Azathioprine and Risk of Skin Cancer in Organ Transplant Recipients: Systematic Review and Meta-Analysis.

Azathioprine, a purine antimetabolite immunosuppressant, photosensitizes the skin and causes the production of mutagenic reactive oxygen species. It is postulated to increase the risk of squamous cell carcinoma (SCC) and other skin cancers in organ transplant recipients (OTRs), but evidence from multiple, largely single-center studies to date has been inconsistent. We aimed to resolve the issue of azathioprine's carcinogenicity by conducting a systematic review of the relevant literature and pooling published risk estimates to evaluate the risks of SCC, basal cell carcinoma (BCC), keratinocyte cancers (KCs) overall and other skin cancers in relation to azathioprine treatment. Twenty-seven studies were included in total, with risk estimates from 13 of these studies able to be pooled for quantitative analysis. The overall summary estimate showed a significantly increased risk of SCC in relation to azathioprine exposure (1.56, 95% confidence interval [CI] 1.11-2.18). No significant associations between azathioprine treatment and BCC (0.96, 95% CI 0.66-1.40) or KC (0.84, 95% CI 0.59-1.21) risk were observed. There was significant heterogeneity between studies for azathioprine risk estimates and the outcomes of SCC, BCC and KC. The pooled findings of available evidence support the contention that treatment with azathioprine increases the risk of SCC in OTRs.

Kidney disease health literacy among new patients referred to a nephrology outpatient clinic.

BACKGROUND: Knowledge about kidney disease among the general population is poor but has not been assessed in the population selected for referral to nephrology care. AIM: This study aimed to determine patients' understanding of chronic kidney disease (CKD) when first presenting to a nephrology clinic. METHODS: Newly referred patients to a nephrology clinic were surveyed with open-ended questions about their understanding of CKD causes, symptoms and management. RESULTS: Two hundred and ten patients were surveyed. Median age was 66.5 years (interquartile range 52-77), 50.5% female and mean body mass index 29.7 ± 6.8 kg/m(2) . Prevalence of risk factors for CKD included 31% diabetic, 62% hypertension, 19% family history of CKD and 2% Aboriginal or Torres Strait Islander. CKD stage prevalence was 0 (8%), 1 (24%), 2 (11%), 3 (38.5%), 4 (18%) and 5 (0.5%). Eighty-two per cent were referred by their primary care physician and 29% had seen a nephrologist previously. Kidney Health Australia was mentioned by 2.4%. Sixteen per cent were unsure why they had been referred. CKD causes identified by patients were unsure (40%), alcohol (29%), hypertension (16%) and diabetes (14%). Symptoms identified included asymptomatic (16%), kidney pain (17%) and other (42%). Management suggested by patients was uncertain (51%), dialysis (32%) and anti-hypertensive medication (16%). Eighty-two per cent reported unsatisfactory education from their primary care physician. CONCLUSIONS: New patients referred to a renal outpatient department had poor knowledge about kidney disease. Education of patients should begin in primary care prior to referral. For most patients, education programmes need to be targeted at a simplistic level.

Progressive multifocal leukoencephalopathy with gastrointestinal disease in a pediatric kidney transplant recipient.

PML is a demyelinating disease of the central nervous system caused by infection with JCV. Several cases of PML in bone marrow and solid organ transplant recipients have been reported in recent years. JCV has been isolated from the gastrointestinal mucosa of immunocompromised patients, but there are no published reports of PML associated with symptomatic gastrointestinal involvement in kidney transplant recipients. We report a case of a nine-yr-old girl with a kidney transplant who developed a severe gastrointestinal illness causing pseudo-obstruction in association with PML. JCV was suspected as the causative agent in this patient by the detection of high JCV titer through PCR analysis of the cerebrospinal fluid and blood and positive staining for simian virus 40 in the colon. JCV intestinal infection should be considered in kidney transplant recipients presenting with intestinal pseudo-obstruction.

Effect of MAO-A inhibition on the pharmacokinetics of almotriptan, an antimigraine agent in humans.

AIMS: To assess the effect of a reversible MAO-A inhibitor, moclobemide, on the single-dose pharmacokinetics of almotriptan and assess the clinical consequences of any interaction. METHODS: Twelve healthy volunteers received the following treatments in a randomized, open-label, two-way crossover design (with a 1 week washout between treatments): (A) one 150 mg moclobemide tablet every 12 h for 8 days and one 12.5 mg almotriptan tablet on the morning of day 8; and (B) one 12.5 mg almotriptan tablet on day 8. Plasma almotriptan was quantified by h.p.l.c.-MS-MS, while urinary concentrations were measured by h.p.l.c.-u.v. Vital signs, ECGs, and adverse events were evaluated after almotriptan administration. Treatment effects on pharmacokinetics and vital signs were assessed by analysis of variance. RESULTS: Mean almotriptan AUC was higher (483 +/- 99.9 vs 352 +/- 75.4 ng ml-1 h, P = 0.0001) and oral clearance was lower (26.6 +/- 4.00 vs 36.6 +/- 5.89 l h-1, P = 0.0001) when almotriptan was administered with moclobemide. Mean half-life was longer (4.22 +/- 0.78 vs 3.41 +/- 0.45 h, P = 0.0002) after coadministration with moclobemide. Renal clearance of almotriptan was unaffected by moclobemide. No serious adverse events occurred and no clinically significant vital sign changes were observed. CONCLUSIONS: Moclobemide increased plasma concentrations of almotriptan on average by 37%, but the combined administration of these two compounds was well tolerated. The degree of interaction was much less than that seen previously for sumatriptan or zolmitriptan given with moclobemide.

Pharmacodynamics and pharmacokinetics of the class III antiarrhythmic agent dofetilide (UK-68,798) in humans.

The pharmacodynamics, pharmacokinetics, safety, and tolerance of the class III antiarrhythmic dofetilide (UK-68,798) were evaluated in two groups of healthy volunteers; first, single oral escalating doses (1, 2, 5, 7.5, and 10 micrograms/kg with random insertion of placebo) were administered in a double-blind manner and, second, its intravenous (0.5 mg) and oral (0.5 mg) administration were compared in an open two-way crossover design. Oral dofetilide from 5 micrograms/kg produced significant dose-dependent prolongations of the QTc interval compared to placebo. Maximal mean QTc prolongations were 5 micrograms/kg, 29 ms (7%) at 2 h; 7.5 micrograms/kg, 35 ms (9%) at 6 h; and 10 micrograms/kg, 47 ms (12%). Following i.v. infusion of dofetilide (0.5 mg) (n = 9), the QTc interval significantly increased from 401 +/- 26 to 504 +/- 105 ms at the end of the infusion. One subject exhibited excessive prolongation of his QTc interval (451-808 ms) 5 min after the infusion, which was associated with an asymptomatic run (5 beats) of polymorphic ventricular tachycardia and several multifocal ventricular ectopic beats. Following oral administration of dofetilide (0.5 mg) (n = 9), the QTc interval increased significantly from 396 +/- 27 ms to a maximum of 445 +/- 27 ms at 2 +/- 0.9 h postdosing. No changes occurred in PR intervals and QRS width. Small changes occurred in the heart rate and blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Extended clinical safety profile of lovastatin.

Lovastatin has been available for prescription use in the United States for about 20 months (as of June 1989). Over 1 million patients have received the prescription drug, and approximately 14,000 patients have participated in clinical trials. It is estimated that 500,000 patients have received lovastatin continuously for at least 1 year. This report reviews the extended safety experience from all clinical trials and prescription use. At least 645 patients have received lovastatin for more than 3 years. There are new data from a recently completed 1 year, placebo-controlled trial in 8,245 patients (Expanded Clinical Evaluation of Lovastatin study) and 20 months of health professionals' reports on spontaneous adverse events associated with large prescription usage. Data from recent large clinical trials suggest that the risk of myopathy and asymptomatic sustained liver transaminase elevations is less than reported in prior studies. The early clinical trials enrolled very high risk patients receiving lovastatin at a usual dose of 80 mg/day and often receiving concomitant hypolipidemic agents including gemfibrozil and niacin. After more than 42 months' long-term clinical trial experience, data have not established adverse effects from lovastatin on the human lens. Possible new types of rare drug-related adverse events observed with large prescription use include hypersensitivity reactions such as arthralgia, thrombocytopenia, symptomatic hepatitis and interaction with warfarin. No new, unique adverse-event profile has emerged with extended clinical use, including use in a few patients who have received therapy for more than 5 years. The lovastatin extended safety profile is that of a generally well-tolerated drug.

Phase II trial of trimetrexate in patients with stage III and IV non-small-cell lung cancer.

Trimetrexate is a nonclassical antifolate with greater preclinical antitumor activity than methotrexate. Fourteen patients with stage III or IV non-small-cell lung cancer who had not previously received chemotherapy were given trimetrexate (12 mg/m2 intravenously daily for 5 days) every 3 weeks. No major objective responses were observed (95% confidence limits: 0-20%). Ten of the 14 patients had grade 2 or greater toxicity, with 50% experiencing grade 2 or greater leukopenia and/or thrombocytopenia. Nausea, vomiting, rash, mucositis, diarrhea, and serum glutamic-oxaloacetic transaminase (SGOT) elevations were also seen. At the dosage and schedule of trimetrexate used, no responses occurred in this population of patients with non-small-cell lung cancer. With the low response rate and the observed degree of myelosuppression, trimetrexate appears to have limited utility in this disease.

Phase II study of 10-ethyl-10-deaza-aminopterin in patients with stage III and IV non-small-cell lung cancer.

10-ethyl-10-deaza-aminopterin (10-EDAM) is an analog of methotrexate that differs from its compound by modification of the N10 position and demonstrates greater preclinical antitumor activity and less toxicity. In this phase II trial, 20 patients with stage III or IV non-small-cell lung cancer (NSCLC) were administered 10-EDAM at a dose of 80 mg/m2 once weekly for 5 weeks. No patient had previously received chemotherapy. Nineteen of the 20 patients were adequately treated for response assessment. Six of 19 patients (32%) experienced a major objective response (exact 95% confidence limits, 15% to 55%). The median duration of response has not been reached and will exceed 13 months. Mucositis was the most common toxicity observed. Leukopenia was seen in only 10%, and 15% had platelet nadirs less than 100,000/microL. At the dosage and schedule used, 10-EDAM is an active agent in patients with NSCLC who are previously untreated with chemotherapy with a predicted response rate greater than or equal to 15% (P = .05). Because of its level of antitumor activity and the fact that 10-EDAM causes minimal myelosuppression, it is a suitable agent for further study in combination with other chemotherapeutic agents in this disease.

Preoperative and adjuvant chemotherapy in locally advanced non-small cell lung cancer.

The continued favorable results with surgery in early stage lung cancer have led many investigators to use radiation and chemotherapy to reduce the size of unresectable tumors either before or after definitive surgery. Although earlier results with both radiation and chemotherapy have been poor, the newer cisplatin-containing combination chemotherapy regimens have yielded decreased local recurrence rates when used postoperatively following a complete resection and have produced increased complete resection rates when given preoperatively to patients with locally advanced and unresectable non-small cell lung cancer at diagnosis.

Trial of the combination of mitomycin, vindesine, and cisplatin in patients with advanced non-small cell lung cancer.

In prior trials, mitomycin, vindesine, and cisplatin have each been shown to have reproducible antitumor activity as single agents when used in the treatment of patients with non-small cell lung cancer. The two-drug combinations of vindesine plus high-dose cisplatin or mitomycin have shown an improved major response rate and manageable toxicity in prior trials. In this report, 90 patients with stage III non-small cell lung cancer were treated with the three-drug combination of mitomycin (8 mg/m2), vindesine (3 mg/m2), and high-dose cisplatin (120 mg/m2). Eighty-seven patients (97%) were adequate for both response and toxicity. Major objective responses occurred in 60% of the patients. The toxicity of this regimen was predictable and manageable when established supportive care measures were employed. Based on the response rate observed, the combination of these three agents merits further study in randomized trials against other chemotherapeutic regimens and consideration of its use in adjuvant and preoperative settings.

Phase II trial of oral 4-demethoxydaunorubicin in patients with non-small cell lung cancer.

4-Demethoxydaunorubicin (4-DMDR) is an orally active analog of daunorubicin that in preclinical testing has demonstrated greater antitumor activity and less cardiotoxicity than its parent compound. Thirty-two patients with metastatic non-small cell lung cancer received 4-DMDR at a dose of 40-50 mg/m2 orally every 21 days. Thirteen patients had received no prior chemotherapy. Among the 30 adequately treated patients, one major response lasting 5.2 months was observed. Leukopenia 10-14 days after treatment was the most commonly observed toxicity. With an overall observed major response rate of 3.3% in 30 patients, the predicted true response rate is less than or equal to 16% (p = 0.05). At the dose and schedule studied in this group of patients with non-small cell lung cancer, 4-DMDR had only marginal activity.

Randomized trial comparing vindesine plus cisplatin with vinblastine plus cisplatin in patients with non-small cell lung cancer, with an analysis of methods of response assessment.

One hundred eight patients with stage III non-small cell lung cancer were randomly assigned to receive cisplatin (120 mg/m2) with either vindesine (3 mg/m2) or vinblastine (6 mg/m2). None had previously received chemotherapy. An additional goal was to determine if the observation of visible evaluable lesions was as accurate a method of response assessment as the observation of bidimensionally measurable lesions in non-small cell lung cancer. When vindesine plus cisplatin was compared to vinblastine plus cisplatin, response rates (33% vs 41%), median response durations (8.6 vs 5.6 months), and median survival times of responding patients (18.4 vs 16.2 months) were similar. Response rates, response durations, and survival times of responding patients determined through the observation of evaluable or measurable indicator lesions did not differ significantly. More patients receiving vinblastine plus cisplatin experienced wbc counts less than 2100/mm3 (P = 0.003). The two regimens demonstrated comparable response and survival data but clinically significant leukopenia was more common in vinblastine-treated patients. There was no difference in response data obtained through the study of patients with measurable and evaluable indicator lesions.

Trial of vindesine plus mitomycin in stage-3 non-small cell lung cancer. An active regimen for outpatient treatment.

Ninety patients with stage-3 non-small cell lung cancer were given vindesine (3 mg/sq m) plus mitomycin (10 mg/sq m). Data on response are available for 84 adequately treated individuals (93 percent). For patients who had received no prior chemotherapy, the rate of major objective response was 36 percent (20/55). For previously treated patients the rate of major response was 17 percent (5/29). The drugs were routinely administered in the outpatient department without difficulty. Moderate or severe myelosuppression, neurotoxic, nephrotoxic, or pulmonary toxic effects, nausea, and vomiting occurred in less than 15 percent of all studied patients. Three-drug extravasation ulcerations occurred in 1,129 administrations of chemotherapy (0.3 percent). There were two treatment-related deaths, one from sepsis and one from the combination of mitomycin-induced pulmonary and renal toxic effects. The combination of vindesine plus mitomycin is an active, well-tolerated outpatient regimen for patients with non-small cell lung cancer who have not previously received chemotherapy. Further trials are warranted to compare this regimen to other active combinations and to use it as a component of a program of treatment using alternating regimens of chemotherapy.

Dyspnea following vinblastine or vindesine administration in patients receiving mitomycin plus vinca alkaloid combination therapy.

Pulmonary toxicity is not commonly associated with the vinca alkaloids vinblastine and vindesine. Three patients receiving the combination of mitomycin plus vindesine or vinblastine developed acute dyspnea 1-5 hours following vinca alkaloid administration. Two of the three patients continued to receive therapy and both experienced symptoms with each subsequent vinblastine or vindesine injection. No other cause for the dyspnea could be detected. We conclude that, as in the three previously reported cases, shortness of breath can occur after the injection of vinblastine or vindesine in patients receiving mitomycin plus vinca alkaloid combination therapy.