Dapsone-Induced Methemoglobinemia: A Case Report.

Here, we present the case of a 64-year-old male with a rare cause of cyanosis due to dapsone-induced methemoglobinemia who was treated successfully with methylene blue and high-dose Vitamin C. Our case emphasizes the importance of history taking, knowledge, and high index of suspicion of drug-induced methemoglobinemia, especially in the presence of saturation gap. This condition can be fatal if left untreated.

Disease Burden and Current Therapeutical Status of Leprosy with Special Emphasis on Phytochemicals.

BACKGROUND: Leprosy (Hansen's disease) is a neglected tropical disease affecting millions of people globally. The combined formulations of dapsone, rifampicin and clofazimine (multidrug therapy, MDT) is only supportive in the early stage of detection, while "reemergence" is a significant problem. Thus, there is still a need to develop newer antileprosy molecules either of natural or semi-synthetic origin. OBJECTIVES: The review intends to present the latest developments in the disease prevalence, available therapeutic interventions and the possibility of identifying new molecules from phytoextracts. METHODS: Literature on the use of plant extracts and their active components to treat leprosy was searched. Selected phytoconstituents were subjected to molecular docking study on both wild and mutant types of the Mycobacterium leprae. Since the M. leprae dihydropteroate synthase (DHPS) is not available in the protein data bank (PDB), it was modelled by the homology model method and validated with the Ramachandran plot along with other bioinformatics approaches. Two mutations were introduced at codons 53 (Thr to Ile) and 55 (Pro to Leu) for docking against twenty-five selected phytoconstituents reported from eight plants that recorded effective anti-leprosy activity. The chemical structure of phytochemicals and the standard dapsone structure were retrieved from the PubChem database and prepared accordingly for docking study with the virtual-screening platform of PyRx-AutoDock 4.1. RESULTS: Based on the docking score (kcal/mol), most of the phytochemicals exhibited a higher docking score than dapsone. Asiaticoside, an active saponin (-11.3, -11.2 and -11.2 kcal/mol), was proved to be the lead phytochemical against both wild and mutant types DHPS. Some other useful phytoconstituents include echinocystic acid (-9.6, -9.5 and -9.5 kcal/mol), neobavaisoflavone (-9.2, -9.0 and -9.0 kcal/mol), boswellic acid (-8.90, -8.90 and -8.90 kcal/mol), asiatic acid (-8.9, -8.8 and -8.9 kcal/mol), corylifol A (-8.8, 8.0, and -8.0), etc. Overall, the computational predictions support the previously reported active phytoextracts of Centella asiatica (L.) Urban, Albizia amara (Roxb.) Boivin, Boswellia serrata Roxb. and Psoralea corylifolia L. to be effective against leprosy. CONCLUSION: A very small percentage of well-known plants have been evaluated scientifically for antileprosy activity. Further in vivo experiments are essential to confirm anti-leprosy properties of such useful phytochemicals.

[Flame figures-eosinophils setting the skin on fire]. / Flammenfiguren ­ Eosinophile, die die Haut in Brand setzen.

A 50-year-old female farmer was initially diagnosed with generalized granuloma annulare and treated with local steroids and ultraviolet (UV) light therapy for 10 years, albeit without success. A histopathological examination in our clinic changed the diagnosis to Wells' syndrome, based on the typical findings of eosinophilic cellulitis together with flame figures. A systemic approach with pulse steroid therapy resulted in complete remission of pruritus and skin manifestations. This case demonstrates successful treatment of a patient with eosinophilic cellulitis.

A Case Report of Cyanosis With Refractory Hypoxemia: Is It Methemoglobinemia?

Dapsone is used in the treatment of a variety of dermatological conditions and prophylaxis of opportunistic infections. However, if consumed at a dose of more than 200 mg/day, it can cause methemoglobinemia, a condition characterized by elevated methemoglobin levels in the blood; methemoglobin is an abnormal form of hemoglobin, containing iron in the ferric state (Fe3 +) rather than the reduced ferrous form (Fe2 +) found in hemoglobin. A small amount of it is produced in the body due to oxidant damage to the red blood cells. Methemoglobinemia can cause varied clinical manifestations involving the cardio-respiratory and nervous systems depending upon the level of methemoglobin. While it could be congenital, it is commonly caused by exposure to drugs that cause oxidation of hemoglobin, such as benzocaine, dapsone, and nitrates. We report a case of dapsone-induced methemoglobinemia in a previously healthy young female who had consumed 15 tablets of dapsone 100 mg with suicidal intent. She presented with central cyanosis, breathlessness, and altered sensorium after five days of consumption. While the pulse-oximeter showed oxygen saturation (SaO2) of 84%, arterial blood gas (ABG) analysis showed partial pressure of oxygen (PaO2) of 427 mmHg and SaO2 of 98%. This "saturation gap" occurred due to the presence of the abnormal hemoglobin variant. Her cyanosis did not improve despite giving 100% supplemental oxygen. There was no cardiac or respiratory cause to account for her cyanosis. Her methemoglobin level was 45.8%. She was successfully treated with specific antidote methylene blue, mechanical ventilation, and other symptomatic measures. The purpose of this presentation is to help clinicians recognize this condition early, because, if left untreated, it might prove fatal. The diagnostic clues include refractory hypoxemia, central cyanosis in the absence of cardiac and respiratory causes, saturation gap, and chocolate-colored blood.

Lagerstroemia speciosa (L.) Pers., ethanolic leaves extract attenuates dapsone-induced liver inflammation in rats.

Drug-induced liver injury is a common cause of acute liver failure. Dapsone is increasingly used in combination with rifampicin for the treatment of leprosy and also for several dermatological disorders. Clinically, abnormal liver function and focal bile duct destruction were reported after dapsone therapy. Lagerstroemia speciosa Pers., commonly known as Banaba has been traditionally used to treat various ailments including diabetes and obesity due to its antioxidant and anti-inflammatory efficacies. This study investigated the hepatoprotective effect of ethanolic banaba leaves extract (EBLE) against dapsone-induced hepatotoxicity in rats. Dapsone (30 mg/kg, i.p.) was administered twice daily for 30 days. In separate groups, rats were post-treated orally with EBLE (250 and 500 mg/kg) and silymarin (100 mg/kg) once daily for 30 days after dapsone administration. The marker enzymes of hepatotoxicity, oxidative stress markers, inflammatory markers and histopathology of liver were done. HPTLC analysis confirmed the presence of 12.87 µg of corosolic acid per mg of EBLE. Dapsone administration-induced significant (p < 0.001) elevation of marker enzymes of hepatotoxicity in serum. This treatment also increased lipid peroxidation (p < 0.001) and pro-inflammatory markers (tumor necrosis factor-alpha, transforming growth factor-beta, and nuclear factor kappa-B) expressions (p < 0.001) and decreased antioxidants (p < 0.001) such superoxide dismutase, catalase and glutathione in the liver tissue. All these abnormalities were significantly (p < 0.001) mitigated after EBLE (500 mg/kg) and silymarin post-treatments. The results of this study suggest that silymarin and EBLE can be used for dapsone-induced hepatotoxicity.

Endometriosis Susceptibility to Dapsone-Hydroxylamine-Induced Alterations Can Be Prevented by Licorice Intake: In Vivo and In Vitro Study.

Endometriosis, an estrogen-dependent chronic gynecological disease, is characterized by a systemic inflammation that affects circulating red blood cells (RBC), by reducing anti-oxidant defenses. The aim of this study was to investigate the potential beneficial effects of licorice intake to protect RBCs from dapsone hydroxylamine (DDS-NHOH), a harmful metabolite of dapsone, commonly used in the treatment of many diseases. A control group (CG, n = 12) and a patient group (PG, n = 18) were treated with licorice extract (25 mg/day), for a week. Blood samples before (T0) and after (T1) treatment were analyzed for: i) band 3 tyrosine phosphorylation and high molecular weight aggregates; and ii) glutathionylation and carbonic anhydrase activity, in the presence or absence of adjunctive oxidative stress induced by DDS-NHOH. Results were correlated with plasma glycyrrhetinic acid (GA) concentrations, measured by HPLC-MS. Results showed that licorice intake decreased the level of DDS-NHOH-related oxidative alterations in RBCs, and the reduction was directly correlated with plasma GA concentration. In conclusion, in PG, the inability to counteract oxidative stress is a serious concern in the evaluation of therapeutic approaches. GA, by protecting RBC from oxidative assault, as in dapsone therapy, might be considered as a new potential tool for preventing further switching into severe endometriosis.

Comparative assessment of interventions for treating cutaneous leishmaniasis: A network meta-analysis of randomized clinical trials.

INTRODUCTION: Various interventions including laser therapy, heat therapy, and several drugs have been trialed in patients with cutaneous leishmaniasis. Due to the lack of an evidence-based comparison of all these interventions, we carried out the present network meta-analysis. METHODS: Electronic databases were searched for randomized clinical trials evaluating the efficacy and safety of any interventions in patients with cutaneous leishmaniasis. The proportion of patients with complete cure was the primary outcome. The proportion of lesions cured at the end of treatment, the proportion of lesions with minimal/no response to treatment, and proportion of wounds with minimal/no change were the secondary outcomes. Random-effects modeling was used for generating pooled estimates. Rankogram plot was used for identifying the 'best intervention'. For interventions containing a combination of treatments, backslash (/) has been used for depicting the same. RESULTS: One-hundred and thirty-one studies were included. Intralesional meglumine, topical paromomycin/gentamicin, topical paromomycin, parenteral sodium stibogluconate, topical honey/intralesional meglumine, topical liposomal amphotericin B, oral zinc sulphate, oral miltefosine, parenteral meglumine, heat therapy, topical liposomal azithromycin, intralesional meglumine/silver dressing, intralesional sodium stibogluconate, parenteral meglumine/intralesional meglumine, oral allopurinol/parenteral meglumine, topical trichloroacetic acid/heat therapy, oral zinc sulphate/oral ketoconazole, topical imiquimod/cryotherapy, intralesional meglumine/cryotherapy, topical herbal extract of Z-HE, parenteral pentamidine, topical trichloroacetic acid/intralesional meglumine, carbon-dioxide laser, topical recombinant granulocyte-macrophage colony-stimulating factor/parenteral meglumine, intralesional dapsone, carbon-dioxide laser/intralesional meglumine, moist wet dressing with sodium hypochlorite, parenteral sodium stibogluconate/intralesional recombinant granulocyte-macrophage colony-stimulating factor, oral dapsone, intralesional sodium stibogluconate/oral ketoconazole, intralesional sodium stibogluconate/parenteral sodium stibogluconate and electrocautery/moist wet dressing with sodium hypochlorite were observed with significantly greater proportion of patients with complete cure compared to placebo/untreated controls. Rankogram analysis revealed that parenteral pentamidine has the highest statistical probability of being the best in the pool. CONCLUSION: We observed several interventions to be effective for treating cutaneous leishmaniasis. However, greater caution is required in interpreting the results as the estimates are likely to change with the advent of results from future studies.

Time-Dependent Effects in Chronic Urticaria: A Time-Series Perspective of Omalizumab Treatment.

BACKGROUND: Chronic spontaneous urticaria (CSU, or CU) is a disease that significantly affects the quality of life of patients. It is a chronic disease and requires a specialized approach to diagnosis and treatment. In recent years, the disease has been of great interest due to the existence of new targeted therapeutic approaches. AIM: The present study aims at analyzing CU score concerning time, as a time-series. The authors have attempted to model the investigated time-series to unravel possible causative relationships. METHODS: 108 patients (25Males/83Females) admitted to our department were diagnosed with CU. CU was estimated on a score basis, which was used to define disease severity. Urticaria score was assessed on the basis of Urticaria Activity Score 7 (UAS7). The mean CU score, the mean CU score rate concerning the first month at diagnosis as well as the monthly CU score rate were calculated. RESULTS: Gender is a factor that influences CU score with time. In addition, there was a significant finding that time-series differ with the administration of monotherapy or complementary therapy. CONCLUSION: We have found that females are more prone to CU, while omalizumab monotherapy has more beneficial results as compared to the application of concurrent and maintenance therapies. Further, patients with co-morbidities were more likely to interrupt treatment. Finally, and most significantly, it was shown that monthly CU score rate manifested an oscillatory pattern, which was modelled with the sum of sines functions, highlighting a relative immunological pattern.

Effect of Three Chinese Herbs Processed with Different Proportions of Glycyrrhizae Radix et Rhizoma on Pharmacokinetics of Dapsone in Rats / 中国实验方剂学杂志

Objective::To investigate the processing purpose of Morindae Officinalis Radix (MO), Euodiae Fructus (EF) and Polygalae Radix (PR) processed by Glycyrrhizae Radix et Rhizoma (Gly). Method::The content of dapsone in rat plasma was determined by high performance liquid chromatography (HPLC), the mobile phase was acetonitrile (A)-water (B) for gradient elution (0-5 min, 10%-25%A; 5-20 min, 25%A) and detection wavelength was set at 292 nm. PK Solution 2.0 software was used to simulate pharmacokinetic parameters. Result::Within 300 min after dapsone was administrated, compared with the control (CTL) group, the elimination of dapsone was slowed down and its plasma concentration was increased in the unprocessed product of MO (UMO) group. The elimination of dapsone was accelerated and its peak concentration (Cmax) was decreased in the processed products of MO with Gly (GMO) groups, and they had positive correlation with proportion of Gly in GMO. Compared with the CTL group, the elimination of dapsone was slowed down, and its plasma concentration was increased and its peak time (Tmax) was postponed in the unprocessed product of EF (UEF) group, while their Cmax and Tmax were changed in the processed products of EF with Gly (GEF) groups. Compared with the CTL group, the elimination of dapsone was slowed down and its plasma concentration was increased in the unprocessed product of PR (UPR) group, while the elimination was accelerated and its plasma concentration was decreased in the processed products of PR with Gly (GPR) groups. Conclusion::The elimination of dapsone is slowed down in rats administered with UMO, UEF and UPR, while its elimination is accelerated in rats administered with the processed products of these three herbs with different proportions of Gly. Among the proportions, effect of processed products of these three herbs with 100∶6 (ratio of unprocessed product-Gly) on pharmacokinetics of dapsone is not significant.

Dapsone Resistance in Leprosy Patients Originally from American Samoa, United States, 2010-2012.

Skin biopsies from US leprosy patients were tested for mutations associated with drug resistance. Dapsone resistance was found in 4 of 6 biopsies from American Samoa patients. No resistance was observed in patients from other origins. The high rate of dapsone resistance in patients from American Samoa warrants further investigation.

Dapsone-Loaded Invasomes as a Potential Treatment of Acne: Preparation, Characterization, and In Vivo Skin Deposition Assay.

Dapsone (DPS) is a unique sulfone with antibiotic and anti-inflammatory activity. Owing to its dual action, DPS has a great potential to treat acne. Topical DPS application is expected to be effective in treatment of mild to moderate acne conditions. Invasomes are novel vesicles composed of phosphatidylcholine, ethanol, and one or mixture of terpenes of enhanced percutaneous permeation. In this study, DPS-loaded invasomes were prepared using the thin film hydration technique. The effect of different terpenes (Limonene, Cineole, Fenchone, and Citral) in different concentrations on the properties of the prepared DPS-loaded invasomes was investigated using a full factorial experimental design, namely, the particle size, drug entrapment, and release efficiency. The optimized formulation was selected for morphological evaluation which showed spherical shaped vesicles. Further solid-state characterization using differential scanning calorimetry and X-ray diffractometry revealed that the drug was dispersed in an amorphous state within the prepared invasomes. Finally, the ability of the prepared DPS-loaded invasomes to deliver DPS through the skin was investigated in vivo using wistar rats. The maximum in vivo skin deposition amount of DPS was found to be 4.11 mcg/cm2 for invasomes versus 1.71 mcg/cm2 for the drug alcoholic solution, representing about 2.5-fold higher for the invasomes compared to the drug solution. The AUC0-10 calculated for DPS-loaded invasomes was nearly 2-fold greater than that of DPS solution (14.54 and 8.01 mcg.h/cm2 for the optimized invasomes and DPS solution, respectively). These results reveal that the skin retention of DPS can be enhanced using invasomes.

Antimicrobial resistance in leprosy: results of the first prospective open survey conducted by a WHO surveillance network for the period 2009-15.

OBJECTIVES: Antimicrobial resistance (AMR) is a priority for surveillance in bacterial infections. For leprosy, AMR has not been assessed because Mycobacterium leprae does not grow in vitro. We aim to obtain AMR data using molecular detection of resistance genes and to conduct a prospective open survey of resistance to antileprosy drugs in countries where leprosy is endemic through a WHO surveillance network. METHODS: From 2009 to 2015, multi-bacillary leprosy cases at sentinel sites of 19 countries were studied for resistance to rifampicin, dapsone and ofloxacin by PCR sequencing of the drug-resistance-determining regions of the genes rpoB, folP1 and gyrA. RESULTS: Among 1932 (1143 relapse and 789 new) cases studied, 154 (8.0%) M. leprae strains were found with mutations conferring resistance showing 182 resistance traits (74 for rifampicin, 87 for dapsone and 21 for ofloxacin). Twenty cases showed rifampicin and dapsone resistance, four showed ofloxacin and dapsone resistance, but no cases were resistant to rifampicin and ofloxacin. Rifampicin resistance was observed among relapse (58/1143, 5.1%) and new (16/789, 2.0%) cases in 12 countries. India, Brazil and Colombia reported more than five rifampicin-resistant cases. CONCLUSIONS: This is the first study reporting global data on AMR in leprosy. Rifampicin resistance emerged, stressing the need for expansion of surveillance. This is also a call for vigilance on the global use of antimicrobial agents, because ofloxacin resistance probably developed in relation to the general intake of antibiotics for other infections as it is not part of the multidrug combination used to treat leprosy.

[Topical corticosteroids as a therapeutic alternative in linear immunoglobulin A bullous dermatosis in childhood: case report]. / Corticoides tópicos como alternativa terapéutica en la dermatosis ampollosa por inmunoglobulina A lineal de la infancia: caso clínico.

Linear immunoglobulin A dermatosis of childhood is a rare autoimmune disorder. Its etiology remains unknown, although it has been linked to drugs, infections, immunological diseases and lymphoproliferative processes. We report the case of a 6 year old girl who consulted for perioral bullous lesions without other symptoms. Neither treatment with mupirocin nor methylprednisolone therapy achieved remission of cutaneous lesions. Skin biopsy showed a linear immunoglobulin A dermatosis. It was not possible to start treatment with dapsone because of a partial glucose-6-phosphate dehydrogenase deficiency, so topical treatment was maintained with good evolution of lesions. Linear immunoglobulin A dermatosis is a rare disease whose differential diagnosis includes other bullous diseases. Pathology is essential for diagnosis. When treatment with dapsone is not possible, topical corticosteroids may be an alternative, either alone or associated with other treatments.

La dermatosis por inmunoglobulina A lineal de la infancia es un trastorno autoinmunitario poco frecuente. Su etiología es desconocida, aunque se ha relacionado con fármacos, infecciones, enfermedades inmunológicas y procesos linfoproliferativos. Presentamos el caso de una niña de 6 años que consultaba por lesiones ampollosas periorales, sin otra sintomatología. Se pautó un tratamiento con mupirocina tópica primero y luego con metilprednisolona tópica, sin resolución del cuadro. Se realizó una biopsia cutánea, compatible con dermatosis por inmunoglobulina A lineal. No fue posible iniciar el tratamiento con dapsona por déficit parcial de glucosa-6-fosfato deshidrogenasa, por lo que se mantuvo el tratamiento tópico, con buena evolución de las lesiones. La dermatosis por inmunoglobulina A lineal es una enfermedad poco frecuente, cuyo diagnóstico diferencial incluye otras enfermedades ampollosas. La anatomía patológica es esencial para el diagnóstico. Si no es posible el tratamiento con dapsona, los corticoides tópicos pueden ser una alternativa, tanto en monoterapia como asociados a otros tratamientos.

Dapsone in the treatment of pemphigus vulgaris: adverse effects and its importance as a corticosteroid sparing agent

Pemphigus vulgaris is an autoimmune disease characterized by suprabasal blisters with acantholysis, which has a fatal course in a large number of untreated patients. Systemic corticosteroid therapy is considered first-line therapy. Adjuvant treatment with the goal of sparing corticosteroids include, among others, dapsone. This drug is not without side effects and its use requires clinical and laboratory control. We present a patient with PV initially managed with suboptimal dose of prednisone, evolving into drug-induced hepatitis after introduction of dapsone.

Synthesis and evaluation of novel dapsone-thalidomide hybrids for the treatment of type 2 leprosy reactions.

We synthesized a series of novel dapsone-thalidomide hybrids (3a-i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125 µM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions.

High-dose Vitamin C therapy in Methemoglobinemia

Methylene blue is the first choice antidote for management of methemoglobinemia, however, some patients are refractory to methylene blue and in most cases, methylene blue cannot be available instantly in Korean emergency departments because of import suspension. A 69-year-old woman visited our emergency department for tachypnea and cyanosis after ingesting 30 tablets of dapsone. Because methylene blue was not available, we intravenously administrated 10 g of vitamin C for symptomatic methemoglobinemia. Repeated i.v. administrations of 10 g of vitamin C in patient without preexisting renal insufficiency successfully treated dapsone-induced methemoglobinemia without causing renal complications. Thus, we recommend that if methylene blue is unavailable or methemoglobinemia is refractory to methylene blue, repeated administrations of 10 g of vitamin C may be considered for the treatment of methemoglobinemia in patients without renal insufficiency.

Dapsone as an alternative therapy in children with familial mediterranean Fever.

OBJECTIVE: Familial Mediterranan Fever is an hereditary autoinflammatory disease that presents with recurrent febrile attacks and poly serositis. Colchicine is the only known treatment in this diease. However, nearly 5-10% of patients are resistant to colchicines. There are many different modalities in colchicine resistant patients, biologic and immunosupressive drugs being the known ones. We studied the efficacy of Dapsone as an anti inflammatory drug in children with FMF who did not tolerate colchicine well. METHODS: This is a case series study in 10 patients who had FMF on the base of Tel-Hashomer criteria and did not tolerate colchicine or did not respond to it well. Patients took 2mg/kg dapsone in single dose, during 6 months. FINDINGS: In four patients episodic attacks returned after 27 days, so the drug was discontinued. One patient refused to continue the study; in five patients dapsone was taken in average for 8 months and 6 days, at least for 6 months. These five patients had no episodes of attack during the following observation. CONCLUSION: Dapsone could control episodic attacks of FMF in 50% of cases. It might be considered as an alternative therapy in FMF cases not responding to colchicine.

L-arginine, a nitric oxide precursor, reduces dapsone-induced methemoglobinemia in rats

Dapsone use is frequently associated to hematological side effects such as methemoglobinemia and hemolytic anemia, which are related to N-hydroxylation mediated by the P450 enzyme system. The aim of the present study was to evaluate the influence of L-arginine supplementation, a precursor for the synthesis of nitric oxide, as single or multiple dose regimens on dapsone-induced methemoglobinemia. Male Wistar rats were treated with L-arginine at 5, 15, 30, 60 and 180 mg/kg doses (p.o., gavage) in single or multiple dose regimens 2 hours prior to dapsone administration (40 mg/kg, i.p.). The effect of the nitric oxide synthase inhibitor L-NAME was investigated by treatment with multiple doses of 30 mg/kg (p.o., gavage) 2 hours before dapsone administration. Blood samples were collected 2 hours after dapsone administration. Erythrocytic methemoglobin levels were assayed by spectrophotometry. The results showed that multiple dose supplementations with 5 and 15 mg/kg L-arginine reduced dapsone-induced methemoglobin levels. This effect is mediated by nitric oxide formation, since the reduction in methemoglobin levels by L-arginine is blocked by simultaneous administration with L-NAME, a nitric oxide synthase inhibitor.

O uso da dapsona é frequentemente associado a efeitos adversos hematológicos, como a metemoglobinemia e anemia hemolítica, ambos relacionados com a N-hidroxilação mediada pelo sistema P450. O objetivo do estudo foi avaliar a influência da suplementação de L-arginina, um precursor da síntese de óxido nítrico, administrado em regime de dose única ou múltipla na metemoglobinemia induzida pela dapsona. Ratos machos Wistar foram tratados com L-arginina (po, gavagem) em dose única ou múltipla de 5, 15, 30, 60 e 180 mg/kg 2 horas antes da administração de dapsona (40 mg/kg, ip). O efeito do L-NAME, um inibidor de óxido nítrico sintase (NOS), foi avaliado através do tratamento com doses múltiplas de 30 mg/kg. Amostras de sangue foram coletadas duas horas após a administração de dapsona. A concentração de metemoglobina eritrocitária foi analisada por espectrofotometria. Os resultados mostraram que a suplementação em dose múltipla de 5 e 15 mg/kg de L-arginina reduziu os níveis de metemoglobina induzida pela dapsona. Este efeito é mediado pela formação de óxido nítrico, uma vez que a redução nos níveis de metemoglobina pela L-arginina é bloqueada pela administração simultânea de L-NAME, um inibidor da óxido nítrico sintase.

Effects of traditional Chinese medicine Panax notoginoside(血塞通) and Tetramethylpyrazine(川芎嗪)on cytochrome P450 subtype enzymes / 中国中西医结合急救杂志

Objective To study the effects of traditional Chinese medicine Panax notoginoside(PNS,血塞通) and Tetramethylpyrazine(TMPz,川芎嗪) on different subtypes of cytochrome P450(CYP450),based on that,to forecast the inter-reaction between these two drugs and between each one of them and another drug,and also to estimate the safety assessment of them.Methods The metabolic changes of caffeine and dapsone which are the specific probe drugs for subtypes of CYP450,CYP1A2 and CYP3A4,were studied in vitro to estimate the inhibition or induction effects of PNS and TMPz.Results The concentrations of caffeine and dapsone,the probe drugs in liver cytochrome P450,in control group,PNS group and TMPz group were all declined with time prolongation,and there were no significant differences among the three groups.The half life time(t1/2) of caffeine in PNS group was obviously shorter than that in control group((19.24?2.37) minutes vs.(25.15?2.02) minutes, P0.05).It was suggested that TMPz have no effect on both CYP1A2 and CYP3A4.Conclusion Different drugs have different effects on different CYP450 subtype enzymes.When PNS is used in combination with other drugs which are related to the metabolism of CYP1A2 enzyme,its induction effect on CYP1A2 should be considered fully to avoid toxic effect or the potential adverse reactions.