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2.
Obstet Gynecol ; 140(2): 316-319, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35852284

RESUMO

BACKGROUND: Human papillomavirus, one of the most common viral infections worldwide, frequently manifests as condyloma acuminata, or anogenital warts. First-line treatment of this condition includes the use of imiquimod, a topical immunomodulator. CASE: We describe a case of a localized skin ulceration necessitating surgical debridement after the use of topical imiquimod for 24 hours in a patient with uncontrolled type 2 diabetes mellitus. After debridement, the patient's wound healed appropriately, with regular wound clinic visits and diabetes education. CONCLUSION: Health care professionals should use caution when prescribing imiquimod in patients with uncontrolled type 2 diabetes mellitus.


Assuntos
Condiloma Acuminado , Diabetes Mellitus Tipo 2 , Adjuvantes Imunológicos/efeitos adversos , Administração Tópica , Aminoquinolinas/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Imiquimode/efeitos adversos
3.
J Korean Med Sci ; 37(27): e212, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35818703

RESUMO

BACKGROUND: Plasmodium vivax malaria has a persistent liver stage that causes relapse, and introducing tafenoquine to suppress relapse could aid in disease eradication. Therefore, we assessed the impact of tafenoquine introduction on P. vivax malaria incidence and performed a cost-benefit analysis from the payer's perspective. METHODS: We expanded the previously developed P. vivax malaria dynamic transmission model and calibrated it to weekly civilian malaria incidences in 2014-2018. Primaquine and tafenoquine scenarios were considered by assuming different relapse probabilities, and relapse and total P. vivax malaria cases were predicted over the next decade for each scenario. We then estimated the number of cases prevented by replacing primaquine with tafenoquine. The cost and benefit of introducing tafenoquine were obtained using medical expenditure from a nationwide database, and a cost-benefit analysis was conducted. A probabilistic sensitivity analysis was performed to assess the economic feasibility robustness of tafenoquine introduction under uncertainties of model parameters, costs, and benefits. RESULTS: Under 0.04 primaquine relapse probability, the introduction of tafenoquine with relapse probability of 0.01 prevented 129 (12.27%) and 35 (77.78%) total and relapse cases, respectively, over the next decade. However, under the same relapse probability as primaquine, introducing tafenoquine had no additional preventative effect. The 14-day primaquine treatment cost was $3.71. The tafenoquine and the glucose-6-phosphate dehydrogenase rapid diagnostic testing cost $57.37 and $7.76, totaling $65.13. The average medical expenditure per malaria patient was estimated at $1444.79. The cost-benefit analysis results provided an incremental benefit-cost ratio (IBCR) from 0 to 3.21 as the tafenoquine relapse probability decreased from 0.04 to 0.01. The probabilistic sensitivity analysis showed an IBCR > 1, indicating that tafenoquine is beneficial, with a probability of 69.1%. CONCLUSION: Tafenoquine could reduce P. vivax malaria incidence and medical costs and bring greater benefits than primaquine.


Assuntos
Antimaláricos , Malária Vivax , Aminoquinolinas , Antimaláricos/uso terapêutico , Análise Custo-Benefício , Humanos , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Malária Vivax/prevenção & controle , Primaquina/uso terapêutico , Recidiva
4.
J Inorg Biochem ; 234: 111905, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35752063

RESUMO

A small library of aminoquinoline and imidazolopiperidine (IMP)-based ligands, containing the 1,2,3-triazole moiety, and their corresponding tricarbonyl rhenium complexes were synthesised and their inhibitory activities evaluated against the chloroquine-sensitive (CQS) and multidrug-resistant (MDR) strains (NF54 and K1, respectively) of P. falciparum. The quinoline-based compounds (L1, L2, ReL1, and ReL2) were at least six-fold more potent than their IMP-based counterparts (L3, L4, ReL3, and ReL4) against both strains of P. falciparum, with the most promising compound (L1) displaying activity comparable to chloroquine diphosphate (CQDP) in the MDR strain. Additionally, all of the synthesised compounds have resistance indices less than CQDP. To gain insight into a possible mechanism of action, in silico hemozoin docking simulations were performed. These studies proposed that the tested compounds may act via hemozoin inhibition, as the new aminoquinoline-derivatives, with the exception of complex ReL2 (binding affinity: -12.62 kcal/mol), showed higher binding affinities than the reference drug chloroquine (CQ, -13.56 kcal/mol). Furthermore, the ligands exhibited superior binding affinity relative to their corresponding Re(I) complexes, which is reflected in their antiplasmodial activity.


Assuntos
Antimaláricos , Rênio , Aminoquinolinas/química , Antimaláricos/química , Cloroquina/farmacologia , Resistência a Medicamentos , Inosina Monofosfato/farmacologia , Ligantes , Plasmodium falciparum , Rênio/farmacologia
5.
J Cell Mol Med ; 26(13): 3675-3686, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35665597

RESUMO

Primaquine (PQ) and Tafenoquine (TQ) are clinically important 8-aminoquinolines (8-AQ) used for radical cure treatment of P. vivax infection, known to target hepatic hypnozoites. 8-AQs can trigger haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd), yet the mechanisms of haemolytic toxicity remain unknown. To address this issue, we used a humanized mouse model known to predict haemolytic toxicity responses in G6PDd human red blood cells (huRBCs). To evaluate the markers of eryptosis, huRBCs were isolated from mice 24-48 h post-treatment and analysed for effects on phosphatidylserine (PS), intracellular reactive oxygen species (ROS) and autofluorescence. Urinalysis was performed to evaluate the occurrence of intravascular and extravascular haemolysis. Spleen and liver tissue harvested at 24 h and 5-7 days post-treatment were stained for the presence of CD169+ macrophages, F4/80+ macrophages, Ter119+ mouse RBCs, glycophorin A+ huRBCs and murine reticulocytes (muRetics). G6PDd-huRBCs from PQ/TQ treated mice showed increased markers for eryptosis as early as 24 h post-treatment. This coincided with an early rise in levels of muRetics. Urinalysis revealed concurrent intravascular and extravascular haemolysis in response to PQ/TQ. Splenic CD169+ macrophages, present in all groups at day 1 post-dosing were eliminated by days 5-7 in PQ/TQ treated mice only, while liver F4/80 macrophages and iron deposits increased. Collectively, our data suggest 8-AQ treated G6PDd-huRBCs have early physiological responses to treatment, including increased markers for eryptosis indicative of oxidative stress, resulting in extramedullary haematopoiesis and loss of splenic CD169+ macrophages, prompting the liver to act as the primary site of clearance.


Assuntos
Antimaláricos , Deficiência de Glucosefosfato Desidrogenase , Malária Vivax , Aminoquinolinas/toxicidade , Animais , Modelos Animais de Doenças , Deficiência de Glucosefosfato Desidrogenase/complicações , Hemólise , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Camundongos , Primaquina/uso terapêutico
6.
J Am Chem Soc ; 144(26): 11878-11887, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35749293

RESUMO

The nucleic acid G-quadruplex (G4) has emerged as a promising therapeutic target for a variety of diseases such as cancer and neurodegenerative disease. Among small-molecule G4-binders, pyridostatin (PDS) and its derivatives (e.g., PyPDS) exhibit high specificity to G4s, but the structural basis for their specific recognition of G4s remains unknown. Here, we presented two solution structures of PyPDS and PDS with a quadruplex-duplex hybrid. The structures indicate that the rigid aromatic rings of PyPDS/PDS linked by flexible amide bonds match adaptively with G-tetrad planes, enhancing π-π stacking and achieving specific recognition of G4s. The aliphatic amine side chains of PyPDS/PDS adjust conformation to interact with the phosphate backbone via hydrogen bonding and electrostatic interactions, increasing affinity for G4s. Moreover, the N-H of PyPDS/PDS amide bonds interacts with two O6s of G-tetrad guanines via hydrogen bonding, achieving a further increase in affinity for G4s, which is different from most G4 ligands. Our findings reveal from structural perspectives that the rational assembly of rigid and flexible structural units in a ligand can synergistically improve the selectivity and affinity for G4s through spatial selective and adaptive matching.


Assuntos
Quadruplex G , Doenças Neurodegenerativas , Amidas , Aminoquinolinas , DNA/química , Humanos , Ligantes , Ácidos Picolínicos
7.
Dalton Trans ; 51(30): 11241-11254, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35731231

RESUMO

A variety of transition metal complexes bearing aminoquinoline PNHH'-R ligands R = Ph (L1H), Cy (L2H) and their amido analogues are reported for rhodium(I) ([Rh(L1H)(PPh3)]+1 and Rh(L1)(PPh3) 2), cobalt(II) (Co(L2)(Cl) 3), and iron(II) ([Fe(L1H)2]2+5, Fe(L1)26, and [Fe(C5Me5)(L1H)]PF67). The acid-base and redox properties of the amido complexes 2, 6, and their protio parent complexes 1, and 5 permit the determination of the pKa and bond dissociation free energy (BDFE) of their N-H bonds while the ligand scaffold is coordinated to metal centres of square planar and octahedral geometry, respectively. From relative concentrations obtained by the use of 31P{1H} NMR spectroscopy, a pKaTHF value of 14 is calculated for rhodium complex 1, 6.4 for iron complex 5, and 24 for iron complex 7. These data, when combined with elecrochemical potentials obtained via cyclic voltammetry, allow the calculations of BDFE values for the N-H bond of 69 kcal mol-1 for 1, and of 55 kcal mol-1 for 5.


Assuntos
Ródio , Aminoquinolinas , Cobalto , Eletrônica , Ferro/química , Ligantes , Ródio/química
8.
Methods Appl Fluoresc ; 10(3)2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35697038

RESUMO

3-Aminoquinoline (3AQ) has been used as a fluorescent probe for preferential solvation in hexane-ethanol solvent mixtures. Results of the present experiment have been put into context by comparison with prior observations with 5-aminoquinoline (5AQ) as the probe. 3AQ exhibits a relatively small change of dipole moment (Δµ= 2.2 D) upon photoexcitation, compared to 5AQ (Δµ= 6.1D), which might appear to be a hindrance in the way of its use as a solvation probe. Indeed, the values of parameters like spectral shifts are smaller for the present experiment with 3AQ. At the smallest concentration of alcohol used, its local mole fraction around the probe is significantly lower than in the previous experiments with 5AQ. However, these apparent disadvantages are outweighed by the significant increase in fluorescence intensity and lifetime observed with increasing concentration of ethanol in the solvent mixture, as opposed to the drastic fluorescence quenching that occurs for 5AQ. This is a marked advantage in the use of 3AQ in studies like the present one. The local mole fraction of ethanol and preferential solvation index experienced by 3AQ are in line with those reported for 5AQ. The disadvantage of the smaller magnitude of Δµpersists in the time resolved fluorescence experiments, for solvent mixtures with very low ethanol content. Negligible wavelength dependence of fluorescence transients of 3AQ is observed forxp= 0.002,. However, this effect is outweighed at higher alcohol concentrations, for which nanosecond dynamics of preferential solvation is observed.


Assuntos
Etanol , Corantes Fluorescentes , Aminoquinolinas , Solventes , Espectrometria de Fluorescência
9.
Exp Oncol ; 44(1): 75-82, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35548968

RESUMO

AIM: To evaluate the efficacy of combination of alpha-lipoic acid and acetylcholinesterase inhibitor (ipidacrine hydrochloride) to prevent the development and improve the course of paclitaxel-induced peripheral neuropathy (PIPN) in patients with breast cancer according to the Total Neuropathy Score. MATERIALS AND METHODS: 32 patients with breast cancer T1-4N0-3M0 received six cycles of polychemotherapy according to the AT scheme (paclitaxel, doxorubicin) or ET scheme (paclitaxel, epirubicin). Patients were randomized into two groups - without (group I) or with (group II) medication for prevention of neuropathy. A comprehensive neurological examination of patients was performed according to all ten parameters of the Total Neuropathy Score before chemotherapy, and after third and sixth cycles of chemotherapy. Each parameter was evaluated from 0 (no deficit) to 4 (no function/the most severe deficit). The scores obtained from the scale were summarized to obtain a total score from 0 to 40. RESULTS: The use of alpha-lipoic acid in combination with an acetylcholinesterase inhibitor (ipidacrine hydrochloride) significantly reduces the symptoms and severity of PIPN. The manifestations of PIPN in patients of the control group were significantly more severe compared to the group in which the study drugs were used. The average severity of neuropathy after 3 and 6 cycles was 1.75 and 2.62 in group I, and 1.12 and 1.62 - in group II, respectively (improvement by 15.75% (p < 0.05) and 25.00% (p < 0.001) after 3 and 6 cycles). CONCLUSIONS: Proposed combination of alpha-lipoic acid and ipidacrine hydrochloride led to a statistically significant reduction in the severity of PIPN, and thus to improvement of the functional capacity and quality of life of patients.


Assuntos
Neoplasias da Mama , Doenças do Sistema Nervoso Periférico , Ácido Tióctico , Acetilcolinesterase/efeitos adversos , Aminoquinolinas , Neoplasias da Mama/tratamento farmacológico , Inibidores da Colinesterase/efeitos adversos , Feminino , Humanos , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/prevenção & controle , Qualidade de Vida , Ácido Tióctico/uso terapêutico
10.
Actas Dermosifiliogr ; 113(4): T407-T412, 2022 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-35623739

RESUMO

Topical imiquimod has been used off-label as monotherapy or adjuvant treatment for lentigo maligna. Our aim is to describe treatment modalities, clinical outcomes, and management of recurrence in patients receiving imiquimod for lentigo maligna. Patients from our unit with lentigo maligna or lentigo maligna melanoma treated with imiquimod 5% as monotherapy or in combination with surgery were included in this study. Fourteen cases were recruited (85.7% lentigo maligna and 14.3% lentigo maligna melanoma). Eight patients (57.1%) received imiquimod without surgery, and six (42.9%) underwent narrow excision before beginning treatment. During the follow-up period, pigmentation reappeared in 6 patients (4 postinflammatory hyperpigmentation and 2 relapses). Relapses were managed with very narrow excision (1 mm margin) and retreatment with imiquimod 5%. All imiquimod modalities showed well-tolerated side effects and low recurrence rates, with long periods of follow-up. Imiquimod appears to be a versatile option for treating LM in suitable candidates.


Assuntos
Sarda Melanótica de Hutchinson , Neoplasias Cutâneas , Aminoquinolinas/efeitos adversos , Humanos , Sarda Melanótica de Hutchinson/tratamento farmacológico , Imiquimode/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Cutâneas/terapia
12.
Org Biomol Chem ; 20(21): 4342-4351, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35575175

RESUMO

Herein, we report emissive aminoquinoline derivatives (TFMAQ) containing alkylmorpholine and arylmorpholine groups and their photophysical properties, acid-responsiveness, and organelle targeting. The alkylmorpholine group is well-known to favour accumulation in lysosomes and be acid-responsive, but, counterintuitively, the TFMAQ derivatives containing ethylmorpholine groups showed limited accumulation in lysosomes and, instead, preferential accumulation in lipid droplets. The findings reported here will aid the development of organelle/tissue specific dyes for cell imaging and diagnosis.


Assuntos
Aminoquinolinas , Corantes Fluorescentes , Lisossomos , Imagem Óptica , Organelas
13.
Lancet Microbe ; 3(5): e336-e347, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35544095

RESUMO

BACKGROUND: Tafenoquine was recently approved as a prophylaxis and radical cure for Plasmodium vivax infection, but its Plasmodium falciparum transmission-blocking efficacy is unclear. We aimed to establish the efficacy and safety of three single low doses of tafenoquine in combination with dihydroartemisinin-piperaquine for reducing gametocyte density and transmission to mosquitoes. METHODS: In this four-arm, single-blind, phase 2, randomised controlled trial, participants were recruited at the Clinical Research Unit of the Malaria Research and Training Centre of the University of Bamako in Mali. Eligible participants were aged 12-50 years, with asymptomatic P falciparum microscopy-detected gametocyte carriage, had a bodyweight of 80 kg or less, and had no clinical signs of malaria defined by fever. Participants were randomly assigned (1:1:1:1) to standard treatment with dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus a single dose of tafenoquine (in solution) at a final dosage of 0·42 mg/kg, 0·83 mg/kg, or 1·66 mg/kg. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. Dihydroartemisinin-piperaquine was administered as oral tablets over 3 days (day 0, 1, and 2), as per manufacturer instructions. A single dose of tafenoquine was administered as oral solution on day 0 in parallel with the first dose of dihydroartemisinin-piperaquine. Tafenoquine dosing was based on bodyweight to standardise efficacy and risk variance. The primary endpoint, assessed in the per-protocol population, was median percentage change in mosquito infection rate 7 days after treatment compared with baseline. Safety endpoints included frequency and incidence of adverse events. The final follow-up visit was on Dec 23, 2021; the trial is registered with ClinicalTrials.gov, NCT04609098. FINDINGS: From Oct 29 to Nov 25, 2020, 1091 individuals were screened for eligibility, 80 of whom were enrolled and randomly assigned (20 per treatment group). Before treatment, 53 (66%) individuals were infectious to mosquitoes, infecting median 12·50% of mosquitoes (IQR 3·64-35·00). Within-group reduction in mosquito infection rate on day 7 was 79·95% (IQR 57·15-100; p=0·0005 for difference from baseline) following dihydroartemisinin-piperaquine only, 100% (98·36-100; p=0·0005) following dihydroartemisinin-piperaquine plus tafenoquine 0·42 mg/kg, 100% (100-100; p=0·0001) following dihydroartemisinin-piperaquine plus tafenoquine 0·83 mg/kg, and 100% (100-100; p=0·0001) following dihydroartemisinin-piperaquine plus tafenoquine 1·66 mg/kg. 55 (69%) of 80 participants had a total of 94 adverse events over the course of the trial; 86 (92%) adverse events were categorised as mild, seven (7%) as moderate, and one (1%) as severe. The most common treatment-related adverse event was mild or moderate headache, which occurred in 15 (19%) participants (dihydroartemisinin-piperaquine n=2; dihydroartemisinin-piperaquine plus tafenoquine 0·42 mg/kg n=6; dihydroartemisinin-piperaquine plus tafenoquine 0·83 mg/kg n=3; and dihydroartemisinin-piperaquine plus tafenoquine 1·66 mg/kg n=4). No serious adverse events occurred. No significant differences in the incidence of all adverse events (p=0·73) or treatment-related adverse events (p=0·62) were observed between treatment groups. INTERPRETATION: Tafenoquine was well tolerated at all doses and accelerated P falciparum gametocyte clearance. All tafenoquine doses showed improved transmission reduction at day 7 compared with dihydroartemisinin-piperaquine alone. These data support the case for further research on tafenoquine as a transmission-blocking supplement to standard antimalarials. FUNDING: Bill & Melinda Gates Foundation. TRANSLATIONS: For the French, Portuguese, Spanish and Swahili translations of the abstract see Supplementary Materials section.


Assuntos
Artemisininas , Malária Falciparum , Malária , Aminoquinolinas , Animais , Artemisininas/efeitos adversos , Humanos , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Mali/epidemiologia , Piperazinas , Plasmodium falciparum , Quinolinas , Método Simples-Cego
14.
Int J Mol Sci ; 23(10)2022 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-35628455

RESUMO

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. Current therapeutic strategies mainly involve surgery and chemoradiotherapy; however, novel antitumor compounds are needed to avoid drug resistance in CRC, as well as the severe side effects of current treatments. In this study, we investigated the anticancer effects and underlying mechanisms of Arylquin 1 in CRC. The MTT assay was used to detect the viability of SW620 and HCT116 cancer cells treated with Arylquin 1 in a dose-dependent manner in vitro. Further, wound-healing and transwell migration assays were used to evaluate the migration and invasion abilities of cultured cells, and Annexin V was used to detect apoptotic cells. Additionally, Western blot was used to identify the expression levels of N-cadherin, caspase-3, cyclin D1, p-extracellular signal-regulated kinase (ERK), p-c-JUN N-terminal kinase (JNK), and phospho-p38, related to key signaling proteins, after administration of Arylquin 1. Xenograft experiments further confirmed the effects of Arylquin 1 on CRC cells in vivo. Arylquin 1 exhibited a dose-dependent reduction in cell viability in cultured CRC cells. It also inhibited cell proliferation, migration, and invasion, and induced apoptosis. Mechanistic analysis demonstrated that Arylquin 1 increased phosphorylation levels of ERK, JNK, and p38. In a mouse xenograft model, Arylquin 1 treatment diminished the growth of colon tumors after injection of cultured cancer cells. Arylquin 1 may have potential anticancer effects and translational significance in the treatment of CRC.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Aminoquinolinas , Animais , Apoptose , Movimento Celular , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/patologia , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Secretagogos/farmacologia
15.
Expert Opin Pharmacother ; 23(7): 759-768, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35379070

RESUMO

INTRODUCTION: Plasmodium vivax malaria causes significant disease burden worldwide, especially in Latin America, Southeast Asia, and Oceania. P. vivax is characterized by the production of liver hypnozoites that cause clinical relapses upon periodic activation. Primaquine, an 8-aminoquinoline drug, has been the standard of care for decades to treat liver-stage P. vivax malaria; however, it requires long treatment regimens (one to two weeks) that lead to poor adherence and thus clinical relapses. Tafenoquine (TFQ), a newly available and efficacious single-dose 8-aminoquinoline, aims to address this challenge. Safe administration is possible when paired with the use of glucose-6-phosphate dehydrogenase (G6PD) diagnostics to prevent 8-aminoquinoline-induced hemolysis in patients with underlying G6PD deficiency (G6PDd). AREAS COVERED: In this review, the authors present the recent literature regarding the pharmacology, efficacy, safety, and tolerability of TFQ and highlight regional differences in these areas. The authors also discuss the potential for TFQ, complemented with primaquine PQ and effective screening for G6PDd, to improve P. vivax clinical management and facilitate targeted mass drug administration in communities to decrease transmission. EXPERT OPINION: Clinical studies show therapeutic efficacy of TFQ as well as a good performance in terms of safety and tolerability. Additional research regarding the effectiveness and safety TFQ in malaria elimination strategies, such as targeted or mass drug administration, are needed.


Assuntos
Antimaláricos , Malária Vivax , Aminoquinolinas , Antimaláricos/efeitos adversos , Humanos , Malária Vivax/tratamento farmacológico , Malária Vivax/prevenção & controle , Plasmodium vivax , Primaquina/efeitos adversos , Recidiva
17.
Antimicrob Agents Chemother ; 66(5): e0169621, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35465706

RESUMO

The combination antimalarial therapy of artemisinin-naphthoquine (ART-NQ) was developed as a single-dose therapy, aiming to improve adherence relative to the multiday schedules of other artemisinin combination therapies. The pharmacokinetics of ART-NQ has not been well characterized, especially in children. A pharmacokinetic study was conducted in adults and children over 5 years of age (6 to 10, 11 to 17, and ≥18 years of age) with uncomplicated malaria in Tanzania. The median weights for the three age groups were 20, 37.5, and 55 kg, respectively. Twenty-nine patients received single doses of 20 mg/kg of body weight for artemisinin and 8 mg/kg for naphthoquine, and plasma drug concentrations were assessed at 13 time points over 42 days from treatment. We used nonlinear mixed-effects modeling to interpret the data, and allometric scaling was employed to adjust for the effect of body size. The pharmacokinetics of artemisinin was best described by one-compartment model and that of naphthoquine by a two-compartment disposition model. Clearance values for a typical patient (55-kg body weight and 44.3-kg fat-free mass) were estimated as 66.7 L/h (95% confidence interval [CI], 57.3 to 78.5 L/h) for artemisinin and 44.2 L/h (95% CI, 37.9 to 50.6 L/h) for naphthoquine. Nevertheless, we show via simulation that patients weighing ≥70 kg achieve on average a 30% lower day 7 concentration compared to a 48-kg reference patient at the doses tested, suggesting dose increases may be warranted to ensure adequate exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT01930331.).


Assuntos
Antimaláricos , Artemisininas , Antagonistas do Ácido Fólico , Malária Falciparum , Naftoquinonas , 1-Naftilamina/análogos & derivados , Adolescente , Adulto , Aminoquinolinas , Antimaláricos/efeitos adversos , Artemisininas/efeitos adversos , Peso Corporal , Criança , Humanos , Malária Falciparum/tratamento farmacológico , Naftoquinonas/uso terapêutico , Tanzânia
18.
Molecules ; 27(8)2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35458755

RESUMO

Tuberculosis remains a global health problem that affects millions of people around the world. Despite recent efforts in drug development, new alternatives are required. Herein, a series of 27 N-(4-(benzyloxy)benzyl)-4-aminoquinolines were synthesized and evaluated for their ability to inhibit the M. tuberculosis H37Rv strain. Two of these compounds exhibited minimal inhibitory concentrations (MICs) similar to the first-line drug isoniazid. In addition, these hit compounds were selective for the bacillus with no significant change in viability of Vero and HepG2 cells. Finally, chemical stability, permeability and metabolic stability were also evaluated. The obtained data show that the molecular hits can be optimized aiming at the development of drug candidates for tuberculosis treatment.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Aminoquinolinas/farmacologia , Antituberculosos/química , Humanos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Tuberculose/tratamento farmacológico
19.
Actas Dermosifiliogr ; 113(4): 407-412, 2022 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-35431054

RESUMO

Topical imiquimod has been used off-label as monotherapy or adjuvant treatment for lentigo maligna. Our aim is to describe treatment modalities, clinical outcomes, and management of recurrence in patients receiving imiquimod for lentigo maligna. Patients from our unit with lentigo maligna or lentigo maligna melanoma treated with imiquimod 5% as monotherapy or in combination with surgery were included in this study. Fourteen cases were recruited (85.7% lentigo maligna and 14.3% lentigo maligna melanoma). Eight patients (57.1%) received imiquimod without surgery, and six (42.9%) underwent narrow excision before beginning treatment. During the follow-up period, pigmentation reappeared in 6 patients (4 postinflammatory hyperpigmentation and 2 relapses). Relapses were managed with very narrow excision (1mm margin) and retreatment with imiquimod 5%. All imiquimod modalities showed well-tolerated side effects and low recurrence rates, with long periods of follow-up. Imiquimod appears to be a versatile option for treating LM in suitable candidates.


Assuntos
Sarda Melanótica de Hutchinson , Neoplasias Cutâneas , Aminoquinolinas/efeitos adversos , Humanos , Sarda Melanótica de Hutchinson/tratamento farmacológico , Imiquimode/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico
20.
Am J Obstet Gynecol ; 227(2): 250.e1-250.e8, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35447145

RESUMO

BACKGROUND: Vulvar Paget disease is an extremely rare skin disorder, which is most common in postmenopausal women. Most vulvar Paget disease cases are noninvasive; however, it may be invasive or associated with an underlying vulvar or distant adenocarcinoma. The current treatment of choice for noninvasive vulvar Paget disease is wide local excision, which is challenging because of extensive intraepithelial spread and may cause severe morbidity. Recurrence rates are high, ranging from 15% to 70%, which emphasizes the need for new treatment options. Imiquimod, a topical immune response modifier, has been shown to be effective in a few studies and case reports, and is a promising new treatment modality. OBJECTIVE: To prospectively investigate the efficacy, safety, and effect on quality of life of a standardized treatment schedule with 5% imiquimod cream in patients with noninvasive vulvar Paget disease. STUDY DESIGN: The Paget Trial is a multicenter prospective observational clinical study including 7 tertiary referral hospitals in the Netherlands. A total of 24 patients with noninvasive vulvar Paget disease were treated with topical 5% imiquimod cream 3 times a week for 16 weeks. The primary efficacy outcome was the reduction in lesion size at 12 weeks after the end of treatment. Secondary outcomes were safety, clinical response after 1 year, and quality of life. Safety was assessed by evaluation of adverse events and tolerability of treatment. Quality of life was investigated with 3 questionnaires taken before, during, and after treatment. RESULTS: Data were available for 23 patients, 82.6% of whom responded to therapy. A complete response was reported in 12 patients (52.2%), and 7 patients (30.4%) had a partial response. A histologic complete response was observed in 10 of the 12 patients with a complete response. Patients experienced side effects such as fatigue (66.7%-70.9%) and headaches (16.7%-45.8%), and almost 80% needed painkillers during treatment. Eight patients (34.8%) adjusted the treatment protocol to 2 applications a week, and 3 patients (13.0%) stopped treatment because of side effects after 4 to 11 weeks. Treatment improved quality of life, whereas a slight, temporary negative impact was observed during treatment. Two patients with a complete response developed a recurrence within 1 year after treatment. Follow-up showed 6 patients with a noninvasive recurrence after a median of 31 months (14-46 months) after the end of treatment. CONCLUSION: Topical 5% imiquimod cream can be an effective and safe treatment alternative for noninvasive vulvar Paget disease, particularly when compared with treatment with surgical excision.


Assuntos
Antineoplásicos , Neoplasias da Mama , Doença de Paget Extramamária , Neoplasias Vulvares , Aminoquinolinas/efeitos adversos , Aminoquinolinas/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Imiquimode/uso terapêutico , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/patologia , Qualidade de Vida , Neoplasias Vulvares/patologia
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