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1.
Eur Rev Med Pharmacol Sci ; 27(3): 1207-1221, 2023 02.
Article in English | MEDLINE | ID: mdl-36808370

ABSTRACT

OBJECTIVE: COVID-19 clinical presentation ranges from asymptomatic infection to an inflammatory cytokine storm with multi-organ failure and fatal outcomes. The identification of high-risk patients for severe disease is crucial to plan an early treatment and intensive follow-up. We aimed to investigate negative prognostic factors in a group of patients hospitalized for COVID-19. PATIENTS AND METHODS: 181 patients (90 men and 91 women, mean age 66.56 ± 13.53 years) were enrolled. Each patient received a work-up including medical history, clinical examination, arterial blood gas analysis, laboratory blood tests, feasible ventilatory support required during hospital stay, intensive care setting required, duration of illness and length of hospital stay (>or<25 days). For the assessment of the severity of COVID-19, three main indicators were considered: 1) the intensive care unit (ICU) admission 2) the hospitalization length >25 days; 3) the need of non-invasive ventilation (NIV). RESULTS: The independent risk factor associated with the ICU admission were lactic dehydrogenase elevation (p=0.046), C reactive protein elevation (p=0.014) at hospital admission and direct oral anticoagulant home therapy (p=0.048); for hospital length >25 days: early corticosteroid therapy (p=0.035); for NIV treatment: ferritin elevation at hospital admission (p=0.006). CONCLUSIONS: The presence of the above factors may be useful to identify patients at high risk of developing a severe COVID-19 that need an early treatment and intensive follow-up.


Subject(s)
COVID-19 , Male , Humans , Female , Middle Aged , Aged , Aged, 80 and over , SARS-CoV-2 , Case-Control Studies , Prognosis , Hospitalization , Intensive Care Units
2.
Eur J Obstet Gynecol Reprod Biol ; 276: 174-178, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35926246

ABSTRACT

OBJECTIVE: To investigate the correlation between epidural analgesia (EA) administered during labour and the risk of requiring an operative delivery (caesarean section or operative vaginal delivery). METHODS: This was a retrospective, multicentric cohort study. All singleton births of viable foetuses in cephalic presentation with a gestational age ≥ 37 weeks delivered between 2016 and2019 were included. A propensity score (PS) matching analysis was used to obtain comparable groups, balancing the maternal and pregnancy characteristics that required epidural analgesia during labour. The risk of operative delivery in women with and without epidural analgesia was estimated following PS-matching analysis (1:1 ratio). RESULTS: As per the unmatched analysis, the occurrence of Caesarean section (CS) was significantly higher in women administered EA compared with the non-EA group (14.0 % vs 5.0 %; p < 0.001). The incidence of operative vaginal delivery (OVD) (9.1 % vs 4.0 %; p < 0.001) showed a similar pattern. The PS algorithm matched 16.301 cases who were administered EA with 16.301 cases not administered EA and found a significantly increased risk of CS (OR, 1.6; 95 %CI 1.5-1.7) and OVD (OR, 1.2; 95 % CI 1.1-1.2) in the former group. CONCLUSION: The risk of operative delivery almost halved in the EA group compared with the non-EA group, compared with the baseline risk of the unmatched subjects.


Subject(s)
Analgesia, Epidural , Analgesia, Obstetrical , Analgesia, Epidural/adverse effects , Analgesia, Obstetrical/adverse effects , Cesarean Section/adverse effects , Cohort Studies , Female , Humans , Infant , Pregnancy , Propensity Score , Retrospective Studies
3.
Facts Views Vis Obgyn ; 11(4): 307-313, 2020 Mar 27.
Article in English | MEDLINE | ID: mdl-32322826

ABSTRACT

BACKGROUND: Treatment of obese female patients represents a real challenge. Indeed, obesity among women has reached epidemic levels not only elevating the cardiovascular and endocrinological risks, but also increasing the incidence of various gynecological pathologies (e.g. endometrial cancer and hyperplasia, uterine fibroids, genital prolapse) which commonly require hysterectomy as a surgical solution. In the last decade, minimally invasive surgery has emerged as an approach reducing the invasiveness of the standard laparoscopic surgical procedures while maintaining efficacy and feasibility. As such, in this study we aimed to evaluate the feasibility of percutaneous hysterectomy (PSS-H) approach in obese patients by reporting the first prospective comparison between the PSS-H to laparoscopic hysterectomy (LPS-H). METHODS: In this multicentric comparative prospective study, 45 patients affected by benign and malignant gynecological conditions were considered eligible for minimally invasive surgery (MIS). Fifteen patients received PSS-H and 30 LPS-H. All patients enrolled received a total hysterectomy ± bilateral salpingo-oophorectomy, with or without lymph nodal staging. RESULTS: No statistically significant differences were noted in operative time and estimated blood loss between the two groups. Four patients in PSS-H group and 3 in LPS-H group received lymph node staging. A multifunctional energy device was used in all PSS-H and 73.3% of LPS-H procedures (p=0.038). There were no conversions to laparotomy in either group and similarly there were no conversions to conventional laparoscopy in the PSS-H group. In the LPS-H group, there was one (3.3%) case of major bleeding( ≥ 500 mls). We recorded one vaginal cuff bleeding in PSS-H, whereas for LPS-H we reported 4 (13.3%) 30-days complications (p=0.651). No differences in visual analogue scale (VAS) score were recorded. A significant disparity was noted in cosmetic outcome at discharge (p=0.001), but not after 30 days. CONCLUSION: We demonstrated for the first time, in a prospective comparison between PSS and LPS approaches, that PSS-H may represent a valid alternative to performing total hysterectomy in obese patients.

4.
Eur J Obstet Gynecol Reprod Biol ; 234: 218-222, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30731335

ABSTRACT

OBJECTIVE: To investigate the safety, feasibility and oncological adequacy of the Percutaneous Surgical System - PSS in a consecutive series of low-risk endometrial cancer staging. STUDY DESIGN: From May 2015 to April 2017, we prospectively performed 30 consecutive percutaneous staging for low/intermediate risk endometrial cancer (FIGO stage IA G1-G2, IB G1-G2, IA G3). All patients were divided in two different groups on the basis of surgical procedure received: Group A included patients submitted to radical Class A hysterectomy and bilateral salpingo-oophorectomy; Group B concerned patients that received a lymph nodal assessment also. RESULTS: The time needed to install percutaneous instruments and suprapubic trocar was 4 min. (range 2-10). The recorded median operative time (OT) was 80 min. (range 65-120) for Gr.A and 143 min. (range 107-190) for Gr.B, in which the median time of lymph nodal assessment was 55 min. (range 20-76). The median time for hysterectomy was 60 min. (range 40-110) in all cases. Lymph nodal assessment was performed in 14 (46.6%) cases: 7 sentinel node mapping, 7 pelvic lymphadenectomy. No intraoperative complications or LPS/LPT conversions were recorded. Median discharge time was 2 days (range 1-4), 5 patients were discharged in 3rd post-op day, and only 1 patient was discharged in 4th day for fever. All patients conveyed high satisfaction with the cosmetic results. A progressive overall reduction of pain perception was observed at 24 h after surgery. Median follow-up was of 14 months (range 12-36), no recurrences have been detected. CONCLUSIONS: PSS seems to be a feasible approach for endometrial cancer staging. Larger experiences and prospective comparative studies are important to assess our assumptions and further investigate the real benefits of percutaneous surgical system.


Subject(s)
Endometrial Neoplasms/surgery , Hysterectomy/methods , Lymph Node Excision/methods , Precision Medicine/methods , Salpingo-oophorectomy/methods , Aged , Aged, 80 and over , Endometrial Neoplasms/pathology , Feasibility Studies , Female , Humans , Italy , Laparoscopy/methods , Middle Aged , Neoplasm Staging , Operative Time , Pain, Postoperative/etiology , Prospective Studies , Robotic Surgical Procedures/methods , Treatment Outcome
5.
J Robot Surg ; 12(2): 229-234, 2018 Jun.
Article in English | MEDLINE | ID: mdl-28624984

ABSTRACT

This pilot study was aimed to value the feasibility and safety of Senhance Robotic Platform for hysterectomy in obese patients. Ten obese patients (30 < BMI < 40) underwent elective Senhance total extrafascial hysterectomy with bilateral salpingo-oophorectomy at the Division of Gynecologic Oncology of "Policlinico A. Gemelli" Foundation, Rome, Italy. Perioperative and postoperative outcomes data were recorded. The median age was 60 years (range 51-75) and the median BMI was 33.3 kg/m2 (range 30.4-38.3). The median uterine weight was 112.5 g (range 77-225). Indication to total hysterectomy was early-stage (FIGO Stage IA) endometrial cancer in 100% of patients. The median operative time (OT) was 110 min (70-200). The median docking time was 10.5 min (5-25). The median estimated blood loss was 100 mL (50-200). No conversions to laparotomy were recorded. No intra- and 30-day postoperative complications were registered. The median ileus was 17 h (12-36) and the median time to discharge was 2 days (1-4). The median VAS scores registered at 2, 4, 12, and 24 h were, respectively, 2 (1-3), 2 (1-3), 4 (1-8), and 3 (1-5). Our study results suggest that Senhance platform could be safe for hysterectomy even in obese patients. More clinical data are needed to determine whether this approach would offer any additional benefits in a new middle line between standard laparoscopy and robotics.


Subject(s)
Hysterectomy , Obesity , Robotic Surgical Procedures , Aged , Endometrial Neoplasms/complications , Endometrial Neoplasms/surgery , Female , Humans , Hysterectomy/adverse effects , Hysterectomy/methods , Hysterectomy/statistics & numerical data , Learning Curve , Middle Aged , Obesity/complications , Obesity/epidemiology , Operative Time , Postoperative Complications/epidemiology , Prospective Studies , Robotic Surgical Procedures/adverse effects , Robotic Surgical Procedures/methods , Robotic Surgical Procedures/statistics & numerical data , Surgeons/statistics & numerical data
6.
Eur J Obstet Gynecol Reprod Biol ; 216: 125-129, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28753500

ABSTRACT

OBJECTIVES: During the last decade endoscopic surgical procedures have been constantly evolving. The latest innovation in ultra-minimally invasive surgery (MIS) is the percutaneous technology (Percuvance™ Percutaneous Surgical System (PSS), Teleflex Inc., USA). We compared surgical outcome of hysterectomy, in a retrospective cohort study using the most recent MIS techniques as single-site (LESS) surgery, 3mm laparoscopy (MiniLPS) and percutaneous system (PSS) with standard laparoscopy (LPS). STUDY DESIGN: This is a matched retrospective cohort study. Endometrial Hyperplasia/Early stage endometrial cancer or benign pathology were the indication for surgery. Data of laparoscopic hysterectomies performed between May 2013 and April 2016 using PSS, LPS, MiniLPS, and LESS were collected and compared. RESULTS: The characteristics of each group were similar. The median Operative time (OT) was significantly longer in LESS compared to all other groups (120min [range 55-165] in LESS, 91min [range 60-180] in MiniLPS, 70min [range 55-230] in LPS and 65 [range 40-180] in PSS; p=0.0001). No significant differences among the 4 groups were observed in terms of estimated blood loss, conversion to laparoscopy or laparotomy, and intra e post-operative complications. Statistically significant differences were recorded in median VAS 24h (2 [range 0-3] in PSS, 2 [range 0-3] in MiniLPS, 3 [range 2-5] in LESS and 2 [range 1-5] in LPS; p=0.0001). The average time of discharge was (1day [range 1-3] in PSS, 1day [range 1-2] in MiniLPS, 1days [range 1-2] in LESS and 1day [range 1-3] in LPS; p=0.99). CONCLUSIONS: Data show that the effort to minimize the impact of surgical invasiveness can be feasible and could improve the advantages, not only in terms of aesthetic outcomes, even if the differences among the endoscopic approaches have not a relevant clinical impact. The technology innovations like PSS maintain the same triangulation between instruments as standard LPS with an evident decrease of the invasiveness thanks to reduced instruments size, even if the lack of suitability of bipolar energy, that require a multifunction instrument, remain a limit of these instruments.


Subject(s)
Hysterectomy/methods , Laparoscopy/methods , Minimally Invasive Surgical Procedures/methods , Postoperative Complications/etiology , Uterus/surgery , Adult , Aged , Aged, 80 and over , Cohort Studies , Endometrial Hyperplasia/surgery , Endometrial Neoplasms/surgery , Female , Humans , Hysterectomy/adverse effects , Laparoscopy/adverse effects , Middle Aged , Minimally Invasive Surgical Procedures/adverse effects , Operative Time , Retrospective Studies , Treatment Outcome
8.
Statistics (Ber) ; 50(4): 917-929, 2016 Jul 03.
Article in English | MEDLINE | ID: mdl-27453616

ABSTRACT

Copula modelling has in the past decade become a standard tool in many areas of applied statistics. However, a largely neglected aspect concerns the design of related experiments. Particularly the issue of whether the estimation of copula parameters can be enhanced by optimizing experimental conditions and how robust all the parameter estimates for the model are with respect to the type of copula employed. In this paper an equivalence theorem for (bivariate) copula models is provided that allows formulation of efficient design algorithms and quick checks of whether designs are optimal or at least efficient. Some examples illustrate that in practical situations considerable gains in design efficiency can be achieved. A natural comparison between different copula models with respect to design efficiency is provided as well.

9.
Lab Chip ; 15(11): 2395-9, 2015 Jun 07.
Article in English | MEDLINE | ID: mdl-25920905

ABSTRACT

Glass micromachining is a basic technology to achieve microfluidic networks for lab-on-a-chip applications. Among several methods to microstructure glass, the simplest and most widely applied is wet chemical etching (WE). However, accurate control of the reaction conditions to perform reproducible, fast and safe glass etching is not straightforward. Herein, microwave-assisted WE is demonstrated to intensify the glass etching action under safe working and finely monitored operative conditions and to produce smooth deep channels in short processing times with reduced underetching effects.


Subject(s)
Glass/chemistry , Microfluidic Analytical Techniques/instrumentation , Microtechnology/methods , Microwaves
10.
Epidemiol Psychiatr Sci ; 24(4): 342-52, 2015 Aug.
Article in English | MEDLINE | ID: mdl-24785980

ABSTRACT

AIM: To determine whether disparities exist in mental health care provision to immigrants and Italian citizens with severe mental illness in Bologna, Italy. METHODS: Records of prevalent cases on 31/12/2010 with severe mental illness and ≥1 contact with Community Mental Health Centers in 2011 were extracted from the mental health information system. Logistic and Poisson regressions were carried out to estimate the probability of receiving rehabilitation, residential or inpatient care, the intensity of outpatient treatments and the duration of hospitalisations and residential care for immigrant patients compared to Italians, adjusting for demographic and clinical covariates. RESULTS: The study population included 8602 Italian and 388 immigrant patients. Immigrants were significantly younger, more likely to be married and living with people other than their original family and had a shorter duration of contact with mental health services. The percentages of patients receiving psychosocial rehabilitation, admitted to hospital wards or to residential facilities were similar between Italians and immigrants. The number of interventions was higher for Italians. Admissions to acute wards or residential facilities were significantly longer for Italians. Moreover, immigrants received significantly more group rehabilitation interventions, while more social support individual interventions were provided to Italians. CONCLUSIONS: The probability of receiving any mental health intervention is similar between immigrants and Italians, but the number of interventions and the duration of admissions are lower for immigrants. Data from mental health information system should be integrated with qualitative data on unmet needs from the immigrants' perspective to inform mental health care programmes and policies.

11.
Arch Environ Contam Toxicol ; 53(4): 607-16, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17882475

ABSTRACT

Residual biological effects of the 1991 HAVEN oil spill off the Ligurian (Arenzano) coast were assessed in this study. Samples of the fish species Boops boops, Mullus barbatus, and Uranoscupus scaber were collected from two polluted sites near the HAVEN wreck and from an uncontaminated area. In addition to this, mussels were caged along the coast affected by the HAVEN disaster. The physiological status of fish and mussels was assessed using a battery of stress and exposure biomarkers. The PAH content of mussel and fish tissues was also analyzed. Significant biological responses were observed in lysosomal membrane stability, neutral lipid and lipofuscin accumulation and micronucleus frequency for mussels caged at two sites close to the HAVEN wreck. Chemical analyses indicated, however, that these effects are not caused by aromatic hydrocarbons. For this reason, we suggest that the aftermath of the HAVEN disaster contributes very little to coastal ecosystem pollution. This was also confirmed by the few biological effects observed in fish specimens (Boops boops) collected from surface waters. Nevertheless, it is important to point out that benthic fish displayed a stress syndrome potentially caused by aromatic hydrocarbons released from the oil tanker, as witnessed by an enhanced EROD activity and increased lipofuscin and neutral lipid lysosomal contents.


Subject(s)
Environmental Monitoring/methods , Petroleum , Water Pollutants, Chemical/toxicity , Animals , Biomarkers , Bivalvia/drug effects , DNA Damage , Fishes , Italy , Micronucleus Tests , Water Pollutants, Chemical/analysis
12.
Environ Pollut ; 142(1): 65-72, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16289776

ABSTRACT

A year-round biomonitoring study on blue mussels (Mytilus galloprovincialis) was carried out in 4 selected sites along the Gulf of Oristano (Sardinia, Italy): a commercial port (Port), the outlet of the S'Ena Arrubia and Marceddì lagoons (in the catchment area of intensive agricultural and diary activities, and abandoned mining), and a reference site (North). Heavy metal concentrations in sediments from Marceddì were 2-3 to 10-20 times higher in Pb, Cd and Zn, respectively, than those found at North and S'Ena Arrubia. Higher values (P<0.05) of micronuclei frequency were detected in mussels from Marceddì and Port compared to those detected in mussels from North and S'Ena Arrubia. DNA damage in animals from North was significantly lower than that at the other sites. Results of acetylcholinesterase inhibition consistently showed the strongest effects in mussels from Port and Marceddì. Our results suggest that these biomarkers can be used in coastal marine biomonitoring as early signals of exposure and adverse effects along a pollution gradient.


Subject(s)
Agriculture , Environmental Monitoring/methods , Mining , Mytilus/enzymology , Water Pollution/analysis , Acetylcholinesterase/analysis , Acetylcholinesterase/metabolism , Animals , DNA Damage , Geologic Sediments/chemistry , Italy , Mediterranean Sea , Micronucleus Tests , Mytilus/chemistry , Water Pollutants, Chemical/toxicity
13.
Braz. j. vet. res. anim. sci ; 40: 169-169, 2003.
Article in Portuguese | LILACS-Express | LILACS, VETINDEX | ID: biblio-1470584

ABSTRACT

O artigo não apresenta resumo.

14.
Braz. j. vet. res. anim. sci ; 40: 215-215, 2003.
Article in Portuguese | LILACS-Express | LILACS, VETINDEX | ID: biblio-1470637

ABSTRACT

O artigo não apresenta resumo.

16.
Clin Cancer Res ; 5(12): 4013-20, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10632333

ABSTRACT

Several genetic epidemiological studies have provided data to support the hypothesis that there are genes on the X chromosome that may contribute to prostate cancer susceptibility. A recent linkage study of 360 prostate cancer families described evidence for a prostate cancer predisposition gene, termed HPCX, which maps to Xq27-28. To confirm the potential contribution of this locus to prostate cancer susceptibility in an independent dataset, we studied 153 unrelated families who are participants in the University of Michigan Prostate Cancer Genetics Project. Families selected for this analysis have at least two living family members with prostate cancer that are related in a way that they could potentially share a common ancestral copy of an X chromosome. DNA samples were genotyped using a panel of seven polymorphic markers spanning 30 cM and containing the HPCX candidate region. The resulting data were analyzed using both nonparametric and parametric linkage methods. Analysis of all 153 families using multipoint non-parametric linkage (NPL) methods resulted in positive NPL Z-scores across the entire candidate interval (NPL Z-scores of 0.23-1.06, with corresponding one-sided Ps of 0.41 and 0.15, respectively). The 11 African-American families had negative NPL Z-scores across the same 30-cM interval. Analysis of the 140 Caucasian families produced a maximal NPL Z-score of 1.20, with a corresponding one-sided P of 0.12 at marker DXS1113. The subset of families with no evidence of male-to-male disease transmission and with early-onset prostate cancer (average age at diagnosis within a family < or = 65 years) contributed disproportionately to the evidence for linkage for the entire dataset in the HPCX candidate region (near marker DXS1113). In conclusion, this study of 153 families, each with two or more living members with prostate cancer, provides some additional support for the existence of a prostate cancer susceptibility gene at Xq27-28.


Subject(s)
Genetic Linkage , Genetic Predisposition to Disease , Prostatic Neoplasms/genetics , X Chromosome , Aged , Chromosome Mapping , Female , Genetic Markers , Genotype , Humans , Male , Pedigree , Sex Factors , Statistics, Nonparametric
17.
Vet Hum Toxicol ; 37(6): 544-6, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8588292

ABSTRACT

Riedeliella graciflora is a plant mainly found in southeast South America and related to bovine mortality in Sao Paulo State, Brazil. Our laboratory showed that cattle intoxicated with 10 g R graciflora leaves/kg had organ congestion, edema and hemorrhage. The aim of this study was to determine which laboratory animal species would present the same lesions found in cattle. We also studied the effects of administering parts of the fruits or leaves po, sc, ip or im. All the laboratory species developed organ congestion, edema and hemorrhage and severe nephrosis regardless which plant part was given or the route of administration used. The effects were more intense in animals dosed with R graciflora fruits ip.


Subject(s)
Cattle Diseases/mortality , Plant Extracts/toxicity , Plant Poisoning/veterinary , Animals , Brain/drug effects , Brain/pathology , Brazil , Cattle , Cattle Diseases/etiology , Cricetinae , Disease Models, Animal , Guinea Pigs , Heart/drug effects , Kidney/drug effects , Kidney/pathology , Liver/drug effects , Liver/pathology , Lung/drug effects , Lung/pathology , Male , Mice , Plant Extracts/administration & dosage , Plant Leaves/metabolism , Plant Poisoning/mortality , Rabbits , Rats , Species Specificity
18.
Vet Hum Toxicol ; 37(5): 447-8, 1995 Oct.
Article in English | MEDLINE | ID: mdl-8592833

ABSTRACT

Three calves received 10 g Riedeliella graciflora dry leaves/kg body weight by gavage. Blood samples were taken immediately before plant administration and at 2, 4, 6, 12 and 24 hours later; serum ALT, AST, AP, TB, urea and creatinine were determined. After R graciflora administration, the calves had anorexia, profound depression and recumbency prior to death. Creatinine levels increased markedly until death. Severe tubular nephrosis was consistently observed.


Subject(s)
Cattle Diseases/chemically induced , Plant Poisoning/veterinary , Plants, Toxic , Alkaline Phosphatase/blood , Animals , Bilirubin/blood , Cattle , Cattle Diseases/blood , Cattle Diseases/pathology , Creatinine/blood , Plant Poisoning/blood , Plant Poisoning/physiopathology , Tissue Distribution , Transferases/blood , Urea/blood
19.
Neuroradiology ; 37(5): 365-9, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7477835

ABSTRACT

Diagnosis of brain death must be certain to allow discontinuation of artificial ventilation and organ transplantation. Brain death is present when all functions of the brain stem have irreversibly ceased. Clinical and electrophysiological criteria may be misinterpreted due to drug intoxication, hypothermia or technical artefacts. Thus, if clinical assessment is suboptimal, reliable early confirmatory tests may be required for demonstrating absence of intracranial blood flow. We have easily carried out and interpreted 99mTc HM-PAO SPECT in a consecutive series of 40 comatose patients with brain damage, without discontinuing therapy. Brain death was diagnosed in 7 patients, by recognising absence of brain perfusion, as shown by no intracranial radionuclide uptake. In patients in whom perfusion was seen on brain scans, HM-PAO SPECT improved assessment of the extent of injury, which in general was larger than suggested by CT.


Subject(s)
Brain Death/diagnostic imaging , Brain/blood supply , Organotechnetium Compounds , Oximes , Tomography, Emission-Computed, Single-Photon , Adolescent , Adult , Aged , Aged, 80 and over , Brain Damage, Chronic/diagnostic imaging , Child , Coma/diagnostic imaging , Female , Humans , Life Support Care , Male , Middle Aged , Prognosis , Regional Blood Flow/physiology , Technetium Tc 99m Exametazime
20.
J Med Chem ; 37(23): 4003-19, 1994 Nov 11.
Article in English | MEDLINE | ID: mdl-7966161

ABSTRACT

Studies on cephem sulfones as inhibitors of human leukocyte elastase (HLE) have been extended to the new class of cephem 4-ketones. tert-Butyl and phenyl ketones were prepared from 4-carboxycephem derivatives, at either the sulfide or sulfone oxidation level, by chemoselective Grignard reaction. Obtained products were functionalized with heterocyclothio and acyloxy substituents at C-3', C-2, or both positions. tert-Butyl ketones of the 7 alpha-chlorocephem series were in general at least as potent as the corresponding esters at inhibiting the enzyme, but improvements in hydrolytic stability were only marginal. On the other hand, tert-butyl ketones of the 7 alpha-methoxycephem series combined potent biochemical activity with acceptable hydrolytic stability, thus overstepping the esters, thiolesters, and amides reported previously. In particular, the tert-butyl ketones possessing a heterocyclothio group at C-3' or C-2 were at least as active as the corresponding tert-butyl esters but 1 order of magnitude more stable in physiologic buffers (pH 7.4, 37 degrees C). Introduction of acyloxy groups at C-2 delivered the most potent HLE inhibitors of the cephem class ever reported, with inhibition parameters often outside the determination limits of our standard protocol (second-order rate constant kon > 2,000,000 M-1 s-1; Ki at steady state < 2 nM). Keto-enol tautomerism was found to depress activity and boost hydrolytic stability. Thus, double substitution with heterocyclic thiols produced compounds with diverging properties, according to the extent of enolate formation at the investigated pH (7.4): the weakly acidic tert-butyl ketones (pKa > or = 5.8) proved to be potent inhibitors (kon over 10(4) M-1 s-1) with reasonable hydrolytic stability (t1/2 = 30-75 h), while the phenyl ketones (pKa < 4) were fair inhibitors (kon over 10(3) M-1 s-1; Ki at steady state approximately 50 nM) with hydrolytic half-lives exceeding 1000 h. Selected compounds efficiently inhibited the degradation of insoluble bovine neck elastin by HLE in a concentration-dependent manner. Intracellular HLE of polymorphonuclear leukocytes was in general unaffected; however, a lipophilic cephem sulfone apparently able to inactivate the enzyme in living cells was identified.


Subject(s)
Cephalosporins/pharmacology , Ketones/pharmacology , Pancreatic Elastase/antagonists & inhibitors , Sulfones/pharmacology , Cells, Cultured , Cephalosporins/chemical synthesis , Drug Stability , Elastin/metabolism , Humans , Hydrolysis , Ketones/chemical synthesis , Leukocyte Elastase , Neutrophils/enzymology , Sulfones/chemical synthesis
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