A randomized trial of high- versus low-dose subcutaneous interleukin-2 outpatient therapy for early human immunodeficiency virus type 1 infection.
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Forty-nine outpatients infected with human immunodeficiency virus with baseline CD4 cell counts >/=500/mm3, who were on stable antiretroviral therapy, were randomized to receive 5-day cycles of either low-dose (1.5 million IU [MIU] twice a day) or high-dose (7.5 MIU twice a day) subcutaneous (sc) interleukin (IL)-2 every 4 or every 8 weeks. High-dose recipients experienced mean slopes of +116.1 cells/month and +2.7 %/month in CD4 cells and percents, respectively, whereas low-dose recipients displayed mean slopes of +26.7 and +1.3% in the same parameters. At month 6, high-dose recipients achieved a 94.8% increase in mean CD4 cells over baseline compared with a 19.0% increase in low-dose recipients. While high-dose recipients encountered more constitutional side effects, these were generally not dose-limiting. High-dose scIL-2 therapy in outpatients with early HIV-1 infection was well tolerated and induced dramatic, sustained rises in CD4 cells. (+info)
Suppression of experimental abdominal aortic aneurysms by systemic treatment with a hydroxamate-based matrix metalloproteinase inhibitor (RS 132908).
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BACKGROUND: Abdominal aortic aneurysms (AAAs) are associated with chronic inflammation, disruption of medial elastin, and increased local production of elastolytic matrix metalloproteinases (MMPs). The purpose of this study was to investigate how treatment with a hydroxamate-based MMP antagonist (RS 132908) might affect the development of experimental AAAs. METHODS: Male Wistar rats underwent intraluminal perfusion of the abdominal aorta with 50 units of porcine pancreatic elastase followed by treatment for 14 days with RS 132908 (100 mg/kg/day subcutaneously; n = 8) or with vehicle alone (n = 6). The external aortic diameter (AD) was measured in millimeters before elastase perfusion and at death, with AAA defined as an increase in AD (DeltaAD) of at least 100%. Aortic wall elastin and collagen concentrations were measured with assays for desmosine and hydroxyproline, and fixed aortic tissues were examined by light microscopy. RESULTS: AAAs developed in all vehicle-treated rats, with a mean AD (+/- SE) that increased from 1.60 +/- 0.03 mm before perfusion to 5.98 +/- 1.02 mm on day 14 (DeltaAD = 276.4 +/- 67.7%). AAAs developed in only five of eight animals (62.5%) after MMP inhibition, with a mean AD that increased from 1.56 +/- 0.05 mm to 3.59 +/- 0.34 mm (DeltaAD = 128.1 +/- 18.7%; P <.05, vs vehicle). The overall inhibition of aortic dilatation attributable to RS 132908 was 53.6 +/- 6.8%. Aortic wall desmosine fell by 85.4% in the vehicle-treated rats (1210.6 +/- 87.8 pmol/sample to 176.7 +/- 33.4 pmol/sample; P <.05) but only by 65.6% in the animals treated with RS 312908 (416.2 +/- 120.5 pmol/sample). In contrast, hydroxyproline was not significantly affected by either elastase perfusion or drug treatment. Microscopic examination revealed the preservation of pericellular elastin and a greater degree of fibrocollagenous wall thickening after MMP inhibition, with no detectable difference in the extent of inflammation. CONCLUSIONS: Systemic MMP inhibition suppresses aneurysmal dilatation in the elastase-induced rodent model of AAA. Consistent with its direct inhibitory effect on various MMPs, RS 132908 promotes the preservation of aortic elastin and appears to enhance a profibrotic response within the aortic wall. Hydroxamate-based MMP antagonists may therefore be useful in the development of pharmacologic approaches to the suppression of AAAs. (+info)
Early short-term 9-[2-(R)-(phosphonomethoxy)propyl]adenine treatment favorably alters the subsequent disease course in simian immunodeficiency virus-infected newborn Rhesus macaques.
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Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of human pediatric AIDS to study disease pathogenesis and to develop intervention strategies aimed at delaying disease. In the present study, we demonstrate that very early events of infection greatly determine the ultimate disease course, as short-term antiviral drug administration during the initial viremia stage significantly delayed the onset of AIDS. Fourteen newborn macaques were inoculated orally with uncloned, highly virulent SIVmac251. The four untreated control animals showed persistently high virus levels and poor antiviral immune responses; they developed fatal immunodeficiency within 15 weeks. In contrast, SIV-infected newborn macaques which were started on 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) treatment at 5 days of age and continued for either 14 or 60 days showed reduced virus levels and enhanced antiviral immune responses. This short-term PMPA treatment did not induce detectable emergence of SIV mutants with reduced in vitro susceptibility to PMPA. Although viremia increased in most animals after PMPA treatment was withdrawn, all animals remained disease-free for at least 6 months. Our data suggest that short-term treatment with a potent antiviral drug regimen during the initial viremia will significantly prolong AIDS-free survival for HIV-infected infants and adults. (+info)
BACKGROUND: Sufentanil is a potent but short-acting spinal analgesic used to manage perioperative pain. This study evaluated the influence of transdermal nitroglycerine on the analgesic action of spinal sufentanil in patients undergoing orthopedic surgery. METHODS: Fifty-six patients were randomized to one of four groups. Patients were premedicated with 0.05-0.1 mg/kg intravenous midazolam and received 15 mg bupivacaine plus 2 ml of the test drug intrathecally (saline or 10 microg sufentanil). Twenty to 30 min after the spinal puncture, a transdermal patch of either 5 mg nitroglycerin or placebo was applied. The control group received spinal saline and transdermal placebo. The sufentanil group received spinal sufentanil and transdermal placebo. The nitroglycerin group received spinal saline and transdermal nitroglycerine patch. Finally, the sufentanil-nitroglycerin group received spinal sufentanil and transdermal nitroglycerine. Pain and adverse effects were evaluated using a 10-cm visual analog scale. RESULTS: The time to first rescue analgesic medication was longer for the sufentanil-nitroglycerin group (785+/-483 min) compared with the other groups (P<0.005). The time to first rescue analgesics was also longer for the sufentanil group compared with the control group (P<0.05). The sufentanil-nitroglycerin group group required less rescue analgesics in 24 h compared with the other groups (P<0.02) and had lesser 24-h pain visual analog scale scores compared with the control group (P<0.005), although these scores were similar to the sufentanil and nitroglycerin groups (P>0.05). The incidence of perioperative adverse effects was similar among groups (P>0.05). CONCLUSIONS: Transdermal nitroglycerine alone (5 mg/day), a nitric oxide generator, did not result in postoperative analgesia itself, but it prolonged the analgesic effect of spinal sufentanil (10 microg) and provided 13 h of effective postoperative analgesia after knee surgery. (+info)
Low molecular weight heparin (dalteparin) as adjuvant treatment of thrombolysis in acute myocardial infarction--a pilot study: biochemical markers in acute coronary syndromes (BIOMACS II).
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OBJECTIVES: This randomized, double blind, placebo-controlled pilot trial evaluated the effect of dalteparin as an adjuvant to thrombolysis in patients with acute myocardial infarction regarding early reperfusion, recurrent ischemia and patency at 24 h. BACKGROUND: Low-molecular-weight heparin, given subcutaneously twice daily without monitoring, might be an attractive alternative to conventional intravenous heparin in the treatment of acute myocardial infarction. METHODS: In 101 patients dalteparin/placebo 100 IU/kg was given just before streptokinase and a second injection 120 IU/kg after 12 h. Monitoring with continuous vector-ECG was done to obtain signs of early reperfusion and later ischemic episodes. Blood samples for myoglobin were obtained at start and after 90 min to evaluate signs of reperfusion. Coronary angiography was performed after 20-28 h to evaluate TIMI-flow in the infarct-related artery. RESULTS: Dalteparin added to streptokinase tended to provide a higher rate of TIMI grade 3 flow in infarct-related artery compared to placebo, 68% versus 51% (p = 0.10). Dalteparin had no effects on noninvasive signs of early reperfusion. In patients with signs of early reperfusion, there seemed to be a higher rate of TIMI grade 3 flow, 74% versus 46% (myoglobin) (p = 0.04) and 73% versus 52% (vector-ECG) (p = 0.11). Ischemic episodes 6-24 h. after start of treatment were fewer in the dalteparin group, 16% versus 38% (p = 0.04). CONCLUSIONS: When dalteparin was added as an adjuvant to streptokinase and aspirin, there were tendencies for less ECG monitoring evidence of recurrent ischemia and better patency at 24 h, warranting further study. (+info)
Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome.
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PURPOSE: Subcutaneous (SC) octreotide acetate effectively relieves the diarrhea and flushing associated with carcinoid syndrome but requires long-term multiple injections daily. A microencapsulated long-acting formulation (LAR) of octreotide acetate has been developed for once-monthly intramuscular dosing. PATIENTS AND METHODS: A randomized trial compared double-blinded octreotide LAR at 10, 20, and 30 mg every 4 weeks with open-label SC octreotide every 8 hours for the treatment of carcinoid syndrome. Seventy-nine patients controlled with treatment of SC octreotide 0.3 to 0.9 mg/d whose symptoms returned during a washout period and who returned for at least the week 20 evaluation constituted the efficacy-assessable population. RESULTS: Complete or partial treatment success was comparable in each of the four arms of the study (SC, 58.3%; 10 mg, 66.7%; 20 mg, 71.4%; 30 mg, 61.9%; P> or =.72 for all pairwise comparisons). Control of stool frequency was similar in all treatment groups. Flushing episodes were best controlled in the 20-mg LAR and SC groups; the 10-mg LAR treatment was least effective in the control of flushing. Treatment was well tolerated by patients in all four groups. CONCLUSION: Once octreotide steady-state concentrations are achieved, octreotide LAR controls the symptoms of carcinoid syndrome at least as well as SC octreotide. A starting dose of 20 mg of octreotide LAR is recommended. Supplemental SC octreotide is needed for approximately 2 weeks after initiation of octreotide LAR treatment. Occasional rescue SC injections may be required for possibly 2 to 3 months until steady-state octreotide levels from the LAR formulation are achieved. (+info)
ATP-sensitive potassium channels regulate in vivo dopamine release in rat striatum.
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ATP-sensitive K+ channels (K(ATP)) are distributed in a variety of tissues including smooth muscle, cardiac and skeletal muscle, pancreatic beta-cells and neurons. Since K(ATP) channels are present in the nigrostriatal dopamine (DA) pathway, the effect of potassium-channel modulators on the release of DA in the striatum of conscious, freely-moving rats was investigated. The extracellular concentration of DA was significantly decreased by the K(ATP)-channel opener (-)-cromakalim but not by diazoxide. (-)-Cromakalim was effective at 100 and 1000 microM concentrations, and the maximum decrease was 54% below baseline. d-Amphetamine significantly increased extracellular DA levels at the doses of 0.75 and 1.5 mg/kg, s.c. with a 770% maximum increase. (-)-Cromakalim had no effect on d-amphetamine-induced DA release, while glyburide, a K(ATP) blocker, significantly potentiated the effects of a low dose of d-amphetamine. These data indicate that K+ channels present in the nigrostriatal dopaminergic terminals modulate basal release as well as evoked release of DA. (+info)
Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons.
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Nitric oxide (NO) has been proposed to contribute to the development of hyperalgesia by activating the NO/guanosine 3',5'-cyclic monophosphate (cGMP) signal transduction pathway in the spinal cord. We have examined the effects of NO on the responses of primate spinothalamic tract (STT) neurons to peripheral cutaneous stimuli and on the sensitization of STT cells following intradermal injection of capsaicin. The NO level within the spinal dorsal horn was increased by microdialysis of a NO donor, 3-morpholinosydnonimine (SIN-1). SIN-1 enhanced the responses of STT cells to both weak and strong mechanical stimulation of the skin. This effect was preferentially on deep wide dynamic range STT neurons. The responses of none of the neurons tested to noxious heat stimuli were significantly changed when SIN-1 was administered. Intradermal injection of capsaicin increased dramatically the content of NO metabolites, NO-2/NO-3, within the dorsal horn. This effect was attenuated by pretreatment of the spinal cord with a nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Sensitization of STT cells induced by intradermal injection of capsaicin was also prevented by pretreatment of the dorsal horn with the NOS inhibitors, L-NAME or 7-nitroindazole. Blockade of NOS did not significantly affect the responses of STT cells to peripheral stimulation in the absence of capsaicin injection. The data suggest that NO contributes to the development and maintenance of central sensitization of STT cells and the resultant mechanical hyperalgesia and allodynia after peripheral tissue damage or inflammation. NO seems to play little role in signaling peripheral stimuli under physiological conditions. (+info)