A randomized controlled trial of single-class maintenance therapy with abacavir/lamivudine/zidovudine after standard triple antiretroviral induction therapy: final 96-week results from the FREE study.

OBJECTIVES: The aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI). METHODS: An open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naïve patients with CD4 count ≤ 350 cells/µL and HIV-1 RNA >30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA <50 copies/mL on two consecutive occasions between weeks 12 and 24 after baseline, 120 patients (baseline: median HIV-1 RNA 5.19 log10 copies/mL; median CD4 count 180 cells/µL) were randomized to receive abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (n=61) or to continue the PI-based ART (n=59). RESULTS: For the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA <400 copies/mL (PI group, 66%; ABC/3TC/ZDV group, 71%) and <50 copies/mL (PI group, 63%; ABC/3TC/ZDV group, 62%) at 96 weeks, switching to ABC/3TC/ZDV was noninferior compared with continuing the PI regimen; the difference in failure rate (ABC/3TC/ZDV minus PI) was -4.4 percentage points [95% confidence interval (CI) -21.0 to +12.3 percentage points] and +0.4 percentage points (95% CI -16.9 to +17.7 percentage points), respectively. In the per protocol analysis, the difference in virological failure for HIV-1 RNA >400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA >50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm. CONCLUSIONS: A single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI-based regimen at 96 weeks after baseline, with improved serum lipids.

Effects of nonsteroidal anti-inflammatory drugs on proteinuria.

Most nonsteroidal anti-inflammatory drugs are anti-proteinuric agents, especially if the patient is sodium-depleted. The decline in urinary protein excretion induced by these agents always markedly exceeds the decrease in glomerular filtration rate. Moreover, the remaining proteinuria appears to be more selective. Together, these findings suggest that the anti-proteinuric effect of nonsteroidal anti-inflammatory drugs is hemodynamically mediated. Nonsteroidal anti-inflammatory agents that reduce renal prostaglandin E2 excretion also decrease proteinuria, whereas sulindac decreases neither prostaglandin E2 nor protein excretion. In a retrospective study, it appeared that administration of indomethacin improved renal survival of nephrotic patients with an initial serum creatinine concentration of less than 110 mumol/liter. The anti-proteinuric effect of indomethacin itself or indomethacin-induced hemodynamic changes might explain this observation.

Current status of systemic chemotherapy in the treatment of advanced ovarian cancer with emphasis on CHAP-5.

In patients with advanced ovarian cancer, initial treatment with combination chemotherapy, including cyclophosphamide and cis-platinum diamminedichloride (cis-platinum), produces response and progression-free survival results which are superior to those achieved with alkylating single-agent chemotherapy. Unfortunately most schedules have not resulted in a statistically significant improvement of overall survival. So far one of the most effective combination regimens is the four-drug regimen CHAP-5 that consists of cyclophosphamide, hexamethylmelamine, adriamycin, and cis-platinum. This regimen is the first schedule to result in significant improved survival times compared with a second combination schedule, i.e. Hexa-CAF, which is at least as good as alkylating therapy alone. The CHAP-5 regimen was rather toxic but it was manageable and easy to apply in daily practice. Further improvement of the treatment results in advanced ovarian carcinoma will be difficult because no effective new drugs are available. In future clinical research it must be tried to decrease the toxicity and morbidity of the current schedules without reducing efficacy and survival.

Hemolytic uremic syndrome in a patient on cis-platinum, vinblastine and bleomycin.

A 23-year-old woman with metastatic Sertoli-Leydig cell tumor was treated with cisplatin, vinblastine, and bleomycin. Hemolytic uremic syndrome appeared, while no evidence of residual tumor was found. Infusion of fresh frozen plasma together with aspirin and dipyridamole resulted in recovery of microangiopathic hemolytic anemia and thrombocytopenia. Renal insufficiency, however, persisted.

Prediction of normal tissue damage induced by cancer chemotherapy.

Cancer chemotherapeutic agents have a low therapeutic index and require a precise and safe prescription. Hematological toxicity is the most common dose limiting side effect of cancer drugs. Therefore, Hemopoietic Stem Cells (HSC) are the most relevant targets for dose determination. Studies of total body irradiation with or without autologous bone marrow transplantation showed that HSC concentrations differ between mouse, rat, rhesus monkey, dog and man. A highly significant correlation was found between bone marrow rescue dose and kg body weight and not between bone marrow rescue dose and BSA. Kg body weight appears to offer a better prescription unit for cancer chemotherapy than BSA, because it correlates better with dose limiting, normal tissue, target cells. This prediction is borne out by the results of chemotherapy in neonates. BSA has also been used as dose unit for drugs with non hematological side effects (e.g., cardiotoxicity of anthracyclines or neurotoxicity of methotrexate). The target for such drug side effects need to be determined before the proper dose unit can be selected. A review of available data shows that for at least some non hematological side effects BSA does not offer the proper prescription unit. The historical justifications for BSA as dose unit are re-examined (simplicity, correlation with blood volume, correlation with area under the curve) and considered invalid. The ultimate long term improvements from better prescription methods for cancer chemotherapeutic agents are less normal tissue side effects and better tumor control. The indiscriminate use of BSA as a universal dose unit for cancer chemotherapy would prevent such improvements and is discouraged. Instead, drug doses are to be expressed in units that correlate with dose limiting normal tissue cells.

Fatal cerebral oedema associated with primary dengue infection.

Encephalopathy associated with dengue fever is considered to be a rare condition in adults. We describe a patient with a primary dengue infection who, in the absence of overt signs of dengue shock syndrome, died due to progressive cerebral oedema. Autopsy findings demonstrated loss of integrity of cerebral vascular endothelium and involvement of complement activation.

Reduction of urinary protein and prostaglandin E2 excretion in the nephrotic syndrome by non-steroidal anti-inflammatory drugs.

Seven salt depleted patients with the idiopathic nephrotic syndrome were treated with various non-steroidal anti-inflammatory drugs. Indomethacin, diclofenac-sodium and flurbiprofen decreased proteinuria, glomerular filtration rate, plasma renin activity and renal prostaglandin E2 excretion by 59%, 19%, 55% and 68% respectively. Sulindac induced no major changes in proteinuria, glomerular filtration rate, plasma renin activity and renal prostaglandin E2 excretion. The relative change in proteinuria and glomerular filtration rate during non-steroidal anti-inflammatory drug treatment correlated strongly with that of the renal prostaglandin E2 excretion (r = 0.89 and r = 0.70, respectively p less than 0.05). It is likely that the anti-proteinuric effect of non-steroidal anti-inflammatory drugs is dependent on their potency to inhibit renal prostaglandin synthesis and it is suggested that this effect is mediated by lowering transcapillary glomerular hydraulic pressure.

Immune restoration disease in HIV-infected individuals receiving highly active antiretroviral therapy: clinical and immunological characteristics.

BACKGROUND: HIV-infected patients responding to HAART can show a diverse spectrum of symptoms caused by inflammatory reaction. The pathogenesis of this phenomenon, called immune restoration disease (IRD), is unclear. This study describes the spectrum of IRD and analyses the immunological and clinical parameters that could be related to its development. METHODS: In a retrospective, matched case-control study, 17 HIV-infected individuals who developed inflammatory symptoms < 12 months after initiation of HAART were included. HIV-infected controls were matched for age, gender and CDC classification. Factors included in the analysis were: CD4+ and CD8+ cell counts, deltaCD4+ and deltaCD8+, CD4/CD8 ratios, HIV-1-RNA load (VL), AVL and the number of CDC events prior to HAART. RESULTS: The median time after initiation of HAART and developing IRD (n = 17) was 72 days (range 2-319). In nine cases (53%) a mycobacterial infection was identified as the underlying cause. HAART was started at a mean CD4+ count (+/- SD) of 55 x 10(6) /l (+/- 59) and 85 x 10(6) /l (+/- 78.0) for cases and controls, respectively (p = 0.13). After initiation of HAART, the CD4+ count showed a 10.6 fold increase at the onset of IRD in the cases and a 2.7 fold increase in the controls in an equal period of time (p = 0.020). The other parameters analysed did not differ significantly between cases and controls. CONCLUSION: We conclude that the risk of developing IRD is associated with a high-fold increase in CD4+ lymphocytes. In this study, mycobacteria are the pathogens most frequently associated with IRD.

Prophylactic gastrostomy placement and early tube feeding may limit loss of weight during chemoradiotherapy for advanced head and neck cancer, a preliminary study.

OBJECTIVES: Most patients with advanced head and neck cancer receiving chemoradiotherapy need tube feeding for at least some weeks. For these periods gastrostomy tubes have advantages over nasogastric tubes. Tube feeding may start earlier and thus loss of weight may be limited if the gastrostomy tube already is in place. The objective of this study is to analyse the results of prophylactic percutaneous endoscopic gastrostomy (PEG) tube placement and early tube feeding. DESIGN: Retrospective chart review. SETTING: Multidisciplinary head and neck oncology team in a general hospital. PARTICIPANTS: Fifty consecutive patients with unresectable stage III and IV head and neck cancer treated with concurrent chemoradiotherapy. In all patients prophylactic PEG placement was performed. Tube feeding was initiated if food-intake became insufficient or loss of weight occurred. MAIN OUTCOME MEASURES: Loss of weight during treatment, complication rate, PEG duration. RESULTS: The mean loss of weight during treatment for all patients was only 2.8%. One complication of tube placement occurred: a colon perforation, treated successfully by surgery. The median duration of the PEG was 178 days. Three of the 17 patients (18%) with no evidence of disease (NED) still had a PEG at their last follow-up visit. Of the 26 patients who died of their cancer, 13 used the PEG until death. CONCLUSIONS: Loss of weight was limited after prophylactic gastrostomy placement and early tube feeding. Moreover, the complication rate was low. In 82% of the NED patients the PEG could eventually be removed.

Additive antiproteinuric effect of the NSAID indomethacin and the ACE inhibitor lisinopril.

Both angiotensin-converting enzyme (ACE) inhibitors like lisinopril and nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin have been shown to lower urinary protein excretion in renal disease. If this effect is caused by different mechanisms of action, the combination of these agents could have an additive antiproteinuric effect. We studied the effects of lisinopril and indomethacin separately and in combination in 10 patients with the nephrotic syndrome. Proteinuria was lowered from 10.5 +/- 1.8 g/24 h in the control period to 4.5 +/- 1.1 g/24 h on indomethacin, 4.3 +/- 1.0 g/24 h on lisinopril and to 2.4 +/- 0.8 g/24 h on the combination. Glomerular filtration rate (GFR) fell on either monotherapy, but particularly on the combination of drugs. The renal hemodynamic changes suggested a preglomerular vasoconstriction by indomethacin and a postglomerular vasodilation by lisinopril. Severe hyperkalemia occurred in 3 patients on the combination therapy. We conclude that the combination of indomethacin and lisinopril has an additive antiproteinuric effect. This, as well as the more pronounced fall in GFR on the combination, may suggest that both drugs lower proteinuria by decreasing intraglomerular capillary pressure but via different mechanisms. Combining these drugs may be useful in the symptomatic treatment of nephrotic syndrome, but renal function and serum potassium should be monitored carefully.

High-dose teniposide for refractory malignancies: a phase I study.

To evaluate the dose-limiting toxicity of teniposide (VM-26), a phase I study was conducted. VM-26, a semisynthetic podophyllotoxin derivative, was administered on 3 consecutive days. The initial total dose per course was 0.3 g/m2, with dose escalation to 0.6 and 1 g/m2. The most prominent side effects observed were severe skin rash in all three patients in the highest dose group and a dose-dependent degree of leukocytopenia and thrombocytopenia. In the highest dose group the leukocyte count in all courses was less than 1 X 10(9) cells/L and in three of five courses the platelet count was less than 25 X 10(9) cells/L. Of the 13 evaluable patients, five had partial remission, one had minor response, and four had stable disease. Further study should be centered on phase II studies in selected tumor groups at a VM-26 dose of 0.6 g/m2.

Pharmacokinetics of trimazosin and its effects on blood pressure, renal function and proteinuria during short-term therapy of patients with impaired renal function and hypertension.

The kinetics and short-term (10 weeks) effects of trimazosin, an alpha 1-adrenoreceptor antagonist, on renal function and blood pressure in patients with moderate chronic renal insufficiency and hypertension, have been studied for the first time. Eight patients in whom the blood pressure was not normalized with a diuretic alone underwent pharmacokinetic studies and assessment of the renal function during a 10-week period of trimazosin therapy. Trimazosin significantly lowered blood pressure (recumbent and upright) without significantly altering renal function. Renal vascular resistance was decreased by 14%. Fractional sodium excretion, proteinuria and laboratory serum tests remained unchanged. Neither body weight nor pulse rate were affected. Moderate renal insufficiency did not modify the pharmacokinetics of the drug. Thus, trimazosin, as second-step antihypertensive agent, appeared to be safe and effective in patients with moderate renal insufficiency and hypertension, without exerting favourable or adverse renal effects during short-term therapy.

Antiproteinuric drugs in patients with idiopathic membranous glomerulopathy.

We studied the effects of symptomatic, antiproteinuric treatment with NSAID's (n = 28) and ACE-inhibitors (n = 14) in patients with proteinuria due to idiopathic membranous glomerulopathy (MGP). These two treatment groups were compared with a group of patients who did not receive antiproteinuric medication (n = 14). Urinary protein loss was effectively lowered by NSAID and ACE inhibitor therapy from 9.5 +/- 1.0 to 4.5 +/- 0.5 g/day (mean +/- SEM) and from 9.8 +/- 1.4 to 3.9 +/- 0.7 g/day respectively, whereas the control group showed a slight fall in proteinuria from 6.9 +/- 0.8 to 5.5 +/- 0.8 g/day. As a result of this treatment hypoalbuminaemia and hypercholesterolaemia improved significantly: serum albumin rose in the NSAID group from 25.4 +/- 1.2 to 29.0 +/- 1.0, and in the ACEi group from 29.9 +/- 1.8 to 32.7 +/- 1.2 g/l (control group from 27.4 +/- 1.6 to 27.8 +/- 1.6 g/l, while cholesterol was lowered in the NSAID group from 8.5 +/- 0.5 to 7.5 +/- 0.4 and in the ACEi group from 8.7 +/- 0.5 to 7.6 +/- 0.4 mmol/l (control group from 9.7 +/- 1.1 to 8.5 +/- 1.0 mmol/l). The antiproteinuric effect of both drugs was well maintained during an 18-month follow-up. Progression towards end-stage renal failure was observed especially in patients with impaired renal function at entry. Remission of proteinuria occurred particularly in patients with lower baseline values of proteinuria, irrespective of the treatment modality.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiproteinuric effect of naproxen and indomethacin. A double-blind crossover study.

In a double-blind crossover study in 10 salt-depleted nephrotic patients the reduction of proteinuria was significantly larger during indomethacin 50 mg three times daily than during naproxen 250 or 500 mg three times daily (72 vs. 44%, p less than 0.05; 77 vs. 46%, p less than 0.05, respectively). Both drugs induced similar reversible intrarenal hemodynamic changes, but indomethacin had more pronounced effects than naproxen. A common pathway, such as the reduction of the glomerular filtration rate and a reduction of the glomerular transcapillary hydraulic pressure, is likely to explain the observed phenomena and is most probably mediated by inhibition of intrarenal prostaglandin synthesis. If treatment with a nonsteroidal anti-inflammatory drug is considered in patients with the idiopathic nephrotic syndrome, indomethacin appears up to now the most effective agent in reducing urinary protein loss.

Absence of an additional fibrotic response caused by oxygen in the lungs of rats after the intratracheal administration of bleomycin.

Bleomycin 0.4, 0.6, 1.0 or 3.5 mg/kg body weight was administered via the trachea in rats. After various time intervals some of the animals were exposed to 50% oxygen for either 4 or 24 h. The rats were then sacrificed at different times. Control rats remained untreated or received physiological saline. Lung histology was studied by light microscopy. In a number of rats the lung content of hydroxyproline was determined. Mild reactions, namely increases in pneumocytes type II and macrophages, oedema and prefibrotic alterations were observed after the instillation of bleomycin. The reactions were comparable to those observed after additional hyperoxia alone. Lung hydroxyproline concentration was not increased after bleomycin plus oxygen as compared with bleomycin alone. We conclude that no added toxicity is caused by 50% oxygen supplied for 4 or 24 h subsequent to doses of bleomycin that lead to mild pulmonary abnormalities in the absence of hyperoxia.

High-dose etoposide for refractory malignancies: a phase I study.

Etoposide is active against a number of solid tumors when used in a standard dose. The toxicity at a standard dose level is mild myelosuppression without extramedullary toxicity. Recent studies in man support the dose-response relationship of etoposide. In a group of 22 patients with progressive disseminated malignancies, the dose of etoposide was escalated to define dose-limiting extramedullary toxicity, which was oropharyngeal mucositis at a dose level of 3.5 g/m2. Bone marrow toxicity was completely reversible. No cumulative toxicity was seen. Partial responses were seen in nine patients. In two of three patients with CNS metastases, improvement was seen. Etoposide is a suitable drug for high-dose chemotherapy.

No narcosis for bone marrow harvest in autologous bone marrow transplantation.

A prospective study with mild general analgesia and sedation together with local anesthesia during bone marrow harvest was performed. Thirty-one patients underwent 33 bone marrow collections. Pretreatment consisted of 100 mg meperidine i.m. and 20 mg diazepam i.m. 1 h before start of procedure. Eight patients got additional meperidine and diazepam during the procedure, all patients got lidocaine 1% locally. A mean volume of 1.321 was obtained with 42.5 punctures. Twenty-two patients had no complications, 4 vomited, 4 had easily correctable hypotension of short duration, one got oxygen for cyanosis of short duration. Acceptance was good in 23 patients, in 6 reasonably well, in two bad. Only one patient experienced pain problems, due to suction. Anxiety was no major problem due to good information before the procedure and mild sedation. This form of anesthesia for bone marrow collection is a safe procedure, it is generally well accepted by the patient and it can be performed on an out-patient basis.