Experience of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in a Regional Hospital: 70 Cases in 7 Years / 대한내과학회지

BACKGROUND/AIMS: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions that frequently result in fatal outcomes. We investigated cases of SJS and TEN in a regional hospital. METHODS: From 2008 to 2014, SJS and TEN cases were enrolled retrospectively by allergy and dermatology specialists, and their clinical features and severity-of-illness score for TEN (SCORTEN) were assessed. RESULTS: During the 7-year study period, 56 SJS and 14 TEN cases were recruited. The majority (71%) were 40-70 years of age (mean age of male and female patients, 55 and 54 years, respectively). Regarding drugs, anticonvulsants (42.8%) were the most frequently causative, followed by carbonic anhydrase inhibitors (20.0%), antimicrobials (15.7%), allopurinol (7.1%), and non-steroidal anti-inflammatory drugs (7.1%). No fatal case of SJS was seen. However, 7 of the 14 patients with TEN died (50%; mean age, 67 years; 1 of 5 [20%] males and 6 of 9 females [66.7%]). The mortality rate was reflected in the SCORTEN values. Vancomycin, allopurinol, methazolamide (two cases each) and megestrol (one case) were the causative drugs in the seven fatal TEN cases. Treatment modality did not affect the likelihood of death due to TEN. CONCLUSIONS: The causative drugs of, and frequency of mortality due to, SJS and TEN should be recognized by physicians. Elderly females with TEN are at high risk of mortality. SCORTEN values reflect the mortality rate of TEN patients. Early recognition and proper management of SJS and TEN may reduce the mortality rate.

A quantitative approach for cardiovascular safety evaluation of a generic drug

In generic drug development, comparative pharmacokinetic (PK) studies are conducted to assess equivalence in pharmacokinetics and safety profiles between test and reference formulations. However, there is no established quantitative approach available for safety assessment. This study aimed to propose a method for drug safety evaluation in generic drug development, as assessed by drug influence on blood pressure and heart rate change. Data were taken from a randomized, open label, 2-way cross-over comparative PK study for megestrol conducted in 39 healthy male volunteers. Vital signs of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured at 0 (pre-dose), 4, 8, 12, 24, 48, 72, 96 and 120 hours after the dose. Safety parameters used in the analysis were area under vital sign change versus time curve to the last measured time (AUVlast) and maximum vital sign change (Vmax). Considering highly variable nature of vital signs, the scaled bioequivalence approach developed by US FDA was adopted as a decision rule for safety evaluation between formulations. With the FDA scaled approach, 90% confidence intervals of geometric mean ratio for DBP, 0.7969~1.0377 for Vmax and 0.7304~1.0660 for AUVlast, were both included in the equivalence ranges of 0.7694~1.2997 and 0.6815~1.4674, respectively, and similarly, those for HR were included in their respective scaled equivalence limits, while SBP satisfied the conventional equivalence criterion of 0.8-1.25. These results illustrate the feasibility of applying the suggested approach in cardiovascular safety evaluation in a generic drug.

LC-MS/MS method for determination of megestrol in human plasma and its application in bioequivalence study / 华中科技大学学报（医学）（英德文版）

A rapid and highly selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the determination of megestrol in human plasma was described using medrysone as internal standard (IS). Blood samples were collected from 20 healthy volunteers after oral administration of 160 mg megestrol acetate dispersible tablets. The analytes were extracted by liquid-liquid extraction procedure and separated on a hanbon lichrospher column with the mobile phase of methanol and water containing 0.1% formic acid and 20 mmol/L ammonium acetate (5:1, v/v). Positive ion electrospray ionization with multiple reaction-monitoring mode (MRM) was employed by monitoring the transitions m/z 385.5-325.4 and m/z 387.5-327.4 for megestrol and medrysone, respectively. Under the isocratic separation conditions, the chromatographic run time was approximately 2.54 min for megestrol and 2.59 min for medrysone. The calibration curve range was from 0.5 to 200.0 ng/mL. The inter-batch and intra-batch precision and accuracy were less than 5.2% relative standard deviation (RSD) and 6.4% relative error (RE). The proposed method was successfully applied in the bioequivalence study of megestrol acetate dispersible tablets.

Evaluation of Prescribing Medications for Terminal Cancer Patients near Death: Essential or Futile / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study is to evaluate the prescription of essential or futile medications for terminal cancer patients during their final admission. MATERIALS AND METHODS: We conducted a retrospective review of the medical charts of terminally ill cancer patients admitted to the Hemato-oncology Department of two teaching hospitals from March 1, 2007 to December 31, 2009. Essential medications were based on the drugs listed by the International Association for Hospice and Palliative Care, while futile medications were defined when short-term benefit to patients with respect to survival, quality of life, or symptom control was not anticipated. RESULTS: A total of 196 patients were included. Among essential medications, strong opioids were the most frequently prescribed drugs during the last admission (62.2% fentanyl, 44.3% morphine), followed by megestrol (46.0%), and metoclopramide (37.2%); 51% of gastric protectors were prescribed with potential futility. Anti-hypertensive and antiglycemic agents were administered to those who experienced arterial blood pressure below 90 mm Hg (47.3%) or presented with a single measurement of fasting glucose below 50 mg/dL (10.7%), respectively. Statins were prescribed to 6.1% (12/196) of patients, and 75% of those prescriptions were regarded as futile. CONCLUSION: Our data suggest that effective prescription of essential medications and withdrawal from futile medications should be actively reconciled for improvement of a patient's end-of-life care.

Analysis of the initial efficacy of nedaplatin combined with megestrol in concurrent chemoradiotherapy for advanced cervical cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the early efficacy of nedaplatin combined with megestrol in concurrent chemoradiotherapy for advanced cervical cancer.</p><p><b>METHODS</b>Forty-two cases of cervical cancer (FIGO IIb to IVa) were divided randomly into two groups: radiotherapy alone (21 cases) and radiation plus chemotherapy (Nedaplatin) group. The same radiotherapy was given to the two groups. Patients of the RT + C group received nedaplatin 30 mg/m2 in intravenous drip infusion once weekly on day 1, for 4 to 5 weeks, and megestrol 160 mg orally every day during the radiation therapy.</p><p><b>RESULTS</b>The early outcome: the complete remission rate was 81.0% and partial remission rate was 19.0% in the RT + C group, significantly better than the CR (38.1%) and PR (42.9%) in the RT group. The 1-year survival rates in the two groups were 100% (21/21) and 81.0% (17/21), respectively, with a significant difference between the two groups (P<0.05).</p><p><b>CONCLUSIONS</b>The combination of nedaplatin and megestrol with concurrent chemoradiotherapy can improve the early outcome of advanced cervical cancer, with somewhat increased but tolerable adverse effects.</p>

Low Dose Megestrol Acetate for Maintenance Hemodialysis Patients / 대한신장학회지

PURPOSE: Maintenance hemodialysis (HD) patients have a high prevalence of malnutrition and inflammation. Megestrol acetate (MA) has been shown to increase appetite in cancer patients but the usual dose of MA (400-800 mg/day) was associated with serious side effects in HD patients. We evaluated the changes in nutritional and inflammatory parameters after low dose of MA treatment in malnourished HD patients METHODS: Inclusion criteria were maintenance HD patients who showed serum albumin <3.5 g/dL or <4.0 g/dL with anorexia. Serum chemical parameters, cytokines, Subjective Global Assessment, dry weight, Kt/V, nPCR, SF36 quality of life, fat free mass (FFM), and body fat mass (BFM) were measured. Patients were instructed to take 5 mL (200 mg) of MA solution once a day. RESULTS: Fourteen patients (seven male, age 52+/-10 years, mean HD duration 48+/-59 months) were included. One patient died of pneumonia. Seven patients dropped out because they refused to take the drug after one to three months of treatment; two of them complained of thirst, three of them ate too much, and two had both. Six patients (four male and two female) have completed six months of study. Serum albumin (3.1+/-0.5 to 3.6+/-0.4 g/dL), TIBC (184.2+/-27.9 to 205.0+/-25.8 microgram/ dL), BFM (11.9+/-5.7 to 16.6+/-7.4 kg), protein intake (57.0+/-32.5 to 68.7+/-39.2 g/day), and energy intake (1,521+/-690 to 1,724+/-879) were increased. Serum CRP and IL-6 decreased without statistical significance. No significant adverse effects were observed in all patients who had completed study. CONCLUSION: Low dose MA can improve the nutritional status, inflammation, and anorexia in maintenance HD patients.

Secondary Adrenal Insufficiency Associated with Megestrol Acetate in a Patient with Lung Cancer / 결핵및호흡기질환

Loss of appetite is an important factor in the quality of life for advanced cancer patients. Megestrol acetate is used to stimulate appetite, but it can cause suppression of the pituitary adrenal axis due to the affinity of the glucocorticoid receptor. Adrenal insufficiency is a life threatening disorder if left, untreated, but the initial clinical symptoms of the patients are vague. Awareness of the glucocorticoid-like activity of megestrol acetate and its side effects are important for the diagnosis of adrenal insufficiency. We present a case of secondary adrenal insufficiency associated with megestrol acetate in a patient with lung cancer.

A case of treatment using high-dose Megestrol Acetate (Megace(R)) combined with PDT (Photodynamic Therapy) on early stage of endometrial carcinoma, in nulliparous woman / 대한산부인과학회지

Endometrial carcinoma is predominantly a disease of postmenopausal women, so we don't have to consider fertility. But in case of young women who want to preserve their fertility, it is very difficult to approach. We experienced one case of treatment using high-dose Megestrol Acetate (Megace(R)) combined with PDT (Photodynamic Therapy) on early stage of endometrial carcinoma, in young aged woman who wanted to preserve her fertility. And, we described briefly clinicopathologic findings, reviews of literatures and possibility of combined therapy with Megestrol and PDT.

Inibidores da aromatase no câncer de mama: da doença metastática ao tratamento adjuvante / Aromatase inhibitors in breast cancer: from metastatic disease to adjuvant treatment

Os tratamentos hormonais continuam a ter papel importante no manejo clínico das pacientes com câncer de mama. Entre os avanços mais recentes, os inibidores da aromatase de terceira geração vêm ocupando lugar de destaque no contexto da doença metastática. A aromatase, presente em diversos tecidos, é responsável pela conversão de andrógenos em estradiol e estrona. Antes da menopausa, a maior parte dos estrógenos femininos se origina nos ovários. Com a insuficiência ovariana, as glândulas supra-renais passam a ser a principal fonte de andrógenos, que são convertidos pela aromatase em estrógenos; esta conversão ocorre em tecidos periféricos como gordura, músculos, fígado e o próprio tumor de mama. A inibição da aromatase é uma estratégia com base racional sólida, e comprovadamente eficaz no sentido de reduzir os níveis séricos de estrógenos em mulheres pós-menopausa. Os inibidores de aromatase de primeira e segunda geração caracterizaram-se por alta toxicidade ou baixa eficácia, quando comparados ao tamoxifeno. No entanto, o tamoxifeno apresenta, além de sua ação antiestrogênica, um efeito pró-estrogênico, responsável por efeitos colaterais, tais quais proliferação do endométrio e fenômenos tromboembólicos. Estudos recentes, discutidos neste artigo, demonstraram a superioridade dos inbidores da aromatase de terceira geração, com relação ao megestrol, no tratamento hormonal de segunda linha do câncer de mama metastático em mulheres pós-menopausa. Além disto, estas drogas têm conquistado papel de destaque no tratamento de primeira linha da doença metastática, no tratamento neo-adjuvante, e no tratamento adjuvante de pacientes com câncer de mama.

Reversal of nomegestrol acetate on multidrug resistance in drug-resistant human breast cancer cell line MCF7/ADR / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the reversal effect of nomegestrol acetate (NOM) on mutidrug resistance (MDR) in MCF7/ADR and its mechanism.</p><p><b>METHODS</b>Using tetrazolium dye assay, effects of various concentrations of NOM on sensitivity to ADR in MCF7/ADR was studied. Expression of MDR related genes MDR1, glutathoine S-transferase Pi (GSTpi), Topoisomerase II alpha (Topo II alpha) and MDR related protein (MRP) were assayed by reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry assay. Using flow cytometry (FCM), intracellular ADR concentration effects on cell cycle were observed.</p><p><b>RESULTS</b>NOM significantly reversed MDR in MCF7/ADR. After NOM 20, 10 and 5 micromol/L treatment, the chemosensitivity to ADR increased to 21, 12 and 8 times. The reversal activity of NOM was stronger than that of the precursor compound megestrol acetate, and was comparable to that of verapamail. After treatment with NOM 5 micromol/L both MDR1 and GSTpi mRNA genes expression began to decline on D2 (P < 0.05, & P < 0.01) and reached the lowest level on D3 (both P < 0.01), but the expression levels began to rise on D6 again (both P < 0.05). The expression of MRP and Topo II alpha gave no significant change. Changes of P-gp and GSTpi protein expressions were similar to those of their mRNA expressions, showing early decline and late rise. Two hours after NOM 20, 10, and 5 micromol/L treatment, intracellular ADR concentration increased 2.7, 2.3 and 1.5 times, respectively. FCM data showed that after forty-eight hours, combined administration of NOM (20 micromol/L) and ADR (from low concentration to high concentration), MCF7/ADR cells showed gradual arrest in the G(2)M phase with the increase of ADR dose.</p><p><b>CONCLUSION</b>NOM has strong reversal effects on MDR in MCF7/ADR. The reversal takes place via different routes, i.e. down regulating mRNA and protein expression levels of MDR1 and GSTpi, increasing intracellular drug concentration, and enhancing the arrest of ADR in cells at G(2)M phase.</p>

Treatment Efficacy of High-Dose Megestrol Acetate (Megace) in Young Women with Early Stage of Endometrial Carcinoma / 대한부인종양콜포스코피학회잡지

The effectiveness of progestogens in advanced and recurrent endometrial carcinoma has been widely accepted. But the use of progestogens in young women with early stage of endometrial carcinoma (Stage Ia) is controversial. Some authors reported that progestogens alone therapy improved or cured the endometrial pathology in young patients with early stage of endometrial carcinoma. The response to the progestogens has known to be better in cases of early stage, well-differentiated histologic type and narrow depth of invasion. We used the high-dose megestrol acetate (Megace(R)) as the primary treatment in four young women with early stage of endometrial carcinoma (Stage Ia) for the purpose of saving the fertility. We made the patients to have 320~400 mg of Megace(R) per day for 3 months, and then repeated the endometrial curettage for the purpose of finding changes of endometrial pathology. Three cases revealed no response to the Megace(R), so they were operated later. One case showed the resolution of endometrial pathology and delivered a baby following therapy. There have been no evidences of clinical recurrence in all cases. Even though the therapeutic efficacy is limited, high-dose therapy with megestrol acetate can be used as primary therapy in young women with early stage of endometrial carcinoma.

Avaliaçäo anátomo histopatológica do efeito do acetato de medroxiprogesterona e do acetato de megestrol sobre o útero de cadelas adultas / Anatomo histopathologic evaluation of the effect of medroxiprogesterone acetate and megestrol acetate on the uterus of adult bitches

No presente experimento foram utlizadas 18 fêmeas caninas adultas, clinicamente sadias, sem sintomas clínicos de estro, as quais foram subdivididas aleatoriamente em 6 grupos contendo 3 animais cada. Após biópsia uterina para controle, foi administrado acetato de medroxiprogesterona nas fêmeas dos grupos I, II e III e acetato de megestrol nas fêmeas dos grupos IV, V, VI. Observou-se que ambas as drogas utilizadas induziram a ocorrência de endometrite, porém este foi mais discreto nos animais dos grupos IV, V e VI. Näo foi registrada a ocorrência de poliúra, polidipsia, distençäo abdominal, corrimento vaginal purulento ou sanguinolento, leucocitose e anemia

Megestrol acetate as the supportive treatment of Thai patients with advanced cancer.

We studied the effect of the standard oral dose (160 mg/d) of megestrol acetate on the weight gain of 115 advanced cancer patients. All were underweight and were receiving only supportive or symptomatic care. The median treatment time was 74 weeks (range: 4 weeks to 2 years). The mean body weight gain of all patients was 4.84 kg (range: -3 to 18 kg) regardless of the disease status. Weight gain was dependent on the length of treatment time. The performance status after therapy also shifted to the better status with significant statistical difference. All patients felt an increase of appetite and also had an improved sense of well-being. No serious side-effects of the treatment were noted in this study.