Despigmentação precoce em caso de ceratopigmentação / Early depigmentation in case of keratopigmentation

RESUMO A ceratopigmentação teve seu primeiro registro pelo filósofo Galeno há muitos séculos como uma estratégia utilizada para o tratamento estético de pacientes com leucomas. As córneas com leucoma são patológicas e, muitas vezes, intolerantes a lentes de contato cosméticas ou próteses oculares, sendo comum a queixa de desconforto excessivo, proporcionado pela superfície corneana irregular. Assim, a ceratopigmentação é uma alternativa para a melhora estética de pacientes com opacidades corneanas. Descrevemos o caso de um paciente do sexo masculino, 39 anos, que apresentou despigmentação precoce em caso de ceratopigmentação associado a quadro de ceratite herpética necrotizante. O paciente foi submetido ao tratamento com aciclovir 2g ao dia e doxiciclina 200mg ao dia, evoluindo com melhora do quadro clínico, apesar da má adesão medicamentosa.

ABSTRACT Keratopigmentation was first recorded many centuries ago by the philosopher Galeno, as a strategy used for the aesthetic treatment of patients with leukomas. Corneas with leucoma are pathological and often intolerant of cosmetic contact lenses or ocular prostheses, with complaints of excessive discomfort provided by the irregular corneal surface being common. Therefore, keratopigmentation is an alternative for the aesthetic improvement of patients with corneal opacities. We describe the case of a 39-year old male patient, who presented early depigmentation in a case of keratopigmentation associated with necrotizing herpetic keratitis. The patient was treated with Acyclovir 2g/day and Doxycycline 200mg/day, evolving with clinical improvement, despite poor medication adherence.

Intralesional Acyclovir: A Potential Therapeutic Option for Cutaneous Warts.

BACKGROUND: The treatment of warts is challenging and the development of an antiviral drug that can eradicate the human papilloma virus (HPV) is difficult. The viral origin of warts suggests that acyclovir, an antiviral drug with a proven efficacy in DNA viruses, may be a potential therapeutic option. AIM: To evaluate the efficacy and safety of intralesional acyclovir in the treatment of cutaneous warts. METHODS: Thirty-one patients with cutaneous warts were allocated into 2 groups. Group A (19 patients) had intralesional acyclovir (70 mg/ml) injected into the warts, while group B (12 patients) received intralesional saline as control. The treatment was repeated at 2 week intervals until complete clearance or for a maximum of 5 sessions. RESULTS: Complete clearance of warts was observed in 52.6%, partial response in 36.8%, and no response in 10.5% of the patients in the acyclovir group. Partial response was reported in 16.7%, and no response in 83.3% of the patients in the control group. A high statistically significant difference was found between the treatment and control groups (P < .01). Adverse effects included pain during injection in 89.5%, blistering in 52.6% and erythema in5.3% of the patients. No recurrence was detected during the follow-up period. CONCLUSION: Intralesional acyclovir can be an effective and well-tolerated treatment modality for cutaneous warts.

Pseudoboehmite as a drug delivery system for acyclovir.

Herpes simplex virus is among the most prevalent sexually transmitted infections. Acyclovir is a potent, selective inhibitor of herpes viruses and it is indicated for the treatment and management of recurrent cold sores on the lips and face, genital herpes, among other diseases. The problem of the oral bioavailability of acyclovir is limited because of the low permeability across the gastrointestinal membrane. The use of nanoparticles of pseudoboehmite as a drug delivery system in vitro assays is a promising approach to further the permeability of acyclovir release. Here we report the synthesis of high purity pseudoboehmite from aluminium nitrate and ammonium hydroxide containing nanoparticles, using the sol-gel method, as a drug delivery system to improve the systemic bioavailability of acyclovir. The presence of pseudoboehmite nanoparticles were verified by infrared spectroscopy, transmission electron microscopy, and X-ray diffraction techniques. In vivo tests were performed with Wistar rats to compare the release of acyclovir, with and without the addition of pseudoboehmite. The administration of acyclovir with the addition of pseudoboehmite increased the drug content by 4.6 times in the plasma of Wistar rats after 4 h administration. We determined that the toxicity of pseudoboehmite is low up to 10 mg/mL, in gel and the dried pseudoboehmite nanoparticles.

Bi-polymeric Spongy Matrices Through Cross-linking Polymerization: Synthesized and Evaluated for Solubility Enhancement of Acyclovir.

In this study, two hydrophilic polymers hydroxypropyl methyl cellulose and beta-cyclodextrin (ß-CD) are used to synthesize highly responsive and spongy polymeric matrices. Porous and stimulus-responsive polymeric network was developed to improve the solubility of acyclovir (ACV) at significant level. Grafting was successfully carried out by free radical polymerization technique. Spongy matrices were characterized by percentage entrapment efficiency, drug loading, solubility studies, FTIR, powder X-ray diffraction, TGA, DSC, XRD, SEM, swelling studies, and in vitro studies. Acute oral toxicity studies were conducted to determine the safety of oral administration of prepared HPMC-ßCD-g-poly(AMPS) formulation. Porous and spongy structures were depicted in SEM images. Complex formation and thermal stability of constituents and drug (ACV) were analyzed by FTIR, TGA, and DSC spectra. XRD analysis revealed reduction in acyclovir crystallinity in spongy matrices. Particle size of optimized formulation was found in the range of 197 ± 2.55 nm. The momentous difference with reference product committed that drug solubility and release characteristics were markedly enhanced by the developed spongy matrices. Toxicity studies endorsed that developed spongy matrices were non-toxic and compatible to biological system. The efficient method of preparation, enhanced solubility, excellent physico-chemical characteristics, high dissolution, and non-toxic HPMC-ßCD-g-poly(AMPS) spongy matrices may be a promising approach for oral delivery of poorly soluble drugs.

Rheological and in vitro release measurements of manufactured acyclovir 5% creams: confirming sensitivity of the in vitro release.

Previous evaluation of marketed acyclovir 5% creams using in vitro release testing (IVRT) and its correlation with the qualitative composition confirmed the discriminative characteristics of this methodology. This was in line with the principles of Topical drug Classification System (TCS). For the current research, experimental formulations were designed and prepared by applying controlled changes in manufacturing process, sources of raw materials, and amount of the excipients. The topical semisolids were representative for the four classes of TCS. The outcome of the IVRT and rheological assessments was evaluated in relation with the nature of the change and the functional role of the excipients. The variations in propylene glycol content from 5% to 40% impacted both the in vitro release rates (gradual decrease from 16.23 to 8.97 µg/cm2/min0.5) and the microstructural characteristics (proportional increase of yield stress from 17.98 to 46.40 Pa). The inert excipients e.g. cetostearyl alcohol or white soft paraffin altered majorly the rheological behavior, as their functionality is mainly related to vehicle properties. IVRT was discriminative for the microstructural differences induced by both categories of excipients according to TCS dichotomy. This simple, reliable, and reproducible test reflected the impact of difference in quantitative composition and characteristics of excipients.

ß-cyclodextrin chitosan-based hydrogels with tunable pH-responsive properties for controlled release of acyclovir: design, characterization, safety, and pharmacokinetic evaluation.

In this work, series of pH-responsive hydrogels (FMA1-FMA9) were synthesized, characterized, and evaluated as potential carrier for oral delivery of an antiviral drug, acyclovir (ACV). Different proportions of ß-cyclodextrin (ß-CD), chitosan (CS), methacrylic acid (MAA) and N' N'-methylenebis-acrylamide (MBA) were used to fabricate hydrogels via free radical polymerization technique. Fourier transform infrared spectroscopy confirmed fabrication of new polymeric network, with successful incorporation of ACV. Scanning electron microscopy (SEM) indicated presence of slightly porous structure. Thermal analysis indicated enhanced thermal stability of polymeric network. Swelling studies were carried out at 37 °C in simulated gastric and intestinal fluids. The drug release data was found best fit to zero-order kinetics. The preliminary investigation of developed hydrogels showed a pH-dependent swelling behavior and drug release pattern. Acute oral toxicity study indicated no significant changes in behavioral, clinical, or histopathological parameters of Wistar rats. Pharmacokinetic study indicated that developed hydrogels caused a significant increase in oral bioavailability of ACV in rabbit plasma as compared to oral suspension when both were administered at a single oral dose of 20 mg kg-1 bodyweight. Hence, developed hydrogel formulation could be used as potential candidate for controlled drug delivery of an antiviral drug acyclovir.

Acyclovir-Loaded Nanoemulsions: Preparation, Characterization and Irritancy Studies for Ophthalmic Delivery.

Objective: The main goal of the present work was to develop and evaluate nanoemulsions (NEs) containing acyclovir (ACV) for ophthalmic drug delivery.Method: Firstly, component screening was performed by determining ACV solubility in various oils, surfactants, and co-surfactants. Different NE formulations were developed based on pseudo-ternary phase diagrams, and physicochemical assets were evaluated. Selected formulations were subjected to the drug release efficacy, stability studies, and ex-vivo trans-corneal permeation test. The safety of NEs was investigated by the modified Draize test and hen's egg test-chorioallantoic membrane (HET-CAM).Results: Based on the solubility studies, Tween 20, Triacetin, and Tramsectol®P were chosen to prepare NE formulations. Developed NEs showed desirable physiochemical properties, including a droplet size of less than 15 nm. Selected formulations (F1 and F2) exhibited a sustained drug release pattern compared to the control group (P < .001). ACV penetration from F1 and F2 to the excised bovine cornea was 2.85 and 2.9-fold more than the control, respectively. Furthermore, HET-CAM and modified Draize test confirmed that F1 and F2 were safe for ocular administration.Conclusion: Present investigation revealed that ACV-loaded NEs could be effective, and safe platform for ophthalmic delivery of ACV.

[Varicella-zoster meningoencephalitis and vasculitis after treatment with amenamevir to herpes zoster in the trigeminal nerve area].

A 78-year-old woman was diagnosed with herpes zoster in the first branch of the trigeminal nerve and was treated with amenamevir. Subsequently, she was hospitalized for postherpetic neuralgia. Fever and unconsciousness were observed, and a diagnosis of varicella-zoster virus meningoencephalitis and vasculitis was made. In addition to the antithrombotic therapy, she was treated with intravenous acyclovir and steroid pulse therapy; however, her unconsciousness persisted. Amenamevir was not transferrable to the spinal fluid and resulted in an incomplete treatment of herpes zoster in the cerebral nerve region, suggesting that this case may be related to the severe course of the disease.

Pioderma gangrenoso ampollar como forma de presentación de leucemia mieloide agudo: informe de un caso / Acute myeloid leukemia presented in the form of bullous pyoderma gangrenosum: a case report

El pioderma gangrenoso ampollar es una variedad infrecuente de pioderma gangrenoso, que se asocia en el 50-70% de los casos con trastornos oncohematológicos. Se comunica el caso de una paciente de 59 años, que consultó por fiebre y ampollas purpúricas de rápida progresión, con compromiso cutáneo mucoso. Con sospecha de una enfermedad neutrofílica, ampollar, o infección por gérmenes oportunistas, se realizó biopsia de piel para estudio histopatológico, inmunofluorescencia directa y cultivo. Los cultivos y la inmunofluorescencia directa fueron negativos, y la anatomía patológica reveló un denso infiltrado inflamatorio con predominio neutrofílico en dermis. Ante el diagnóstico de pioderma gangrenoso ampollar, se realizó una punción-aspiración de médula ósea cuyo resultado fue compatible con leucemia mieloide aguda. Se instauró tratamiento con corticosteroides sistémicos, a pesar de lo cual la paciente evolucionó desfavorablemente y falleció a los 15 días de su ingreso hospitalario. Este caso ilustra la asociación de esta enfermedad cutánea con trastornos oncohematológicos y el mal pronóstico que esto implica a corto plazo. (AU)

Bullous pyoderma gangrenosum is an infrequent type of pyoderma gangrenosum, associated with onco hematological diseases in 50-70% of cases. We present the case of a 59-year-old patient with fever and mucocutaneous hemorrhagic bullous of rapid progression. A biopsy for histopathology, direct immunofluorescence (DIF) and skin culture was made, considering the possibility of neutrophilic dermatoses, bullous dermatosis or an opportunistic infection. The results of both the culture and the DIF were negative. The histopathological examination of the specimen revealed a dense dermal polymorphic infiltrate composed primarily of neutrophils. Considering bullous pyoderma gangrenosum as a potential diagnosis, a bone-marrow biopsy was performed. This study revealed an acute myeloid leukemia. Although systemic corticosteroid therapy was begun, the patient presented an unfavorable evolution that led to her death 15 days after her admission at the hospital. This case shows the association between bullous pyoderma gangrenosum and onco hematological diseases. In addition, it highlights the poor prognosis related to these diseases in the short term. (AU)

Unforeseen progressive outer retinal necrosis in a child following bone marrow transplant.

A 10-year-old boy underwent stem cell transplant for Hodgkin's lymphoma and developed vomiting and seizure in the postoperative period. An ophthalmic referral was made from intensive care unit, to rule out papilledema. On examination, there was no papilledema in both eyes, instead there were areas of retinal necrosis with no haemorrhages or vitritis in right eye. Cerebrospinal fluid serology was negative for herpes but MRI showed hyperintensity in temporal lobe. A clinical diagnosis of progressive outer retinal necrosis (PORN) was made and fundus picture was documented with help of a smartphone and 20D lens. High-dose intravenous injection acyclovir was started and PORN lesion improved on treatment.

In Vitro Release Testing of Acyclovir Topical Formulations Using Immersion Cells.

The objective of the study was to reinforce the applicability of the immersion cells for the in vitro release testing (IVRT) of topical formulations by using marketed acyclovir 5% cream formulation (Cream 1) as a model. The method employing the immersion cells was optimized by studying the effect of variables, such as membrane type, media temperature and volume, agitation speed, and cell size, on acyclovir release from the formulation. The in-house formulation similar to the qualitative and quantitative composition of Cream 1 and the other trial formulations with variable compositions were prepared and studied by using the immersion cells. Various other brands of acyclovir topical formulations available in the Indian market were also subjected to IVRT by using the optimized method. An increase in the media temperature from 32°C to 37°C and the stirring speed from 50 to 100 to 150 rpm led to an increase in the drug release. As the immersion cell size increased (0.5, 2 and 4 cm2 surface area), the release rate also increased. Nitrocellulose membrane showed the highest drug release and Fluoropore™the least. The optimized IVRT method could establish the differences in the drug release rates among the formulations with the altered compositions. The method could also prove its discriminatory potential for various marketed formulations. The immersion cell method could serve as a simpler, facile, and reliable aid during product development and also as a quality control tool in assessing stability, aging, and batch-to-batch uniformity of semisolid formulations.

Acyclovir inhibits channel catfish virus replication and protects channel catfish ovary cells from apoptosis.

The channel catfish virus (CCV) can cause lethal hemorrhagic infection in channel catfish, resulting in significant economic losses in the fish industry. Effective drugs for the virus are still lacking. Acyclovir is known as a potent antiviral agent against human herpes viruses and some animal DNA viruses. The present study was undertaken to explore the antiviral response and mechanism of acyclovir against CCV in channel catfish ovary (CCO) cells. Acyclovir was able to significantly inhibit the expression of viral genes related to CCV viral DNA synthesis and suppress viral replication at a safe concentration. Furthermore, acyclovir blocked the cytopathic effects and apoptosis induced by CCV, thereby maintaining the normal cellular morphological structure, as shown by the protection of CCO cells from the formation of apoptotic bodies or nuclear fragmentation. Moreover, reverse transcript quantitative polymerase chain reaction (RT-qPCR) demonstrated that acyclovir suppressed the expression of caspase 3, caspase 8 and caspase 9, while there was no significant impact on the expression of the apoptosis-inhibiting gene bcl-2 in CCV-infected cells. In addition, acyclovir did not promote the expression of immune-related genes such as MyD88, Mx1, IRF3, IRF7, IFN-I, NF-kB and IL-1ß, suggesting that the antiviral activity of acyclovir to CCV infection is not achieved by facilitating the expression of immune-related genes in CCO cells. Taken together, the results from this study suggest that acyclovir could effectively regulate CCV-induced infection, and thus is a promising therapeutic agent against CCV. Our results will aid our understanding of the pharmacological mechanisms of antiviral agents.

Impact of Adherence (Compliance) to Oral Acyclovir Prophylaxis in the Recurrence of Herpetic Keratitis: Long-Term Results From a Pediatric Cohort.

PURPOSE: To evaluate the long-term role of adherence to oral acyclovir prophylaxis in reducing the risk for recurrent herpes simplex virus keratitis (HSK) in children. METHODS: A retrospective cohort study was performed including all pediatric patients 16 years or younger) with their first HSK diagnosis and treatment at our center. Children were started on a standardized oral acyclovir prophylactic regimen after the acute phase. Adherence to prophylaxis was assessed monthly through parent interviews. The possible association between any recurrence (not only the first) and exposure to acyclovir prophylaxis was evaluated using random-effects multivariate logistic regression. RESULTS: A total of 20 eyes of 17 patients (8 boys and 9 girls) were included. The mean follow-up time was 3.5 years. Adherence to acyclovir prophylaxis was registered in 100% of patients with no recurrences and in 36.4% of patients with 1 or more recurrences (P = 0.035). All other tested variables (time of follow-up, sex, age, infectious diseases, underlying hematological diseases, eye, and HSK type) did not differ between the 2 groups. The multivariate model confirmed the lower risk for recurrence in patients who were compliant to therapy (adjusted odds ratio 0.04, 95% confidence intervals 0.00-0.42, P = 0.008). No adverse effects were recorded during follow-up. CONCLUSIONS: Oral acyclovir prophylaxis is a safe and an effective medical treatment for recurrent HSK and its long-term efficacy is associated with compliance to the therapy.

Erupción variceliforme de Kaposi y enfermedad de Darier / Kaposi's varicelliform rash and Darier's disease

La erupción variceliforme de Kaposi es una infección cutánea diseminada, causada en la mayor parte de los casos por el virus Herpes simple tipo 1. Se suele presentar en pacientes con alteraciones preexistentes de la barrera cutánea, especialmente en niños con dermatitis atópica. Se comunica el caso de un paciente de 84 años, quien negaba enfermedades cutáneas previas, que consultó por lesiones dolorosas y pruriginosas, en la piel del tórax y el abdomen, de 3 semanas de evolución. Con sospecha de una enfermedad infecciosa viral, bacteriana, ampollar o neutrofílica, se realizó inmunofluorescencia directa para herpes, cultivo y biopsia de piel para estudio histológico. La inmunofluorescencia fue positiva para Herpes simple tipo 1 y el estudio histopatológico mostró cambios compatibles con infección herpética y enfermedad de Darier. La enfermedad de Darier es una genodermatosis infrecuente que se suele manifestar en la adolescencia. Si bien su diagnóstico en la ancianidad es excepcional, este caso ilustra que se debe considerar en todos los pacientes que presenten erupción variceliforme. (AU)

Kaposi's varicelliform rash is a disseminated cutaneous infection, caused by Herpes virus 1. It usually presents in patients with pre-existing skin barrier disorders, especially in children with atopic dermatitis. We report the case of an 84-year-old patient, who reported having no previous skin diseases, who consulted for painful, itchy, 3-week-old skin lesions. As we suspected viral, bacterial, bullous or neutrophilic disease, direct immunofluorescence, culture, and skin biopsy for histological study were performed. Immunofluorescence was positive for Herpes simplex type 1 and the histopathological study showed changes compatible with herpetic infection and Darier's disease. Darier's disease is a rare genodermatosis that usually manifests in adolescence. Although its diagnosis in old age is anecdotal, it should be considered in patients with a varicelliform rash. (AU)

[An autopsy case of elderly-onset herpes simplex encephalitis with acute respiratory failure caused by brainstem lesions].

An 89-year-old man was admitted because of persistent fever and impaired consciousness. On admission, his consciousness level was E3V3M4 according to the Glasgow Coma Scale. MRI of the brain showed high intensity lesions in the bilateral cingulate gyri. In the cerebrospinal fluid, both cell counts and glucose level were in the normal ranges. He had received antibiotics and intravenous isotonic saline. On the fifth day of hospitalization, blood examination revealed elevation of anti-herpes simplex virus (HSV) immunoglobulin M antibody, and herpes simplex encephalitis (HSE) was diagnosed. Despite treatment with acyclovir, his respiratory function and consciousness level deteriorated rapidly. On the eighth day, he died of respiratory failure. At autopsy, the brain showed multiple softenings of the gray and white matter in the hippocampus, amygdala, and temporal, insular, and cingulate cortices. Some of these lesions were hemorrhagic. Microscopic examination revealed that the lesions were necrotic and associated with perivascular inflammatory cell infiltration in the limbic system, hypothalamus, brainstem tegmentum area, and medulla. Eosinophilic intranuclear inclusions were rarely found in the astrocytes in the medulla. Immunohistochemistry revealed anti-HSV-1 antibody positive neurons in the brainstem tegmentum including reticular formation and the raphe nuclei. HSV-DNA was also detected in the postmortem cerebrospinal fluid. This was a rare case of HSE in which inflammation in the brainstem proved to be the cause of lethal respiratory failure.