RESUMO
We present the case of a 66-year-old female after renal transplant with severe course of herpes zoster (HZ). Although HZ represents a common infectious complication of transplant patients, its variable manifestation and ability to disseminate warrants serious consideration. Prompt diagnosis and treatment are essential in preventing further spread and disastrous complications.
Assuntos
Herpes Zoster/etiologia , Transplante de Rim/efeitos adversos , Idoso , Feminino , Gangrena , Herpes Zoster/diagnóstico , Herpes Zoster/tratamento farmacológico , Herpes Zoster/patologia , HumanosRESUMO
Neurovascular regulation, which is critical to the efficient functioning of the brain, is impaired in Alzheimer's disease and in transgenic mice overexpressing Abeta. Although senile plaques and neurofibrillary tangles represent neuropathological hallmarks of Alzheimer's disease, deposition of Abeta in cerebral blood vessels also likely plays a significant role in this debilitating and fatal disease. Further, soluble Abeta, which shows greater correlation with disease progression and severity than deposited plaques or tangles, displays strong vasoactive properties. The aim of this study was to develop a non-invasive model of cerebral vasoactivity that would ultimately be translatable to Alzheimer's disease as a marker for disease-modifying efficacy of novel small molecule and biologics drugs. Relative changes in cerebral blood volume following relevant doses of soluble Abeta(1-40) (0.01 or 0.1 mg/mouse), PBS, or the reverse peptide, Abeta(40-1) (0.01 or 0.1 mg/mouse), were monitored non-invasively by contrast-enhanced functional magnetic resonance imaging in anesthetized C57BL/6 mice. Experiments were performed on a 7T horizontal bore scanner using gradient echo echo-planar imaging. As expected, PBS and Abeta(40-1) did not induce any significant change in vascular response. In contrast, Abeta(1-40) significantly decreased CBV in a quantifiable, dose-related and region-specific manner. These data demonstrate for the first time the feasibility of characterizing pathogenic Abeta(1-40)-induced vascular dysfunction in vivo using a non-invasive approach. Further, this technique can be readily applied to preclinical screening in a longitudinal manner for novel drugs or antibodies targeting disease modification.
Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Fragmentos de Peptídeos , Animais , Mapeamento Encefálico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Processamento de Imagem Assistida por Computador/métodos , Camundongos , Oxigênio/sangueRESUMO
BACKGROUND AND PURPOSE: The non-selective beta-adrenoceptor antagonist, D,L-sotalol (sotalol) is commonly employed as a positive control during preclinical cardiovascular safety pharmacology testing, mainly because of its ability to prolong QT interval duration. However, no information appears in the literature, except in abstract form, regarding the dose-response effects of sotalol in unanesthetized monkeys. The current study was conducted to determine the dose- and plasma-response effects of orally administered sotalol on cardiovascular function in conscious non-human primates. EXPERIMENTAL APPROACH: Male cynomolgus monkeys were implanted with telemetry devices and the effects of sotalol hydrochloride (5, 10 and 30 mg kg(-1) of body weight, p.o.) on arterial blood pressure, heart rate, body temperature and electrocardiogram waveform were continuously monitored for 6 h after dosing. Blood was sampled for the measurement of plasma concentrations of sotalol. KEY RESULTS: Sotalol dose dependently decreased heart rate and prolonged RR, PR, QT and corrected QT intervals, while having little or no effects on the QRS complex, arterial pressure or body temperature, over the dose range tested. When the data were related to plasma concentrations of sotalol, it was clear that the cardiovascular effects occurred in a similar pattern and to a comparable degree as those reported in human studies. CONCLUSIONS AND IMPLICATIONS: The current study helps demonstrate the validity of utilizing telemetry-instrumented non-human primates for the cardiovascular safety pharmacology assessment of drugs prior to first-in-human testing, and its findings may serve as a reference source for the dose- and plasma-response effects of orally administered sotalol in conscious monkeys.
Assuntos
Antagonistas Adrenérgicos beta/toxicidade , Eletrocardiografia , Sotalol/toxicidade , Administração Oral , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/farmacocinética , Animais , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Macaca fascicularis , Masculino , Modelos Animais , Sotalol/administração & dosagem , Sotalol/farmacocinética , Especificidade da Espécie , Telemetria/métodosRESUMO
BACKGROUND AND PURPOSE: Inhibition of bradykinin metabolizing enzymes (BMEs) can cause acute angioedema, as demonstrated in a recent clinical trial in patients administered the antihypertensive, omapatrilat. However, the relative contribution of specific BMEs to this effect is unclear and confounded by the lack of a predictive pre-clinical model of angioedema. EXPERIMENTAL APPROACH: Rats were instrumented to record blood pressure and heart rate; inhibitors were infused for 35 min and bradykinin was infused during the last 5 min to elicit hypotension, as a functional marker of circulating bradykinin and relative angioedema risk. KEY RESULTS: In the presence of omapatrilat bradykinin produced dose-dependent hypotension, an effect abolished by B(2) blockade. In the presence of lisinopril (ACE inhibitor), but not candoxatril (NEP inhibitor) or apstatin (APP inhibitor), bradykinin also elicited hypotension. Lisinopril-mediated hypotension was unchanged with concomitant blockade of NEP or NEP/DPPIV (candoxatril+A-899301). However, hypotension was enhanced upon concomitant blockade of APP and further intensified in the presence of NEP inhibition to values not different from omapatrilat alone. CONCLUSIONS AND IMPLICATIONS: We demonstrated that bradykinin is degraded in vivo with an enzyme rank-efficacy of ACE>APP>>NEP or DPPIV. These results suggest the effects of omapatrilat are mediated by inhibition of three BMEs, ACE/APP/NEP. However, dual inhibition of ACE/NEP or ACE/NEP/DPPIV elicits no increased risk of angioedema compared to ACE inhibition alone. Thus, novel BME inhibitors must display no activity against APP to avoid angioedema risk due to high prevalence of ACE inhibitor therapy in patients with diabetes and cardiovascular disease.
Assuntos
Angioedema/etiologia , Bradicinina/metabolismo , Inibidores Enzimáticos/farmacologia , Hipotensão/etiologia , Aminopeptidases/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Bradicinina/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Indanos/farmacologia , Lisinopril/farmacologia , Masculino , Neprilisina/antagonistas & inibidores , Peptídeos/farmacologia , Propionatos/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Tiazepinas/administração & dosagem , Tiazepinas/farmacologiaRESUMO
BACKGROUND AND PURPOSE: Activation of cannabinoid CB1 and/or CB2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB1 from CB2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. EXPERIMENTAL APPROACH: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB1/CB2 (A-834735) and selective CB2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB1 (rimonabant) or CB2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. KEY RESULTS: The non-selective CB1/CB2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB1 receptor density binding maps. Pretreatment with a CB1 antagonist but not with a CB2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB2 selective agonist. CONCLUSION AND IMPLICATIONS: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB1 and CB2 receptors using phMRI. Further, as the presence of CB2 receptors in the brain remains controversial, our data suggest that if CB2 receptors are expressed, they are not functional under normal physiological conditions.
Assuntos
Encéfalo/efeitos dos fármacos , Agonistas de Receptores de Canabinoides , Algoritmos , Animais , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Circulação Cerebrovascular/efeitos dos fármacos , Humanos , Interpretação de Imagem Assistida por Computador , Inflamação/complicações , Imageamento por Ressonância Magnética , Masculino , Atividade Motora/efeitos dos fármacos , Dor/tratamento farmacológico , Dor/etiologia , Doenças do Sistema Nervoso Periférico/complicações , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidoresRESUMO
During preliminary studies of the rostral ventrolateral medulla as a relay site for responses activated from forebrain, loss of the marked depressor effect of lidocaine, microinjected into lateral rostral ventrolateral medulla, was observed when rats were ventilated spontaneously rather than by artificial ventilation. The mechanism of this effect was studied in rats ventilated at a tidal volume of 2.5 ml. Bilateral injection of 4% lidocaine into lateral rostral ventrolateral medulla decreased mean arterial pressure by -47 +/- 8 mm Hg and heart rate by -68 +/- 21 beats/min. Reduction of tidal volume to 1.5 ml significantly attenuated the fall in mean arterial pressure and heart rate produced by lidocaine to -17 +/- 11 mm Hg and -12 +/- 8 beats/min. The decrease in tidal volume resulted in decreased arterial PO2 and pH, and increased PCO2. However, the depressor effect of lidocaine was not significantly affected by independently changing PO2 and PCO2. The physical stimuli associated with reduction of tidal volume (i.e., changes in lung inflation and chest wall movement) appeared to mediate the attenuated depressor response to the injection of lidocaine into the lateral rostral ventrolateral medulla. These data suggest that 1) tonic vasomotor activity derived from lateral rostral ventrolateral medulla is strongly influenced by altered mechanics of respiration, and 2) the anatomical location of the putative vasomotor center may not be defined by the lateral rostral ventrolateral medulla under all conditions.
Assuntos
Pressão Sanguínea , Frequência Cardíaca , Medidas de Volume Pulmonar , Bulbo/fisiologia , Volume de Ventilação Pulmonar , Sistema Vasomotor/fisiologia , Animais , Lidocaína/farmacologia , Masculino , Ratos , Ratos Endogâmicos , Sistema Vasomotor/efeitos dos fármacosRESUMO
A previous report demonstrated that infusion of adenosine into the forearm increased local vascular production of angiotensin II. We hypothesize that this increase in angiotensin II could attenuate the vasodilator response to adenosine subtype 2 (A2) receptor activation. The depressor and regional hemodynamic responses to the A2-selective adenosine agonist DPMA were measured in the presence and absence of angiotensin subtype 1 (AT1) receptor blockade (losartan, 10 mg/kg IV) in anesthetized rats. Losartan pretreatment (without versus with losartan) significantly potentiated DPMA-induced reductions in renal (-13 +/- 2% versus -22 +/- 4%, P < .05) and mesenteric (-11 +/- 2% versus -23 +/- 4%, P < .05) vascular resistances, resulting in a greater depressor response (-7 +/- 2 versus -18 +/- 3 mm Hg, P < .05). The decrease in hindquarter vascular resistance was not affected. To test the specificity of this interaction, we also evaluated nitroglycerin and nifedipine. Pretreatment with losartan had no effect on the responses to nitroglycerin, whereas the responses to nifedipine either were not affected or were attenuated (percent change in mesenteric vascular resistance: without losartan pretreatment, -30 +/- 1%; with losartan pretreatment, -24 +/- 2%, P < .05). To determine whether the decrease in arterial pressure after losartan pretreatment contributed to the potentiation of the DPMA-mediated effects, we infused nitroglycerin to lower mean arterial pressure comparably to losartan treatment. None of the hemodynamic responses to subsequent DPMA administration were affected. These data suggest that endogenous levels of angiotensin II, whether released locally or systemically, selectively attenuate the A2-mediated reductions in renal and mesenteric vascular resistances.
Assuntos
Adenosina/farmacologia , Angiotensina II/antagonistas & inibidores , Vasodilatação/efeitos dos fármacos , Adenosina/análogos & derivados , Animais , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Imidazóis/farmacologia , Injeções Intravenosas , Losartan , Masculino , Nifedipino/farmacologia , Nitroglicerina/farmacologia , Ratos , Ratos Sprague-Dawley , Tetrazóis/farmacologia , Resistência Vascular/efeitos dos fármacosRESUMO
We showed earlier that the rostral ventral medulla can be functionally and anatomically divided into the rostral ventrolateral medulla (RVLM) and the rostral ventromedial medulla (RVMM). In this study, we examined the relationship between the lateral hypothalamus and these two medullary sites. Electrical stimulation of the lateral hypothalamus produced a pressor response mediated by increases in renal and mesenteric vascular resistance. Inactivating RVLM had no effect on this response whereas inactivating RVMM significantly blunted the pressor response and the increases in renal and mesenteric resistance. In other studies, inactivating dorsomedullary sites significantly reduced arterial pressure. Unlike RVLM, these depressor responses were not significantly altered by reducing tidal volume. Inactivating sites 0.5 mm medial and lateral to the RVMM, as well as a site 0.5 mm caudal to the RVLM, resulted in depressor responses that were unaffected by reducing tidal volume. However, inactivation of a site 1.0 mm caudal to the RVLM but still within the ventrolateral medullary pressor area, resulted in a depressor response that was enhanced by reduced tidal volume. Together, these data demonstrate a functional differentiation of medullary sites controlling vasomotor outflow.
Assuntos
Pressão Sanguínea/fisiologia , Bulbo/fisiologia , Tálamo/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Estimulação Elétrica , Injeções , Rim/irrigação sanguínea , Lidocaína/administração & dosagem , Bulbo/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Veias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/fisiologia , Ratos , Ratos Endogâmicos , Resistência Vascular/efeitos dos fármacos , Resistência Vascular/fisiologiaRESUMO
The interaction of LFA-1 and ICAM-1 plays an important role in the cell adhesion process. On the basis of previously reported SAR and structural information on the binding of our p-arylthiocinnamide series to LFA-1, we have identified the cyclic amide (C-ring) as a site for modification. Improvement in potency and, more importantly, in the physical properties and pharmacokinetic profiles of the leading compounds resulted from this modification. One of the best compounds (11f) is also shown to reduce myocardial infarct size in rat.
Assuntos
Cinamatos/síntese química , Molécula 1 de Adesão Intercelular/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Ácidos Nipecóticos/síntese química , Sulfetos/síntese química , Amidas/síntese química , Amidas/química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Fármacos Cardiovasculares/síntese química , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Cinamatos/química , Cinamatos/farmacocinética , Cinamatos/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Infarto do Miocárdio/patologia , Miocárdio/patologia , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacocinética , Ácidos Nipecóticos/farmacologia , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade , Sulfetos/química , Sulfetos/farmacocinética , Sulfetos/farmacologiaRESUMO
Catheter-directed thrombolysis has gained increasing acceptance for the treatment of patients who present with vascular occlusion; however, intravenous injection may be preferable in selected patients. Recombinant prourokinase (r-proUK) is a recently-developed fibrin-selective thrombolytic agent with specificity for clot-bound plasminogen. To compare the effects of r-proUK on clot lysis and restoration of blood flow when injected by either intraarterial or intravenous routes of administration, we utilized a dog model of arterial thrombosis in which a radiolabelled clot is formed in the femoral artery. The r-proUK was given by intravenous infusion to one group of 18 animals in doses ranging from 10,000 IU/kg to 100,000 IU/kg; a second group of 27 dogs was treated with r-proUK administered by the intra-arterial route in a dose range from 300 IU to 10,000 IU. Clot lysis was measured by monitoring the loss of counts from the radiolabelled clot over time; blood flow was also monitored throughout the experimental period. Animals which received intravenous treatment showed dose-related clot lysis ranging from 14% to 70% at 2 h, while those which received intra-arterial infusions showed lysis ranging from 22% to 79% over the same period. For similar degrees of clot lysis attained at the highest dose levels of 100,000 IU/kg and 10,000 IU, blood flow was restored to 77% and 35% of control levels in dogs which received intravenous and intraarterial treatment, respectively. The hemostatic protein fibrinogen was not reduced in any of the treatment groups. The results indicate that 100 times more intravenous than intra-arterial r-proUK is required to produce similar clot lysis in this canine model, and that the agent can be administered at this level without induction of a systemic lytic state.
Assuntos
Arteriopatias Oclusivas/tratamento farmacológico , Artéria Femoral , Fibrinolíticos/uso terapêutico , Terapia Trombolítica , Trombose/tratamento farmacológico , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico , Animais , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Fibrinolíticos/administração & dosagem , Membro Posterior/irrigação sanguínea , Infusões Intra-Arteriais , Infusões Intravenosas , Injeções Intravenosas , Masculino , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico , Fluxo Sanguíneo Regional/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem , Ativador de Plasminogênio Tipo Uroquinase/genéticaRESUMO
1. The effects of myocardial ischaemia/reperfusion were tested on the coronary vasorelaxant responses to agonists selective for the A1 and A2 adenosine receptor subtypes in the dog. The left anterior descending (LAD) coronary artery was occluded distal to the first diagonal branch. The occlusion was maintained for 1 h, followed by 1 h of reperfusion. 2. In the first series of experiments, LAD and circumflex arteries were excised and contracted with prostaglandin F2 alpha (PGF2 alpha). Ischaemia/reperfusion did not significantly alter the vasorelaxation produced by either sodium nitroprusside (endothelium-independent) or acetylcholine (endothelium-dependent). The A1 selective agonist, cyclopentyladenosine (CPA), produced coronary vasorelaxation in both normally perfused vessels and vessels subjected to ischaemia/reperfusion. In contrast, the relaxation produced by the A2-selective agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl) ethyl] adenosine (DPMA) was significantly attenuated by ischaemia/reperfusion (14 fold shift in EC50). 3. In the second series of experiments, coronary blood flow was increased by administration of the A1 and A2 agonists before and after ischaemia/reperfusion of the LAD in anaesthetized dogs. Both compounds dose-dependently increased coronary blood flow. The slopes of the dose-response functions to CPA or DPMA were not significantly altered in the normally perfused circumflex vascular bed. Similarly, the CPA dose-response function in the LAD was unaltered by ischaemia/reperfusion. However, the slope of the coronary vasodilator response to the A2 agonist was significantly reduced following ischaemia/reperfusion of the LAD. 4. We conclude that ischaemia/reperfusion reduces responsiveness to an adenosine A2 receptor subtype agonist, but not an A1 receptor subtype agonist. These data confirm the independent nature of A1- and A2-mediated coronary vasodilatation.
Assuntos
Adenosina/análogos & derivados , Vasos Coronários/efeitos dos fármacos , Isquemia Miocárdica/fisiopatologia , Reperfusão Miocárdica , Receptores Purinérgicos P1/fisiologia , Vasodilatação/efeitos dos fármacos , Adenosina/farmacologia , Animais , Vasos Coronários/fisiologia , Dinoprosta/farmacologia , Cães , Técnicas In Vitro , Receptores Purinérgicos P1/efeitos dos fármacosRESUMO
Microinjections of lidocaine were used to examine the contributions of two subregions of the RVM, RVLM (2 mm lateral to midline) and RVMM (1 mm lateral to midline) to the maintenance of AP and SNA in urethane-anesthetized rats. Lidocaine microinjected into either site reduced AP to similar levels. Blockade of RVLM and RVMM produced a small further reduction in AP and essentially abolished neurogenic maintenance of AP. Blockade of either RVLM or RVMM elicited similar falls in RSNA. In contrast, inactivation of RVLM elicited larger falls in lumbar chain (LSNA) and splanchnic (SSNA) SNA than did inactivation of the RVMM. Combined blockade of RVLM and RVMM essentially eliminated LSNA, while RSNA and SSNA were reduced only 60%. From these data we conclude that (1) RVLM and RVMM contribute equally to the neurogenic maintenance of AP; (2) RVLM and RVMM differentially control the activity of individual sympathetic nerves; and (3) a substantial portion of RSNA and SSNA originates outside the RVM and may not be involved in vasomotor control.
Assuntos
Pressão Sanguínea/fisiologia , Bulbo/fisiologia , Sistema Nervoso Simpático/fisiologia , Animais , Masculino , Ratos , Ratos EndogâmicosRESUMO
The original definition of hepatic veno-occlusive disease (VOD), which is still widely accepted, includes onset of the clinical syndrome before day +20 following high-dose chemotherapy (HDC) and stem cell transplantation (SCT). We retrospectively identified four patients following HDC and SCT presenting with late onset VOD occurring at day +24, day +27, day +34 and day +42 post SCT. All patients had moderate VOD, with successful resolution of the VOD before day +100 with optimal supportive therapy. Common risk factors for VOD shared by all four patients included an older age (median age: 60 years), and use of a busulphan-containing regimen. Mean and maximum bilirubin levels for all patients during the VOD syndrome were 2.02, 1.76, 5.09, 2.87 mg/dl and 2.5, 2.2, 8.9 and 4.1 mg/dl, respectively, which correlated well with duration of VOD. All patients encountered platelet transfusion-dependent thrombocytopenia during VOD. Ursodeoxycholic acid was used as VOD prophylaxis beginning at a mean of 33 days prior to onset of VOD. As the cellular target of hepatic VOD is as yet unidentified, it is uncertain whether ursodiol or other common characteristics of patients with late onset VOD influence the pathogenesis and natural history of this disease. We believe that the uncommon clinical entity of late onset VOD, a potentially fatal regimen-related toxicity, should not be ignored as a diagnosis of liver disease after 3 or more weeks following HDC and SCT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/etiologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada/efeitos adversos , Feminino , Hepatopatia Veno-Oclusiva/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Transplante AutólogoRESUMO
While high-dose chemotherapy and stem cell transplantation is associated with higher complete response rates than conventional chemotherapy in patients with metastatic breast cancer (MBC), its role in conferring a survival advantage is unproven. We report the results of a prospective phase II trial of 33 patients accrued between 1996 to 1998 with chemosensitive MBC, who received cyclophosphamide (Cy) 2000 mg/m2/day and carboplatin (Cb) 600 mg/m2/day for 3 consecutive days, followed by infusion of peripheral blood stem cells cultured in IL-2 for 24 h on day 0 as adoptive immunotherapy. Low-dose interleukin-2 (IL-2) was administered from day 0 to +4 and/or +7 to +11, +14 to +18, +21 to +25, then 5 days per month for 11 months to augment a graft-versus-tumor effect. The results of this study were compared to those of a historical control group treated with an identical high-dose Cb + Cy regimen with SCT but without IL-2 treatment. Only gastrointestinal (GI) toxicity was more frequent in the IL-2 cohort (P = 0.0031). At a median follow-up of 18.6 months, the median progression-free survival (PFS) is 9 months (2.4-40) and the median OS has not been reached yet. The Kaplan-Meier estimated 2 year PFS is 35%, compared with 17% in the control arm (P = 0.73), and the estimated 2 year OS is 78%, compared with 61% in the control arm (P = 0.22). Multivariate analysis showed that ER status was an independent predictor for OS and PFS, and less chemotherapy prior to HDCSCT predicted for a better PFS. These results show that augmenting HDC with IL-2 activated SCT is well-tolerated. Whether a therapeutic advantage is achievable in patients with MBC remains to be determined. Bone Marrow Transplantation (2000) 25, 19-24.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/terapia , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Interleucina-2/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Feminino , Mobilização de Células-Tronco Hematopoéticas/métodos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sobrevida , Transplante AutólogoRESUMO
The lateral reticular nucleus (LRN) in the caudal ventrolateral medulla has been implicated in the regulation of spinal nociceptive transmission and hemodynamics. Experiments were undertaken to examine the relationship between inhibition of the tail flick reflex and cardiovascular effects produced by electrical stimulation in the LRN in rats lightly anesthetized with pentobarbital. Intensity- and frequency-dependent increases in mean arterial pressure and vascular resistance in the hindquarter, mesenteric, renal and caudal arterial beds were observed. Inhibition of the tail flick reflex, however, occurred at intensities of electrical stimulation which produced no significant changes in mean arterial pressure or vascular resistance in any of the arterial beds studied. Selective stimulation of cell bodies in the LRN by microinjection of glutamate similarly inhibited the tail flick reflex but produced significant reductions in mean arterial pressure, without substantially affecting regional vascular resistances. These results suggest that the antinociceptive and depressor effects of stimulation in the LRN are mediated by activation of cell bodies, while pressor effects produced by focal electrical stimulation are mediated by activation of fibers of passage. The descending inhibition produced by stimulation in the LRN is independent of stimulation-produced cardiovascular responses.
Assuntos
Fenômenos Fisiológicos Cardiovasculares , Bulbo/fisiologia , Dor/fisiopatologia , Formação Reticular/fisiologia , Animais , Pressão Sanguínea , Mapeamento Encefálico , Estimulação Elétrica , Glutamatos/farmacologia , Ácido Glutâmico , Masculino , Bulbo/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Formação Reticular/efeitos dos fármacos , Resistência VascularRESUMO
The benzoylthiophene analog, PD 81,723, has been shown to allosterically enhance agonist binding and functional activation of the mammalian adenosine (ADO) A(1) receptor subtype by putatively maintaining the receptor in a high affinity state. The present studies were conducted to evaluate the ability of PD 81,723 to enhance the binding of [3H]cyclohexyladenosine ([3H]CHA) to A(1) receptors of neural (cerebral cortex) and non-neural (adipocyte) origin in three different species; rat, guinea pig and dog. PD 81, 723 (0.3-100 microM) produced a concentration-dependent enhancement of [3H]CHA binding to rat brain A(1) receptors. These effects were also species-dependent with larger enhancements (150-200% of control) observed in guinea pig and dog brain membranes as compared to the rat (120% of control). In contrast, PD 81,723 did not produce any enhancement of [3H]CHA binding to A(1) receptors in adipocyte membranes from any of the species examined. Additional binding studies were conducted using pharmacological manipulations that have previously been shown to enhance the allosteric effects of PD 81,723. In the presence of 1 mM GTP, the allosteric effects of PD 81,723 (15 microM) were increased in rat, guinea pig and dog brain membranes, however, in adipocyte membranes from each species, no significant alteration in agonist binding was observed. Similarly, the A(1) receptor selective antagonist 8-cyclopentyl-1, 3-dipropylxanthine (added to effectively reduce the intrinsic antagonist properties of PD 81,723) was found to enhance the allosteric effects of PD 81,723 (15 microM) in brain, but produce no alteration of agonist binding in adipocyte membranes from each species. Examination of the dissociation kinetics of [3H]CHA binding from rat brain and adipocyte membranes revealed that PD 81,723 (15 microM) differentially slowed agonist dissociation from brain, but not adipocyte, membranes. Taken together, the present data support the hypothesis that in tissues that are sensitive to PD 81,723, this benzyolthiophene functions to maintain the A(1) receptor in a high-affinity state and that the relative proportions of high-affinity A(1) receptors present in specific tissues may contribute, at least in part, to the apparent differential effects of PD 81,723 on agonist binding. The tissue specific modulation of A(1) receptor function by PD 81,723 also illustrates the possibility that the locus of allosteric modulation by PD 81,723 may be manifest via a specific, but indirect and tissue-dependent, interaction with the A(1) receptor.
Assuntos
Adipócitos/metabolismo , Encéfalo/metabolismo , Agonistas do Receptor Purinérgico P1 , Receptores Purinérgicos P1/efeitos dos fármacos , Tiofenos/farmacologia , Adenosina/análogos & derivados , Adenosina/metabolismo , Adipócitos/efeitos dos fármacos , Regulação Alostérica , Animais , Encéfalo/efeitos dos fármacos , Cães , Cobaias , Cinética , Masculino , Membranas/efeitos dos fármacos , Membranas/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
INTRODUCTION: The increased availability of transgenic mice prompts a need for the adaptation to mice of whole-animal assays traditionally performed in larger laboratory animals. Gastric emptying studies are frequently conducted in dogs and rats. Mouse-based gastric emptying models currently available often use inert, nonnutrient liquid meals containing nonabsorbable markers or radionuclides. We have developed a mouse gastric emptying assay that features a favorable throughput and the use of a semisolid, high-calorie meal. METHODS: A carbohydrate- and protein-rich semisolid test meal was prepared from common laboratory reagents. Gastric emptying was determined by subtracting the mass of test meal remaining in the stomach from the mass of test meal administered. A time-course study of basal emptying of a semisolid, paste-like test meal high in carbohydrate and protein from the stomachs of overnight-fasted mice was conducted. Agents known to either inhibit (propantheline, 0.3-10 mg/kg sc; corticotropin-releasing factor [CRF], 3-100 nmol/kg ip) or accelerate (metoclopramide, 1-10 mg/kg ip; bethanechol, 1-30 mg/kg ip) gastric emptying were tested. A single time-point variation of the assay can be used for quickly screening compounds for effects on gastric emptying. RESULTS: In time-course studies, the test meal emptied from the stomach with a half-emptying time of 30.6 min (95% CI: 27.3-34.7). The gastric emptying data were successfully modeled by a two-parameter exponential decay function. No lag phase was observed, indicating that the meal empties from the stomach as a liquid. The anticholinergic agent propantheline increased gastric half-emptying time (t(1/2)) approximately threefold, while metoclopramide decreased gastric half-emptying time approximately twofold compared to basal emptying. Single time-point screening studies correctly detected the gastrokinetic activity of bethanechol and the inhibitory effect of CRF. DISCUSSION: The mouse gastric emptying assay reported here is simple, inexpensive, and not labor-intensive. It is capable of detecting either stimulation or inhibition of gastric motor activity. This assay should prove useful for identifying drug-evoked changes in gastric emptying as well as for assessing the gastric motility effects of altered gene expression in genetically modified mice.
Assuntos
Esvaziamento Gástrico/efeitos dos fármacos , Ração Animal , Animais , Betanecol/farmacologia , Caseínas/análise , Hormônio Liberador da Corticotropina/farmacologia , Carboidratos da Dieta/análise , Conteúdo Gastrointestinal , Masculino , Metoclopramida/farmacologia , Camundongos , Camundongos Transgênicos , Propantelina/farmacologia , Amido/análise , Estômago/efeitos dos fármacos , Estômago/fisiologia , Fatores de TempoRESUMO
OBJECTIVE AND DESIGN: P2X(7) receptor activation by ATP results in the release of IL-1beta and IL-18. Prolonged stimulation can lead to pore formation and cell death. In this study we pharmacologically characterized P2X(7) receptors on rat peritoneal cells (RPC) and on 1321N1 cells transfected with rat P2X(7) receptor (1321rP2X(7)-11). MATERIALS AND METHODS: RPC were isolated from rats by lavage. P2X(7) agonist induced pore formation in RPC was measured by EtBr uptake. P2X(7)-stimulated pore formation and Ca(++) influx in 1321rP2X(7)-11 cells were measured by a fluorometric imaging plate reader. The effects of pyridoxal phosphate-6-azo phenyl -2'-4'-disulfonic acid (PPADS) on pore formation and Ca(++) influx were examined in both RPC and 1321rP2X(7)-11. P2X(7)-mediated IL-1beta release in RPC and the effect of PPADS were determined. RESULTS: RPC express functional P2X(7) receptors that were activated by ATP analogs with a rank order of potency of 2'- 3'-O-(4-Benzoylbenzoyl) adenosine 5'-triphosphate (BzATP) > ATP > alpha,beta-methylene ATP. Activation of P2X(7) receptors by BzATP was inhibited by PPADS. Similar results were also obtained in 1321rP2X(7)-11 cells. Activation of P2X(7) receptors on RPC resulted in IL-1 beta secretion, which was inhibited by PPADS. CONCLUSIONS: RPC express functional P2X(7) receptors that form pores and mediate the release of IL-1beta.
Assuntos
Trifosfato de Adenosina/análogos & derivados , Peritônio/citologia , Fosfato de Piridoxal/análogos & derivados , Receptores Purinérgicos P2/fisiologia , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Animais , Complexo CD3/biossíntese , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Etídio/farmacologia , Citometria de Fluxo , Inflamação , Interleucina-1/metabolismo , Interleucina-18/metabolismo , L-Lactato Desidrogenase/metabolismo , Ligantes , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Fosfato de Piridoxal/farmacologia , Ratos , Receptores Purinérgicos P2/química , Receptores Purinérgicos P2X7 , Fatores de Tempo , TransfecçãoRESUMO
We examined the role of pontine sites in the tonic control of vasomotor tone under normal and reduced tidal volumes. Lidocaine was microinjected in pons at the level of the Kölliker-Fuse nucleus (KFN). Injections were made bilaterally 6, 7, 8, and 9 mm below dura, and 0.9 and 2.5 mm lateral to midline. Lidocaine in KFN produced a fall (-14 mmHg) in mean arterial pressure (MAP) at normal and reduced tidal volumes. These effects were mediated primarily by a reduction in hindquarter vascular resistance. Lidocaine into a ventromedial site (8.0 mm beneath dura, 0.9 mm lateral to midline) increased MAP by increasing renal, mesenteric, and hindquarter vascular resistance. After sino-aortic deafferentation (SAD), reduced tidal volume augmented the pressor and blunted the tachycardic responses to lidocaine injected into the ventromedial pons (9.0 mm beneath dura, 0.9 mm lateral to midline). SAD also enhanced the pressor response to lidocaine injected into ventromedial pons. This work demonstrates a role for supra-medullary sites in the tonic control of vasomotor tone.
Assuntos
Pressão Sanguínea/fisiologia , Ponte/fisiologia , Sistema Vasomotor/fisiologia , Vias Aferentes/fisiologia , Animais , Artérias , Pressão Sanguínea/efeitos dos fármacos , Denervação , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica , Lidocaína/farmacologia , Masculino , Microinjeções , Ratos , Ratos Endogâmicos , Seio Aórtico/inervaçãoRESUMO
We examined two functionally and anatomically distinct subregions of rostral ventral medulla, rostral ventrolateral medulla (RVLM, 2 mm lateral to midline) and an area we term rostral ventromedial medulla (RVMM, 1mm lateral to midline). Reducing tidal volume attenuated the depressor response to microinjection of lidocaine (200nl, 4%) into RVLM, but not into RVMM. Lidocaine reduced renal (RVR), mesenteric (MVR), and hindquarter (HQVR) vascular resistances, when injected into both sites, however HQVR was markedly reduced when RVMM was blocked. Selective stimulation with microelectrodes increased RVR, MVR, and HQVR, with RVMM producing the strongest response in HQVR and RVLM the strongest effect on RVR. Cardiovascular responses to stimulation of RVLM required the integrity of RVMM, however, the converse was not found. The integrity of RVMM, but not RVLM, was required for the cardiovascular responses produced by electrical stimulation of lateral hypothalamus. Together, these data suggest that RVLM and RVMM are both important for tonic regulation of vasomotor tone, however, these sites differ in their responses to afferent input and in the control of regional vascular resistances.