The risks associated with short-term placebo-controlled antihypertensive clinical trials: a descriptive meta-analysis.

Short-term (4-8 weeks) placebo-controlled trials are used to evaluate new antihypertensive drug treatment. To evaluate the consequences of such practice, a descriptive meta-analysis was conducted, consisting of blinded review of original case report forms for all patients who died or left a study before its completion for all short-term, placebo-controlled hypertension trials submitted to the Food and Drug Administration from 1973 through 2001. There were 93 marketing applications or supplements involving 590 individual trials that involved 86137 randomized patients (64438 randomized to experimental drug and 21 699 randomized to placebo) with 12658 patient years of observation. There were 9636 dropouts (mean time to dropout was 28 days) and relative risk (RR (placebo/drug))= 1.33 (95% confidence limits, 1.28, 1.39; P < 10(-16)). As expected, lack of blood pressure (BP) control was far more common in patients randomized to placebo; therapeutic failure, RR = 2.53 (2.35, 2.73; P < 10(s15)) and hypertensive emergency, RR = 2.75 (2.19, 3.57; P < 10(-15)). When administrative dropouts and dropouts resulting from inadequate BP control were excluded, the remaining 38% of dropouts were disproportionately more from drug (2810 drug, 816 placebo), RR = 0.80 (0.74, 0.86; P < 10(-8)). There were 43 deaths, RR=0.72 (0.33, 1.45; P=0.37); 40 strokes, RR = 1.43 (0.68, 2.81; P=0.33) and 77 myocardial infarctions, RR=1.06 (0.62, 1.75; P= 0.82). Irreversible harm (a combination of death, stroke and myocardial infarction, 160 total events) was equally distributed between the drug and placebo groups, RR=1.03 (0.71, 1.47; P=0.86).

Acute hepatic failure in a child treated with lamotrigine.

An 8-year-old boy with a known seizure disorder that was being treated with lamotrigine developed acute hepatic failure. The patient, who had been well previously, presented with jaundice, elevated liver enzymes, and a coagulopathy. After discontinuation of lamotrigine and aggressive resuscitation, the patient made an uneventful recovery. We believe that the hepatic failure in our patient was secondary to the use of lamotrigine. We recommend careful monitoring of liver function when lamotrigine is administered.

Use of neomycin as the prophylaxis against recurrent cholangitis after Kasai portoenterostomy.

Ascending cholangitis after portoenterostomy for biliary atresia often leads to significant morbidity. The long-term prognosis also involves recurrent and frequently recalcitrant bouts of cholangitis. Attempts at prophylaxis with use of oral antibiotics are frequently unsuccessful. The authors describe three patients who, after successful portoenterostomies, were plagued with recurrent bouts of cholangitis, despite the use of a variety of antibiotics. The authors instituted oral neomycin as prophylaxis and nearly eliminated this serious complication.

Regulatory considerations for oligonucleotide drugs: updated recommendations for pharmacology and toxicology studies.

This article describes pharmacology and toxicity studies for oligonucleotide drugs that are recommended for inclusion in the initial Investigational New Drug Application (IND), a first request to use an investigational drug in clinical trials. Recent observations of non-sequence-dependent cardiovascular toxicity and deaths in monkeys following intravenous infusions of phosphorothioates have raised a potential safety concern for oligonucleotide drugs. This concern should be considered by drug sponsors in designing pre-IND nonclinical development programs and Phase I clinical protocols. Pre-IND conduct of pharmacodynamic cardiovascular screening is highly recommended for defining safe clinical dosing regimens for phosphorothioate (and, possibly, other charged-backbone) oligomers. Additionally, drug sponsors are encouraged to (1) conduct research into-the mechanisms responsible for this dose-limiting toxicity, (2) institute liberal publication policies for research conducted under industrial sponsorship, and (3) communicate with reviewing divisions at FDA for updated guidance in this field when planning pre-IND safety studies. Recommendations for nonclinical studies during development of oligonucleotides will be modified as new information regarding the biological properties of oligonucleotides becomes available.

Low methionine ingestion by rats extends life span.

Dietary energy restriction has been a widely used means of experimentally extending mammalian life span. We report here that lifelong reduction in the concentration of a single dietary component, the essential amino acid L-methionine, from 0.86 to 0.17% of the diet results in a 30% longer life span of male Fischer 344 rats. Methionine restriction completely abolished growth, although food intake was actually greater on a body weight basis. Studies of energy consumption in early life indicated that the energy intake of 0.17% methionine-fed animals was near normal for animals of their size, although consumption per animal was below that of the much larger 0.86% methionine-fed rats. Increasing the energy intake of rats fed 0.17% methionine failed to increase their rate of growth, whereas restricting 0.85% methionine-fed rats to the food intake of 0.17% methionine-fed animals did not materially reduce growth, indicating that food restriction was not a factor in life span extension in these experiments. The biochemically well-defined pathways of methionine metabolism and utilization offer the potential for uncovering the precise mechanism(s) underlying this specific dietary restriction-related extension of life span.

Association of congenital hepatic fibrosis with autosomal dominant polycystic kidney disease. Report of a family with review of literature.

The association of autosomal recessive polycystic kidney disease (ARPKD) with congential hepatic fibrosis (CHF) is well known; a rare occurrence is that of congenital hepatic fibrosis with autosomal dominant polycystic kidney disease (ADPKD). We report a family with ADPKD in which congenital hepatic fibrosis with severe portal hypertension (PHT) presented in a 4-year-old girl; the kidneys were initially normal. Typical changes of autosomal dominant polycystic kidney disease developed in the next decade and were also found in the mother and sister (neither of whom had any evidence of portal hypertension). Severe variceal bleeding was treated by sclerotherapy and beta receptor blocade.

Obstruction of the Roux limb after portoenterostomy for biliary atresia: a delayed complication.

We report the case of a 5-year-old girl who underwent a Kasai portoenterostomy for extrahepatic biliary atresia. The conduit was exteriorized until 11 months of age. She was doing well, with stable portal hypertension until she suddenly developed jaundice, acholic stools, and bacteremia not responsive to a course of steroids and intravenous antibiotics. Suspecting obstruction at the site of the previously exteriorized anastomosis, a percutaneous cannulation of the conduit was performed. Catheterization of the conduit obstruction unkinked it and reestablished bile flow. She has remained anicteric with stable liver function.

Essential fatty acid deficiency mimicking porphyria cutanea tarda in a patient with chronic cholestasis.

Essential fatty acid deficiency was documented in a 3-year-old boy with chronic cholestasis secondary to paucity of intrahepatic bile ducts (Alagille's syndrome). Dietary management had consisted almost exclusively of a proprietary formula with over 80% of the fat as medium-chain triglycerides. The bullous lesions involved mostly sun-exposed areas and were diagnosed initially as being compatible with acquired porphyria cutanea tarda. Improvement followed correction of the fatty acid abnormalities with a polyunsaturated fat supplement administered orally. We postulate that the association of fatty acid deficiency and abnormal vitamin E status contributed to skin damage, possibly involving photosensitizing compounds poorly cleared by the markedly cholestatic liver.

Beneficial hemodynamic effects of milrinone in conscious rabbits with chronic aortic regurgitation.

Aortic regurgitation (AR) was induced in rabbits by aortic valve puncture. Two years later, echocardiography [two-dimensional (2-D) and M-mode; Doppler] was used to monitor acute left ventricular (LV) effects of milrinone. At that time, two of eight AR survivors had hindlimb edema and/or ascites. Baseline LV diameter and wall thickness of AR rabbits was 125-145% for that of sham-operated subjects; mean stroke volume and total LV output (TLVO) were approximately 2.5 x normal; regurgitant fraction was 0.57; and effective (forward) cardiac output (CO) was normal. Basal LV fractional shortening (FS) and mean circumferential fiber shortening velocity (Vcf) were not significantly depressed. Milrinone (10 micrograms/kg/min. i.v.) decreased mean LV stroke volume and TLVO by 25-33% (p less than 0.05). However, forward CO was maintained as regurgitant stroke volume fell an average of 52%. Milrinone significantly reduced aortic mean reverse/mean forward blood flow velocity ratio (-16%) and LV end-diastolic (ED) chamber diameter (-7%), consistent with reduced regurgitation. Mean Vcf was 39% greater than that seen after saline infusion (p less than 0.05). Thus, milrinone promoted Vcf and maintained forward CO in rabbits with chronic compensated AR while appreciably reducing LV regurgitation, chamber size, and total output. These beneficial effects may reflect vasodilating and positive inotropic activities confirmed in normal rabbits.

Beneficial hemodynamic effects of milrinone and enalapril in conscious rats with healed myocardial infarction.

Milrinone and enalapril, which inhibit PDE-III and ACE, respectively, are able to prolong survival of myocardially infarcted (MI) rats. This study sought to identify oral hemodynamic effects of these agents which could underlie such efficacy in this heart failure model. Four weeks after ligation of the left main coronary artery, basal left ventricular (LV) systolic pressure and dP/dtmax, heart rate and mean blood pressure of the MI rats were significantly less than that of sham-operated controls, and LV end-diastolic pressure (LVEDP) was markedly elevated. Milrinone, at 2.0 mg/kg, reduced LVEDP and renal blood flow of these 4-week MI rats by an average of 39 and 18%, respectively (P less than 0.05) within 1 h. At 4.0 mg/kg, it reduced LVEDP by 46% and raised heart rate by 16% (P less than 0.05). Enalapril (1.0 mg/kg) increased small intestine blood flow of these compromised rats by 16% (P less than 0.05), and tended to reduce LVEDP (-28%) within 1.5 h. Treatment with milrinone (2.0 mg/kg) plus enalapril (1.0 mg/kg) promoted LV dP/dtmax, coronary blood flow, and heart rate by 48, 40 and 13%, and reduced LVEDP by 40% (P less than 0.05 for all effects). Thus these agents can reduce LVEDP and redistribute cardiac output of MI rats. Furthermore, the combination of enalapril and milrinone can restore LVEDP and LV dP/dtmax of MI rats to near normal and promote coronary blood flow without compromising cardiac output or renal blood flow. Such effects, it timely or sustained, may prolong survival.

Time course of hemodynamic changes in rats with healed severe myocardial infarction.

Male rats were monitored for 8 mo after severe myocardial infarction (MI) to chronicle hemodynamic and left ventricular (LV) functional changes. Blood pressure (BP), heart rate (HR), cardiac output index (CO), regional blood flow, and systemic vascular resistance (SVR) were measured with catheters and radiolabeled microspheres at 4, 7, 10, 20, and 35 wk after coronary artery ligation (n = 10-16/group) or sham operation (control; n = 9-14/group). At 4 wk, 43 +/- 1% of the LV circumference was scarred, peak LV BP, LV dP/dtmax, mean BP, SVR, and HR were 11-38% less than control (P less than 0.05), and LV end-diastolic pressure (LVEDP) was increased by 313% (P less than 0.05). Mean BP, LVEDP, LVBP, and LV dP/dtmax did not further deviate after 4 wk. However, CO and SVR changed progressively and were 67 and 33%, respectively, of control by 35 wk (P less than 0.05) when blood flow to stomach, small intestine, and kidney was 55, 38, and 27% of control. Lung and heart weights were significantly increased by 148 and 22% at 4 wk, and remained elevated, and lung dry weight-to-wet weight ratio was reduced at 7 and 10 wk. Thus the trajectory of rats with healed severe MI reflects progressive cardiac decompensation, cardiac output redistribution, and terminal heart failure.

Natriuretic and vasodilating activities of intrarenally administered atriopeptin II, substance P and bradykinin in the dog.

The mechanism of the diuretic effect of atrial natriuretic factor is unclear. In this study, we compared the renal vasodilating and diuretic effects of renal arterial infusions of rat atriopeptin II in anesthetized dogs to see if natriuresis and increases in total renal blood flow were associated. The vasodilators substance P and bradykinin also were tested. Volume (V), Na+ and K+ concentration and Na+ and K+ content (UNaV; UkV) of urine from the infused and contralateral kidneys (IK; CK) were measured as well as mean total renal blood flow (RBF) of the IK. Atriopeptin II (30-1000 ng/kg/min) slightly promoted RBF by up to 20%, but raised V, UNaV and UkV by a maximum of 79, 190 and 100%, respectively. Substance P (0.01-30 ng/kg/min) raised RBF of IK by a maximum of 59%, reduced mean blood pressure by 26% and had a biphasic effect on IK excretion: V, UNaV and UkV were increased maximally by 105, 154 and 42% at 1.0 ng/kg/min, whereas progressively less diuresis, natriuresis and kaliuresis occurred at higher (hypotensive) doses. CK excretion was unchanged. Bradykinin (1-100 ng/kg/min) raised RBF, V, UNaV, and UkV of IKs by a mean maximum of 97, 70, 201 and 47%, respectively, with no changes in mean blood pressure or CK excretion. The natriuretic and hyperemic effects of nonhypotensive doses of each peptide were significantly correlated. However, atriopeptin II uniquely promoted Na+ excretion, but not RBF at the lowest dose tested, and, after 10 min washout of the 1000-ng/kg/min dose, and did not appreciably promote RBF after 10 min of infusion. It also caused CK diuresis.(ABSTRACT TRUNCATED AT 250 WORDS)

Potassium-sparing effect of trilostane in hydrochlorothiazide-treated rats and dogs.

Trilostane, which inhibits three beta-hydroxysteroid dehydrogenase and aldosterone synthesis in rats and monkeys, significantly attenuated the oral potassium-wasting effect of hydrochlorothiazide (HCTZ) in rats and dogs when coadministered with the diuretic. The steroid reduced the kaliuretic and enhanced the natriuretic (and hyperreninemic) activity of HCTZ in rats, thereby promoting the urinary sodium/potassium ratio. Trilostane completely prevented HCTZ-induced hypokalemia in dogs and tended to reduce the degree of secondary aldosteronism. The combination also promoted hematocrit of dogs by 8% and decreased serum Na+ concentration by 7 meq/liter. When administered alone, trilostane increased canine serum potassium levels slightly and promoted rat urinary Na+/K+ ratio. Results confirm previous reports of antikaliuretic activity of trilostane in diuretic-treated rats. Further, the data indicate that frank hypokalemia induced in dogs by hydrochlorothiazide can be prevented by adjunctive trilostane therapy without eliciting hyperkalemia.

3,4-Diphenyl-1H-pyrazole-1-propanamine antidepressants.

A small series of compounds is described in which a narrow SAR has identified N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine, 3, as a potential antidepressant with reduced side effects. The isomeric N,N-dimethyl-4,5-diphenyl-1H-pyrazole-1-propanamine was completely inactive in the primary antidepressant screens. Compounds were synthesized by Michael addition of acrylonitrile to diphenylpyrazole followed by reductive alkylation of the resultant diphenylpyrazolepropionitriles. Compound 3 was equipotent with imipramine in standard antidepressant assays in animals but showed no significant anticholinergic action and did not antagonize the antihypertensive effects of clonidine and guanethidine.

Effect of Win 44441-3 and naloxone on endotoxin-induced hypotensive shock in anesthetized hypertensive rats.

A model of endotoxin-induced shock was developed in anesthetized spontaneously hypertensive rats. E. coli lipopolysaccharide (13 mg/kg i.v.) reduced systolic and diastolic blood pressure by at least 51 mm Hg in 80-90% of rats. Naloxone (1.25-10.0 mg/kg i.v.) partially restored blood pressure of hypotensive rats for 6-15 minutes after injection. Win 44441-3 (0.25-2.0 mg/kg i.v.) raised blood pressure for 3-12 minutes after injection. Ten minute pretreatment with naloxone (10 mg/kg i.v.) or Win 44441-3 (0.5 mg/kg i.v.) did not appreciably reduce the hypotensive effect of E. coli lipopolysaccharide. This model is a rapid and convenient bioassay for evaluating the effects of opioid antagonists in endotoxin shock. In this model naloxone and Win 44441-3 exhibited beneficial effects but a prolonged duration of action of the Win compound over naloxone was not observed.

The pharmacokinetics and pharmacodynamics of sulfinalol hydrochloride in dogs after intravenous administration.

The pharmacokinetic behavior of sulfinalol hydrochloride, an antihypertensive agent with vasodilator and beta-adrenergic blocking activity, was determined in dogs after intravenous administration. The plasma concentrations of sulfinalol HCl were fit to an open two-compartment body model. The mean values for the alpha- and beta-phase constants were 33.3 hr-1 and 0.52 hr-1, respectively. The mean plasma clearance was 2.30 L/kg X hr. The steady-state volume of distribution was approximately four times the body weight of the animals. The urine data gave renal clearance rates approximately equal to the normal glomerular filtration rate in the dog. About 7.5% of the administered dose was excreted in the urine as free sulfinalol hydrochloride. The time course of the hypotensive effect of sulfinalol appears to be better correlated with calculated tissue levels of drug than with observed plasma levels.