Evaluation of the antimalarial properties of Solanum incanum L. leaf extract fractions and its ability to downregulate delta aminolevulinate dehydratase to prevent the establishment of malaria infection.

ETHNOPHARMACOLOGICAL RELEVANCE: Solanum incanum L. is commonly used in traditional herbal medicine (THM) in Kenya for treating various ailments. Recent developments in disease treatment have introduced the concept of host-directed therapy (HDT). This approach involves targeting factors within the host cell that can impede the growth or replication of a pathogen. One such host factor is delta aminolevulinate dehydratase (δ-ALAD), the second enzyme in the heme biosynthesis pathway utilized by Plasmodium for growth. Studies using mice models have shown an increase in δ-ALAD expression during Plasmodium berghei infection. Another plant in the Solanum genus, S. guaranticum, has been found to inhibit δ-ALAD in red blood cells in vitro and in the brain in vivo. Is it possible that the bioactive compounds in S. incanum extracts could also be effective in HDT for malaria treatment? AIM OF STUDY: To better assess the effectiveness of S. incanum leaf extracts as a curative and prophylaxis in malaria parasite infection, and to test the plant's ability to decrease δ-ALAD expression. MATERIALS AND METHODS: The leaves of S. incanum were collected, dried, and pulverized before being subjected to a successive extraction protocol to obtain crude, hexane, ethyl acetate, and aqueous extract fractions. Phytochemical analysis was conducted on all extract fractions, followed by GC-MS analysis of the fraction with the most potent antimalarial activity. An acute toxicity study was also performed on the extracted fractions. The potency of the extract fractions as curative and prophylactic antimalarial was then evaluated in THM using Plasmodium berghei-infected mice at a dose of 100 mg/kg. The extract fraction with the highest activity was further evaluated at varying doses and its effect on δ-ALAD was measured using RT-qPCR. The percentage of parasitemia and chemosuppression, and mean survival time were used as indices of activity. RESULTS: Phytochemical analysis revealed that the ethyl acetate and aqueous extract fractions contained high terpenoids, flavonoids, and phenols levels. However, alkaloids were only present in moderate quantities in the aqueous extract, and quinones were found in high levels only in the crude extract. Additionally, all extract fractions contained saponins in high levels but lacked tannins. While the plant extracts were found to be non-toxic, they did not exhibit curative antimalarial activity. However, all extract fractions showed prophylactic antimalarial activity, with the ethyl acetate extract having the highest percentage of chemosuppression even at doses of 250 and 1000 mg/kg. In the negative control, the expression of δ-ALAD was 5.4-fold, but this was significantly reduced to 2.3-fold when mice were treated with 250 mg/kg of the ethyl acetate fraction. GC-MS analysis of the ethyl acetate fraction revealed high percentages of 2-methyloctacosane, tetracosane, and decane. CONCLUSION: The fractions extracted from S. incanum leaves have been found to possess only antimalarial prophylactic properties, with the ethyl acetate extract fraction showing the most effective results. The activity of this fraction may be attributed to its ability to decrease the expression of δ-ALAD, as it contains an alkane compound implicated with enzyme-inhibitory activity.

[Acute hepatic porphyrias]. / Akute hepatische Porphyrien.

Acute porphyrias are caused by rare hereditary disorders of hepatic heme biosynthesis. Episodes of accumulating neurotoxic metabolites lead to multisystemic symptoms such as visceral pain, autonomic dysregulation, neurocognitive impairment, hyponatremia, and occasionally motor paralysis. In addition to protracted non-emergency courses, acute life-threatening crises can occur, often triggered by infection, medication, fasting, or hormonal stimuli. Since the clinical presentation is nonspecific and multifaceted, many patients have gone through a long odyssey until they receive a diagnosis. Acute attacks often lead to presenting initially to the emergency department, where acute hepatic porphyria (AHP) is easily overlooked in the differential diagnosis. Establishing the diagnosis requires a high level of genuine suspicion (e.g., cluster of signs and symptoms along with certain patterns of health care resource utilization). The initial diagnostic work-up requires the measurement of metabolites in the urine. Emergency management consists of infusions of glucose and heme arginate along with symptomatic therapy. However, porphyrinogenic agents must be strictly avoided ( www.drugs-porphyria.org ). After initial diagnosis, a thorough work-up should be done at a porphyria center (confirming the diagnosis, education, genetic counselling) and issuance of an emergency identification card is mandatory. If the frequency of relapses is high, new targeted prophylactic therapies have proven effective. Patients with known porphyria require special attention in any acute medical condition in order to avoid porphyrinogenic triggers and to exclude threatening differential diagnosis (e.g., sepsis) by consistent basic diagnostics.

Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives.

Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks, characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion, hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, [Formula: see text]-aminolaevulinic acid and porphyrins using a single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe, potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges, and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations.

Terapia fotodinámica con luz de día en el tratamiento de la queilitis actínica / Actinic Cheilitis Treated With Daylight Photodynamic Therapy

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Documento de consenso hispano-portugués para el uso de la terapia fotodinámica con metil aminolevulinato y luz de día en el tratamiento de las queratosis actínicas / Spanish-Portuguese Consensus Statement on Use of Daylight-Mediated Photodynamic Therapy With Methyl Aminolevulinate in the Treatment of Actinic Keratosis

INTRODUCCIÓN: La terapia fotodinámica con luz de día (TFDLD) es una nueva modalidad de terapia fotodinámica (TFD) que, manteniendo la misma eficacia en queratosis actínicas (QA) grado Iy II que la técnica convencional, disminuye sus efectos adversos y la hace más eficiente. Los condicionantes meteorológicos propios de la España y Portugal hacen necesario el establecimiento de un protocolo adecuado y consensuado por expertos adaptado a los mismos. OBJETIVO: Establecer un protocolo para la TFDLD con metil-aminolevulinato (MAL) para el tratamiento de las QA grado I y II adecuado y consensuado a las características epidemiológicas, meteorológicas y clínicas que se dan en España y Portugal. MÉTODO: Doce dermatólogos de diferentes áreas geográficas de ambos países, con experiencia en el tratamiento de las QA con TFD, se reunieron para elaborar un documento de consenso para la realización de TFDLD con MAL. De la revisión de la bibliografía y de su experiencia se elaboró el procedimiento recomendado para su realización. RESULTADOS: Las recomendaciones adoptadas establecen que los pacientes con QA grado I y II múltiples, especialmente en el contexto de campo de cancerización, son los candidatos a realizar este tratamiento. La TFDLD se puede realizar durante todo el año, siendo limitaciones las temperaturas menores de 10°C o las excesivamente elevadas, así como los días de lluvia, nieve o niebla. El procedimiento es sencillo y requiere la aplicación de un fotoprotector FPS>30 que solo contenga filtros orgánicos, la preparación adecuada de las lesiones, la aplicación del MAL sin oclusión y su activación con la luz del día durante 2h. CONCLUSIÓN: Este documento de consenso supone una guía práctica y detallada para la realización de la TFDLD con MAL en España y Portugal destinada a la consecución de la máxima efectividad con mínimos efectos adversos

INTRODUCTION: Daylight-mediated photodynamic therapy (PDT) is a new type of PDT that is as effective as conventional PDT in grade 1 and 2 actinic keratosis but with fewer adverse effects, resulting in greater efficiency. The climatic conditions in the Iberian Peninsula require an appropriately adapted consensus protocol. OBJECTIVE: We describe a protocol for the treatment of grade 1 and 2 actinic keratosis with daylight-mediated PDT and methyl aminolevulinate (MAL) adapted to the epidemiological and clinical characteristics of Spanish and Portuguese patients and the climatic conditions of both countries. METHODS: Twelve dermatologists from different parts of Spain and Portugal with experience in the treatment of actinic keratosis with PDT convened to draft a consensus statement for daylight-mediated PDT with MAL in these countries. Based on a literature review and their own clinical experience, the group developed a recommended protocol. RESULTS: According to the recommendations adopted, patients with multiple grade 1 and 2 lesions, particularly those at risk of developing cancer, are candidates for this type of therapy. Daylight-mediated PDT can be administered throughout the year, although it is not indicated at temperatures below 10°C or at excessively high temperatures. Likewise, therapy should not be administered when it is raining, snowing, or foggy. The procedure is simple, requiring application of a sunscreen with a protection factor of at least 30 based exclusively on organic filters, appropriate preparation of the lesions, application of MAL without occlusion, and activation in daylight for 2hours. CONCLUSION: This consensus statement represents a practical and detailed guideline to achieve maximum effectiveness of daylight-mediated PDT with MAL in Spain and Portugal with minimal adverse effects

Estudio retrospectivo, descriptivo y observacional del tratamiento de queratosis actínicas múltiples con metilaminolevulinato tópico y luz roja: resultados en la práctica clínica y correlación con la imagen de fluorescencia / Retrospective, descriptive, observational study of treatment of multiple actinic keratoses with topical methyl aminolevulinate and red light: results in clinical practice and correlation with fluorescence imaging

Introducción. Las queratosis actínicas (QA) son una de las patologías cutáneas más frecuentes en la práctica clínica. En los últimos 5 años se han publicado varios estudios que evaluaban la eficacia de la terapia fotodinámica (TFD) en el tratamiento de múltiples QA. Objetivo. Evaluar los resultados de la TFD de múltiples QA por localizaciones y su correlación con la imagen de fluorescencia. Material y métodos. Realizamos un estudio retrospectivo, descriptivo y observacional de los pacientes tratados por múltiples QA con TFD en nuestro hospital. Se describe la edad, el sexo y la localización de las lesiones (cara, cuero cabelludo y dorso de las manos) de los 57 pacientes. Se trató a todos los pacientes usando los mismos parámetros: ácido metilaminolevulínico (MAL, Metvix®) ocluido tres horas e irradiación con luz roja de 630 nm, 37 J/cm2, 7,5 minutos (Aktilite®). Se describe la respuesta, período de remisión, tolerancia, número de sesiones y la fluorescencia según localizaciones. Con la prueba Chi-cuadrado se evalúan las diferencias entre localizaciones y la correlación de la imagen de fluorescencia con la respuesta clínica. Resultados. En la cara se obtiene mayor grado de mejoría, se requieren menor número de sesiones y mayores períodos de remisión que en el resto de las localizaciones. El dorso de las manos es la zona mejor tolerada. Existe una correlación alta y significativa entre el área de fluorescencia y su disminución al aplicar el tratamiento, con el grado de respuesta clínica. Conclusiones. Los resultados en el tratamiento de múltiples QA con TFD son mejores, globalmente, en la cara que en el cuero cabelludo y en el dorso de manos. El diagnóstico de fluorescencia puede ser una herramienta eficaz para predecir la respuesta al tratamiento (AU)

Background. Actinic keratosis (AK) is one of the most common skin diseases seen in clinical practice. In the last 5 years, several studies assessing the efficacy of photodynamic therapy in the treatment of multiple AKs have been published. Objective. We aimed to assess the clinical outcomes of photodynamic therapy in patients with multiple AKs and the correlation of those outcomes with fluorescence imaging. Material and methods. In this retrospective, descriptive, observational study of 57 patients treated in our hospital with photodynamic therapy for multiple AKs, we recorded age, sex, and lesion site (face, scalp, and dorsum of the hands). All patients were treated in the same way: methyl aminolevulinic acid (Metvix®) was applied for 3 hours and the skin then irradiated with red light at630 nm, 37 J/cm2, for 7.5 minutes (Aktilite®). The response, remission duration, tolerance, number of sessions, and fluorescence images were recorded by site. The X2 test was used to assess between-site differences and the correlation between fluorescence imaging and clinical response. Results. The greatest improvements were obtained for facial lesions; these required fewer sessions and remission lasted longer than lesions at other sites. The treatment was best tolerated on the dorsum of the hands. The fluorescence area and the reduction in intensity on applying treatment were found to be strongly and significantly correlated with the extent of clinical response. Conclusions. Overall, the outcomes of treatment of multiple AKs with photodynamic therapy are better for the face than for the scalp and dorsum of the hands. Fluorescence imaging may be an effective tool for predicting response to treatment (AU)

Photodynamic therapy of head and neck tumors and non-tumor like disorders.

In conclusion, we would like to emphasize that photodynamic therapy can be used as a convenient and promising tool in the treatment of various malignancies in the head and neck area. It has to be stressed that PDT is still less effective in the treatment of more advanced cases of head and neck cancer. As the method of treatment which improves the quality of life, its usefulness can be considered as well as palliative treatment of non-operative cases. Although the method is not free of several side effects, such skin phototoxicity, burning, slight pain and edema in the irradiated location. All these side effects are transient and usually they disappear within 24 hours. The photodynamic treatment always results in excellent cosmetic effects without scarring or marring which are usually encountered after routine surgical operation.

Enzyme replacement therapy in porphyrias--IV. First successful human clinical trial of delta-aminolevulinate dehydratase-loaded erythrocyte ghosts.

A patient with chronic lead intoxication was treated with only one course of highly purified human blood aminolaevulinate dehydratase entrapped in autologous erythrocyte ghosts given intravenously. No untoward effects were observed during or after infusion. An immediate increase in the patient's erythrocyte dehydratase activity was detected 1 hr after enzyme administration, reaching its maximum and nearly normal level 2 days later, values remained unchanged for a week, to slowly diminish after 2 weeks of initiated the treatment, and finally recovered activity was kept practically leveled off for weeks. This novel therapeutic trial produced complete improvement both clinical and biochemical, showing that enzyme infusion has been beneficial and can be safely and successfully used in the treatment of human lead intoxication.