The Effect of Hyperemesis Gravidarum on Macular Thickness, Corneal Thickness, and Intraocular Pressure in Pregnancy.

AIM: Physiological changes in intraocular pressure as well as in the cornea and macula may occur during pregnancy. Therefore, we decided to investigate the effect of hyperemesis gravidarum on macular thickness, corneal thickness and intraocular pressure (IOP). MATERIAL AND METHODS: A total of 110 people, 55 of whom were diagnosed with hyperemesis gravidarum and 55 of whom were in the control group, were included in the study. The inclusion criteria for the study were as follows: first trimester (8-14 weeks of gestation) pregnancy with positive fetal heartbeat and no history of systemic disease, no continuous use of medication, diagnosis of hyperemesis gravidarum (ketonuria and weight loss of more than 3 kilograms or 5% of body weight), body mass index (BMI) within normal limits, age between 18 and 40, no alcohol use or smoking. RESULTS: In the HG group compared to the control group, there was a difference between the CCT values of both the right and left eyes (p<0.01). There was a difference in both right and left IOP values in patients in the HG group compared to the control group (p<0.05), and there was no correlation between ketonuria scores and right and left eye CCT values, right and left eye macular thickness, and right and left eye pressure in patients diagnosed with HG (p>0.05). CONCLUSION: In hyperemesis gravidarum, changes occur in IOP, corneal thickness, and macular thickness. In ophthalmic examinations in the pregestational period, especially for women with systemic disease, it may be important for clinicians to take the necessary precautions in this regard.

Laparoscopic removal of heterotopic cesarean scar pregnancy.

OBJECTIVE: To present the laparoscopic management of heterotopic cesarean scar pregnancy and discuss other treatment options. DESIGN: Surgical video article. The Institutional Ethics Committee approved the video reproduction. SETTING: Tertiary referral to a university hospital PATIENT: A 29-year-old woman with spontaneous heterotopic cesarean scar pregnancy presented for vaginal spotting. Ultrasound revealed two gestational sacs at 7 weeks and 6 days of gestation with fetal cardiac activity. One sac was in a normal intrauterine (IU) location, and the other was in a previous cesarean section scar. INTERVENTIONS: Scar pregnancy was excised laparoscopically, preserving IU pregnancy. No additional measures were taken to reduce bleeding. The bladder was filled with 150 cc isotonic to determine its boundaries. The peritoneum was dissected away from the cervix. After removing the ectopic pregnancy material, the myometrial defect was excised. The uterine wall was closed in three layers using 2-0 V-Loc sutures. MAIN OUTCOME MEASURES: Ongoing IU pregnancy after laparoscopic removal of cesarean scar pregnancy and term delivery. RESULTS: The procedure was completed in 67 minutes. Total blood loss was <100 cc. The ongoing pregnancy follow-up was uneventful. Delivery was planned for the 37th-38th weeks. Although instructed to visit immediately after experiencing pain, the patient arrived after the 38th week and reported having pain for 2 days. During the cesarean section, a rupture was observed at the previous incision site, which was fortunately incomplete. A healthy male infant (weight, 3,210 g; Apgar score, 9/10) was delivered. CONCLUSIONS: The most common approach for heterotopic scar pregnancy is embryo reduction with potassium chloride injection. However, the mass persists in the scar area, resulting in complications associated with excessive bleeding during a cesarean section in approximately half of cases. Moreover, almost all published cases of embryo reduction resulted in premature births before week 36. Considering the present case, laparoscopic surgery may be appropriate for managing heterotopic cesarean scar pregnancy by preserving IU pregnancy.

Involvement of small leucine-rich proteoglycans and telocytes in thin and thick human endometrium: immunohistochemical and ultrastructural examination.

Thin endometrium, defined as an endometrial thickness of less than 7 mm during the late follicular phase, is a common cause of frequent cancelation of embryo transfers or recurrent implantation failure during assisted reproductive treatment. Small proteoglycans regulate intracellular signaling cascades by bridging other matrix molecules and tissue elements, affecting cell proliferation, adhesion, migration, and cytokine concentration. The aim of the study is to investigate the role of small leucine-rich proteoglycans in the pathogenesis of thin and thick human endometrium and their differences from normal endometrium in terms of fine structure properties. Normal, thin, and thick endometrial samples were collected, and small leucine-rich proteoglycans (SLRPs), decorin, lumican, biglycan, and fibromodulin immunoreactivities were comparatively analyzed immunohistochemically. The data were compared statistically. Moreover, ultrastructural differences among the groups were evaluated by transmission electron microscopy. The immunoreactivities of decorin, lumican, and biglycan were higher in the thin endometrial glandular epithelium and stroma compared to the normal and thick endometrium (p < .001). Fibromodulin immunoreactivity was also higher in the thin endometrial glandular epithelium than in the normal and thick endometrium (p < .001). However, there was no statistical difference in the stroma among the groups. Ultrastructural features were not profoundly different among cases. Telocytes, however, were not seen in the thin endometrium in contrast to normal and thin endometrial tissues. These findings suggest a possible role of changes in proteoglycan levels in the pathogenesis of thin endometrium.

The relationship between maternal thyroid volume, TSH levels, and Healthy Eating Index scores in BMI-matched pregnant women with hyperemesis gravidarum.

OBJECTIVE: The aim is to investigate the relationship between thyroid volume measurement and healthy nutrition questionnaire scoring in pregnant women diagnosed with hyperemesis gravidarum (HEG). METHODS: One hundred and fifty pregnant women with a BMI of 15-25 kg/m2 and between the ages of 17 and 42 who were diagnosed with HEG at 11-14 weeks of gestation were included in the study. Patients with a history of any disease, drug use, and previously diagnosed eating disorders were excluded. All patients were subjected to the Healthy Eating Index (HEI) questionnaire. The cutoff value for HEI score was determined as 80 points. Patients were evaluated in two groups: group 1 (HEI <80 score) and group 2 (HEI ≥80 score). Complete urine analysis including ketonuria, and thyroid function tests including TSH, T3, and T4 levels were performed for all patients. In addition, the thyroid gland volume of every patient was measured by the same radiologist. RESULTS: Increased thyroid gland volume was significantly associated with lower TSH levels (p = .02) and lower HEI scores (p < .001). On the other hand, it was not significantly associated with ketonuria (p = .47), and parity status (p = .82). CONCLUSIONS: In our study, we found that there may be an increase in thyroid volume in pregnant women with HEG with lower TSH levels and eating scores. Thyroid volume may predict the patients with probable eating disorders and further studies on thyroid volume in patients with HEG may contribute to the literature.

Evaluation of new biomarkers in stage III and IV endometriosis.

OBJECTIVE: To investigate the efficacy of new endometriosis biomarkers in diagnosis and treatment. METHODS: Thirty women with Stage III-IV endometriosis who were given an indication for surgery and 49 control patients were compared. Preoperative and postoperative serum levels of Annexin A5 (ANXA5), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), soluble vascular cell adhesion molecule-1 (sVCAM-1), vascular endothelial growth factors (VEGF) and Ca-125 measurements were compared. RESULTS: AUCs of ANXA5, sICAM-1, IL-6, TNF-α, VCAM-1, VEGF biomarkers were not found to be significant in diagnosing endometriosis when evaluated alone (p > 0.05). Only the AUC of the Ca-125 biomarker values were found to be significant with 73% sensitivity and 98% specificity (p < 0.001). However, when Ca-125 and ANXA5 were evaluated together, it was concluded that the diagnosis of endometriosis could be made with 73% sensitivity and 100% specificity. CONCLUSION: When Ca-125 and ANXA5 are evaluated together, it seems to be more valuable than Ca-125 alone in diagnosing endometriosis.

Ovarian Response can be Predicted in Women with PCOS who have Ovulation Induction with Letrozole.

OBJECTIVE: To compare the clinical, metabolic, and hormonal characteristics of patients with and without selected dominant follicles in infertile women with PCOS who used letrozole for ovulation induction. STUDY DESIGN: A descriptive cohort study. PLACE AND DURATION OF STUDY: Department of Obstetrics and Gynaecology of Bagcilar Research and Training Hospital, Istanbul, Turkey, from October 2019 to November 2021. METHODOLOGY: Eighty-eight female patients with PCOS, who underwent ovulation induction by giving 5 mg/day letrozole, were screened for demographic characteristics, laboratory values, and dominant follicle development. Those who were given letrozole as the first treatment agent, those who took clomiphene citrate (CC) and started letrozole the following month, and those who were treated with letrozole and given letrozole again were recorded separately. Seventy-five patients responded to letrozole and developed a dominant follicle; 13 patients did not develop a dominant follicle. Threshold values were determined for statistically significant parameters between patients with and without dominant follicles. RESULTS: Follicle development occurred in 85.2% of the women. A statistically significant variable in clinical and metabolic values, between ovulating and non-ovulating groups could not be found. There was a significant difference between the two groups for the serum AMH value, total testosterone value, and FSH level. The authors found that follicle response was higher in those with AMH values less than 11.89 ng/mL, FSH levels higher than 6.25 Iu/L, and total testosterone less than 0.96 ng/mL. In this study, the pregnancy rate was found to be lower than in the literature (11%). CONCLUSION: Among the women with PCOS who had ovulation induction with letrozole, follicle development was higher in women with lower FSH, androgen and AMH values. KEY WORDS: Letrozole, Aromatase inhibitor, Androgens, Ovulation induction, AMH.

Hormonal changes in consecutive clomiphene citrate stimulation cycles and their effect on pregnancy rates.

Objective: To determine the relationship between the cumulative effect of sequential clomiphene citrate (CC) treatments in unexplained infertile women with intercycle and intracycle serum hormone changes. Materials and Methods: Patients who received CC 50 mg in the first cycle (group I, n=34) as ovulation induction and those who received CC 50 mg in the second consecutive cycle (group II, n=18) were compared. Basal (cycle days 2-5) and trigger day (the day that recombinant human chorionic gonadotropin is given) levels of gonadotropin and steroid hormones were measured. Results: The 17OHP increase on trigger day was found to be statistically significantly higher in group II compared to the basal day (p=0.083). The testosterone (T) response on the trigger day of the patients in group II was found to be statistically significantly higher than that in group I (p=0.023). The number of selected follicles was negatively correlated with a follicle-stimulating hormone decrease and positively correlated with an estradiol increase. Endometrial thickness was positively correlated with a luteinizing hormone increase, and cycle cancelation was positively correlated with decreased estradiol. Conclusion: Based on this study, it was concluded that the reason for the increased efficiency rate in successive cycles of CC may be the cumulative increase in T and 17OHP levels. However, this result was found not to affect the clinical pregnancy rate.

Association of Endometrioma Size with Serum Anti-mullerian Hormone.

OBJECTIVE: To evaluate the relationship between the size of endometrioma and serum Anti-mullerian hormone (AMH). STUDY DESIGN: A Descriptive study. PLACE AND DURATION OF STUDY: This study was conducted at the Bagcilar Training and Research Hospital, Istanbul, Turkey, from January 2015 to January 2020. METHODOLOGY: Healthy women of reproductive age, who were found to have unilateral endometrioma in ultrasonography, were included in the study group. There were 82 female patients with unilateral endometrioma in the study group and 96 healthy female patients with male factor infertility in the control group. Women with autoimmune disease, a history of pelvic infection or surgery, polycystic ovary syndrome, pregnancy, those undergoing infertility treatment, family history of premature ovarian failure, and those with atypical or suspected endometrioma were excluded. Age, gravida, serum AMH value, and endometrioma size of the study and control groups were recorded. In addition, the endometrioma group was divided into 2 groups with a cut-off size of greater or less than 40 mm. AMH values ​​were evaluated in these two groups. RESULTS: AMH values ​​of women with endometrioma were significantly lower than the control group (2.03 ng/ml and 3.87 ng/ml, respectively, p<0.001). When the relationship between endometrioma size (greater than 40 mm and less than 40 mm) and AMH was examined, no statistically significant difference was found among serum AMH values (1.89 ng/ml and 2.07 ng/ml, respectively, p=0.65). CONCLUSION: The presence of endometrioma was associated with lower AMH suggesting lower ovarian reserve, but endometrioma size was not associated with significant difference in the AMH values. KEY WORDS: Endometrioma, AMH, Ovarian reserve, Endometrioma size.

Diagnostic office hysteroscopy; why is it still painful procedure despite the surgical experience and mini-hysteroscope?

AIM: To evaluate the effect of cervical canal features on pain during outpatient hysteroscopy performed by experienced surgeons using mini-hysteroscope. METHODS: A prospective observational study was conducted on 303 women undergoing diagnostic hysteroscopy without anesthesia. Pain intensity was evaluated using the visual analog scale (VAS) when the cervical canal was passed. The patients were divided into two groups according to the VAS score: painless or mild pain (VAS <4) and moderate or severe pain (VAS ≥ 4). The relationship between cervical canal characteristics (length, version, and flexion positions, history of cervical intervention, stenosis, synechiae), obstetric and gynecological history, preoperative anxiety level, procedure duration, and pain intensity was examined. RESULTS: Moderate pain (4 ≤ VAS < 7) was observed in 38% of patients (n = 117) and 14 patients (5%) experienced severe pain (VAS ≥ 7). In multivariate analysis, nulliparity (p = 0.01; OR, 4.6; 95% CI, 1.7-13.2), postmenopausal state (p = 0.02; OR, 2.2; 95% CI, 1.2-4.3), excessive flexion of the cervix and retroverted uterus (p <0.001; OR, 4.1; 95% CI, 2.0-8.5) were identified as risk factors for a painful procedure. Diagnostic hysteroscopy was successful in 98% of the patients. The pain was the primary cause of the failed hysteroscopy. CONCLUSION: In addition to nulliparity and postmenopausal status, unfavorable features of the cervical canal, such as the excessive flexion position of the cervix and uterine retroversion are significant causes of pain during outpatient hysteroscopy.

Comparison of ICSI and conventional IVF in non-male factor patients with less than four oocytes.

BACKGROUND: We aimed to analyse our clinical results for a particular subgroup of patients with poor ovarian response (POR) to clarify if lower number of oocytes is a drawback for proceeding to C-IVF. MATERIALS AND METHODS: In this retrospective study, patient files of all couples (#1733) who underwent oocyte retrieval between January 2017 and December 2019 were reviewed and 191 cases diagnosed with non-male factor infertility in which ≤ 3 cumulus-oocyte complexes available for fertilisation were analysed. Exclusion criteria were: woman age > 42, patients with a history of previous ART trial, prenatal genetic testing cycles and couples undergoing total cryopreservation for any indication. Three groups were constructed depending on the method of fertilisation and on semen quality as follows: IVF non-male factor (Group 1, n = 77); ICSI non-male factor (Group 2, n = 65); ICSI male factor-ICSI/MF n = 49 according to WHO reference values. Main outcome parameters were: fertilisation rate, implantation rate and live birth rate. RESULTS: Fertilisation rate per collected COC was significantly higher in group 1 compared to the other two groups (85.68%, 72.58%, 73.33% respectively, p = 0.004). FR per inseminated oocyte also tended to be higher in group 1 but not reaching a statistically significant level. Both techniques yielded similar implantation rates (20.42%, 28.49%, 23.33% respectively, p = 0.407) and live birth rates (26.8%, 30.6%, 31.1%, respectively, p = 0.643). CONCLUSION: In the presence of normal semen parameters, low egg number is not an indication to perform ICSI. The choice of fertilisation method should be based primarily on semen quality, in combination with the patient's previous history regardless of the ovarian reserve.

Hormonal Changes in Clomiphene Citrate Cycles in Unexplained Infertility Can Predict Follicle Development?

OBJECTIVES: To examine the intra-cycle and inter-cycle hormonal changes in the clomiphene citrate (CC) cycle in women with unexplained infertility; and to determine the factors that may predict follicle development or CC failure. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: This study was conducted at the Bagcilar Training and Research Hospital, Istanbul, Turkey from August 2019 to March 2020. METHODOLOGY: Fifty-two women with unexplained infertility were included. Fifty-two cycles given 50 mg of CC but without follicle development were accepted as Group I. In the next cycle, 48 cycles given 100 mg of CC were accepted as Group II. During every cycle, serum hormone (FSH, LH, E2, P4, A4, DHEA­S, T, 17­OHP) levels were measured on days 2, 3, 4 or 5 of the cycle (basal day), and on the days when the leading follicle was triggered (trigger day). Endogenous hormone changes were compared in both the groups with and without follicle development as well as in those who could conceive and those who could not conceive. RESULTS: Basal day FSH and DHEA­S values were found to be statistically significantly higher in women with follicle development than those without follicle development (p = 0.02 and p = 0.039, respectively). The trigger day FSH value was found to be significantly lower in women who conceived compared to the basal day value (p = 0.004). The relatively high P4 value (p = 0.008) on the basal day (contingent upon it was not exceeding the 0.5 ng/mL threshold) and the low FSH value (p = 0.015) on the trigger day were found to be statistically significantly different in women who had conceived compared to those who had not. CONCLUSION: Basal serum FSH, P4 and DHEA­S levels can be used as predictors of ovulation in CC cycles in women with unexplained infertility by determining a threshold value with more comprehensive studies to be conducted in the future. Key Words: Androgens, Ovarian stimulation, Clomiphene citrate, Unexplained infertility, Induction of ovulation, Prediction.

Sultam based Carbonic Anhydrase VII inhibitors for the management of neuropathic pain.

We report a series of compounds 1-17 derived from the antiepileptic drug Sulthiame (SLT) from which both the benzenesulfonamide and the sultam moiety were retained. All compounds were tested in vitro for their inhibition activity against the human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) I, II, VII, IX and XII isoforms. Among the series, derivatives 1 and 11 showed great enhancement of both inhibition potency and selectivity towards the hCA VII isoform, when compared to the reference SLT drug. The binding mode of 11 within the hCA VII active site was deciphered by means of X-ray crystallography and revealed the sultam moiety being exposed to the rim of the active site. In vivo experiments on a model of neuropathic pain induced by oxaliplatin clearly showed 11 being an effective pain relieving agent and therefore worth of further exploitation towards the validation of the hCA VII as new target for the management of neuropathies.

Taurultams incorporating arylsulfonamide: First in vitro inhibition studies of α-, ß- and γ-class Carbonic Anhydrases from Vibrio cholerae and Burkholderia pseudomallei.

A new series of taurultambenzenesulfonamides 1-17 were prepared and considered for their inhibitory activity in vitro against the Carbonic Anhydrases from Vibrio cholerae (VchCA-α, VchCA-ß and VchCA-γ) and Burkholderia pseudomallei (BpsCA-ß and BpsCA-γ). Among the compounds tested, derivatives 4, 5, 7, 10, 12, and 16 resulted in highly effective VchCAα inhibitors (KI values spanning within the 6.1-9.6 nM range) and endowed with excellent Selectivity Indexes (SIs; KI VchCA-α/KI hCA II) all comprised between 0.04 and 0.09. Potent in vitro inhibitors for the BpsCA-γ were also identified (KIs of 18.9-19.5 nM). The results here reported may represent the blueprint for the future development of a new generation of CA-based antibiotics integrated with free of resistance mechanisms of action adopted from known drugs.

Handling drug-target selectivity: A study on ureido containing Carbonic Anhydrase inhibitors.

Here we report the synthesis of a series of taurine substituted sulfonamide derivatives 1-29 having the ureido moiety installed at the tail section as selective inhibitors of the tumor associated human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) IX and XII. The series was deeply investigated for their kinetic features which demonstrated a strong dependence on the ureido moiety. High resolution X-ray crystallographic investigation on selected ligand adducts complexed with hCA II and hCA IX-mimic revealed a strong correlation between the ureido moiety and the amino acid residues Q92 and Q67 in both the hCA II and hCA IX-mimic, contributing to highly stabilized ligand-protein complex.

Effects of New NSAID-CAI Hybrid Compounds in Inflammation and Lung Fibrosis.

Pulmonary fibrosis is a severe lung disease with progressive worsening of dyspnea, characterized by chronic inflammation and remodeling of lung parenchyma. Carbonic anhydrases are a family of zinc-metallo-enzymes that catalyze the reversible interconversion of carbon-dioxide and water to bicarbonate and protons. Carbonic Anhydrase Inhibitor (CAI) exhibited anti-inflammatory effects in animals with permanent-middle-cerebral artery occlusion, arthritis and neuropathic pain. The pharmacological profile of a new class of hybrid compounds constituted by a CAI connected to a Nonsteroidal-Anti-Inflammatory Drug (NSAID) was studied in the modulation of inflammation and fibrosis. In-vitro tests were performed to assess their effects on cyclo-oxygenase enzyme (COX)-1 and COX-2, namely inhibition of platelet aggregation and thromboxane B2 production in the human-platelet-rich plasma, and reduction of Prostaglandin-E2 production in lipopolysaccharide-treated-RAW-264.7 macrophage cell line. The activity of compound 3, one of the most active, was studied in a model of bleomycin-induced lung fibrosis in C57BL/6 mice. The hybrid compounds showed a higher potency in inhibiting PGE2 production, but not in modifying the platelet aggregation and the TXB2 production in comparison to the reference molecules, indicating an increased activity in COX-2 inhibition. In the in-vivo murine model, the compound 3 was more effective in decreasing inflammation, lung stiffness and oxidative stress in comparison to the reference drugs given alone or in association. In conclusion, these CAI-NSAID hybrid compounds are promising new anti-inflammatory drugs for the treatment of lung chronic inflammatory diseases.

Unconventional amino acids in medicinal chemistry: First report on taurine merged within carbonic anhydrase inhibitors.

This study reports the design, synthesis of a series of taurine containing benzenesulfonamide derivatives which were all screened in vitro against the physiological relevant human (h) expressed Carbonic Anhydrase (CA; EC 4.2.1.1) I, II, IX, XII isozymes. Compound 2, 5, 11-16 displayed superior inhibitory activities against the tumor associated hCA IX over the reference drug Acetazolamide (AAZ). Both hCA IX and XII isoforms were selectively inhibited only by compound 3, whereas the chloro-containing compound 12 was showed as the most selective and effective inhibitor profile for the CA IX isoforms. To the best of our knowledge the data reported herein are the first of this kind and introduce in the literature new compounds worth for future development within the Medicinal Chemistry field.

Design, synthesis, cytotoxic activity, and apoptosis inducing effects of 4- and N-substituted benzoyltaurinamide derivatives.

In this study, a group of 4-substituted benzoyltaurinamide derivatives were designed, synthesized, and investigated for their anticancer activity against three cancer cell lines and one nontumorigenic cell line by MTT assay. Among the final compounds, methoxyphenyl derivatives 14, 15, 16 were found to be effective against all the tested cancerous cell lines with promising selectivity. The most active compounds were further evaluated to determine the molecular mechanism of their anticancer activity by using western blot assay and the Annexin V-FITC/PI test. Compound 14 (in SH-SY5Y and MDA-MB-231 cell lines) and 15 (in SH-SY5Y cell line) were found to induce intrinsic apoptotic pathway by upregulating BAX, caspase-3, and caspase-9, while downregulating Bcl-2 and Bcl-xL expression levels. According to mechanistic studies, compounds displayed their anticancer activity via three different mechanisms: a. caspase-dependent, b. caspase-independent, and c. caspase-dependent pathway that excluded caspase-9 activation. As a result, this study provides interesting data which can be used to design new taurine-based anticancer derivatives.

Pain Relieving Effect of-NSAIDs-CAIs Hybrid Molecules: Systemic and Intra-Articular Treatments against Rheumatoid Arthritis.

: To study new target-oriented molecules that are active against rheumatoid arthritis-dependent pain, new dual inhibitors incorporating both a carbonic anhydrase (CA)-binding moiety and a cyclooxygenase inhibitor (NSAID) were tested in a rat model of rheumatoid arthritis induced by CFA intra-articular (i.a.) injection. A comparison between a repeated per os treatment and a single i.a. injection was performed. CFA (50 µL) was injected in the tibiotarsal joint, and the effect of per os repeated treatment (1 mg kg-1) or single i.a injection (1 mg ml-1, 50 µL) with NSAIDs-CAIs hybrid molecules, named 4 and 5, was evaluated. The molecules 4 and 5, which were administered daily for 14 days, significantly prevented CFA-induced hypersensitivity to mechanical noxious (Paw pressure test) and non-noxious stimuli (von Frey test), the postural unbalance related to spontaneous pain (Incapacitance test) and motor alterations (Beam balance test). Moreover, to study a possible localized activity, 4 and 5 were formulated in liposomes (lipo 4 and lipo 5, both 1 mg ml-1) and directly administered by a single i.a. injection seven days after CFA injection. Lipo 5 decreased the mechanical hypersensitivity to noxious and non-noxious stimuli and improved motor coordination. Oral and i.a. treatments did not rescue the joint, as shown by the histological analysis. This new class of potent molecules, which is able to inhibit at the same time CA and cyclooxygenase, shows high activity in a preclinical condition of rheumatoid arthritis, strongly suggesting a novel attractive pharmacodynamic profile.

Discovery of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs-CAIs) for the Management of Rheumatoid Arthritis.

Herein we report the design as well as the synthesis of a new series of dual hybrid compounds consisting of the therapeutically used nonsteroidal-anti-inflammatory drugs (NSAIDs; i.e., indometacin, sulindac, ketoprofen, ibuprofen, diclofenac, ketorolac, etc., cyclooxygenase inhibitors) and the carbonic anhydrase inhibitor (CAIs) fragments of the sulfonamide type. Such compounds are proposed as new tools for the management of ache symptoms associated with rheumatoid arthritis (RA) and related inflammation diseases. The majority of the hybrids reported were effective in inhibiting the ubiquitous human (h) CA I and II as well as the RA overexpressed hCAs IX and XII isoforms, with KI values comprised of the low-medium nanomolar ranges. The antihyperalgesic activity of selected compounds was assessed by means of the paw-pressure and incapacitance tests using an in vivo RA model, and among them the hybrids 6B and 8B showed potent antinociceptive effects lasting up to 60 min after administration.

Substituent position effect on the crystal structures of N-phenyl-2-phthalimidoethanesulfonamide derivatives.

In order to determine the impact of different substituents and their positions on intermolecular interactions and ultimately on the crystal packing, unsubstituted N-phenyl-2-phthalimidoethanesulfonamide, C16H14N2O4S, (I), and the N-(4-nitrophenyl)-, C16H13N3O6S, (II), N-(4-methoxyphenyl)-, C16H16N3O6S, (III), and N-(2-ethylphenyl)-, as the monohydrate, C18H18N2O4S·H2O, (IV), derivatives have been characterized by single-crystal X-ray crystallography. Sulfonamides (I) and (II) have triclinic crystal systems, while (III) and (IV) are monoclinic. Although the molecules differ from each other only with respect to small substituents and their positions, they crystallized in different space groups as a result of differing intra- and intermolecular hydrogen-bond interactions. The structures of (I), (II) and (III) are stabilized by intermolecular N-H...O and C-H...O hydrogen bonds, while that of (IV) is stabilized by intermolecular O-H...O and C-H...O hydrogen bonds. All four structures are of interest with respect to their biological activities and have been studied as part of a program to develop anticonvulsant drugs for the treatment of epilepsy.