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1.
Acta Diabetol ; 57(7): 867-874, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32114643

RESUMO

AIMS: To evaluate the timing and spectral-domain optical coherence tomography (SD-OCT) features of diabetic macular oedema (DME) recurrence according to baseline OCT patterns in patients treated with dexamethasone implant (DEX-I). METHODS: This is a retrospective observational study (72 eyes/65 patients). Best-corrected visual acuity, timing of DME recurrence, and SD-OCT pattern [intraretinal cysts (IRC), IRC plus subretinal fluid (mixed), external limiting membrane (ELM), ellipsoid (IS/OS) layer integrity] were assessed at baseline and monthly until first DME recurrence. RESULTS: Forty-two (58.3%) and 30 (41.6%) DME eyes had an IRC and mixed DME pattern at baseline, respectively. Twenty-four out of thirty mixed eyes (80%) relapsed without subretinal fluid. At baseline, mixed eyes showed similar changes in ELM and IS/OS (60 and 76.6% of eyes, respectively) versus IRC eyes (42.8 and 80.9% of eyes). After DME recurrence, more mixed eyes at baseline showed ELM and IS/OS changes (63.3 and 86.6%) than IRC eyes (50 and 76.2%). 33.3% of mixed eyes had DME recurrence at ≥ 6 months from first DEX-I implant versus 19% of IRC eyes. CONCLUSIONS: Mixed DME eyes were treated with DEX-I relapse later and more frequently without subretinal fluid than IRC eyes. SD-OCT characteristics of different DME patterns at baseline can predict morphological features and timing of DME recurrence.


Assuntos
Dexametasona/administração & dosagem , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/tratamento farmacológico , Edema Macular/diagnóstico , Edema Macular/tratamento farmacológico , Tomografia de Coerência Óptica/métodos , Idoso , Retinopatia Diabética/patologia , Implantes de Medicamento/administração & dosagem , Feminino , Angiofluoresceinografia , Humanos , Injeções Intravítreas , Edema Macular/patologia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Prognóstico , Recidiva , Retina/diagnóstico por imagem , Retina/efeitos dos fármacos , Retina/patologia , Retina/fisiopatologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Acuidade Visual/efeitos dos fármacos
2.
PLoS One ; 15(3): e0230473, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214321

RESUMO

BACKGROUND: While prior epidemiologic studies have suggested that injectable progestin-based contraceptive depot medroxyprogesterone acetate (DMPA) use may increase a woman's risk of acquiring HIV, recent data have suggested that DMPA users may be at a similar risk for HIV acquisition as users of the copper intrauterine device and levonorgestrel implant. Use of the etonogestrel Implant (Eng-Implant) is increasing but there are currently no studies evaluating its effect on HIV acquisition risk. OBJECTIVE: Evaluate the potential effect of the Eng-Implant use on HIV acquisition risk by analyzing HIV target cells and cytokine profiles in the lower genital tract and blood of adult premenopausal HIV-negative women using the Eng-Implant. METHODS: We prospectively obtained paired cervicovaginal lavage (CVL) and blood samples at 4 study visits over 16 weeks from women between ages 18-45, with normal menses (22-35 day intervals), HIV uninfected with no recent hormonal contraceptive or copper intrauterine device (IUD) use, no clinical signs of a sexually transmitted infection at enrollment and who were medically eligible to initiate Eng-Implant. Participants attended pre-Eng-Implant study visits (week -2, week 0) with the Eng-Implant inserted at the end of the week 0 study visit and returned for study visits at weeks 12 and 14. Genital tract leukocytes (enriched from CVL) and peripheral blood mononuclear cells (PBMC) from the study visits were evaluated for markers of activation (CD38, HLA-DR), retention (CD103) and trafficking (CCR7) on HIV target cells (CCR5+CD4+ T cells) using multicolor flow cytometry. Cytokines and chemokines in the CVL supernatant and blood plasma were measured in a Luminex assay. We estimated and compared study endpoints among the samples collected before and after contraception initiation with repeated-measures analyses using linear mixed models. RESULTS: Fifteen of 18 women who received an Eng-Implant completed all 4 study visits. The percentage of CD4+ T cells in CVL was not increased after implant placement but the percentage of CD4+ T cells expressing the HIV co-receptor CCR5 did increase after implant placement (p = 0.02). In addition, the percentage of central memory CD4+ T-cells (CCR7+) in CVL increased after implant placement (p = 0.004). The percentage of CVL CD4+, CCR5+ HIV target cells expressing activation markers after implant placement was either reduced (HLA-DR+, p = 0.01) or unchanged (CD38+, p = 0.45). Most CVL cytokine and chemokine concentrations were not significantly different after implant placement except for a higher level of the soluble lymphocyte activation marker (sCD40L; p = 0.04) and lower levels of IL12p70 (p = 0.02) and G-CSF (p<0.001). In systemic blood, none of the changes noted in CVL after implant placement occurred except for decreases in the percentage CD4 T-cells expressing HLA-DR+ T cells (p = 0.006) and G-CSF (p = 0.02). CONCLUSIONS: Eng-Implant use was associated with a moderate increase in the availability of HIV target cells in the genital tract, however the percentage of these cells that were activated did not increase and there were minimal shifts in the overall immune environment. Given the mixed nature of these findings, it is unclear if these implant-induced changes alter HIV risk.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Colo do Útero/imunologia , Citocinas/imunologia , Desogestrel/administração & dosagem , Vagina/imunologia , Linfócitos T CD4-Positivos/patologia , Colo do Útero/patologia , Implantes de Medicamento/administração & dosagem , Feminino , Humanos , Vagina/patologia , Adulto Jovem
3.
J Fr Ophtalmol ; 43(2): 103-110, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31952876

RESUMO

PURPOSE: To observe the rate of hypotony and intraocular pressure (IOP) fluctuations immediately following intravitreal dexamethasone implantation in vitrectomized eyes. METHODS: The study included previously vitrectomized eyes scheduled to receive intravitreal dexamethasone implants. IOP measurements were performed at minute 1, minute 10, hour 1, hour 2, hour 3 and day 1. The primary outcome measure of the study was the rate of hypotony at the various time points, while the secondary outcome measure was the IOP profile over time. RESULTS: A total of 26 eyes were enrolled in the study. Immediately following the injection, 11 (42.3%) of the eyes exhibited an IOP<6mm Hg. Hypotony was observed in one eye (3.8%) at hour 3 and day 1. After the immediate IOP reduction, IOP recovered rapidly and showed a peak at hour 1, with 5 eyes (19.2%) exhibiting IOP levels ≥25mmHg and 1 eye (3.8%) ≥30mm Hg. Aside from the eye with persistent hypotony resulting in a choroidal effusion, no other complication was observed. CONCLUSIONS: Injection of dexamethasone implants in vitrectomized eyes resulted in immediate IOP reduction. Hypotony showed a short, self-limited course in the majority of eyes. In the presence of additional risk factors for wound incompetency, regular follow-up in the early post-injection period appears to be needed.


Assuntos
Dexametasona/administração & dosagem , Implantes de Medicamento/administração & dosagem , Pressão Intraocular/efeitos dos fármacos , Hipotensão Ocular/tratamento farmacológico , Vitrectomia , Idoso , Oftalmopatias/complicações , Oftalmopatias/tratamento farmacológico , Oftalmopatias/fisiopatologia , Oftalmopatias/cirurgia , Feminino , Humanos , Pressão Intraocular/fisiologia , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Hipotensão Ocular/complicações , Hipotensão Ocular/fisiopatologia , Hipotensão Ocular/cirurgia , Estudos Retrospectivos , Tonometria Ocular , Vitrectomia/reabilitação , Corpo Vítreo/efeitos dos fármacos
4.
Curr Diab Rep ; 19(11): 122, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31696345

RESUMO

PURPOSE OF REVIEW: The aim of this review is to summarize the development of the photoactivated depot (PAD) approach for the minimally invasive and continuously variable delivery of insulin. RECENT FINDINGS: Using an insulin PAD, we have demonstrated that we can release native, bioactive insulin into diabetic animals in response to light signals from a small external LED light source. We have further shown that this released insulin retains bioactivity and reduces blood glucose. In addition, we have designed and constructed second generation materials that have high insulin densities, with the potential for multiple day delivery. The PAD approach for insulin therapy holds promise for addressing the pressing need for continuously variable delivery methods that do not rely on pumps, and their myriad associated problems.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Implantes de Medicamento/administração & dosagem , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Luz , Fármacos Fotossensibilizantes/administração & dosagem , Animais , Glicemia/análise , Preparações de Ação Retardada/administração & dosagem , Diabetes Mellitus Tipo 1/sangue , Injeções Subcutâneas
5.
S Afr Med J ; 109(10): 756-760, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31635573

RESUMO

BACKGROUND: Evidence-informed priority setting is vital to improved investment in public health interventions. This is particularly important as South Africa (SA) makes the shift to universal health coverage and institution of National Health Insurance. OBJECTIVES: To measure the financial impact of increasing the demand for modern contraceptive methods in the SA public health sector. We estimated the total cost of providing contraceptives, and specifically the budgetary impact of premature removals of long-acting reversible contraceptives. METHODS: We created a deterministic model in Microsoft Excel to estimate the costs of contraception provision over a 5-year time horizon (2018 - 2023) from a healthcare provider perspective. Only direct costs of service provision were considered, including drugs, supplies and personnel time. Costs were not discounted owing to the short time horizon. Scenario analyses were conducted to test uncertainty. RESULTS: The base-case cost of current contraceptive use in 2018 was estimated to be ZAR1.64 billion (ZAR29 per capita). Injectable contraceptives accounted for ~47% of total costs. To meet the total demand for family planning, SA would have to spend ~30% more than the estimate for current contraceptive use. In the year 2023, the 'current use' of modern contraceptives would increase to ZAR2.2 billion, and fulfilling the total demand for family planning would require ZAR2.9 billion. The base-case cost of implantable contraceptives was estimated at ZAR54 million. Assuming a normal removal rate, the use of implants is projected to increase by 20% during the 5-year period between 2019 and 2023, with an estimated 46% increase in costs. The cost of early removal of Implanon NXT is estimated at ZAR75 million, with total contraception costs estimated at ZAR102 million in 2019, compared with ZAR56 million when a normal removal rate is applied. CONCLUSIONS: The costs of scaling up modern contraceptives in SA are substantial. Early and premature removals of implantable contraceptives are costly to the nation and must be minimised. The government should consider conducting appropriate health technology assessments to inform the introduction of new public health interventions as SA makes the shift to universal health coverage by means of National Health Insurance.


Assuntos
Comportamento Contraceptivo/estatística & dados numéricos , Anticoncepção/estatística & dados numéricos , Anticoncepcionais/administração & dosagem , Programas Nacionais de Saúde/economia , Cobertura Universal do Seguro de Saúde/economia , Anticoncepção/economia , Anticoncepção/tendências , Comportamento Contraceptivo/tendências , Anticoncepcionais/economia , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/economia , Serviços de Planejamento Familiar , Humanos , Contracepção Reversível de Longo Prazo/economia , Contracepção Reversível de Longo Prazo/estatística & dados numéricos , Contracepção Reversível de Longo Prazo/tendências , Modelos Teóricos , Setor Público/economia , Setor Público/tendências , África do Sul
6.
J Neuroinflammation ; 16(1): 195, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31665042

RESUMO

BACKGROUND: IL-10 knockout (KO) mice are protected from experimental autoimmune encephalomyelitis (EAE) with low-dose estrogen (E2) treatment similar to wild-type (WT) mice. Previous studies have demonstrated a decrease in tumor necrosis factor in all E2-treated groups, which led to the protection of the mice. METHODS: This study used IL-10 KO mice and WT mice treated either with E2 or sham pellets 7 days prior to induction of EAE. Mice were observed for 21 days post-immunization. The spleen, inguinal lymph nodes, and brain were evaluated by flow cytometry. Spinal cords were evaluated using a cytokine/chemokine array, RT-PCR, and histology. RESULTS: This study demonstrates that E2 treatment induced three heightened regulatory mechanisms that potentially protect IL-10 KO mice from EAE: (1) an increase in programmed death-ligands 1 and 2 on monocytes and macrophages in the periphery and within the CNS; (2) an increase in CD73 in the inflamed CNS, which can increase the production of the anti-inflammatory molecule adenosine; and (3) a decrease in CD4+CD25+FoxP3+ regulatory T cells in the spleen. Together, these factors comprise an alternative compensatory mechanism that significantly downregulates key pro-inflammatory cytokine, chemokine, and chemokine receptor genes which are enhanced in the spinal cord of IL-10 KO mice. This group of E2-treated mice remained asymptomatic after EAE challenge similar to E2-treated WT mice, despite their having more T and B lymphocytes in the brain, and modestly increased demyelination in the spinal cord. CONCLUSION: These results indicate that previously unrecognized compensatory mechanisms of EAE protection are stimulated by E2 in the absence of IL-10, which can provide disease protection comparable to the IL-10-dependent effects induced by E2 in WT mice.


Assuntos
Implantes de Medicamento/administração & dosagem , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/prevenção & controle , Estrogênios/administração & dosagem , Interleucina-10/deficiência , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
7.
AAPS PharmSciTech ; 20(7): 300, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482251

RESUMO

Implantable drug delivery systems, such as drug pumps and polymeric drug depots, have emerged as means of providing predetermined drug release profiles at the desired site of action. While initial implants aimed at providing an enduring drug supply, developments in polymer chemistry and pharmaceutical technology and the growing need for refined drug delivery patterns have prompted the design of sophisticated drug delivery implants such as on-demand drug-eluting implants and personalized 3D printed implants. The types of cargo loaded into these implants range from small drug molecules to hormones and even therapeutic cells. This review will shed light upon recent advances in materials and composites used for polymeric implant fabrication, highlight select approaches employed in polymeric implant fabrication, feature medical applications where polymeric implants have a significant impact, and report recent advances made in these areas.


Assuntos
Implantes de Medicamento/química , Polímeros/química , Impressão Tridimensional , Animais , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/tendências , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/farmacocinética , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Humanos , Bombas de Infusão Implantáveis/tendências , Polímeros/administração & dosagem , Polímeros/farmacocinética , Impressão Tridimensional/tendências , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/tendências
8.
Int J Pharm ; 571: 118703, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31536761

RESUMO

Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Portadores de Fármacos/química , Implantes de Medicamento/administração & dosagem , Fraturas por Osteoporose/tratamento farmacológico , Cloridrato de Raloxifeno/administração & dosagem , Animais , Conservadores da Densidade Óssea/farmacocinética , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/lesões , Química Farmacêutica , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Implantes de Medicamento/farmacocinética , Liberação Controlada de Fármacos , Humanos , Injeções Intralesionais , Masculino , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Porosidade , Cloridrato de Raloxifeno/farmacocinética , Ratos , Propriedades de Superfície
9.
J Anim Sci ; 97(11): 4371-4385, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31541251

RESUMO

Predominately Angus steers (n = 24; initial BW = 435 ± 28.3 kg) were used to evaluate non-coated (NC) and coated implants (CI) containing equal amounts of trenbolone acetate (TBA; 200 mg) and estradiol benzoate (EB; 28 mg) in finishing steers on sera metabolite responses, gene expression, and immunohistochemical analyses of the Longissimus muscle (LM). Performance data were analyzed as a randomized complete block design, and all other data were analyzed as repeated measures for a completely randomized design. Treatments were no implant (NI), NC (Synovex-PLUS; Zoetis, Parsippany, NJ), and CI (Synovex-One Feedlot) implant. There were 2 pen replicates per treatment (n = 4 steers/pen). LM biopsies, blood, and BW were collected before feeding on days 0, 14, 28, 56, 84, 112, and 133, with final BW being captured on day 140. Genes of interest were determined by RT-qPCR using two housekeeping genes. Sera was analyzed for estradiol-17ß (E2),17ß-trenbolone (TbOH), insulin-like growth factor 1 (IGF-I), NEFA, and urea-N (SUN). An α of 0.10 determined significance for performance and sera data; α of 0.05 was used for gene and histology data. No performance differences (P ≥ 0.10) were detected. An implant × day interaction (P ≤ 0.10) for E2, IGF-I, and SUN was detected; implants elevated (P ≤ 0.10) E2, 17ß-TbOH, and IGF-I; and decreased SUN across day of the study, meaning sera metabolites are not altered with time on feed. An implant × day interaction was detected for myogenic factor 5 (MYF-5) positive cells and proportions of MHCIIX. In LM, CI had greater (P < 0.10) IGF-I in LM over NI. CI increased (P < 0.05) G protein-coupled estrogen receptor 1 (GPER1) expression, as well as, GPER1 semi-quantitative scores over NI and NC. An implant × day interaction (P ≤ 0.05) for estrogen and androgen receptor-positive nuclei was detected; implants had increased (P ≤ 0.05) estrogen and androgen receptor-positive nuclei compared to NI. CIs increase genes associated with muscle tissue growth.


Assuntos
Anabolizantes/administração & dosagem , Bovinos/fisiologia , Estradiol/análogos & derivados , Esteroides/administração & dosagem , Acetato de Trembolona/administração & dosagem , Anabolizantes/sangue , Ração Animal , Animais , Bovinos/sangue , Dieta/veterinária , Implantes de Medicamento/administração & dosagem , Ingestão de Alimentos , Estradiol/administração & dosagem , Estradiol/sangue , Imuno-Histoquímica/veterinária , Fator de Crescimento Insulin-Like I/análise , Masculino , Músculo Esquelético/metabolismo , Distribuição Aleatória , Carne Vermelha/análise , Acetato de Trembolona/sangue
10.
Drug Dev Res ; 80(7): 958-969, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31359488

RESUMO

To minimize the gastric and esophageal injury effect, a system to deliver doxycycline hyclate (DOXY) to the duodenum area is needed. DOXY-containing modified-release oral pellets (DMOP) coated with hydroxypropyl methylcellulose phthalate HP-55 (HPMCP HP-55) and hydroxypropyl methylcellulose E15 (HPMC E15) appear to be a reasonable choice. This coating layer dissolves at pH 5.5, which is the pH of the duodenum, but not at a gastric pH (1.2). The formulation and preparation of DMOP were optimized, and a scale-up test was performed. The results showed that the production reproducibility was acceptable, and the quality of DMOP well met the standards of Chinese Pharmacopeia (Ch.P, 2015 edition). Notably, the accumulated DOXY release was lower than 50% at pH 1.2 (20 min) and higher than 85% at pH 5.5, which met the USP40-NF35 standard for DOXY modified-release formulations. Moreover, the storage stability of DMOP with different packages was investigated by stress testing, accelerated and long-term testings. The stability of DMOP was maintained up to 12 months, in terms of DOXY content and in vitro release behavior. The results seem to suggest that DMOP could be a promising duodenum delivery system.


Assuntos
Doxiciclina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Administração Oral , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Derivados da Hipromelose/química , Metilcelulose/análogos & derivados , Metilcelulose/química , Tamanho da Partícula , Comprimidos com Revestimento Entérico/administração & dosagem , Comprimidos com Revestimento Entérico/química
12.
Int J Pharm ; 567: 118459, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31247275

RESUMO

Despite eye drops generally represent the most convenient, simple and patient-friendly formulations to treat ocular diseases, they suffer from poor retention on the ocular surface and low drug bioavailability leading to the necessity of prolonged and continuous treatment over time. Therefore, ocular insert could represent an innovative way to benefit from ocular topical administration while minimizing all the relevant limitation related to this route of administration. Polymeric non-erodible mucoadhesive ocular inserts should be comfortable and should rapidly adhere on the ocular surface, remain in situ for prolonged period, assure a reproducible and controlled drug release as well as act as transcorneal absorption promoters. In this study, a well-known aliphatic polyester, poly(1,4-butylene succinate) (PBS), was used as starting material to produce hydrophobic microfibrillar scaffolds by means of electrospinning technique. Plasma-assisted chemical surface functionalization of the PBS scaffolds with appropriate biopolymers (inulin, α,ß-poly(N-2-hydroxyethyl)-D,L-aspartamide, heparin) was carried out to confer to the final ocular inserts ad hoc properties as wettability, mucoadhesion and cytocompatibility on human corneal epithelial cells, by improving surface hydrophilicity without modifying the bulk properties of the material. The lipophilic drug triamcinolone acetonide was loaded into the obtained ocular insert and release studies were carried out to demonstrate the ability of drug loaded inserts to release the active until 30 days.


Assuntos
Implantes de Medicamento/administração & dosagem , Glucocorticoides/administração & dosagem , Triancinolona Acetonida/administração & dosagem , Administração Oftálmica , Animais , Butileno Glicóis , Bovinos , Implantes de Medicamento/química , Liberação Controlada de Fármacos , Olho/metabolismo , Glucocorticoides/química , Humanos , Polímeros , Triancinolona Acetonida/química
13.
Int J Pharm ; 567: 118458, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31247277

RESUMO

Successful treatment of age-related macular diseases requires an effective controlled drug release system with less invasive route of administration in the eye to reduce the burden of frequent intravitreal injections for patients. In this study, we developed an episcleral implantable device for sustained release of ranibizumab, and evaluated its efficacy on suppression of laser-induced choroidal neovascularization (CNV) in rats. We tested both biodegradable and non-biodegradable sheet-type devices consisting of crosslinked gelatin/chitosan (Gel/CS) and photopolymerized poly(ethyleneglycol) dimethacrylate that incorporated collagen microparticles (PEGDM/COL). In vitro release studies of FITC-labeled albumin showed a constant release from PEGDM/COL sheets compared to Gel/CS sheets. The Gel/CS sheets gradually biodegraded in the sclera during the 24-week implantation; however, the PEGDM/COL sheets did not degrade. FITC-albumin was detected in the retina during 18 weeks implantation in the PEGDM/COL sheet-treated group, and was detected in the Gel/CS sheet-treated group during 6 weeks implantation. CNV was suppressed 18 weeks after application of ranibizumab-loaded PEGDM/COL sheets compared to a placebo PEGDM/COL sheet-treated group, and to the intravitreal ranibizumab-injected group. In conclusion, the PEGDM/COL sheet device suppressed CNV via a transscleral administration route for 18 weeks, indicating that prolonged sustained ranibizumab release could reduce the burden of repeated intravitreal injections.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Neovascularização de Coroide/tratamento farmacológico , Implantes de Medicamento/administração & dosagem , Ranibizumab/administração & dosagem , Inibidores da Angiogênese/química , Animais , Quitosana/administração & dosagem , Quitosana/química , Colágeno/administração & dosagem , Colágeno/química , Implantes de Medicamento/química , Liberação Controlada de Fármacos , Olho/efeitos dos fármacos , Olho/metabolismo , Olho/patologia , Fluoresceína-5-Isotiocianato/administração & dosagem , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/química , Gelatina/administração & dosagem , Gelatina/química , Lasers , Masculino , Metacrilatos/administração & dosagem , Metacrilatos/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Ranibizumab/química , Ratos Sprague-Dawley , Albumina Sérica/administração & dosagem , Albumina Sérica/química
14.
Protein Pept Lett ; 26(9): 691-701, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31215364

RESUMO

BACKGROUND: Both biodegradable and non-biodegradable peptide-loaded implants are already developed for the long-term treatment of patients, thereby reducing the frequency of drug administration. To further improve peptide formulation, extending the scope of implant-based drug delivery systems towards other polymers and processing techniques is highly interesting. OBJECTIVE: In this study, as a proof-of-principle, the feasibility of hot-melt processing of a peptide active pharmaceutical ingredient was assessed by developing a non-biodegradable poly(ethylenevinyl acetate) (33% VA) implant loaded with 20% (w/w) buserelin acetate. METHODS: Cross-sectional implant characterization was performed by Raman microscopy. The stability of buserelin acetate in the polymeric matrix was evaluated for 3 months under ICH stability conditions and the quantity as well as the degradation products analyzed using LC-UV methods. An in vitro dissolution study was performed as well and buserelin acetate and its degradants analyzed using the same chromatographic methods. RESULTS: No significant quantities of buserelin acetate-related degradation products were formed during the hot-melt preparation as well as during the stability study. Together with the consistent buserelin acetate assay values over time, chemical peptide stability was thus demonstrated. The in vitro buserelin acetate release from the implant was found to be diffusion-controlled after an initial burst release, with stable release profiles in the stability study, demonstrating the functional stability of the peptide implant. CONCLUSION: These results indicate the feasibility of preparing non-biodegradable peptide-loaded implants using the hot-melt production method and may act as a proof of principle concept for further innovation in peptide medicinal formulations.


Assuntos
Busserrelina/química , Portadores de Fármacos/química , Implantes de Medicamento/química , Polivinil/química , Busserrelina/administração & dosagem , Composição de Medicamentos/métodos , Implantes de Medicamento/administração & dosagem , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Estudos de Viabilidade , Temperatura Alta , Estudo de Prova de Conceito , Solubilidade
15.
Drug Discov Today ; 24(8): 1694-1700, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31173915

RESUMO

Topical eye-drop administration and intravitreal injections are the current standard for ocular drug delivery. However, patient adherence to the drug regimen and insufficient administration frequency are well-documented challenges to this field. In this review, we describe recent advances in intraocular implants designed to deliver therapeutics for months to years, to obviate the issues of patient adherence. We highlight recent advances in monolithic ocular implants in the literature, the commercialization pipeline, and approved for the market. We also describe design considerations based on material selection, active pharmaceutical ingredient, and implantation site.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Implantes de Medicamento/administração & dosagem , Olho/efeitos dos fármacos , Soluções Oftálmicas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Humanos
16.
Acta Diabetol ; 56(10): 1141-1147, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31089929

RESUMO

AIM: Main failure of diabetic tractional retinal detachment (TRD) surgery is the development of proliferative vitreoretinopathy (PVR), causing higher re-detachment rates. We investigated whether the use of dexamethasone (DEX) implant at the end of pars plana vitrectomy (PPV) with silicone oil tamponade might have an impact on these outcomes. DESIGN: Comparative, nonrandomized, retrospective study. PARTICIPANTS: A total of 148 eyes from 148 patients that underwent PPV with silicone oil tamponade for diabetic TRD (with DEX implant, n = 52; without DEX implant, n = 96). METHODS: Consecutive patients' records were reviewed for time between TRD diagnosis and surgery; lens status before surgery and after 6, 12, and 24 months; retina attachment rate after primary PPV; change in postoperative PVR severity; rate of re-detachment at 6, 12, and 24 months; use of IOP lowering treatment after 6, 12, and 24 months; surgery details; intra- and postoperative complications. Correlations between outcome measures, postoperative PVR severity, and re-detachment rates were analyzed. MAIN OUTCOME MEASURES: Change in postoperative PVR severity and retinal re-detachment rates with and without the adjuvant use of DEX implant. RESULTS: Retinal re-detachment rates were significantly higher in the group of patients that did not receive DEX implant [11/96 (11.5%) vs. 0/52 (0%), p = 0.049; 11/84 (12.9%) vs. 4/52 (7.7%), p = 0.007; 14/71 (19.7%) vs. 5/52 (10%) p < 0.001 at 6, 12, and 24 months, respectively]. PVR severity correlated with retinal status at 12 and 24 months (p = 0.018 and p = 0.027, respectively). The difference in PVR severity between the two groups was statistically significant at 6, 12, and 24 months (p < 0.001). CONCLUSIONS: DEX implant at the end of PPV in patients with diabetic TRD improves PVR severity and decreases re-detachment rates. This should be considered as an option in the customized treatment of TRD.


Assuntos
Dexametasona/administração & dosagem , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/cirurgia , Descolamento Retiniano/tratamento farmacológico , Descolamento Retiniano/cirurgia , Vitrectomia/métodos , Adulto , Idoso , Terapia Combinada , Dexametasona/efeitos adversos , Retinopatia Diabética/complicações , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/efeitos adversos , Feminino , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Período Pós-Operatório , Retina/efeitos dos fármacos , Retina/fisiopatologia , Estudos Retrospectivos , Óleos de Silicone/administração & dosagem , Óleos de Silicone/efeitos adversos , Acuidade Visual/efeitos dos fármacos , Vitrectomia/efeitos adversos , Vitreorretinopatia Proliferativa/tratamento farmacológico , Vitreorretinopatia Proliferativa/etiologia , Vitreorretinopatia Proliferativa/cirurgia
17.
Drug Deliv ; 26(1): 208-215, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30835582

RESUMO

Cisplatin is the most commonly used antitumor drug in the chemotherapy of a variety of malignancies. However, the severe side effects and drug resistance limit its clinical application. The aim of this study was to develop PLGA-based cisplatin-loaded implants and evaluate the antitumor efficacy of continuous intratumoral chemotherapy with the implants. The cisplatin-loaded implants were prepared by the direct compression method and characterized regarding drug content, micromorphology, in vitro and in vivo drug release profiles. Furthermore, the antitumor activity of the implants was conducted in sarcoma 180 tumor-bearing mice. The SEM images showed smooth surface of the implants and the mean drug content of the tested implants was (37.7% ± 0.5%, w/w). Both in vitro and in vivo release profiles of the implants were characterized by initial burst release followed by the sustained-release of cisplatin. Intratumoral implantation of the cisplatin-loaded implants could effectively inhibit the tumor growth. Additionally, intratumoral chemotherapy with the implants significantly reduced the systemic toxicity compared with intravenous injection of cisplatin. It is worth noting that an increase in the dose of the implants led to a higher tumor suppression rate without additional systemic toxicity. These results demonstrated that cisplatin-loaded implants enhanced the antitumor efficacy and reduced the dose-related side effects in sarcoma 180 tumor-bearing mice.


Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Portadores de Fármacos/administração & dosagem , Implantes de Medicamento/administração & dosagem , Sarcoma 180/tratamento farmacológico , Animais , Antineoplásicos/metabolismo , Cisplatino/metabolismo , Portadores de Fármacos/metabolismo , Implantes de Medicamento/metabolismo , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Camundongos , Distribuição Aleatória , Sarcoma 180/metabolismo , Resultado do Tratamento , Células Tumorais Cultivadas
18.
Trop Anim Health Prod ; 51(6): 1763-1765, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30827002

RESUMO

The goal of this study was to assess the efficacy of the re-utilization of an ear implant impregnated with norgestomet on estrus synchronization response and pregnancy rates in sheep. Fifty-five Texel ewes were classified according to body condition (3.5) and live weight (65 kg), and randomly assigned to two experimental groups: NORN-new (n = 30) and NORU-used (n = 25). The dose of norgestomet used in the treatments was half of that recommended for bovine (1.5 mg). The synchronization protocol consisted of an ear implant inserted on day 0 (beginning of the experiment) and kept for 6 days. The removal of the implant on day 6 was followed by an injection of a prostaglandin analogue (0.263 mg) and eCG (250 IU). Rams with paint applied to their chest were used to facilitate estrus detection for 5 days following implant withdrawal. Estrus behavior was observed in 93.3% (28/30) and 90% for NORN and NORU, respectively. Pregnancy rates for NORN were 73.3% and for NORU were 68%. Estrus behavior and pregnancy rates between treatment groups did not differ statistically. Therefore, the re-utilization of ear implants impregnated with norgestomet, in addition to eCG and a prostaglandin analogue in short-term estrus synchronization protocols, allow acceptable estrus response and pregnancy rates in sheep.


Assuntos
Implantes de Medicamento/farmacologia , Sincronização do Estro/métodos , Estro/efeitos dos fármacos , Pregnenodionas/farmacologia , Ovinos , Animais , Gonadotropina Coriônica/administração & dosagem , Gonadotropina Coriônica/farmacologia , Implantes de Medicamento/administração & dosagem , Detecção do Estro , Feminino , Gravidez , Pregnenodionas/administração & dosagem , Progestinas/administração & dosagem , Progestinas/farmacologia , Prostaglandinas/administração & dosagem , Prostaglandinas/farmacologia , Distribuição Aleatória
19.
Eur J Pharm Biopharm ; 139: 142-152, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30902733

RESUMO

Nifedipine and nicardipine loaded PLGA extrudates have a great potential to prevent cerebral vasospasms after subarachnoid hemorrhage or surgical clipping of aneurysm. A constant release over approx. two weeks is desired. Although in vivo studies on humans have been reported, there is limited knowledge about the release kinetics and the underlying mechanisms. Therefore, nifedipine and nicardipine loaded PLGA implants with different drug loads were manufactured by extrusion and investigated. In addition to the measurements of the release kinetics, GPC, DSC, X-ray diffraction and light microscopic investigations were performed for a detailed characterization. The water uptake and polymer erosion studies showed an initial lag phase of 5-7 days and an acceleration of both processes thereafter. With 5% loaded implants a higher drug release compared to 10% drug loaded polymers could be achieved and not only the relative amount of drug release (% of loaded drug), but surprisingly also the absolute amount of the released drug increased. The drugs were initially in an amorphous state. For nifedipine, formation of drug crystals with time has been observed by light microscopy and X-ray diffraction. The analysis of the drug content in the degrading polymer showed a very large increase from 10% to about 20% (nifedipine) and over 50% (nicardipine). In contrast, no or only a moderate increase of the drug content occurred for initially 5% loaded polymer implants. We postulate that water penetration and polymer degradation induced changes of the microenvironment lead to supersaturated systems. A supersaturated state is faster reached for polymers with higher drug load and therefore, drug precipitation takes place at earlier time points. As a result, drug release might be incomplete for poorly soluble drugs and paradoxically, the total amount of drug release might be higher for systems with a lower drug load. Drug release is initially controlled by the PLGA matrix, but later by the dissolution kinetics of the precipitated drug which are very slow for poorly soluble drugs according to the Noyes-Whitney equation.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacocinética , Portadores de Fármacos/química , Implantes de Medicamento/farmacocinética , Liberação Controlada de Fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Plásticos Biodegradáveis/química , Bloqueadores dos Canais de Cálcio/administração & dosagem , Varredura Diferencial de Calorimetria , Composição de Medicamentos/métodos , Implantes de Medicamento/administração & dosagem , Humanos , Nicardipino/administração & dosagem , Nicardipino/farmacocinética , Nifedipino/administração & dosagem , Nifedipino/farmacocinética , Solubilidade , Difração de Raios X
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