Correlation between the female pelvic floor biomechanical parameters and the severity of stress urinary incontinence.

BACKGROUND: Stress urinary incontinence (SUI) is a common condition that requires proper evaluation to select a personalized therapy. Vaginal Tactile Imaging (VTI) is a novel method to assess the biomechanical parameters of the pelvic floor. METHODS: Women with SUI were enrolled in this cross-sectional study. Participants completed the Medical, Epidemiologic, and Social Aspects of Aging (MESA) questionnaire and the Patient Global Impression of Severity Question (PGI-S) and underwent a VTI examination. Based on the MESA and PGI-S questionnaires, participants were divided into mild, moderate, and severe SUI groups. Fifty-two biomechanical parameters of the pelvic floor were measured by VTI and compared between the groups (mild vs. moderate and severe). SUI Score and Index were calculated from the MESA questionnaire. Pearson correlation was used to determine the strength of association between selected VTI parameters and the MESA SUI Index and MESA SUI Score. RESULTS: Thirty-one women were enrolled into the study. Significant differences were observed in the VTI parameters 16, 22-24, 38, 39 when the difference between mild and severe subgroups of SUI based on the PGI-S score was examined. Parameter 16 refers to the maximum gradient at the perineal body, parameter 22-24 refers to the pressure response of the tissues behind the vaginal walls, and parameter 38, 39 refers the maximum pressure change and value on the right side at voluntary muscle contraction. VTI parameter 49, describing the displacement of the maximum pressure peak in the anterior compartment, showed a significant difference between the mild SUI and the moderate-severe SUI according to the MESA SUI score (mean ± SD 14.06 ± 5.16 vs. 7.54 ± 7.46, P = 0.04). The MESA SUI Index and SUI Score displayed a positive correlation concerning VTI parameters 4 (the maximum value of the posterior gradient) and 27 (the displacement of the maximum pressure peak in the anterior compartment) (VTI4 vs. MESA SUI Index r = 0.373, P = 0.039; VTI4 vs. MESA SUI Score r = 0.376, P = 0.037; VTI27 vs. MESA SUI Index r = 0.366, P = 0.043; VTI27 vs. MESA SUI Score r = 0.363, P = 0.044). CONCLUSIONS: Female pelvic floor biomechanical parameters, as measured by VTI, correlate significantly with the severity of SUI and may help guide therapeutic decisions.

Fractional CO2 laser treatment effect on cervicovaginal lavage zinc and copper levels: a prospective cohort study.

BACKGROUND: The basic principle of vaginal laser therapy is the rejuvenation of the affected tissue. Zinc and copper are essential nutritional trace elements and have a key role in connective tissue homeostasis. We aimed to investigate the effect of vaginal, fractional CO2 laser treatment on cervicovaginal lavage (CVL) zinc and copper levels. METHODS: Twenty-nine postmenopausal women with symptoms of vaginal dryness were enrolled in our prospective cohort study. Three treatments with MonaLisa Touch CO2 laser system were performed four weeks apart. At each treatment CVL was collected, Vaginal Health Index (VHI) was obtained, and Visual Analog Scale (VAS) for vaginal dryness was assigned by patients. Zinc and copper concentrations were measured with optical emission spectrometry before each treatment and six weeks after the 3rd treatment. RESULTS: The VHI scores significantly improved after each laser treatment (mean ± SD VHI score, 13.03 ± 4.49 before vs. 15.55 ± 4.35 after the 1st, 17.79 ± 4.57 after the 2nd and 19.38 ± 4.39 after the 3rd treatment, P < 0.01). Similarly, VAS scores reflected improvement (mean ± SD VAS score 6.59 ± 2.86 before vs. 4.17 ± 2.86 after the 1st, 2.45 ± 2.43 after the 2nd and 1.41 ± 1.94 after the 3rd treatment, P < 0.01). CVL zinc levels were significantly higher compared to copper levels (0.06 ± 0.04 vs. 0.006 ± 0.006 mg/L, P < 0.01) at baseline. While copper levels remained the same through treatments, the CVL zinc level was significantly higher after the second laser treatment compared to the baseline. CONCLUSIONS: Fractional CO2 laser treatment of the vagina impacts CVL zinc and copper levels differently. While CVL copper levels were not different after each laser treatment, zinc levels were significantly higher after the second treatment before returning to baseline values.

Vaginal elasticity is significantly decreased in vaginal atrophy: a strain elastography study.

OBJECTIVES: Strain elastography is a novel method to assess the elasticity of tissues. We aimed to evaluate the value of vaginal strain elastography in women with vulvovaginal atrophy (VVA). METHODS: Women with or without VVA were enrolled in this prospective study. Participants underwent vaginal cytology and vaginal wall elastography. Vaginal Health Index (VHI) was calculated. Based on Vaginal Maturation Value (VMV), participants were divided into atrophic and nonatrophic groups. Elastography parameters of the vaginal walls were measured in nine regions of interest (ROI). Elastography Index (EI) was defined by the average color score of nine ROIs. Groups were compared with unpaired t test or Mann-Whitney U test. Pearson correlation was used to determine the strength of association between EI and selected parameters. Multiple regression was used to evaluate the association between EI and age, VMV, and vaginal atrophy. RESULTS: Ten women were diagnosed with VVA, and twenty had no cytological signs of vaginal atrophy (age-range 38-79 y). VHI score was significantly lower in the atrophic group (mean ±â€ŠSD, 9.4 ±â€Š2.011 vs 16.6 ±â€Š4.22, P < 0.0001). In the atrophic group, EI was significantly lower than in nonatrophic group (mean ±â€ŠSD, 20 ±â€Š21 vs 47 ±â€Š4, P < 0.01). We found a strong negative correlation between EI and vaginal atrophy (r =  -0.706, P < 0.0001; 95% CI: 0.8501 to -0.4639). In the multiple regression model, only atrophy remained statistically significant for the prediction of EI (P = 0.004). CONCLUSIONS: Vaginal elasticity is significantly decreased in women with vaginal atrophy, measured by EI. Our results suggest that strain elastography might be useful in the diagnosis of vaginal atrophy.

Randomized controlled trial for improved recovery of the pelvic floor after vaginal delivery with a specially formulated postpartum supplement.

OBJECTIVE: To improve pelvic floor recovery after vaginal delivery with daily supplementation of a specially formulated postpartum recovery supplement. METHODS: Within 48 hours of vaginal delivery, primipara women were randomized in a 1:1 ratio to receive daily oral supplementation for 6 weeks with either a combination of regular prenatal vitamin (PNV), leucine (4 g/day), zinc (30 mg/day) and omega-3 fatty acid (900 mg/day) (treatment group), or only a PNV daily (control group). Co-primary outcomes were vaginal squeeze pressure as measured by perineometer and levator muscle injury as measured by transperineal 3-dimensional tomographic ultrasound at 6 weeks postpartum. RESULTS: Twenty-six women in the control group and 27 in the treatment group completed the trial. Weak pelvic floor muscle strength was significantly less frequent in the treatment group compared to the control group at 6 weeks after delivery (28% vs. 58%, P=0.03). Both right and left-sided levator-urethra gap was significantly larger in the control group compared to the treatment group indicating more levator injury being present in the control group at 6 weeks after delivery. Anterior vaginal wall prolapse at or beyond the hymenal ring was significantly more common in the control group compared to the treatment group (19% vs. 0%, P=0.02). Significantly more women reported bothersome bulge symptoms in the control group compared to the treatment group at 6 weeks postpartum (19% vs. 0%, P=0.02). CONCLUSION: Postpartum women who received a specially formulated postpartum recovery supplement had improved recovery of the pelvic floor after vaginal delivery.

Cervicovaginal lavage fluid zinc level as a marker of vaginal atrophy.

OBJECTIVES: This study aimed to investigate the correlation between cervicovaginal fluid zinc levels and participants' menopausal status and the presence of vulvovaginal symptoms of genitourinary syndrome of menopause. METHODS: Women included in the study underwent a pelvic examination, collection of vaginal cytology, and cervicovaginal lavage was performed in a standardized fashion. The cervicovaginal lavage zinc content was determined. The vaginal health index was calculated, and the visual analog scale was obtained based on the participant's burning, itching, vaginal pain, dyspareunia, dryness, and dysuria. RESULTS: One hundred twenty women participated in the study. Eighty-two participants were menopausal. The mean vaginal health index was 15 ±â€Š6, while the total visual analog scale score was 14 ±â€Š14. We found significant differences between cervicovaginal lavage zinc level and age group, menopausal status, presence of vaginal dryness, and vaginal atrophy. We also found a moderate positive correlation between Vaginal Maturation Value and cervicovaginal lavage zinc levels (r = 0.495, P value < 0.01) in the correlation analysis. However, in the multivariate regression model, including all significant factors, only vaginal atrophy remained significant. CONCLUSIONS: We found a significant association between vaginal atrophy (vaginal maturation value < 50) and cervicovaginal lavage zinc levels. Zinc levels of cervicovaginal lavage could be used as a new marker of vaginal atrophy. : Video Summary:http://links.lww.com/MENO/A575.

Video Summary:http://links.lww.com/MENO/A575.

The effect of oral zinc supplementation on cervicovaginal lavage fluid zinc level.

OBJECTIVES: To investigate the effect of oral zinc supplementation on cervicovaginal lavage fluid (CVL) zinc level in pre and postmenopausal women. STUDY DESIGN: A prospective interventional cohort study was carried out by the enrollment of twelve premenopausal and ten postmenopausal women without significant gynecological conditions. Women received daily oral supplementation with 30 mg of zinc for two weeks. Clinical and demographic variables were stored in a dedicated database. Vaginal Health Index was calculated, and vaginal cytology was obtained. CVL and serum samples were collected in a standardized fashion before and after completion of the oral supplementation. Zinc and copper levels were measured by inductively coupled plasma optical emission spectrometry. Paired t-test was used to compare the before and after treatment results. RESULTS: Serum zinc levels increased significantly both in the pre and postmenopausal women (0.88 ± 0.17 vs. 1.06 ± 0.23, p < 0.01 and 0.83 ± 0.24 vs. 0.96 ± 0.33, p < 0.01) after two weeks of daily oral zinc supplementation. CVL zinc level was significantly higher in the premenopausal group compared to the postmenopausal group before and after supplementation (0.13 ± 0.05 vs. 0.06 ± 0.04, p < 0.01 and 0.10 ± 0.03 vs. 0.05 ± 0.01, p < 0.01). Zinc supplementation had no significant impact on the CVL zinc level in either group. Neither serum nor CVL copper levels were affected by the zinc supplementation. There was no significant correlation between serum and CVL zinc or copper levels. CONCLUSION: Daily oral supplementation with 30 mg of zinc had no significant impact on CVL zinc level despite a significant rise in serum zinc level.

The Effect of Vaginal Microablative Fractional CO2 Laser Treatment on Vaginal Cytology.

BACKGROUND AND OBJECTIVES: Most recently vaginal laser treatment was introduced as a new option for women with genitourinary syndrome of menopause, vaginal dryness. Our objective was to assess the effects of intravaginal CO2 laser treatment on vaginal cytology. STUDY DESIGN/MATERIALS AND METHODS: Fifty-two women with symptoms of vaginal dryness were enrolled and underwent vaginal laser treatment using a fractional CO2 laser. Patients received three vaginal laser treatments 4 weeks apart. Vaginal cytology was obtained before the first treatment and 4 weeks after each additional treatment. Vaginal dryness was assessed by using a Visual Analog Scale (VAS). RESULTS: Out of the 52 women enrolled, 34 were in menopause. Postmenopausal women had significantly lower vaginal maturation values (VMV) compared with premenopausal women at the baseline visit (mean ± standard deviation [SD], 42 ± 23 vs. 68 ± 13, P < 0.01). The vaginal dryness VAS was higher (worse) in postmenopausal women compared with premenopausal cases (mean ± SD, 5.7 ± 4 vs. 2.4 ± 3, P < 0.01). The VMV did not change significantly over time after vaginal laser treatment. However vaginal dryness VAS improved significantly after each treatment. Both in the premenopausal and postmenopausal groups, vaginal dryness scores improved significantly from baseline after the three treatments (postmenopausal 5.7 ± 4 vs. 1.6 ± 2.5, P < 0.01 and premenopausal 2.4 ± 3 vs. 0.2 ± 0.5, P < 0.01). Those patients who had improvement in VMV had significantly better (lower) dryness VAS compared with those women without an improvement in VMV after the three treatments (mean ± SD, 0.3 ± 0.8 vs. 1.6 ± 2.6, P = 0.04). CONCLUSIONS: Vaginal dryness VAS improved significantly in a cohort of premenopausal and postmenopausal women undergoing vaginal CO2 laser treatment despite no significant change in vaginal cytology. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.

Biocompatibility and zinc release testing of a zinc-containing vaginal gel.

OBJECTIVE: To test the biocompatibility of a zinc-containing vaginal gel, evaluate its ability to release zinc, and to assess the transepithelial permeability of zinc on human vaginal epithelium. METHODS: The release and membrane diffusion of zinc from the vaginal gel was tested by a vertical Franz-diffusion cell system. The biocompatibility of the gel was tested on HaCaT cells and reconstructed human vaginal epithelium. MTT assay was used to detect cell viability. Lactate dehydrogenase (LDH) assay was used to access cytotoxicity. The permeability of zinc was tested on the reconstructed human vaginal epithelium. The integrity of the reconstructed human vaginal epithelium after the permeability experiments was measured by transepithelial electric resistance. Zinc levels were determined by inductively coupled plasma optical emission spectrometry. RESULTS: 20 µM zinc sulfate did not decrease cell viability during the 24 and 72-hour treatment. Similarly, cell viability did not decrease significantly after 60 minutes of incubation with the gel and no toxic compound released from the vaginal gel during the 120 minutes diffusion experiment. A total of 72-hour exposure to the zinc-containing vaginal gel showed no cytotoxicity using LDH assay. Using cellulose-acetate membranes, 24.6% of the zinc content of the gel was released and appeared in the acceptor phase after 15 minutes. Zinc had high permeability (2.2 ±â€Š0.8 × 10 cm/s) from the vaginal gel on reconstructed human vaginal epithelium. CONCLUSIONS: The zinc-containing (20 µM) vaginal gel was not toxic. The release of zinc is rapid from the vaginal gel. Zinc permeated rapidly through the vaginal epithelial cell layers.

[Short-term efficacy of vaginal CO2 laser therapy as a treatment modality for genitourinary syndrome of menopause]. / A hüvelyi CO2-lézer-kezelés rövid távú hatásai a menopausalis genitourinalis szindróma tüneteire.

Introduction: Genitourinary syndrome of menopause (GSM) affects up to 40-57% of postmenopausal women. Intravaginal microablative fractional CO2 laser is a new proposal for the management of GSM, although the evidence of safety and efficacy of the procedure appears to be insufficient. Aim: The aim of the study was to assess the efficacy of fractional CO2 laser for the treatment of GSM at the Department of Obstetrics and Gynecology of the University of Debrecen. Method: Postmenopausal women with symptoms of GSM underwent three sessions of microablative fractional rejuvenation CO2 laser therapy at 4-6 weeks intervals. Vaginal health index (VHI) scores were completed before each treatment and at 6 weeks follow-up as an objective measurement and visual analog scale was used to assess subjective complaints. Statistical analysis included Student's paired two-sampling t-test for the measure of statistical significance using the standard cutoff for significance p<0.05. Results: 51 women participated (mean age 57.0 ± 9.9 y). Average VHI score was 14.0 ± 4.9 before treatment, 15.0 ± 4.7 after the first session, 18.2 ± 4.6 after the second treatment and 19.5 ± 4.9 at follow-up. The improvement of VHI score was statistically significant between all sessions. Average VAS score was 15.6 ± 14.1 before treatment, 9.0 ± 10.8 after the first session, 5.9 ± 9.2 after the second treatment and 3.4 ± 7.5 at follow-up. The improvement of VAS score was statistically also significant between all sessions. Conclusions: Our study suggests that the fractional CO2 laser is an effective and safe treatment of symptoms associated with GSM. Orv Hetil. 2019; 160(41): 1617-1622.

Large fetal weight alone in Robson-1 parturients doesn't translate into a risk of Caesarean delivery higher then that of a vaginal birth.

OBJECTIVE: The authors analysed the Caesarean section rate as a function of birth weight among Robson-1 parturients and compared with that among the unselected obstetric population. STUDY DESIGN: A retrospective analysis of birth weight, maternal height and the route of delivery was carried out in an unselected obstetric population of 26,012 parturients. The authors compared birth weight centile distributions of vaginally, and that of abdominally delivered fetuses between Robson-1 parturients as well as those of the total obstetric population. RESULTS: The 90th birth weight centile of fetuses delivered at 37, 38, 39, 40, 41, and 42 weeks gestation were 3960 g, 3960 g, 4000 g, 3950 g, 4000 g and 3820 g, respectively. Among Robson-1 parturients, 677 fetuses weighed >4000 g, and 448 patients (66%) were delivered vaginally. Maternal height did not influence either the birth-weight-percentiles or the Caesarean-rates substantially. Above the birth weight of 4000 g, the Caesarean-rate among Robson-1 parturient rose similarly to that of the total obstetric population. In the knowledge of the most accurately estimated fetal weight, the odds of Caesarean delivery among Robson-1 parturients was not different from that of the total obstetric population. Among pregnancies with fetuses weighing less than 5000 g, the Caesarean-rate was below 50% in both Robson-1 parturients and the total obstetric population of 10 years. CONCLUSION: Even the best possible estimation of fetal weight cannot give a valid reason to downplay the intent of vaginal birth based on the fetal size above 3900 g that would be associated with increased odds of Caesarean delivery.

The Effect of Fractional CO2 Laser Treatment on the Symptoms of Pelvic Floor Dysfunctions: Pelvic Floor Distress Inventory-20 Questionnaire.

BACKGROUND AND OBJECTIVES: To assess the improvement on pelvic floor distress (PFD)-related urogenital symptoms using validated questionnaires after intravaginal CO2 laser treatment. STUDY DESIGN/MATERIALS AND METHODS: Forty postmenopausal women with genitourinary symptoms of menopause (GSM) were enrolled into this prospective cohort study and underwent vaginal laser treatment using MonaLisa Touch® fractional CO 2 laser system. Patients received three vaginal laser treatments with 360° probe 4 weeks apart. A three-component Pelvic Floor Distress Inventory (PFDI-20) validated questionnaire was filled out by each patient before each session and 4 weeks after the final treatment. Wilcoxon rank sum test was used to compare the before and after treatment scores. RESULTS: Pelvic Organ Prolapse Distress Inventory (POPDI-6) scores were not significantly different after the first treatment compared with baseline (mean ± standard deviation [SD], 21 ± 18 vs. 17 ± 15, P = 0.44). However, each subsequent treatment resulted in further, statistically significant improvement in symptom scores (14 ± 15, P = 0.03 and 13 ± 13, P = 0.01, after the second and third treatments, respectively). Similarly, Urinary Distress Inventory (UDI-6) scores were not significantly different after the first laser treatment (mean ± SD, 36 ± 25 vs. 29 ± 23, P = 0.36). After the second and third treatments there were significant improvement in the standardized scores (24 ± 20, P = 0.03 and 22 ± 21, P = 0.01). Colorectal-Anal Distress Inventory (CRADI-8) scores did not change significantly after three laser treatments. CONCLUSIONS: Three sessions of microablative fractional CO2 vaginal laser treatment significantly improves patient reported urinary and pelvic organ prolapse symptoms. Lasers Surg. Med. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

A few atoms make the difference: synthetic, CD, NMR and computational studies on antiviral and antibacterial activities of glycopeptide antibiotic aglycon derivatives.

Despite the close structural similarity between the heptapeptide cores of the glycopeptide antibiotics teicoplanin and ristocetin, synthetically modified derivatives of their aglycons show significantly different antibacterial and antiviral properties. The teicoplanin aglycon derivatives with one exception proved to be potent antibacterials but they did not exhibit anti-influenza virus activity. In contrast, the aglycoristocetin derivatives generally showed high anti-influenza virus activity and possessed moderate antibacterial activity. A systematic structure-activity relationship study has been carried out on ristocetin and teicoplanin aglycon derivatives, to explore which structural differences are responsible for these markedly different biological activities. According to electronic circular dichroism and in silico conformational studies, it was found that the differences in anti-influenza virus activity are mainly determined by the conformation of the heptapeptide core of the antibiotics controlled by the presence or absence of chloro substituents. Knowledge of the bioactive conformation will help to design new analogs with improved anti-influenza virus activity. For the teicoplanin derivatives, it was shown that derivatization to improve the antiviral efficacy was accompanied by a significant decrease in antibacterial activity.

Chiral differentiation of the noscapine and hydrastine stereoisomers by electrospray ionization tandem mass spectrometry.

Energy-dependent collision-induced dissociation (CID) of the dimers [2 M + Cat](+) of the noscapine and hydrastine stereoisomers was studied where Cat stands for Li(+), Na(+), K(+) and Cs(+) ions. These dimers were generated 'in situ' from the electrosprayed solution. The survival yield (SY) method was used for distinguishing the noscapine and hydrastine dimers. Significant differences were found between the characteristic collision energies (CE50, i.e. the collision energy necessary to obtain 50% fragmentation) of the homo- (R,R; S,S) and heterochiral (R,S; S,R) stereoisomers. To distinguish the enantiomer pairs L-, D-tyrosine ([M + Tyr + Cat](+)) and L-, D-lysine ([M + Lys + Cat](+)) were used as chiral selectors. Furthermore, these heterodimers [M + amino acid + Cat](+) were also applied to determine the stereoisomeric composition. It was found that the characteristic collision energy (CE50) of the noscapine and hydrastine homodimers ([2 M + Cat](+)) was inversely proportional to the ionic radius of the cations. Furthermore, the structures of the dimers [2 M + Cat](+) were studied by high level quantum chemical calculations.

Novel 9'-substituted-noscapines: synthesis with Suzuki cross-coupling, structure elucidation and biological evaluation.

Tubulin is a major molecular target for anticancer drugs. The dynamic process of microtubule assembly and disassembly can be blocked by various agents that bind to distinct sites on tubulin, usually its ß-subunit. Among the antimitotic agents that perturb microtubule dynamics, noscapinoids represent an emerging class of agents. In particular, 9'-bromonoscapine (EM011) has been identified as a potent noscapine analog. Here we present high yielding, efficient synthetic methods based on Suzuki coupling of 9'-alkyl and 9'-arylnoscapines and an evaluation of their antiproliferative properties. Our results showed that 9'-alkyl and 9'-aryl derivatives inhibit proliferation of human cancer cells. The most active compounds were the 9'-methyl and the 9'-phenyl derivatives, which showed similar cytotoxic potency in comparison to the 9'-brominated derivative. Interestingly these newly synthesized derivatives did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. All of these derivatives, except 9'-(2-methoxyphenyl)-noscapine, efficiently induced a cell cycle arrest in the G2/M phase of the cell cycle in HeLa and Jurkat cells. Furthermore, we showed that the most active compounds in HeLa cells induced apoptosis following the mitochondrial pathway with the activation of both caspase-9 and caspase-3. In addition, these compounds significantly reduced the expression of the anti-apoptotic proteins Mcl-1 and Bcl-2.

Fragmentation study of noscapine derivatives under electrospray conditions.

RATIONALE: Noscapine is a biologically active molecule with anticancer activity among other things. Therefore, from an analytical point of view, knowledge of the mass spectrometric properties of noscapine and its derivatives is essential. The goal of the present study is to describe the collision-induced dissociation behavior of noscapine and its seven derivatives ionized by protons and lithium and sodium ions. METHODS: Protonated noscapines were produced using electrospray ionization (ESI) mass spectrometry (MS). For the tandem mass spectrometry (MS/MS) experiments nitrogen was used as the collision gas and the collision energies were varied in the range of 1-53 eV (in the laboratory frame). RESULTS: The ESI-MS/MS measurements showed that the MS/MS spectra of the protonated noscapines were more informative than the lithiated and sodiated ones. Based on the MS/MS studies, the main fragmentation channels of the protonated noscapines were found to be the loss of water and the loss of a meconine moiety from the precursor ion; furthermore, methyl transfer was also observed in the MS/MS spectra. CONCLUSIONS: The MS/MS study of the protonated noscapines gives more structural information than that of lithiated and sodiated noscapines. However, the most important fragmentation channel, which leads to the formation of the most intensive product ion in the MS/MS spectra, is independent of the ionization agent.

1-substituted apomorphines as potent dopamine agonists.

A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5ß-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands.

Synthesis and opioid activity of novel 6-ketolevorphanol derivatives.

Novel 6-ketolevorphanol analogs with diverse substitution patterns at ring C were synthesized and their binding affinities at the µ,δ and κ opioid receptors were investigated. The in vitro activity of the new analogs was then evaluated in the functional assay based on the electrically-stimulated contractions of the mouse ileum. It was shown that analogs with Δ7,8 bond had no significant potency at any of the opioid receptor types. In contrast, analogs with the saturated ring C were either potent κ agonist or antagonist depending on the absence or presence of the hydroxyl group in position 14.

Synthesis of fluorescent ristocetin aglycon derivatives with remarkable antibacterial and antiviral activities.

Isoindole and benzoisoindole derivatives of ristocetin aglycon have been prepared by reaction with o-phthalaldehyde or naphthalene-2,3-dialdehyde and various thiols. The new compounds exhibited potent antibacterial and anti-influenza virus activity. The cluster forming and fluorescent properties of the aglycon derivatives were also studied.

Synthesis of isoindole and benzoisoindole derivatives of teicoplanin pseudoaglycon with remarkable antibacterial and antiviral activities.

The primary amino function of teicoplanin pseudoaglycon has been transformed into arylthioisoindole or benzoisoindole and glycosylthioisoindole derivatives, in a reaction with o-phthalaldehyde or naphtalene-2,3-dicarbaldehyde and various thiols. All of the obtained semisynthetic antibiotics exhibited potent antibacterial activities against Gram-positive bacteria in the ng per ml concentration range. A few of them showed antiviral activity, in particular against influenza virus.

Synthesis and characterization of thiazolo- and thiazinomorphinans and their intermediate products as novel opioid-active derivatives.

A new procedure was elaborated for the synthesis of potentially opioid-active thiazolo- and thiazinomorphinans. These derivatives and some intermediates related with the synthesis were tested in opioid receptor binding studies. Two compounds showed remarkable µ opioid activities and specificities. The ligand-stimulated [(35) S]GTPγS assays confirmed for both compounds the potent full agonist profile at the µ receptor and for the benzothiazinomorphinan derivative also the δ receptor full agonist character. The structures of these remarkably effective compounds were analyzed with the aid of computational chemistry calculations.