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1.
Trials ; 22(1): 127, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33568226

RESUMEN

OBJECTIVES: The objective of the study is to measure the efficacy of ionic-iodine polymer complex [1] for clinical and radiological improvement in coronavirus disease 2019 (COVID-19) patients. TRIAL DESIGN: The trial will be closed label, randomized and placebo-controlled with a 1:1:1:1 allocation ratio and superiority framework. PARTICIPANTS: All PCR confirmed COVID-19 adult patients including non-pregnant females, with mild to moderate disease, will be enrolled from Shaikh Zayed Post-Graduate Medical Complex, Ali Clinic and Doctors Lounge in Lahore (Pakistan). Patients with any pre-existing chronic illness will be excluded from the study. INTERVENTION AND COMPARATOR: In this multi-armed study ionic-iodine polymer complex with 200 mg of elemental iodine will be given using three formulations to evaluate efficacy. Patients will be receiving either encapsulated iodine complex of 200 mg (arm A), iodine complex syrup form 40 ml (arm B), iodine complex throat spray of 2 puffs (arm C) or empty capsule (arm D) as placebo; all three times a day. All the 4 arms will be receiving standard care as per version 3.0 of the clinical management guidelines for COVID-19 established by the Ministry of National Health Services of Pakistan. MAIN OUTCOMES: Primary outcomes will be viral clearance with radiological and clinical improvement. SARS-CoV-2 RT-PCR and HRCT chest scans will be done on the admission day and then after every fourth day for 12 days or till the symptoms are resolved. RT-PCR will only be shown as positive or negative while HRCT chest scoring will be done depending on the area and severity of lung involvement [2]. Time taken for the alleviation of symptoms will be calculated by the number of days the patient remained symptomatic. 30-day mortality will be considered as a secondary outcome. RANDOMISATION: Stratification for initial COVID-19 status (or days from initial symptoms as a proxy), age groups, gender, baseline severity of symptoms and co-morbidities will be used to ensure that the study arms remain balanced in size for the 1:1:1:1 allocation ratio. Randomization will be done using the lottery method. As patients are being admitted at different times, they will be recruited after obtaining their voluntary written informed consent following all standard protocols of the infection, control and disinfection. BLINDING (MASKING): This is a quadruple (participants, care providers, investigators and outcomes assessors) blinded study where only the study's Primary Investigator will have information about the arms and their interventions. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 200 patients will be randomized into four groups with three experimental and one placebo arm. TRIAL STATUS: Protocol Version Number is 2.3 and it is approved from IRB Shaikh Zayed Hospital with ID SZMC/IRB/Internal0056/2020 on July 14th, 2020. The recruitment is in progress. It was started on July 30, 2020, and the estimated end date for the trial is August 15, 2021. TRIAL REGISTRATION: Clinical Trial has been retrospectively registered on www.clinicaltrials.gov with registration ID NCT04473261 dated July 16, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). With the intention of expediting dissemination of this trial, the conventional formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.


Asunto(s)
/tratamiento farmacológico , Compuestos de Yodo/administración & dosificación , Polímeros/administración & dosificación , Índice de Severidad de la Enfermedad , Adulto , /mortalidad , Cápsulas , Femenino , Humanos , Masculino , Vaporizadores Orales , Pakistán/epidemiología , Admisión del Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Resultado del Tratamiento
2.
Acta Trop ; 216: 105828, 2021 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-33465353

RESUMEN

Malaria is the world's deadliest parasitic disease. Great progress has been made in the fight against malaria over the past two decades, but this has recently begun to plateau, in part due to the global development of antimalarial drug resistance. The ability to track drug resistance is necessary to achieve progress in treatment, disease surveillance and epidemiology, which has prompted the development of advanced diagnostic methods. These new methods provide unprecedented access to information that can help to guide public health policies. Development of new technologies increases the potential for high throughput and reduced costs of diagnostic tests; improving the accessibility of tools to investigate the forces driving disease dynamics and, ultimately, clinical outcomes for malaria patients and public health. This literature review provides a summary of the methods currently available for the detection of antimalarial drug resistance from the examination of patients' blood samples. While no single method is perfect for every application, many of the newly developed methods give promise for more reliable and efficient characterisation of Plasmodium resistance in a range of settings. By exploiting the strengths of the tools available, we can develop a deeper understanding of the evolutionary and spatiotemporal dynamics of this disease. This will translate into more effective disease control, better-informed policy, and more timely and successful treatment for malaria patients.

3.
Emerg Microbes Infect ; 9(1): 2222-2235, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32967592

RESUMEN

Coronaviruses (CoVs) are enveloped, positive sense, single-stranded RNA viruses. The viruses have adapted to infect a large number of animal species, ranging from bats to camels. At present, seven CoVs infect humans, of which Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is responsible for causing the Coronavirus Disease 2019 (COVID-19) in humans. Since its emergence in late 2019, SARS-CoV-2 has spread rapidly across the globe. Healthcare systems around the globe have been stretched beyond their limits posing new challenges to emergency healthcare services and critical care. The outbreak continues to jeopardize human health, social life and economy. All known human CoVs have zoonotic origins. Recent detection of SARS-CoV-2 in pet, zoo and certain farm animals has highlighted its potential for reverse zoonosis. This scenario is particularly alarming, since these animals could be potential reservoirs for secondary zoonotic infections. In this article, we highlight interspecies SARS-CoV-2 infections and focus on the reverse zoonotic potential of this virus. We also emphasize the importance of potential secondary zoonotic events and the One-Health and One-World approach to tackle such future pandemics.


Asunto(s)
Infecciones por Coronavirus/virología , Neumonía Viral/virología , Zoonosis/virología , Animales , Betacoronavirus/fisiología , Camelus/virología , Quirópteros/virología , Infecciones por Coronavirus/epidemiología , Salud Global , Humanos , Pandemias , Neumonía Viral/epidemiología , Zoonosis/epidemiología , Zoonosis/transmisión
4.
Expert Rev Cardiovasc Ther ; : 1-6, 2020 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-32842817

RESUMEN

INTRODUCTION: The novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory system-coronavirus-2 (SARS-CoV-2), is an important medical problem worldwide. Increased risk of mortality has been reported in patients with cardiovascular disease, such as hypertension (HTN). SARS-CoV-2 invades the pulmonary alveolar epithelial cells by binding to the surface receptor, angiotensin-converting enzyme 2 (ACE2). Renin-angiotensin system (RAS) modulators can increase levels of ACE2. Thus, concerns have been raised regarding an increased risk of severe COVID-19 infection in patients receiving RAS antagonists. AREAS COVERED: We reviewed current literature about the potential association between the utilization of RAS inhibitors, namely angiotensin-converting enzyme inhibitors (ACE-inhibitors) and angiotensin-receptor blockers (ARBs) and likelihood of developing severe COVID-19 infection and whether or not continuation of these medications is appropriate in patients with active disease. EXPERT OPINION: The joint statement from the American College of Cardiology (ACC), American Heart Association (AHA), European Society of Cardiology (ESC) and Heart Failure Society of America (HFSA), strongly recommends that physicians should not initiate or withdraw their usual RAS-related treatments (ACE-inhibitor/ARB) to COVID-19 infected patients with cardiovascular disease. The decision should be made based upon each patient's clinical presentation and hemodynamic status.

5.
Photodiagnosis Photodyn Ther ; 30: 101693, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32173586

RESUMEN

The global emergence of carbapenemases in bacterial pathogens has rendered many life-threatening infections untreatable. Even though using carbapenemase inhibitors are a proven strategy in the battle against bacterial carbapenem resistance, developing inhibitors that could universally inactivate all bacterial carbapenemases is extremely challenging given the large diversity and the continuous evolution of bacterial carbapenemases. Antimicrobial photodynamic therapy (aPDT), an upcoming antimicrobial therapy, is demonstrated here for the first time to be a generalized approach to impair the bacterial carbapenemases without being limited by the molecular identities of the carbapenemases. In addition, aPDT is shown to prevent carbapenem antibiotic degradation, thereby enhancing the efficacy of carbapenem antibiotic against the carbapenemase-producing pathogens. Besides the enzyme activity impairment, aPDT was documented here to be genetically toxic for bacteria, and thus radically damage the carbapenemase genetic determinants in bacteria and prevent the transmission of carbapenemases among pathogens. By leveraging the universal carbapenemase-inactivating property of aPDT, it may be possible to make the incurable infections caused by the bacterial carbapenemases susceptible to carbapenem again.

6.
Emerg Infect Dis ; 26(4): 793-795, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32186503

RESUMEN

We developed a carbapenemase test based on the ability of imipenem to inhibit noncarbapenemase ß-lactamases. The test uses bacterial isolates with a fluorescent ß-lactamase substrate, producing objective results with 100% sensitivity and specificity in 10 minutes. The assay is inexpensive and consists of only 1 mixing step.

7.
Parasitology ; 146(4): 425-437, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30392477

RESUMEN

Control of equine nematodes has relied on benzimidazoles (BZs), tetrahydropyrimidines and macrocyclic lactones. The intensive use of anthelmintics has led to the development of anthelmintic resistance (AR) in equine cyathostomins and Parascaris equorum. Field studies indicate that BZ and pyrantel resistance is widespread in cyathostomins and there are also increasing reports of resistance to macrocyclic lactones in cyathostomins and P. equorum. The unavailability of reliable laboratory-based techniques for detecting resistance further augments the problem of nematode control in horses. The only reliable test used in horses is the fecal egg count reduction test; therefore, more focus should be given to develop and validate improved methodologies for diagnosing AR at an early stage, as well as determining the mechanisms involved in resistance development. Therefore, equine industry and researchers should devise and implement new strategies for equine worm control, such as the use of bioactive pastures or novel feed additives, and control should increasingly incorporate alternative and evidence-based parasite control strategies to limit the development of AR. This review describes the history and prevalence of AR in equine nematodes, along with recent advances in developing resistance diagnostic tests and worm control strategies in horses, as well as giving some perspective on recent research into novel control strategies.


Asunto(s)
Antihelmínticos/farmacología , Resistencia a Medicamentos , Enfermedades Gastrointestinales/veterinaria , Enfermedades de los Caballos , Nematodos/efectos de los fármacos , Infecciones por Nematodos/veterinaria , Animales , Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades de los Caballos/diagnóstico , Enfermedades de los Caballos/tratamiento farmacológico , Caballos , Infecciones por Nematodos/diagnóstico , Infecciones por Nematodos/tratamiento farmacológico
8.
Artículo en Inglés | MEDLINE | ID: mdl-29468054

RESUMEN

Background: Ivermectin is an endectocide against many parasites. Though being a macrocyclic lactone, its activity against bacteria has been less known, possibly due to the fact that micromolar concentrations at tissue levels are required to achieve a therapeutic effect. Among pathogenic bacteria of major medical significance, Staphylococcus aureus cause a number of diseases in a wide variety of hosts including humans and animals. It has been attributed as one of the most pathogenic organisms. The emergence of methicillin resistance has made the treatment of S. aureus even more difficult as it is now resistant to most of the available antibiotics. Thus, search for alternate anti-staphylococcal agents requires immediate attention. Methods: Twenty-one clinical isolates of S. aureus were isolated from bovine milk collected from Lahore and Faisalabad Pakistan. Different anthelmintics including levamisole, albendazole and ivermectin were tested against S. aureus to determine their minimum inhibitory concentrations. This was followed-up by growth curve analysis, spot assay and time-kill kinetics. Results: The results showed that ivermectin but not levamisole or albendazole exhibited a potent anti-staphylococcal activity at the concentrations of 6.25 and 12.5 µg/ml against two isolates. Interestingly, one of the isolate was sensitive while the other was resistant to methicillin/cefoxitin. Conclusions: Our novel findings indicate that ivermectin has an anti-bacterial effect against certain S. aureus isolates. However, to comprehend why ivermectin did not inhibit the growth of all Staphylococci needs further investigation. Nevertheless, we have extended the broad range of known pharmacological effects of ivermectin. As pharmacology and toxicology of ivermectin are well known, its further development as an anti-staphylococcal agent is potentially appealing.


Asunto(s)
Ivermectina/farmacología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación , Animales , Antihelmínticos/farmacología , Antibacterianos/farmacología , Bovinos , Cefoxitina/farmacología , Humanos , Cinética , Meticilina/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Leche/microbiología , Pakistán , Staphylococcus aureus/crecimiento & desarrollo
9.
Sci Rep ; 7: 40608, 2017 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-28102235

RESUMEN

Staphylococcus aureus is one of major pathogens that can cause a series of diseases in different hosts. In the bovine, it mainly causes subclinical and contagious mastitis, but its mechanisms of infection are not fully understood. Considering the fact that virulence factors play key roles in interactions between the bacterium and host cells, this study aimed to identify if a binding partner of S. aureus clumping factor A (ClfA) exists on the bovine mammary epithelial cells. The ClfA protein was used as a bait to pull down lysates of cultured bovine mammary epithelial cells (MAC-T cells). One pull-down protein was identified through use of mass spectrometry and bioinformatics analyses as bovine AnnexinA2. The Western blot and in vitro binding assay confirmed that the full A domain of ClfA was necessary to bind to AnnexinA2. In addition, the interaction between ClfA and AnnexinA2 was validated biochemically by ELISA with a KD value of 418+/-93 nM. The confocal microscopy demonstrated that ClfA and AnnexinA2 partially co-localized in the plasma membrane and that the majority of them were transported into cytoplasm. Taken together, the results demonstrate that ClfA binds with AnnexinA2 and this interaction could mediate S. aureus invasion into bovine mammary epithelial cells.


Asunto(s)
Anexina A2/metabolismo , Coagulasa/metabolismo , Células Epiteliales/metabolismo , Glándulas Mamarias Animales/citología , Staphylococcus aureus/metabolismo , Secuencia de Aminoácidos , Animales , Anexina A2/química , Calcio/farmacología , Bovinos , Línea Celular , Coagulasa/química , Células Epiteliales/efectos de los fármacos , Femenino , Fibrinógeno/farmacología , Dominios Proteicos , Proteínas Recombinantes/metabolismo
10.
Vet Parasitol Reg Stud Reports ; 8: 54-59, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-31014638

RESUMEN

More than 70 species of the family Paramphistomatidae, have been identified in ruminants in different parts of the world. Most are pathogenic, causing amphistomosis. Adult flukes of this Family have a predilection for the rumen, liver or bile duct of ruminants where they may cause damage to the epithelium. Identification of adult paramphistomes to the species level based on morphology alone requires specialized knowledge, whereas, molecular genetic marker analysis is more precise and transferable. In the present study, we performed both morphological and molecular characterization of fifteen adult flukes collected from the liver of domesticated buffalo in the Punjab province of Pakistan. The morphology of five of these flukes was examined in detail and on this basis these were identified as either Explanatum explanatum or Explanatum bathycotyle. PCR and sequencing of the ITS-2 rDNA region from these 5 flukes, plus 10 others, revealed a single haplotype in all cases. This differed by just a single nucleotide polymorphism from a previously described E. explanatum ITS-2 rDNA sequence. Phylogenetic comparison of these E. explanatum ITS2-rDNA sequences with those from other Paramphistomatidae, Fasciola and Dicrocoelium species was performed to assess within and between species variation and validate the use of ITS-2 rDNA as a robust species-specific marker for E. explanatum. This work provides a validated species-specific marker of E. explanatum and the first report of this parasite species from Pakistan.

11.
Vet Parasitol ; 226: 1-4, 2016 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-27514873

RESUMEN

Ivermectin (IVM) is a pharmaceutical used as an anti-parasitic drug in livestock, companion animals and humans. The primary site of action of IVM is believed to be glutamate-gated chloride channels (GluCls). However we have recently reported a direct interaction between IVM and nematode tubulin with micromolar affinity. Here we report that IVM also interacts with mammalian tubulin. To test this possibility, we used the tubulin polymerization assay and found that IVM increased the degree of polymerization of mammalian tubulin. Furthermore when HeLa cells were exposed to IVM it stabilized the mammalian tubulin against the depolymerizing effects of cold temperatures, and prevented the replication of the HeLa cells in vitro. However, the IVM-induced inhibition of HeLa cell division was reversible. The data suggests that mammalian microtubules bound IVM and were stabilized by IVM at micromolar concentrations. IVM may thus affect the dynamics of tubulin polymerization and depolymerization, which in turn can result in cell death. Given that IVM is already approved for use in humans, its development as an anti-mitotic is a potentially appealing option.


Asunto(s)
Antimitóticos/farmacología , Antiparasitarios/farmacología , Ivermectina/farmacología , Mitosis/efectos de los fármacos , Tubulina (Proteína)/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Células HeLa , Humanos , Microtúbulos/química , Microtúbulos/efectos de los fármacos , Polimerizacion/efectos de los fármacos , Tubulina (Proteína)/química
12.
Parasit Vectors ; 9(1): 349, 2016 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-27316714

RESUMEN

BACKGROUND: The impact of drug selection pressure on the overall genetic diversity of parasitic nematode populations in the field is poorly understood. In this study, we address this issue for the small ruminant parasite Haemonchus contortus in the Punjab, Pakistan. This region provides an opportunity to compare H. contortus populations that have been subjected to a prolonged period of frequent benzimidazole drug treatments on government farms with parasite populations that have been exposed to little or no drug treatment in neighbouring pastoral herds. METHODS: Adult H. contortus worms were collected from the abomasa of small ruminants from three government farms frequently using benzimidazole drugs, and closed to animal movement, for over 30 years and also from from eighteen pastoral herds subject to minimal drug selection. The frequency of three known benzimidazole resistance associated mutations was determined in each parasite population. For the seven parasite populations in which resistance mutations were found, the diversity, geographical distribution and phylogenetic relationships of isotype-1 ß-tubulin benzimidazole resistance haplotypes were determined. In addition, the genetic diversity of the parasite populations on the three government farms were compared with those from four pastoral herds. RESULTS: The F200Y (TAC) resistance mutation was present at a very high frequency in H. contortus populations from government herds, but not from pastoral herds, consistent with their respective drug selection histories. Population genetic analysis, using a panel of microsatellite markers, revealed that there was little genetic differentiation among the parasite populations with no significant difference in the overall genetic diversity between government and pastoral herds. In addition, sequence analysis of the isotype-1 ß-tubulin locus revealed multiple F200Y (TAC) haplotypes demonstrating soft selective sweeps even in government herds with little or no contemporary parasite migration. CONCLUSIONS: The results suggest that, although the frequent drug treatment used on government farms has selected for a high frequency of benzimidazole resistance mutations, there has been little or no reduction in the overall genetic diversity of the selected parasite populations.


Asunto(s)
Antihelmínticos/farmacología , Bencimidazoles/farmacología , Haemonchus/efectos de los fármacos , Haemonchus/genética , Repeticiones de Microsatélite , Animales , Clonación Molecular , ADN de Helmintos , Regulación de la Expresión Génica/efectos de los fármacos , Variación Genética/efectos de los fármacos , Enfermedades de las Cabras/tratamiento farmacológico , Enfermedades de las Cabras/epidemiología , Enfermedades de las Cabras/parasitología , Cabras , Pakistán/epidemiología , Filogenia , Selección Genética , Ovinos , Enfermedades de las Ovejas/tratamiento farmacológico , Enfermedades de las Ovejas/epidemiología , Enfermedades de las Ovejas/parasitología , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
13.
Int J Parasitol ; 46(10): 631-40, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27172882

RESUMEN

Dirofilaria immitis, a filarial nematode, causes dirofilariasis or heartworm disease in dogs, cats and wild canids. Effective prevention of the disease is mainly by the use of the macrocyclic lactone class of drugs as heartworm preventives, and no other class of drugs is effective for preventing infection. Macrocyclic lactones have been used for prevention of heartworm infection for more than 26years. However, prevention has been compromised by the development of resistance in recent years. The mechanism of macrocyclic lactone resistance in D. immitis has yet to be established. In other parasitic nematodes, P-glycoproteins (PGPs) have been implicated in macrocyclic lactone resistance. The presence of two polymorphic loci on D. immitis P-glycoprotein-11 (Dim-pgp-11) correlated with loss of efficacy of macrocyclic lactone anthelmintics, suggesting that PGPs may be involved in macrocyclic lactone resistance in D. immitis. We have identified the full length of Dim-Pgp-11 cDNA, expressed it in mammalian cells, and studied the functional activity of the expressed protein. We have characterised its interaction with the four macrocyclic lactone preventives, ivermectin, selamectin, moxidectin and milbemycin oxime, using the transport of different fluorescent substrates. The inhibitory effect of these macrocyclic lactones on the transport of two fluorophore probes, Rhodamine 123 and Hoechst 33342, by Dim-PGP-11 has been studied. The avermectins, ivermectin and selamectin, markedly inhibited Rhodamine 123 transport in a concentration-dependent and saturable manner, whereas the milbemycins, moxidectin and milbemycin oxime, were found to have different inhibition profiles with Rhodamine 123 transport. However, both avermectins and milbemycin preventives inhibited the transport of Hoechst 33342 by Dim-PGP-11 in a concentration-dependent and apparently saturable manner, although differences existed in terms of efficiency and potency of inhibition between the two sub-classes of macrocyclic lactones. We postulate that Dim-PGP-11 may have two to three drug binding sites, as with mammalian Pgp, including the 'R' site for Rhodamine 123 and the 'H' site for Hoechst 33342. The avermectins appear to bind the 'R' binding site unlike the milbemycins, whereas both sub-classes of macrocyclic lactones might interact with the 'H' site of D. immitis PGP-11.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antihelmínticos/metabolismo , Dirofilaria immitis/efectos de los fármacos , Dirofilariasis/prevención & control , Lactonas/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Animales , Antihelmínticos/uso terapéutico , Antihelmínticos/toxicidad , Western Blotting/veterinaria , Clonación Molecular , ADN Complementario/metabolismo , Dirofilaria immitis/química , Dirofilaria immitis/genética , Perros , Relación Dosis-Respuesta a Droga , Expresión Génica , Perfilación de la Expresión Génica/veterinaria , Células LLC-PK1 , Lactonas/uso terapéutico , Lactonas/toxicidad , ARN de Helminto/genética , ARN de Helminto/aislamiento & purificación , Reacción en Cadena en Tiempo Real de la Polimerasa/veterinaria , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/veterinaria , Porcinos
14.
Mol Biochem Parasitol ; 201(2): 128-34, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26253426

RESUMEN

Haemonchus contortus is an abomasal nematode of ruminants that is widely present across the world. Its ability to cause death of infected animals and rapidly develop anthelmintic resistance makes it a dangerous pathogen. Ivermectin (IVM) and moxidectin (MOX) are macrocyclic lactones (MLs). They have been successfully used to treat parasitic nematodes over the last three decades. A genetic association between IVM selection and single nucleotide polymorphisms (SNPs) on the ß-tubulin isotype 1 gene was reported in H. contortus. These SNPs result in replacing phenylalanine (F, TTC) with tyrosine (Y, TAC) at position 167 or 200 on the ß-tubulin protein. Recently we reported a direct interaction of IVM with α- and ß-tubulin. It had been hypothesized that the SNPs (F167Y and F200Y) may change tubulin dynamics and directly affect IVM binding. The goal of the current study was to observe the effects of SNPs (F167Y and F200Y) on tubulin polymerization and IVM binding. It was also of interest to evaluate the differences between IVM and MOX on tubulin polymerization. We conclude that the SNPs cause no difference in the polymerization of wild and mutant tubulins. Furthermore, neither of the SNPs reduced IVM binding. Varying results were obtained in the degree of polymerization of parasitic and mammalian tubulin for IVM and MOX, i.e., the extent of polymerization was greater for IVM compared with MOX, for H. contortus tubulin, and vice versa for mammalian tubulin. Molecular modeling showed that IVM and MOX docked into the taxane binding pocket of both mammalian and parasitic wild type and mutant tubulins. However the binding was stronger for mammalian tubulin as compared to parasitic tubulin.


Asunto(s)
Antihelmínticos/farmacología , Resistencia a Medicamentos , Haemonchus/efectos de los fármacos , Ivermectina/farmacología , Macrólidos/farmacología , Polimorfismo de Nucleótido Simple , Tubulina (Proteína)/genética , Animales , Bencimidazoles/farmacología , Haemonchus/genética , Lactonas/farmacología , Modelos Moleculares , Simulación del Acoplamiento Molecular , Unión Proteica , Multimerización de Proteína
15.
Int J Parasitol ; 45(9-10): 647-54, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25957159

RESUMEN

Haemonchus contortus is a nematode of livestock that can cause severe disease and mortality. Ivermectin, an anti-parasitic drug that targets glutamate-gated chloride channels, is widely used in humans, livestock, companion animals and agriculture. Although an association between genetic changes to ß-tubulin and exposure to ivermectin has been previously reported, direct binding between ivermectin and tubulin has not been demonstrated to date. Tubulin/microtubules are key targets for many anti-mitotic drugs used in anti-parasite and cancer therapies. We now report that ivermectin exposure increased the rate and extent of polymerisation of H. contortus recombinant α- and ß-tubulin, and protected the parasitic α- and ß-tubulins from limited trypsin proteolysis. Direct binding between ivermectin and the tubulin monomers exhibited low micromolar affinities, as determined using surface plasmon resonance. Subsequent equilibrium dialysis indicated that ivermectin and Taxol compete for binding to tubulin, supporting our molecular modelling that predicts ivermectin interacts with the Taxol binding pocket of both parasitic and mammalian tubulins. Collectively, our data indicate that ivermectin can bind to and stabilise microtubules (i.e., alter the tubulin polymerisation equilibrium) and this can then lead to mitotic arrest. This work extends the range of known pharmacological effects of ivermectin, and reveals its potential as an anti-mitotic agent.


Asunto(s)
Antiparasitarios/farmacología , Haemonchus/efectos de los fármacos , Ivermectina/farmacología , Microtúbulos/efectos de los fármacos , Tubulina (Proteína)/metabolismo , Animales , Antiparasitarios/química , Sitios de Unión , Clonación Molecular , Haemonchus/metabolismo , Ivermectina/química , Modelos Moleculares , Paclitaxel/metabolismo , Unión Proteica , Conformación Proteica
16.
Pak J Pharm Sci ; 27(6): 1881-4, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25362612

RESUMEN

The present study is about to prepare stable cream of water-in-oil emulsion containing extracts of Crocus sativus against its base (without extracts) taken as control, to determine its stability on different storage conditions and effects on skin moisture contents and transepidermal water loss. The formulation contains 3% Crocus sativus (Saffron) concentrated extracts, and the base containing no extract, were formulated. Different stability tests were done on samples, which placed at 8°C, 25°C, 40°C and 40°C with 75% relative humidity, for 4 week period. These formulations (Creams) were applied on the cheeks of human volunteers for 8week period. To evaluate any effect produced by these formulations different skin parameters were monitored every week. The significant results of this study explored the fact that water-in-oil emulsion topical cream of saffron formulated from Crocus sativus extract has absolute physical stability at different storage conditions. The increase in skin moisture contents and changes in transepidermal water loss were significant (p<0.05) with respect to base and formulation respectively. Topical cream of Crocus sativus showed significant moisturizing effects on human skin.


Asunto(s)
Crocus , Emolientes/farmacología , Extractos Vegetales/farmacología , Agua Corporal/metabolismo , Emulsiones , Humanos , Concentración de Iones de Hidrógeno , Pomadas , Piel/efectos de los fármacos , Piel/metabolismo
17.
Mol Biochem Parasitol ; 193(1): 20-2, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24525483

RESUMEN

Haemonchus contortus is an important nematode of livestock that is present in most parts of the world. The life cycle comprises free living stages (egg, L1, L2 and L3 larvae), and parasitic stages (L4, adult and egg) in a ruminant. Microtubules are filamentous structures which are made from polymerization of α- and ß-tubulin. In vitro polymerization of α- and ß-tubulin can be achieved by increasing the temperature to 37°C under certain conditions. As part of its normal functioning, in mammals, the microtubules can be depolymerized when the temperature is reduced to 0°C. However, interestingly the microtubules of H. contortus are cold resistant i.e. they do not depolymerize at 0°C. Moreover these microtubules did not depolymerize even in the presence of 5 mM CaCl2 or 50 µM colchicine. These interesting findings may explain how larvae in the free living stages may survive cold temperatures over winter.


Asunto(s)
Haemonchus/fisiología , Haemonchus/efectos de la radiación , Microtúbulos/metabolismo , Microtúbulos/efectos de la radiación , Animales , Cloruro de Calcio/metabolismo , Colchicina/metabolismo , Frío
18.
Drug Chem Toxicol ; 32(3): 191-203, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19538015

RESUMEN

Successful wound healing depends upon angiogenesis, and impaired angiogenesis is a hallmark of the chronic wounds encountered with diabetes and venous or arterial insufficiency. To intervene and improve wound closure, it is essential to investigate the effects of different natural remedies in wound healing. The chicken dorsum skin excisional wound assay was used to investigate the influence of different concentrations of aged garlic solution (AGS) on wound healing. Gross, histopathology, scanning electron microscopy (SEM) and computer-based three-dimensional (3D) image-probing techniques were utilized to determine the effects of AGS on wound closure, re-epithelialization, dermal matrix regeneration, and angiogenesis. Ninety chicks, aged 1 week and divided in 6 groups, were topically exposed to different concentrations of AGS for 6 days: control (group A), 1% (group B), 5% (group C), 10% (group D), 15% (group E), and skin lotion (group F). Different patterns, ranging from incomplete to almost complete wound closure, were observed among different groups with highly significant results (P < 0.001) in group E. Histological investigations revealed a positive augment in the re-epithelialization of all AGS exposed wounds. An increase in the number of new loosely packed collagen and maturation of collagen bundles was observed in all treated wounds at days 4 and 6 post-wounding, respectively. Similar results were achieved through SEM of treated wounds. Histological investigations revealed the profuse dose-dependent neovascularization among AGS-treated wounds. Abbott curve, angular spectrum, and different parameters of 3D surface roughness of wounds were also measured for the precise quantification of angiogenesis. A very highly significant (P < 0.001) increase in angiogenesis was observed among all treated groups. No significant change was observed among control and skin lotion-treated groups. These observations substantiate the beneficial use of AGS in the treatment of wounds. Additional studies are needed to study the specific wound-healing mechanisms of chemical, or group of chemicals, present in AGS.


Asunto(s)
Epidermis/efectos de los fármacos , Ajo/química , Extractos Vegetales/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Pollos , Dermis/efectos de los fármacos , Dermis/ultraestructura , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Epidermis/lesiones , Epidermis/ultraestructura , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Células Epiteliales/fisiología , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/ultraestructura , Procesamiento de Imagen Asistido por Computador , Microscopía Electrónica de Rastreo , Neovascularización Fisiológica/efectos de los fármacos , Neovascularización Fisiológica/fisiología , Propiedades de Superficie/efectos de los fármacos , Factores de Tiempo , Cicatrización de Heridas/fisiología
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