Nesiritide citrate (Scios)

Nesiritide citrate is a human brain natriuretic peptide under development by Scios for the potential treatment of congestive heart failure (CHF). An NDA was submitted to the US FDA in April 1998 for approval to market nesiritide citrate for short-term CHF. Scios is expecting to launch this product by mid-1999. Animal studies at Scios have also indicated that human brain natriuretic peptide may be useful in the management of acute hypertension associated with numerous surgical procedures. Scios has estimated the potential market for this drug to be 250-300 million dollars in the US alone.     

SCIO-469 Scios Inc

SCIO-469 is a small-molecule p38 mitogen-activated protein (MAP) kinase inhibitor under development by Scios Inc as a potential oral therapy for inflammatory disorders. By July 2004, SCIO-469 was in phase lib clinical trials for rheumatoid arthritis.     

奈西立肽——心力衰竭治疗的又一新药

奈西立肽是利用重组DNA技术得到的合成型人类脑利钠肽。通过与利钠肽A型和B型受体结合,奈西立肽具有明确的扩血管和排钠利尿作用。奈西立肽主要用于急性心力衰竭的治疗。临床研究表明奈西立肽可改善心力衰竭病人的血流动力学,改善心力衰竭病人的临床症状。奈西立肽是一个疗效显著、起效快、不良反应少的治疗急性心力衰竭的新药。     

Nesiritide for the treatment of congestive heart failure

Nesiritide (Natrecor) is a recombinant form of the human B-type natriuretic peptide (BNP) that has been shown, through several studies, to have beneficial natriuretic, diuretic and vasodilatory effects in the treatment of congestive heart failure (CHF). Nesiritide mimics the actions of endogenous BNP by binding to and stimulating receptors in the heart, kidney and vasculature. Nesiritide functions as both a potent venous and arterial vasodilator and has been shown to improve cardiac haemodynamics more rapidly and to a greater extent than intravenous nitroglycerin, as well as having fewer side effects. When compared in an open-label trial, nesiritide has also been shown to be less proarrhythmic than dobutamine. The major adverse effect of nesiritide, as with other vasodilators, is symptomatic hypotension, which occurred infrequently in clinical trials. Overall, nesiritide represents an effective and safe therapeutic option for the treatment of decompensated CHF.     

Nesiritide for the treatment of congestive heart failure

Nesiritide (Natrecor^®) is a recombinant form of the human B-type natriuretic peptide (BNP) that has been shown, through several studies, to have beneficial natriuretic, diuretic and vasodilatory effects in the treatment of congestive heart failure (CHF). Nesiritide mimics the actions of endogenous BNP by binding to and stimulating receptors in the heart, kidney and vasculature. Nesiritide functions as both a potent venous and arterial vasodilator and has been shown to improve cardiac haemodynamics more rapidly and to a greater extent than intravenous nitroglycerin, as well as having fewer side effects. When compared in an open-label trial, nesiritide has also been shown to be less proarrhythmic than dobutamine. The major adverse effect of nesiritide, as with other vasodilators, is symptomatic hypotension, which occurred infrequently in clinical trials. Overall, nesiritide represents an effective and safe therapeutic option for the treatment of decompensated CHF.     

Nesiritide: a reappraisal of efficacy and safety

The treatment of acute decompensated heart failure (ADHF) remains a therapeutic challenge. Nesiritide was approved by the FDA in 2001 for the treatment of patients with ADHF who have dyspnea at rest or with minimal exertion. Although widely adopted for the treatment of ADHF due to its ability to decrease ventricular filling pressures and to provide mild symptomatic benefit, recent analyses have suggested that nesiritide worsens renal function and increases mortality. Although some discount these analyses that demonstrate the potential dangers of nesiritide, others have stated that its use at the present time must be weighed against the possibility of worse outcomes. A large outcomes trial in patients with ADHF would help clarify the role of nesiritide.     

Nesiritide therapy in a term neonate with renal disease

A term (39-wk-old) male neonate exhibited respiratory distress and anuria within 2 days of birth. The patient was diagnosed with pulmonary hypertension, polycystic kidney disease, and heart failure; his initial B-type natriuretic peptide concentration was 2460 pg/ml. After minimal response to loop diuretics, the patient was given an infusion of nesiritide 0.01 microg/kg/minute, with no loading dose. Urine output increased over 400%, and cardiac function improved. Nesiritide was titrated to 0.03 microg/kg/minute with no hypotension, decreased renal function, or adverse cardiac sequelae over the next 6 days. No subsequent changes in cardiac function occurred during the infant's stay in a progressive care unit, but he died at age 5.5 months due to sepsis. This case report demonstrates the successful first use of nesiritide therapy in a neonate with renal disease. Further studies are warranted to evaluate the safety and administration of this agent in the neonatal patient population.     

奈西立肽增加心衰病人肾功能损害的危险

一种合成的用于治疗心力衰竭的脑钠肽——奈西立肽，可增加对急性失代偿心力衰竭病人肾功能的不良影响。最近的《循环》杂志报道，这种药物能使肾功能衰竭的危险增加50%。例如，使用FDA通过的奈西立肽剂量会使肾衰的危险提高15％～23％。     

Nesiritide: a review of its use in acute decompensated heart failure

Nesiritide (Natrecor) is a recombinant form of human B-type (brain) natriuretic peptide that has beneficial vasodilatory, natriuretic, diuretic and neurohormonal effects. The drug is administered intravenously for the management of patients with decompensated congestive heart failure (CHF). In the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) study, patients hospitalised with acute decompensated CHF who received nesiritide had significantly greater mean reductions from baseline in pulmonary capillary wedge pressure 3 hours after starting treatment than nitroglycerin or placebo recipients (-5.8 vs -3.8 and -2 mm Hg, respectively); all patients also received standard therapy (e.g. intravenous diuretics). Improvements in other haemodynamic parameters were also seen in nesiritide recipients. In addition, significantly more nesiritide than placebo recipients reported an improvement in dyspnoea after 3 hours' treatment in VMAC, whereas there was no significant difference between nitroglycerin and placebo recipients. Improvements in global clinical status, dyspnoea and fatigue were also seen with nesiritide in another active-comparator study and in a placebo-controlled study. In VMAC, there was no significant difference between nesiritide and nitroglycerin recipients in 6-month mortality. In the other active-comparator trial, 6-month mortality was significantly lower in recipients of nesiritide 0.015 micro g/kg/min than in dobutamine recipients (although mortality was not a prespecified endpoint and this result should be interpreted with caution). In this same study, the 21-day all-cause hospital readmission rate was significantly lower with nesiritide 0.015 micro g/kg/min than with dobutamine and the duration of active drug treatment was significantly shorter with nesiritide than with dobutamine. Nesiritide is generally well tolerated. In VMAC, significantly more adverse events occurred with nitroglycerin than with nesiritide. The most common adverse events reported during the first 24 hours of therapy in nesiritide and nitroglycerin recipients included general pain, abdominal pain, catheter-related pain, headache, nausea, asymptomatic and symptomatic hypotension, nonsustained ventricular tachycardia and angina pectoris. Most episodes of symptomatic hypotension resolved spontaneously or after an intravenous volume challenge of 相似文献   

Nesiritide for secondary pulmonary hypertension in patients with end-stage heart failure.

PURPOSE: The impact of adding nesiritide to standard therapy and positive inotropic agents in patients with end-stage heart failure and secondary pulmonary hypertension (PH) was studied. METHODS: Patients included in this retrospective study were 18 years of age or older, admitted to the hospital with PH secondary to end-stage heart failure (New York Heart Association functional class IV), had received a pulmonary artery catheter, had been treated with nesiritide because of inadequate hemodynamic response to previous therapy (pulmonary capillary wedge pressure [PCWP], >18 mm Hg), and had shown minimal symptomatic benefit from standard heart-failure therapy, continuous infusions of loop diuretics, and positive inotropic agents (milrinone or dobutamine or both). The primary endpoint was change in PCWP. Secondary endpoints included change in mean pulmonary artery pressure (MPAP), change in cardiac index (CI), change in mean arterial pressure (MAP), change in serum creatinine (SCr) concentration, and occurrence of symptomatic hypotension. RESULTS: The study included 33 patients. Mean PCWP was reduced by 31.1% with the addition of nesiritide to previous therapy (p < 0.0001). Significant improvements in other hemodynamic variables, including MPAP (15.6% reduction) and CI (13.0% increase), were also observed. MAP was reduced significantly (by 15.2%), but SCr concentration did not change. There were five episodes of symptomatic hypotension. All patients exhibited relief of dyspnea symptoms. CONCLUSION: The addition of nesiritide to standard therapy and positive inotropic agents improved hemodynamic measures and clinical symptoms in patients with end-stage heart failure and secondary pulmonary hypertension.     

Nesiritide for treatment of heart failure due to right ventricular dysfunction

Little information exists regarding the use of nesiritide for treatment of right-sided heart failure. Similarly, little information is available regarding routine use of combination nesiritide and diuretics as initial therapy to relieve edema due to heart failure. Nesiritide may be beneficial in combination with diuretics because it reduces activity of the renin-angiotensin-aldosterone system. It is unclear how potent nesiritide is as a diuretic. Patients exhibit wide variability in clinical response from the diuretic effects of the drug. Two patients were given a combination of nesiritide and diuretics as initial treatment of right-sided heart failure; both experienced significant diuresis and weight loss. Further literature is needed to clarify the role of nesiritide in the treatment of right-sided heart failure.     

治疗急性失代偿性心力衰竭新药奈西立肽

B型利钠肽由于其在诊断、预后及治疗心力衰竭的特殊价值而备受关注.奈西立肽已成为治疗急性失代偿性心力衰竭的一线药物,它能迅速降低急性失代偿性心力衰竭患者肺毛细血管楔压和周围血管压力,提高心脏每搏输出量、心脏指数,并产生利钠利尿及阻滞肾素-血管紧张素-醛固酮系统的作用.其扩张血管作用呈剂量依赖性,且不引起反应性心动过速,能显著改善呼吸困难等临床症状,与多巴酚丁胺相比疗效相似,但较少引起心律失常;较硝酸甘油更安全有效.其主要不良反应是剂量依赖性的低血压、头痛和腹痛.     

Nesiritide in perspective: evolving approaches to the management of acute decompensated heart failure

Nesiritide is currently indicated for the management of acute decompensated heart failure defined by the presence of volume overload and dyspnea at rest or with minimal activities. Hypotension and cardiogenic shock are the major contraindications to nesiritide use. The recommended dosing schedule is a 2 micro g/kg bolus followed by a 0.01 micro g/kg/min infusion. Some clinicians, however, opt to begin the infusion at the recommended dose without a loading bolus in nonemergency situations. The average duration of infusion in the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial was approximately 28 hours. Clinical efficacy endpoints included resolution of dyspnea and reduction of volume overload. Appropriate oral drug therapy for heart failure management should be initiated during the nesiritide infusion. The 15-year transition of B-type natriuretic peptide from a newly discovered physiologic entity to clinical use in the diagnosis and treatment of heart failure provides a remarkable example of rapid technological improvement and enhanced clinical understanding. As with most advances, the process of rolling back the frontiers of knowledge has posed even more questions. However, we must not overlook the progress to date, simply because all of the answers are not yet available.     

(S)-oxybutynin (Sepracor)

Sepracor is developing (S)-oxybutynin, a single-isomer version of Alza's Ditropan (racemic oxybutynin), a muscarinic acetylcholine receptor antagonist, as a potential treatment for urinary incontinence.     

alpha-glucosidase (CHO) (Genzyme)

Genzyme General is developing recombinant human alpha-glucosidase, produced in mammalian cell culture, as a potential treatment for Pompe disease. By July 2004, enrollment was completed in two clinical trials and an observational study in adults. Genzyme was planning to file for regulatory approval in Europe during 2004, followed by filings in the US and Japan in mid-2005.     

Di(isononyl) phthalate (DINP) and di(isodecyl) phthalate (DIDP) are not mutagenic

Recently there have been reports of liver and kidney tumors in rodents following long-term exposure to di(isononyl) phthalate (DINP). Mechanistic studies suggested that the liver tumors were a consequence of peroxisomal proliferation, whereas the kidney tumors (found only in male rats) were associated with induction of alpha(2u)-globulin. Because both peroxisomal proliferation and alpha(2u)-globulin are considered to be non-genotoxic carcinogenic processes, it seemed appropriate to investigate the genotoxic potential of DINP. Additional studies were also conducted on di(isodecyl) phthalate (DIDP), a structurally related substance that also induces peroxisomal proliferation, although it has not been tested in a carcinogenicity bioassay. The DINP was tested in Salmonella, in vitro cytogenetics and mouse micronucleus assays, whereas DIDP was evaluated in a mouse micronucleus test. All of these tests produced negative results, i.e. neither phthalate was mutagenic in any of the test systems. These data are consistent with results of other published and unpublished genotoxicity tests and provide support for the hypothesis that the liver and kidney tumors induced by DINP were the result of non-genotoxic processes.     

Developmental toxicity of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat

Two phthalate esters, di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), have been assessed for their potential to cause developmental toxicity in the rat. Groups of 22 timed-mated Sprague-Dawley rats were administered 250, 500, or 1000 mg/kg D79P or D911P daily by oral gavage (5 ml/kg) between gestation days (GD) 1 and 19. Control animals received the vehicle (olive oil) alone. On GD20, the animals were sacrificed and the fetuses examined. Treatment resulted in no signs of maternal toxicity, as assessed by adjusted maternal bodyweight gain throughout gestation and clinical examinations, and no effects upon litter size, fetal survival or bodyweight. Pups of the high dose D79P and intermediate and high dose D911P groups showed increased incidences of supernumerary lumbar ribs. There was a significant increase in dilated renal pelves in pups of the low dose D79P and high dose D911P groups, but only for D911P was there a significant trend. Consequently, the no observed adverse effect level (NOAEL) for maternal toxicity for both D79P and D911P is 1000 mg/kg/day. The NOAEL values for developmental toxicity are 500 mg/kg/day D79P and 250 mg/kg/day D911P.     

Allosteric interaction of zinc with recombinant alpha(1)beta(2)gamma(2) and alpha(1)beta(2) GABA(A) receptors

In a recent study we have provided evidence that inhibition of native GABA(A) receptors by zinc depends primarily on the allosteric modulation of receptor gating. Both the kinetics and the sensitivity of the GABA(A) receptor to zinc depend on subunit composition, especially on the presence of the gamma(2) subunit. To analyze the mechanism of action of zinc its effects have been tested on recombinant alpha(1)beta(2)gamma(2) and alpha(1)beta(2) receptors expressed in HEK 293 cells. The currents produced by ultrafast application of GABA have been measured to assess the impact of zinc ions on GABA(A) receptor gating with resolution corresponding to the time scale of synaptic currents. While, as expected, zinc markedly reduced the peak amplitude of alpha(1)beta(2)-mediated currents, its effect on kinetics was significantly different from that observed for alpha(1)beta(2)gamma(2). In particular, unlike alpha(1)beta(2)gamma(2), zinc did not affect the onset of alpha(1)beta(2)-mediated responses. Moreover, zinc increased the extent of desensitisation of alpha(1)beta(2)gamma(2) receptors and reduced desensitisation of alpha(1)beta(2) ones. Quantitative analysis suggests that zinc exerts an allosteric modulation on both alpha(1)beta(2)gamma(2) and alpha(1)beta(2) receptors. Zinc effects on alpha(1)beta(2)gamma(2) were qualitatively similar to those reported for native receptors.     

Two-generation reproduction toxicity studies of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat

Di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), based on high-normality linear oxo-alcohols, have been assessed for their impact upon reproductive performance in Sprague-Dawley rats. Rats were continuously exposed to either D79P or D911P at dietary levels of 0%, 0.1%, 0.5%, or 1.0% over two generations. Selected F(0) offspring (F(1) generation) were exposed to the same dietary concentration of D79P or D911P as the respective F(0) animals, and were mated to produce F(1) offspring. Both D79P and D911P markedly reduced body weight gain in F(0) and F(1) adult males at the highest dose, but females were affected to a lesser extent. There was no impairment of fertility, fecundity, or development in either generation, but body weights of offspring in the 1.0% D79P and 1.0% D911P groups were slightly and transiently reduced over the weaning period. Although decreases in the weight of several organs were accounted for by depressed body weight, ovary weights were reduced in both generations exposed to 1.0% D79P, and epididymidal weights were slightly reduced in adults of both generations exposed to 1.0% D911P. However, ovarian function-assessed by the oestrus cycle and mating behaviour-and epididymidal sperm concentration, motility, and morphology were unaffected by either substance. Treatment resulted in liver changes, particularly in males, characterised by increased liver weight in young animals, histopathologic changes and reduced organ weight in mature animals, and an increase in palmitoyl CoA oxidase activity. In conclusion, neither D79P nor D911P impaired reproductive function in rats when administered in the diet at levels that induce systemic toxicity, and the NOAEL for effects on reproduction in the rat is 0.5% for both D79P and D911P.