Publications by authors named "Tomasz Ostrowski"

33 Publications

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives.

Antioxidants (Basel) 2021 Jun 12;10(6). Epub 2021 Jun 12.

Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.

Recently, small compound-based therapies have provided new insights into the treatment of glioblastoma multiforme (GBM) by inducing oxidative impairment. Kinetin riboside (KR) and newly designed derivatives (8-azaKR, 7-deazaKR) selectively affect the molecular pathways crucial for cell growth by interfering with the redox status of cancer cells. Thus, these compounds might serve as potential alternatives in the oxidative therapy of GBM. The increased basal levels of reactive oxygen species (ROS) in GBM support the survival of cancer cells and cause drug resistance. The simplest approach to induce cell death is to achieve the redox threshold and circumvent the antioxidant defense mechanisms. Consequently, cells become more sensitive to oxidative stress (OS) caused by exogenous agents. Here, we investigated the effect of KR and its derivatives on the redox status of T98G cells in 2D and 3D cell culture. The use of spheroids of T98G cells enabled the selection of one derivative-7-deazaKR-with comparable antitumor activity to KR. Both compounds induced ROS generation and genotoxic OS, resulting in lipid peroxidation and leading to apoptosis. Taken together, these results demonstrated that KR and 7-deazaKR modulate the cellular redox environment of T98G cells, and vulnerability of these cells is dependent on their antioxidant capacity.
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http://dx.doi.org/10.3390/antiox10060950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231124PMC
June 2021

Multiple occlusions in extracranial arteries in patients with aortic arch syndrome: is minimally invasive treatment still possible? Technical aspects of the treatment based on our own experience and a review of the literature.

Wideochir Inne Tech Maloinwazyjne 2021 Mar 20;16(1):183-190. Epub 2020 Apr 20.

Department of General, Endocrine, and Vascular Surgery, Medical University of Warsaw, Warsaw, Poland.

Takayasu arteritis is a large vessel vasculitis of granulomatous nature and unknown aetiology affecting predominantly the aorta and its major branches, which may lead to ischaemic symptoms of many organs including the central nervous system. To decrease the risk of neurological complications and improve the quality of life, an arterial revascularisation may be necessary. The treatment options include pharmacotherapy as well as both open surgical and endovascular procedures, which has to be carefully chosen to obtain clinical success. There is an ongoing debate on the advantages, possibilities, and indications for implementing endovascular and open surgical methods, especially in high-risk patients. In this article we present our own experience in the treatment of an unusually complex and high-risk patient with multiple occlusion of supra-aortic branches, focusing on the technical aspects of the procedures and the decision-making process, as well as to confront with contemporary medical knowledge.
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http://dx.doi.org/10.5114/wiitm.2020.94517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991926PMC
March 2021

Adrenal metastases - long-term results of surgical treatment, single-centre experience.

Contemp Oncol (Pozn) 2020 13;24(1):29-33. Epub 2020 Mar 13.

Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw, Poland.

Introduction: The adrenal gland is a frequent site of metastases in different types of cancer. The aim of this study was to assess the results of metastatic adrenalectomy in a single institution and to identify factors for survival.

Material And Methods: A retrospective, single-centre analysis of outcomes of 39 patients (22 male, 17 female) with adrenal metastases who underwent surgery within 14 years (2004-2017) was performed. The median age at the time of adrenal surgery was 64.8 years (range 49-79 years).

Results: In our study group non-small cell lung cancer (NSCLC) was the most frequent primary tumour type (15 pts), followed by renal cell carcinoma (RCC) (14 pts) and colon cancer (6 pts). Most of the metastases - 36 (92%) - were metachronous (> 6 months). All synchronous metastases were NSCLC. The mean time from primary cancer to adrenalectomy was 42.3 months (range 1-176) and was statistically longer for RCC. In 3 patients (8%) metastases were bilateral and both adrenal glands were removed. In all patients, surgery was limited to the adrenal gland, and no major complications of surgery were observed. The median overall survival after metastasectomy was 18 months (3-81) and was statistically longer for colon cancer - 29.5 months ( = 0.012). In patients who died, tumours were significantly bigger than in survivors, 76.5 mm vs. 52.5 mm ( = 0.026).

Conclusions: Surgery for adrenal metastasis is safe and indications for this procedure should be individualized. In selected patients, surgical removal of adrenal metastasis was associated with longer survival.
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http://dx.doi.org/10.5114/wo.2020.93679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265961PMC
March 2020

Volumetric Carotid Flow Characteristics in Doppler Ultrasonography in Healthy Population Over 65 Years Old.

J Clin Med 2020 May 7;9(5). Epub 2020 May 7.

Department of General, Endocrine and Vascular Surgery, Medical University of Warsaw, Zwirki i Wigury 61 street, 02-091 Warsaw, Poland.

Background: Carotid flow velocity criteria are well established, with age being a factor influencing measurements. However, there are no volumetric standards for the flow in extracranial arteries. The aim of the study was related to volumetric flow assessment of extracranial arteries in a healthy population >65 years old.

Methods: Doppler volumetric measurements of internal carotid (ICA), external carotid (ECA) and vertebral arteries (VA) were performed in 123 healthy volunteers >65 years old and compared with 56 healthy volunteers <65 years old.

Results: The continuous decline in cerebral blood flow (CBF) volume was observed ( < 0.00001). Volumetric reference values were established in study groups: 1., 65-69 years: 898.5 ± 119.1; 2., 70-74 years: 838.5 ± 148.9; 3., 75-79 years: 805.1 ± 99.3; 4., >80 years: 685.7 ± 112.3 (mL/min). Significant differences were observed between groups: 1 and 3.4, as well as 3 and 4 ( = 0.0295, < 0.000001, 0.00446 respectively). CBF volume decreases gradually with age: 28-64 years-6.2 mL/year ( = 0.0019), 65-75 years-11.4 mL/year ( = 0.0121) and >75 years-14.3 mL/year ( = 0.0074). This is a consequence of flow volume decline in ICA ( = 0.00001) and to lesser extent ECA ( = 0.0011). The decrease of peak systolic ( = 0.002) and end diastolic ( = < 0.00001) velocities in ICA and peak systolic velocity in ECA ( = 0.0017) were observed.

Conclusions: CBF decreases with ageing. Volumetric assessment of CBF may play an important additional role in diagnostics of patients with carotid stenosis. Doppler assessment of cerebral flow volume may create an interesting tool for identifying patients with diminished cerebrovascular reserve and higher risk of ischemic symptoms occurrence.
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http://dx.doi.org/10.3390/jcm9051375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291321PMC
May 2020

Anti-CyHV-3 Effect of Fluorescent, Tricyclic Derivative of Acyclovir 6-(4-MeOPh)-TACV .

J Vet Res 2019 Dec 24;63(4):513-518. Epub 2019 Oct 24.

Institute of Ichthyobiology and Aquaculture, Polish Academy of Sciences, 43-520 Chybie, Poland.

Introduction: (CyHV-3) is a virus infecting carp with disease symptoms of gill necrosis, fish discoloration, sunken eyes, and mortality reaching 90%. Several research groups have examined how to potentially abate the consequences of viral activity. Recently we showed that acyclovir inhibits CyHV-3 replication and in the present study we examined the anti-CyHV-3 activity of the tricyclic derivative of acyclovir 6-(4-MeOPh)-TACV (T-ACV), a fluorescent molecule known for higher lipophilicity than acyclovir, and therefore potentially better candidate for application .

Material And Methods: CCB and KF1 cell lines were incubated with T-ACV at concentrations of 0, 66.67, and 133.33 μM for three days and toxicity examined with MTT and CV assays. To investigate the antiviral activity of T-ACV, the lines were infected with CyHV-3 or mock infected and incubated for three days with the drug at concentrations of 0 or 66.67 μM. The activity of T-ACV was evaluated by plaque assay and TaqMan qPCR.

Results: T-ACV at a concentration of 66.67 μM displayed low toxicity and inhibited CyHV-3 activity by 13-29%, varying by cell line and method.

Conclusion: The low anti-CyHV-3 activity of T-ACV indicates that it would be reasonable to screen several tricyclic derivatives of acyclovir for such activity.
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http://dx.doi.org/10.2478/jvetres-2019-0065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950444PMC
December 2019

Prevalence of obstructive sleep apnea in patients with peripheral arterial diseases.

Sleep Breath 2020 Sep 14;24(3):1035-1041. Epub 2019 Nov 14.

Department of Cardiology, Medical University of Warsaw, Warsaw, Poland.

Background: The presence of obstructive sleep apnea (OSA), a novel cardiovascular risk factor, contributes to the development of peripheral arterial diseases (PAD). There is a lack of data showing how often these diseases coexist.

Aims: The aim of the study was to determine the prevalence of OSA in the population of patients with PAD.

Methods: Patients previously qualified for the first revascularization due to PAD were included in the study. All patients underwent an overnight sleep study to detect OSA. Diagnosis of OSA was made when the apnea-hypopnea index (AHI) was ≥5 per hour.

Results: From 141 patients (60% men, age 69.6 ± 9.5 years), OSA was diagnosed in 68 patients (48%). OSA occurred in mild form (5 ≤ AHI < 15/h) in 39 cases (28%), in moderate form (15 ≤ AHI < 30/h) in 21 cases (15%), and in severe form (AHI ≥ 30/h) in 8 cases (6%). Patients without OSA had significantly lower body mass index (BMI; 26.9 ± 5.5 vs. 27.7 ± 5.3 kg/m, p = 0.01) and lower hip circumference (97.4 ± 11.7 vs. 98.7 ± 7.4, p = 0.04). There were no differences in the distribution of other investigated cardiovascular risk factors and diseases between these groups. There were no significant differences in OSA distribution or its severity between patients with lower extremity artery disease and carotid artery disease.

Conclusions: The prevalence of OSA in patients with PAD is very high, affecting nearly half of the studied population.
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http://dx.doi.org/10.1007/s11325-019-01950-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426286PMC
September 2020

Resection of liver metastases from differentiated thyroid cancer: who might benefit? A report of 2 cases with review of literature.

Pol Przegl Chir 2018 Nov;91(4):52-56

Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.

Background: Liver metastases of differentiated thyroid cancers (DTC) are uncommon. Surgery has proven to be effective in patients with 131I-negative hepatic lesions. Here, we present two patients who underwent liver resection for metastatic DTC.

Case Presentation: The first patient is a 36-year-old woman who reported with 70-mm hepatic metastases of papillary thyroid cancer. After primary treatment of cancer, she was disease-free for 8 years when the elevation of TSH levels resulted for the need to search for metastasis. Notably, the 131I SPECT did not show any lesions. The CT scan revealed an 80mm diameter mass in the liver. Histology confirmed metastasis of thyroid cancer. Lack of iodine uptake and the size of lesion excluded treatment with radioactive iodine. Radical resection of the metastasis was performed with good short- and long-term postoperative result. The second patient is a 65-year-old man previously treated for follicular thyroid cancer. When a iodine-negative 70mm diameter metastasis was detected within the liver, he was referred for surgery. Extended right hepatectomy was performed. In a 12-months follow-up, he remained stable, with no signs of recurrence.

Conclusions: These two cases show that resection of hepatic metastases of DTC is an option even in the case of large lesions. Given the effectiveness and safety of liver surgery, we reckon that it should be the treatment of choice when possible. The decision to perform surgical treatment should be based on analysis of the ability to perform radical and safe resection.
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http://dx.doi.org/10.5604/01.3001.0012.7391DOI Listing
November 2018

The impact of lifestyle upon the probability of late bacterial infection after soft-tissue filler augmentation.

Infect Drug Resist 2019 23;12:855-863. Epub 2019 Apr 23.

Department of Microbiology, Medical University of Warsaw, Warsaw, Poland.

Little is known about the influence of lifestyle-related factors upon the risk of late bacterial infection (LBI) emerging at the site of soft-tissue filler augmentation. The aim of this study was to analyze the impact of some such factors on the risk of LBI by comparing their respective prevalence between two groups of previously healthy women: a group in which infection occurred at a site of cross-linked hyaluronic acid (HA) augmentation and a second group which did not have such an infection. The infection group featured 25 women who developed LBI at a site of cross-linked HA augmentation; the control group featured 92 women who did not experience complications during a 24-month period of observation after the same procedure. Data was analyzed statistically using Chi-square tests and logistic regression. : The two groups did not differ significantly in terms of age. However, the frequency of antibiotic therapy, household pet ownership, occupation, hormone replacement therapy or contraception use, and attendance at a swimming pool, sauna, or gym attendance were found to vary with statistical significance, <0.05. Women in the control group practiced a more active lifestyle. Antibiotic therapy in the year preceding cross-linked HA augmentation was a factor which rendered a patient predisposed towards the development of LBI. Pet ownership was more prominent among women who did not suffer LBI than within the group in which soft tissue filler-related complications had occurred.
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http://dx.doi.org/10.2147/IDR.S200357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499440PMC
April 2019

Treatment of late bacterial infections resulting from soft-tissue filler injections.

Infect Drug Resist 2019 20;12:469-480. Epub 2019 Feb 20.

Department of Microbiology, Medical University of Warsaw, Warsaw, Poland,

Purpose: Late bacterial infections (LBIs) after esthetic facial augmentation using hyaluronic acid (HA) fillers are relatively rare yet severe complications that are difficult to treat. No adequate treatment standards have hitherto been formulated. We have bridged this gap by formulating a treatment scheme based on the principles of treating foreign-body implantation-related infections and treating bacterial growth in the form of biofilm. The objective of this study was to evaluate the efficacy of a comprehensive scheme for treating LBI complications after facial augmentation using cross-linked HA fillers.

Methods: A total of 22 patients with LBI symptoms at a site of cross-linked HA injection underwent treatment and observation. The comprehensive treatment scheme formulated by Marusza and Netsvyetayeva (M&N scheme) comprised draining the lesion, dissolution of cross-linked HA with hyaluronidase, broad-spectrum antibiotic combination therapy, and use of probiotics. While 17 patients underwent the M&N scheme, the remaining five were treated with other schemes. Statistical analysis of the data was performed using Mann-Whitney and χ nonparametric tests with SAS 9.4 software.

Results: All 17 patients who underwent the M&N scheme experienced resolution of symptoms, with no recurrence of infection at the HA-injection sites.

Conclusion: To treat LBI at a site of cross-linked HA administration, the principles applicable to infections resulting from implantation of a foreign body must be followed. The treatment period should be sufficiently long for complete resolution of symptoms. The efficacy of treatment is considered proven if 2 months have elapsed without recurrence since the symptoms resolved. The M&N scheme is recommended for use as the first therapeutic option for treating LBI related to soft-tissue fillers.
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http://dx.doi.org/10.2147/IDR.S186996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390860PMC
February 2019

Selective occlusion of splenic artery aneurysms with the coil packing technique: the impact of packing density on aneurysm reperfusion correlated between contrast-enhanced MR angiography and digital subtraction angiography.

Radiol Med 2019 Jun 2;124(6):450-459. Epub 2019 Feb 2.

2nd Department of Clinical Radiology, Medical University of Warsaw, Banacha 1a Street, 02-097, Warsaw, Poland.

Purpose: The aim was to evaluate the relationship between coil packing densities after splenic artery aneurysm (SAA) treatment using detachable microcoils and rates of SAA reperfusion and to suggest a post-treatment surveillance protocol using contrast-enhanced MRA.

Materials And Methods: Evaluated were 16 patients (4 men; mean age 46.7), who underwent true SAA embolization using detachable microcoils (Concerto, Medtronic). SAAs were treated by selective coil packing (CP) or stent-assisted coil exclusion (SAC). Contrast-enhanced magnetic resonance angiography (CE-MRA) and digital subtraction angiography (DSA) were performed at 3 months post-procedure and correlated.

Results: Primary CP was used in 13 patients, while SAC was used in three patients. On follow-up, complete aneurysm occlusion was seen in seven patients (43.8%). Sac reperfusion occurred in nine patients (56.2%) and was demonstrated in all CE-MRA and six DSA studies. Mean aneurysm packing density was 20.10 ± 8.05% for the CP group and 32.90 ± 11.95% for the SAC group (p = 0.038). There was a significant difference in the incidence of aneurysm sac reperfusion on CE-MRA study between CP and SAC (9 vs. 0). No sac reperfusion was seen in aneurysms with packing densities ≥ 29%, irrespective of either embolization method.

Conclusion: Favorable midterm results for coil packing of SAAs seem to depend on the coil packing density with a coil volume approximately a quarter of the aneurysm volume being most effective. Follow-up should involve the use of CE-MRA as this modality has been shown to be superior over DSA in detecting aneurysm reperfusion and coil compaction.

Level Of Evidence: Level IV, therapeutic study.
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http://dx.doi.org/10.1007/s11547-019-00993-2DOI Listing
June 2019

Acyclovir inhibits Cyprinid herpesvirus 3 multiplication in vitro.

J Fish Dis 2018 Nov 24;41(11):1709-1718. Epub 2018 Aug 24.

Institute of Ichthyobiology and Aquaculture, Polish Academy of Sciences, Chybie, Poland.

Cyprinid herpesvirus 3 (CyHV-3), also known as koi herpesvirus (KHV), is an aetiological agent of a virulent and lethal disease in common and koi carp. In this study, we examined in vitro the anti-CyHV-3 activity of acyclovir (ACV), nucleoside analogue commonly used against human herpesviruses, as well as acyclovir monophospate (ACV-MP). The cytotoxicity of the ACV and the ACV-MP for two common carp cell lines, CCB (Common carp brain) and KF1 (Koi carp fin 1), was determined by means of MTT and crystal violet assays. In subsequent studies, the concentration of 66.67 μM was applied. The ACV and the ACV-MP (66.67 μM) inhibited a cytopathic effect (CPE) induced by the CyHV-3 virus in the CCB (ACV by 66%, ACV-MP by 58%) and the KF1 (ACV by 25%, ACV-MP by 37%). The viral load measured by the means of TaqMan qPCR was reduced in a range of 67%-93% depending on the analogue, the cell line and the time of incubation. The expression of viral genes (ORF149, ORF3, ORF134 and ORF78) in CCB cells infected with the CyHV-3 was strongly downregulated within the range of 78%-91%. In summary, both the ACV and the ACV-MP can inhibit CyHV-3 replication in vitro.
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http://dx.doi.org/10.1111/jfd.12880DOI Listing
November 2018

Treatment Algorithm of Peripancreatic Arteries Aneurysm Coexisting with Coeliac Artery Lesion: Single Institution Experience.

Biomed Res Int 2018 18;2018:5745271. Epub 2018 Jul 18.

2nd Department of Radiology, Medical University of Warsaw, Banacha 1a st., 02-097 Warsaw, Poland.

Introduction: True aneurysms of peripancreatic arterial arcades (PAAAs) coexisting with celiac axis lesion are often asymptomatic. However, they may rupture regardless of their size and cause life-threatening hypovolemia. No treatment guidelines exist to date. We present a series of 21 patients and our management algorithm.

Material And Methods: For ruptured aneurysms we preformed endovascular embolization. Further treatment was dependent on patient's condition and control studies. In case of unruptured aneurysms, we assessed collateral circulation between superior mesenteric artery and celiac axis in angio-CT. If there was a pathway free from aneurysms, endovascular approach was chosen. Otherwise, surgical or combined treatment was favored.

Results: Endovascular treatment was performed in 14 patients with no complications. Follow-up studies revealed incomplete occlusion of the aneurysms in two cases. Surgical or combined treatment was performed in 7 patients with three serious perioperative complications. They were managed conservatively in two cases and surgically in one. Follow-up studies showed aneurismal dilatation and stenosis of a renohepatic by-pass in one case.

Conclusion: We present our management algorithm of PAAAs. Our results support the leading role of endovascular treatment. We present its limitations favoring surgical or combined treatment. All patients should be carefully followed.
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http://dx.doi.org/10.1155/2018/5745271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077597PMC
December 2018

Long-term results of endovascular treatment for May-Thurner syndrome.

Kardiol Pol 2017 ;75(8):815

Department of General and Endocrine Surgery, Medical University of Warsaw, Warsaw, Poland, Poland.

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http://dx.doi.org/10.5603/KP.2017.0158DOI Listing
December 2017

Peripheral ARtery Atherosclerotic DIsease and SlEep disordered breathing (PARADISE) trial - protocol for an observational cohort study.

Kardiol Pol 2017 17;75(12):1332-1338. Epub 2017 Jul 17.

I Katedra i Klinika Kardiologii, Warszawski Uniwersytet Medyczny..

Background: Peripheral arterial disease (PAD) is in fact a group of disease entities with different symptoms and course but a common underlying cause, i.e. atherosclerosis. Atherosclerosis is known to be aggravated by several cardiovascular risk factors, including obstructive sleep apnoea (OSA).

Aim: Following paper is a protocol for the Peripheral ARtery Atherosclerotic DIsease and SlEep disordered breathing (PARADISE) trial, which aims to describe the prevalence of OSA in PAD patients scheduled for revascularisation, and to determine the effect of OSA on the procedure outcomes.

Methods: The PARADISE study is an observational cohort trial. It plans to include 200 consecutive patients hospitalised for revascularisation due to PAD. In every patient an overnight sleep study will be performed to diagnose sleep disorders. Accord¬ing to the results of the test, patients will be divided into two groups: group A - patients with OSA, and group B - patients without OSA (control group). All patients will also be screened for classical and non-classical cardiovascular risk factors. In some of the patients, during surgery, a fragment of atherosclerotic plaque will be collected for further testing. Patients will be followed for one year for adverse events and end-points. Primary end-point of the study will be the failure of revascularisa¬tion defined as recurrence or new onset of the symptoms of ischaemia from the treated region, a need for re-operation or procedure revision, or recurrence of ischaemia signs on the imaging tests.

Discussion: The data obtained will help determine the incidence of OSA in the population of patients with PAD. The au¬thors expect to show that, as with other cardiovascular diseases associated with atherosclerosis, also in patients with PAD the incidence of undiagnosed OSA is high and its presence is associated with elevated cholesterol, inflammatory markers, and higher prevalence of arterial hypertension and poor control of other cardiovascular risk factors. In addition, due to increased oxidative stress and vascular endothelial injury associated with OSA, patients afflicted with this condition will not only have more advanced atherosclerotic lesions, but also in their histopathological examination their atherosclerotic plaque will exhibit evidence of greater instability and adverse morphology. We also expect to show that in patients with OSA, achieving cor¬rect control of cardiovascular risk factors will be more difficult. The study may improve PAD control through assuring better multispecialty care in PAD patients.
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http://dx.doi.org/10.5603/KP.a2017.0150DOI Listing
January 2018

A hybrid treatment of Kommerell diverticulum saccular aneurysm in a patient with subclavian steal syndrome.

Kardiol Pol 2017 ;75(7):725

Department of General and Endocrine Surgery, Medical University of Warsaw, Warsaw, Poland, Poland.

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http://dx.doi.org/10.5603/KP.2017.0131DOI Listing
January 2018

2-Aryl-8-aza-3-deazaadenosine analogues of 5'-O-[N-(salicyl)sulfamoyl]adenosine: Nucleoside antibiotics that block siderophore biosynthesis in Mycobacterium tuberculosis.

Bioorg Med Chem 2016 07 20;24(14):3133-43. Epub 2016 May 20.

Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:

A series of 5'-O-[N-(salicyl)sulfamoyl]-2-aryl-8-aza-3-deazaadenosines were designed to block mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) through inhibition of the essential adenylating enzyme MbtA. The synthesis of the 2-aryl-8-aza-3-deazaadenosine nucleosides featured sequential copper-free palladium-catalyzed Sonogashira coupling of a precursor 4-cyano-5-iodo-1,2,3-triazolonucleoside with terminal alkynes and a Minakawa-Matsuda annulation reaction. These modified nucleosides were shown to inhibit MbtA with apparent Ki values ranging from 6.1 to 25nM and to inhibit Mtb growth under iron-deficient conditions with minimum inhibitory concentrations ranging from 12.5 to >50μM.
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http://dx.doi.org/10.1016/j.bmc.2016.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914392PMC
July 2016

HPLC and HPLC/MS/MS Studies on Stress, Accelerated and Intermediate Degradation Tests of Antivirally Active Tricyclic Analog of Acyclovir.

J AOAC Int 2015 Sep-Oct;98(5):1240-7

The degradation behavior of a tricyclic analog of acyclovir [6-(4-MeOPh)-TACV] was determined in accordance with International Conference on Harmonization guidelines for good clinical practice under different stress conditions (neutral hydrolysis, strong acid/base degradation, oxidative decomposition, photodegradation, and thermal degradation). Accelerated [40±2°C/75%±5% relative humidity (RH)] and intermediate (30±2°C/65%±5% RH) stability tests were also performed. For observation of the degradation of the tested compound the RP-HPLC was used, whereas for the analysis of its degradation products HPLC/MS/MS was used. Degradation of the tested substance allowed its classification as unstable in neutral environment, acidic/alkaline medium, and in the presence of oxidizing agent. The tested compound was also light sensitive and was classified as photolabile both in solution and in the solid phase. However, the observed photodegradation in the solid phase was at a much lower level than in the case of photodegradation in solution. The study showed that both air temperature and RH had no significant effect on the stability of the tested substance during storage for 1 month at 100°C (dry heat) as well as during accelerated and intermediate tests. Based on the HPLC/MS/MS analysis, it can be concluded that acyclovir was formed as a degradation product of 6-(4-MeOPh)-TACV.
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http://dx.doi.org/10.5740/jaoacint.15-014DOI Listing
December 2015

Bioactive nucleoside analogues possessing selected five-membered azaheterocyclic bases.

Eur J Med Chem 2015 Jun 3;97:409-18. Epub 2014 Dec 3.

Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland. Electronic address:

This review summarizes briefly literature reports on nucleoside analogues containing five-membered aglycones based on imidazole-4-carboxamide, 1,2,4-triazole-3-carboxamide or 1,2,3-triazole-4-carboxamide structural motifs, which exhibit diverse therapeutically useful or promising biological properties. We do not describe synthetic approaches but try to present the essential activities of compounds and their established or postulated mechanisms of action.
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http://dx.doi.org/10.1016/j.ejmech.2014.11.057DOI Listing
June 2015

Ester groups as carriers of antivirally active tricyclic analogue of acyclovir in prodrugs designing: synthesis, lipophilicity--comparative statistical study of the chromatographic and theoretical methods, validation of the HPLC method.

Comb Chem High Throughput Screen 2014 ;17(7):639-50

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Poznan University of Medical Sciences, 6 Grunwaldzka Str., 60-780 Poznan, Poland.

Knowledge of the lipophilicity of candidate compounds for prodrugs may predict their predetermined course/effect in the body. Acyclovir (ACV) belongs to a class of drugs with low bioavailability. Its tricyclic analogues, the derivatives of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-5H-imidazo[1,2-a]purine (TACV) exhibit similar antiviral activities and are more lipophilic as compared with acyclovir itself. In the search for new antiviral prodrugs 6-(4- methoxyphenyl) tricyclic compound (6-(4-MeOPh)-TACV) was modified by esterification of a hydroxyl group in the aliphatic chain. Selected esters (acetyl, isobutyryl, pivaloyl, ethoxycarbonyl and nicotinoyl) were synthesized and their lipophilicity was determined by the HPLC-RP method. The study compared the log kw calculated from the linear and quadratic equations and proved the correctness of the application of the linear relationship log k as a function of the concentration of ACN in the mobile phase (30-60%). Statistical analyses of the comparative values of log kw and clogP were carried out using computational methods. It was proved that the AC logP algorithm can be useful for the analysis of these compounds, which can have a statistically justified application in the assessment of the quantitative structure- activity relationship (QSAR). The lipophilicity determined by the HPLC method appears as follows: 6-(4-MeOPh)-TACV < Ac- < Nic- < Etc- < iBut- < Piv- (log kw = 0.65-2.26). Finally, the HPLC-RP method was developed and validated for simultaneous determination of synthesized esters.
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http://dx.doi.org/10.2174/1386207317666140526100532DOI Listing
April 2015

Antivirally active ribavirin analogues--4,5-disubstituted 1,2,3-triazole nucleosides: biological evaluation against certain respiratory viruses and computational modelling.

Antivir Chem Chemother 2014 Jan 29;23(4):161-71. Epub 2014 Jan 29.

Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.

Background: Ribavirin is a broad-spectrum antiviral agent that derives some of its activity from inhibition of cellular inosine monophosphate dehydrogenase (IMPDH), resulting in lower guanosine triphosphate (GTP) levels. Here we report the biological activities of three ribavirin analogues.

Methods: Antiviral activities of test compounds were performed by in vitro cytopathic effect inhibition assays against influenza A (H1N1, H3N2 and H5N1), influenza B, measles, parainfluenza type 3 (PIV-3) and respiratory syncytial viruses. Compounds were modelled into the ribavirin 5'-monophosphate binding site of the crystallographic structure of the human type II IMPDH (hIMPDH2) ternary complex. Effects of compounds on intracellular GTP levels were performed by strong anion exchange HPLC analysis.

Results: Of the three compounds evaluated, the 5-ethynyl nucleoside (ETCAR) exhibited virus-inhibitory activities (at 1.2-20 μM, depending upon the virus) against most of the viruses, except for weak activity against PIV-3 (62 μM). Antiviral activity of ETCAR was similar to ribavirin; however, cytotoxicity of ETCAR was greater than ribavirin. Replacing the 5-ethynyl group with a 5-propynyl or bromo substituent (BrCAR) considerably reduced antiviral activity. Computational studies of ternary complexes of hIMPDH2 enzyme with 5'-monophosphates of the compounds helped rationalize the observed differences in biological activity. All compounds suppressed GTP levels in cells; additionally, BrCAR suppressed adenosine triphosphate and elevated uridine triphosphate levels.

Conclusions: Three compounds related to ribavirin inhibited IMPDH and had weak to moderate antiviral activity. Cytotoxicity adversely affected the antiviral selectivity of ETCAR. As with ribavirin, reduction in intracellular GTP may play a role in virus inhibition.
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http://dx.doi.org/10.3851/IMP2564DOI Listing
January 2014

5-Ethynyl-1-β-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide (ETCAR) and its analogues: synthesis and cytotoxic properties.

Bioorg Med Chem 2011 Jul 30;19(14):4386-98. Epub 2011 May 30.

Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.

Efficient Pd(0)-catalysed synthesis of 5-alkynyl-1-β-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide depends on the presence of different protecting groups of the ribose moiety. Peracetylated 5-iodo substrate (15) couples with terminal alkynes or trimethyl-[(tributylstannyl)ethynyl]silane in 50-71% and 72% yield (ETCAR), respectively, although its hydrodehalogenation to 19 is noticeable. On the other hand, hydrodehalogenation of acetonide (16) predominates over coupling with terminal alkyne and slightly decreases a yield of cross-coupling reaction with trimethyl[(tributylstannyl)ethynyl]silane. Alternative conditions of reaction with terminal alkynes, to exclude so far identified hydride sources to produce hydridopalladium species, have been established for acetonide 16 and allowed to achieve 72% of coupling. Fluoromethyl derivative (42) was prepared from its 5-hydroxymethyl precursor by fluorination with DAST. Additionally, X-ray structural analysis of 42 was performed. All 1,2,3-triazolonucleosides and two synthesized cycloSal-pronucleotides were evaluated for cytotoxic activity against K562, HeLa and HUVEC cells.
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http://dx.doi.org/10.1016/j.bmc.2011.05.050DOI Listing
July 2011

Life Threatening Complication during Treatment of Erysipelas due to Undiagnosed Ischemia of the Calf.

Case Rep Med 2009 21;2009:306969. Epub 2009 Dec 21.

Department of General and Thoracic Surgery, Medical University of Warsaw, St. Banacha 1a, 02-097 Warsaw, Poland.

Erysipelas is a superficial skin infection due to streptococci strains, which usually responds well to conservative treatment. Coexisting undiagnosed ischemia of the extremity may lead to severe complications. 57-year-old man developed large, circumflex ulceration of his right calf within two weeks before the admission after three-month treatment of erysipelas. Computer angiography showed chronic occlusion of the superficial femoral artery and the above knee popliteal artery. Rapid debridement of the wound took control over the infection. Patient required complex vascular procedure which allowed to prepare the ulcer for meshed skin grafts. Patient was discharged home on 64th hospital day with completely healed ulcer.
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http://dx.doi.org/10.1155/2009/306969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797375PMC
July 2011

Synthesis and anti-VZV activity of 6-heteroaryl derivatives of tricyclic acyclovir and 9-{[cis-1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl}guanine analogues.

Eur J Med Chem 2009 Aug 21;44(8):3313-7. Epub 2009 Mar 21.

Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.

A series of tricyclic analogues of acyclovir and 9-{[cis-1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl}guanine substituted in the 6 position with thien-2-yl, 5-bromothien-2-yl or furan-2-yl group were synthesized. The new compounds 5a-f were evaluated for their activity in vitro against varicella-zoster virus (VZV) and cytomegalovirus (CMV). The marked anti-VZV activities of 5a-f remained comparable to those of their previously described 6-phenyl-substituted counterparts.
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http://dx.doi.org/10.1016/j.ejmech.2009.03.005DOI Listing
August 2009

Synthesis of 5-ethynyl-1-beta-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide (isosteric to EICAR) and its derivatives.

Nucleic Acids Symp Ser (Oxf) 2008 (52):585-6

Institute of Bioorganic Chemistry, Polish Academy of Sciences, PL-61704 Poznan, Poland.

The synthesis of 5-ethynyl-1H-[1,2,3]triazole-4-carboxylic acid amide riboside 1 and its derivatives exploits Pd(0)-catalyzed cross-coupling reactions. The iodinated key intermediate 3a, when coupled with alkynes affords 5-alkynylated products 1b,c,e,f in diverse yields. Methanolysis of 1b and 1c provides the title compound 1 and the 5-propynyl derivative 1d, respectively. When coupled with methyl acrylate, 3a gives the E-isomer 4c, although in low yield, while the other 5-iodo precursor 3b undergoes reduction to 4b.
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http://dx.doi.org/10.1093/nass/nrn296DOI Listing
November 2010

Aminoacyl-tRNA synthetase inhibitors as potent and synergistic immunosuppressants.

J Med Chem 2008 May 26;51(10):3020-9. Epub 2008 Apr 26.

Laboratory for Medicinal Chemistry, Rega Institute for Medical Research, Catholic University of Leuven, Leuven, Belgium.

The aminoacyl-tRNA synthetase family of enzymes is the target of many antibacterials and inhibitors of eukaryotic hyperproliferation. In screening analogues of 5'-O-(N-L-aminoacyl)-sulfamoyladenosine containing all 20 proteinogenic amino acids, we found these compounds to have potent immunosuppressive activity. Also, we found that combinations of these compounds inhibited the immune response synergistically. Based on these data, analogues with modifications at the aminoacyl and ribose moieties were designed and evaluated, and several of these showed high immunosuppressive potency, with one compound having an IC50 of 80 nM, when tested in a cellular mixed lymphocyte reaction assay. Apart from showing the potential of aminoacyl-tRNA synthetase inhibitors as immunosuppressants, the current study also provides arguments for careful evaluation of the immunosuppressive activity of developmental antibacterials that target these enzymes.
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http://dx.doi.org/10.1021/jm8000746DOI Listing
May 2008

Tricyclic nucleoside analogues as antiherpes agents.

Antiviral Res 2006 Sep 30;71(2-3):134-40. Epub 2006 May 30.

Institute of Bioorganic Chemistry, Polish Academy of Sciences, ul. Noskowskiego 12/14,61-704 Poznan, Poland.

Tricyclic (T) guanine analogues are a class of compounds in which the N1 and N(2) atoms of the guanine system are linked by etheno bridge to form the 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine system. Almost 70 tricyclic derivatives of guanine-type potent antiherpetic agents acyclovir (ACV), ganciclovir (GCV) and 9-{[cis-1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl}guanine were synthesized and evaluated for activity against viruses of the herpes family. Here, we review the most successful compounds in terms of their antiviral activity and physico-chemical properties. These features are modulated by the kind and position of additional substituents present in the appended third ring of aglycone. The best antiherpetic activity-fluorescence combinations as well as activity of compounds in comparison to parent congeners are summarized. The data presented indicate that compounds of the 6-(4-RPh) family are of particular importance because of their advantageous antiviral potency, increased lipophilicity and good or moderate fluorescence properties.
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http://dx.doi.org/10.1016/j.antiviral.2006.05.004DOI Listing
September 2006

Synthesis and biological activity of tricyclic analogues of 9-[[cis-1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine.

Bioorg Med Chem 2006 May 2;14(10):3535-42. Epub 2006 Feb 2.

Institute of Bioorganic Chemistry, Polish Academy of Sciences, ul. Noskowskiego 12/14, 61-704 Poznan, Poland.

The base moiety of the potent antiherpetic agent 9-[[cis-1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine 3 was transformed into that of the tricyclic 3,9-dihydro-9-oxo-6-R-5H-imidazo[1,2-a]purine system. The tricyclic analogues 5a-d were evaluated for their activity against herpes viruses as well as for cytostatic activity against HSV-1 thymidine kinase (TK) gene-transduced human osteosarcoma tumor cells. Marked activity was found against VZV. The 6-phenyl-substituted fluorescent analogues 5c and d were comparable to that of parent 3 in activity against the VZV strain YS and were 3-fold less active against the VZV strain OKA. The compounds 5a-d also showed marked activity against HSV-1 (KOS) and HSV-2 (G)-against the former generally approximately comparable to that of acyclovir 1a and one order of magnitude lower than 3; against the latter comparable to that of 1a and approximately 6- to 30-fold lower than that of 3. The most pronounced cytostatic activity (5-fold lower than that of 3) was exhibited by compounds 5c and d. Tricyclic analogues with pseudosugar moieties are intrinsically bio-active.
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http://dx.doi.org/10.1016/j.bmc.2006.01.014DOI Listing
May 2006

Fluorosubstitution and 7-alkylation as prospective modifications of biologically active 6-aryl derivatives of tricyclic acyclovir and ganciclovir analogues.

Bioorg Med Chem 2005 Mar;13(6):2089-96

Institute of Bioorganic Chemistry, Polish Academy of Sciences, ul.Noskowskiego 12/14, 61-704 Poznan, Poland.

A series of fluorine containing tricyclic analogues of acyclovir (ACV, 1) and ganciclovir (GCV, 2) were synthesized and evaluated for their activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and cytostatic activity against HSV-1 thymidine kinase (TK) gene-transduced human osteosarcoma tumour cells. It was found that fluorine substitution reduced the antiviral activity, but most of the new compounds were pronounced cytostatic agents with potency and selectivity similar to those of parental ACV and GCV. Compounds 12, 13 and 16 seem to be promising as labeled substrates for (19)F NMR studies of the HSV TK-ligand interaction and/or monitoring of their metabolites in cells expressing HSV TK.
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http://dx.doi.org/10.1016/j.bmc.2005.01.004DOI Listing
March 2005

[Quality of life of patients suffering from osteoporosis treated with alendronate and salmon calcitonin].

Wiad Lek 2002 ;55 Suppl 1:444-7

Zakładu Zarzadzania i Ekonomiki Ochrony Zdrowia Akademii Medycznej w Lublinie.

Osteoporosis is a disease of skeletal system characterized by low bone mass, disturbed bone tissue microarchitecture which lead to high risk fractures. Pharmacological treatment of patients suffering from osteoporosis is long-term. Anti reabsorption drugs as alendronate and nasal salmon calcitonin have antifracture effect confirmed in accordance with Evidence Based Medicine but they differ in administration, tolerance, side effects which result in patients' quality of life. The study comparing influence of treatment on quality of life was carried out on the group of 78 women who were patients of Medical Rehabilitation Ward and outpatient clinic of John Paul II Hospital in Zamość. All patients underwent densitometry (DEXA) which confirmed osteoporosis (BMD: T-score < -2.5 SD). Patients' age ranged from 52 to 73. 46 women were treated with nasal calcitonin and 32 with alendronate. The observation lasted 6 months. Questionnaire was used in the study. Comfort and quality of life were evaluated in the study (comfort of administration, painkilling effect, necessity of additional painkillers and drug tolerance. We also studied which of the drugs better improved patients' life activity. Apart from pharmacotherapy patients were also treated with kinesitherapy, physical activity and with 1000 mg Calcium and 400 u. Vit. D. We used test chi 2 in the study. We stated (p < 0.001) better quality of life in those patients who used nasal salmon calcitonin. It is very important when we take into consideration that patients suffering from osteoporosis should be treated till the end of life. Osteoporosis treatment should be joint therapy including prevention, rehabilitation and pharmacology.
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May 2004
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