausal women who discontinued hormone replacement therapy (HRT) after the publication of the women's health initiative (WHI) study and to describe the therapeutic strategies employed to address these symptoms. METHODS: Retrospective analysis of 1000 post-menopausal women seen consecutively at an internal medicine practice from January 2004 to May 2004. RESULTS: Among 1000 post-menopausal women, 205 (21%) had discontinued HRT due to the WHI results. Menopausal symptoms were present in 91/205 (44%) women, with 52/205 (25%) having vasomotor symptoms, 51/205 (25%) urogenital complaints, and 10/205 (5%) mood-related symptoms. Out of the 91 symptomatic women, only 55 (60%) received therapy to relieve their symptoms. The most commonly employed treatments were topical estrogen in 33/91 (36%) women, complementary therapies in 18/91 (20%) women, and venlafaxine in 13/91 (14%) women. Among complementary therapies, the most frequent were black cohosh used by 8/91 (9%) women and soy by 7/91 (8%) women. CONCLUSIONS: Many post-menopausal women developed typical menopausal symptoms after discontinuation of HRT, with vasomotor and urogenital complaints being the most commonly reported. Topical estrogen, complementary therapies, and venlafaxine were the most usual treatments for menopausal symptoms. However, a large number of symptomatic women remained untreated.

Administration, Topical↗
PubMed2006

Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes.

Cannabinoids have been shown to influence the immune system. However, their immunomodulatory effects have not been extensively studied. In this investigation, we have observed that both primary and Jurkat T cells express a functional cannabinoid receptor 2 (CB(2)). Furthermore, both the synthetic cannabinoids CP55,940 and WIN55,212-2, as well as the CB(2)-selective agonist JWH-015, caused a significant inhibition of the chemokine CXCL12-induced and CXCR4-mediated chemotaxis of Jurkat T cells, as well as their transendothelial migration. Involvement of the CB(2) receptor was further confirmed by partial reversal of the inhibition using the CB(2)-specific antagonist, AM630. Similarly, CP55,940 and JWH-015 inhibited the CXCL12-induced chemotaxis of primary CD4(+) and CD8(+) T lymphocytes. Further investigation of signaling studies to delineate the mechanism of inhibition revealed that cannabinoids enhance CXCL12-induced p44/42 MAP kinase activity. However, enhanced MAP kinase activity was not responsible for the inhibition of chemotaxis. This suggests that cannabinoids differentially regulate CXCR4-mediated migration and MAP kinase activation in T cells. Cannabinoids were also found to downregulate the PMA-enhanced enzyme activity of matrix metalloproteinase-9, which is known to play an important role in transendothelial migration. This study provides novel information regarding cannabinoid modulation of functional effects in T cells.

Calcium↗
PubMed2006

Effect of chronic ethanol exposure and its withdrawal on the endocannabinoid system.

The present study investigated the effect of ethanol (EtOH) exposure and its withdrawal on the central endocannabinoid system utilizing an EtOH vapor inhalation model, which is known to produce functional tolerance and dependence to EtOH. Swiss Webster mice (n=24) were exposed to EtOH vapors for 72h. Mice were sacrificed after 72h following EtOH exposure (n=12) and 24h after its withdrawal (n=12). Radioligand binding assays were performed to measure the density of CB(1) receptor and CB(1) receptor agonist-stimulated [(35)S]GTPgammaS binding in crude synaptic membranes isolated from the cortex, hippocampus, striatum and cerebellum. The density of CB(1) receptor was significantly decreased (31-39%) in all the brain regions when compared to the control group. The CB(1) receptor-stimulated G(i/o) protein activation was also found to be decreased (29-40%) in these brain regions of EtOH exposed mice. Recovery of the CB(1) receptor density, in addition to, the CB(1) receptor-mediated G-protein activation was observed after 24h withdrawal from EtOH. The levels of cortical anandamide, which was significantly increased (147%) by EtOH exposure, returned to basal levels after 24h of withdrawal from EtOH exposure. A significant reduction (21%) in the activity of fatty acid amide hydrolase was found in the cortex of EtOH administered mice. Taken together, the neuroadaptation in the EC system may have a potential role in development of tolerance and dependence to EtOH.

Amidohydrolases↗
PubMed2004

Effects of the immunophilin ligand FK506 on nerve regeneration in collagen guides seeded with Schwann cells in rats.

We assessed the effects of FK506 administration on regeneration after 5-mm gap repair with a collagen guide seeded with syngeneic Schwann cells in the rat sciatic nerve. Functional reinnervation was evaluated by non-invasive methods to determine recovery of motor and sensory functions in the hindpaw over 4 months postoperation. Histological analysis of the regenerated nerves was performed at the end of follow-up. Treatment with FK506 (1 mg/kg for the first 2 months) resulted in significant improvement of the onset and the degree of reinnervation. The numbers of myelinated fibers in the distal regenerated nerve were similar between treated and control groups. In conclusion, FK506 improves functional recovery after repair with collagen guides seeded with syngeneic Schwann cells.

Animals↗