Incidence of cutaneous squamous cell carcinoma in a New Zealand population of chronic lymphocytic leukaemia patients.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is associated with an increased incidence and aggressiveness of skin cancers, particularly cutaneous squamous cell carcinoma (cSCC), but little is known about cSCC incidence in Australasian CLL patients. AIM: In this retrospective study, we analysed the incidence of cSCC in patients seen at a tertiary hospital in New Zealand (NZ). METHODS: We retrospectively assessed the clinical history and histology data of CLL patients (n = 371) who presented to the Haematology Department, Christchurch Hospital, NZ during the period 1996-2015. Baseline characteristics, incidence of second cancers, treatment details and overall survival were analysed. RESULTS: During follow-up (median = 11.8 years), 221 second cancers were recorded in 88 patients. Of these cancers, 185 were cSCC, removed from 61 patients. In 56% of these patients, >1 cSCC was removed, and the majority of cSCC occurred following the treatment for CLL. The cumulative incidence of a first cSCC was 11% at 5 years, whereas the cumulative incidence of a subsequent cSCC was 88% at 5 years. The incidence of cSCC in male patients was threefold higher than that reported for the general NZ population. CONCLUSION: NZ CLL patients have a high incidence of cSCC relative to the levels observed in the general population, which are themselves among the highest in the world. The careful monitoring of CLL patients is warranted, particularly those who have a progressive disease or have had a first cSCC removed.

Effect of suckling on the peripheral sensitivity of full-term newborn infants.

BACKGROUND: Sucking may reduce the manifestations of pain in newborn infants. OBJECTIVE: To examine the effect of suckling on the threshold for peripheral somatosensory responses. SUBJECTS AND METHODS: Graded Von Frey filaments were applied to the heel to initiate peripheral somatosensory responses (withdrawal reflex and gross body movements) in term infants. RESULTS: Dummy sucking increases the somatosensory threshold, but breast feeding had a more marked effect, increasing the threshold of the flexion withdrawal reflex (p

The distribution of apolipoprotein E alleles in Scottish perinatal deaths.

BACKGROUND: The apolipoprotein E (ApoE) polymorphism has been well studied in the adult human population, in part because the e4 allele is a known risk factor for Alzheimer's disease. Little is known of the distribution of ApoE alleles in newborns, and their association with perinatal brain damage has not been investigated. METHODS: ApoE genotyping was undertaken in a Scottish cohort of perinatal deaths (n = 261), some of whom had prenatal brain damage. The distribution of ApoE alleles in perinatal deaths was compared with that in healthy liveborn infants and in adults in Scotland. RESULTS: ApoE e2 was over-represented in 251 perinatal deaths (13% v 8% in healthy newborns, odds ratio (OR) = 1.63, 95% confidence interval (CI) 1.13 to 2.36 and 13% v 8% in adults, OR = 1.67, 95% CI 1.16 to 2.41), both in liveborn and stillborn perinatal deaths. In contrast, the prevalence of ApoE e4 was raised in healthy liveborn infants (19%) compared with stillbirths (13%, OR = 1.59, 95% CI 1.11 to 2.26) and with adults (15%, OR = 1.35, 95% CI 1.04 to 1.76). However, no correlation was found between ApoE genotype and the presence or absence of perinatal brain damage. CONCLUSIONS: This study shows a shift in ApoE allelic distribution in early life compared with adults. The raised prevalence of ApoE e2 associated with perinatal death suggests that this allele is detrimental to pregnancy outcome, whereas ApoE e4 may be less so. However, ApoE genotype did not appear to influence the vulnerability for perinatal hypoxic/ischaemic brain damage, in agreement with findings in adult brains and in animal models.

Brain damage and axonal injury in a Scottish cohort of neonatal deaths.

Despite the clinical and medicolegal significance attached to perinatal asphyxia, the neuropathological basis of this condition remains obscure. There are very few studies in the literature which correlate the pathological findings in neonatal brains with detailed epidemiological data, and none which are population based. In a Scotland-wide study of neonatal deaths, 70 brains have been examined. On the basis of glial and macrophage reactions, we previously identified infants with putative antepartum brain damage in this cohort and have related these reactions to signs of birth asphyxia. The present study explores the extent of neuronal/axonal injury in these infants since this is likely to be the basis for neurological deficits in surviving infants. We have also investigated these brains for beta-amyloid precursor protein (betaAPP) positivity to determine whether this is a useful marker of neuronal injury in neonates. Neuronal eosinophilia and karyorrhexes were detected in 43% and 27% of the cohort, respectively; maximally in the subiculum and ventral pons, but often present elsewhere. White matter damage was detected in 24% of cases but without classic cystic lesions of periventricular leucomalacia. betaAPP positivity was present in neuronal soma in 52% of cases and, in axons, in 27% of cases, and was seen from as early as 25-weeks gestation. Axonal bulbs were clearly delineated by betaAPP positivity and were usually located in the cerebral white matter and internal capsule, and infrequently in the brain stem. Although white matter damage and betaAPP axonal positivity were often detected in the same cases (P = 0.034), these features also occurred independently of each other. Both neuronal karyorrhexes and white matter betaAPP positivity were significantly correlated with the features of birth asphyxia, particularly a history of seizures. Immunocytochemistry for both betaAPP and glial fibrillary acidic protein proved useful in detecting neuropathological features which escaped detection on routine examination, particularly in preterm infants. The presence together of recent and older damage in individual brains suggests that there is an ongoing neuronal response to cerebral insults. We find that betaAPP is a useful marker of white matter damage in the neonatal brain. Immunopositivity for betaAPP in these circumstances is not attributable to inflicted or accidental trauma. While birth-related trauma cannot be ruled out, hypoxia/ischaemia is a likely cause in these infants. However, the exact pathogenesis of neuronal/axonal injury in the neonatal brain remains unclear.

Sucrose and non-nutritive sucking for the relief of pain in screening for retinopathy of prematurity: a randomised controlled trial.

BACKGROUND: Screening is necessary for infants at risk of retinopathy of prematurity. Despite local anaesthetic drops, infants find eye examinations distressing, displaying behavioural and physiological changes indicating acute pain. Oral sucrose and non-nutritive sucking reduce pain responses associated with invasive procedures. OBJECTIVE: To evaluate the use of oral sucrose and/or pacifier for reducing pain responses during eye examinations. METHODS: Forty infants <32 weeks gestation or <1500 g birth weight, in two neonatal units, were randomised to one of four interventions administered two minutes before their first screening examination: 1 ml sterile water as placebo (group 1, n = 10), 1 ml 33% sucrose solution (group 2, n = 10), 1 ml sterile water with pacifier (group 3, n = 9), or 1 ml 33% sucrose solution with pacifier (group 4, n = 11). Examinations were videotaped. Two observers, blind to the intervention, assessed recordings. Pain responses were scored using the premature infant pain profile (PIPP). RESULTS: The groups were similar in gestation, birth weight, and age at examination. Mean PIPP scores were 15.3, 14.3, 12.3, and 12.1 for groups 1, 2, 3, and 4 respectively. Analysis of variance showed a significant difference in PIPP score between groups (p = 0.023). Infants randomised to pacifiers scored lower than those without pacifiers (p = 0.003). There was no difference between groups receiving sucrose and those receiving water (p = 0.321). CONCLUSIONS: Non-nutritive sucking reduced distress responses in infants undergoing screening for retinopathy of prematurity. The difference in response was large enough to be detected by a validated assessment tool. No synergistic effect of sucrose and pacifier was apparent in this group.

Low oxygen exposure does not cause pulmonary injury in the newborn rat.

BACKGROUND: Two recent studies have suggested that low levels of supplemental inspired oxygen may cause lung injury in preterm infants. AIMS: To assess lung injury of newborn rats exposed to 14 days of low-level variation of oxygen. STUDY DESIGN: Four groups were compared with 12 animals per group and 4 lung sections per animal. These were, a control group raised in room air and three groups raised in levels of inspired oxygen fluctuating around the following mean values: group Lo (mean FiO(2) 0.179), group N (mean FiO(2) 0.213), and group Hi (mean FiO(2) 0.247). The degree of oxygen variability was identical for each group. Lungs were inflated at 20 cm H(2)O, fixed and stained with H and E and Millers Elastin. SUBJECTS: Sprague Dawley albino newborn rats. OUTCOME MEASURES: Random alveolar areas were studied and analysed using imaging software to assess total amount of tissue and elastin, number of secondary septa, and mean linear intercept. RESULTS: There were no significant differences between the three experimental oxygen groups and the control group in terms of lung/body weight ratio and the measured markers of lung development. CONCLUSION: We conclude that low-level oxygen supplementation during early lung development does not affect alveolar development in the newborn rat.

Resistance to isosorbide dinitrate in patients with severe chronic heart failure: incidence and attempt at hemodynamic prediction.

Oral isosorbide dinitrate has been widely used to lower elevated left ventricular filling pressure in patients with chronic heart failure. Although the recommended dose of this drug is 40 mg every 6 h, failure to respond to this dose has been observed in many patients with heart failure. In the present study the incidence of resistance to isosorbide dinitrate was evaluated and an attempt was made to identify baseline hemodynamic predictors for this phenomenon in 50 patients with severe chronic heart failure due to left ventricular systolic dysfunction (mean left ventricular ejection fraction 0.23 +/- 0.08). Twenty-seven (54%) of the 50 patients responded to 40 mg of isosorbide dinitrate (greater than 20% decrease in mean pulmonary artery wedge pressure sustained greater than or equal to 1 h) and 23 patients (46%) failed to respond. Nonresponders to 40 mg of isosorbide dinitrate had a significantly higher baseline right atrial pressure than did responders (14 +/- 5 versus 10 +/- 6 mm Hg, p less than 0.02). In addition, all 7 patients with a baseline right atrial pressure of less than 7 mm Hg and 12 of 14 patients with a baseline right atrial pressure less than 10 mm Hg responded to 40 mg. No significant differences were noted between responders and nonresponders in any other baseline hemodynamic or clinical variables, or in peak isosorbide dinitrate serum levels (32 +/- 19 ng/ml in nonresponders versus 44 +/- 36 ng/ml in responders). Of the 23 nonresponders to 40 mg, 22 received a higher dose (80 to 120 mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Day to day reproducibility of electrically inducible ventricular arrhythmias in survivors of acute myocardial infarction.

Day to day reproducibility of the response to programmed ventricular stimulation has not been evaluated in survivors of acute myocardial infarction. Programmed ventricular stimulation was performed prospectively on 2 consecutive days in 56 patients on an average of 12 +/- 5 days (range 7 to 29) after an acute myocardial infarction. No patient had a history of documented or suspected sustained ventricular tachycardia or fibrillation occurring greater than 48 h after infarction. During initial programmed ventricular stimulation, 21 patients had induction of sustained ventricular tachycardia or fibrillation (Group I), and 35 patients had induction of either nonsustained ventricular tachycardia or no ventricular tachycardia (Group II). Repeat programmed ventricular stimulation in Group I patients induced sustained ventricular tachycardia or fibrillation in 16 of 21 patients (reproducibility 76%); the maximal induced response in the other 5 patients was nonsustained ventricular tachycardia in 2 patients and fewer than six repetitive ventricular responses in 3 patients. The day to day reproducibility was significantly higher for inducible sustained ventricular tachycardia of cycle length greater than or equal to 240 ms compared with rapid sustained ventricular tachycardia of cycle length less than 240 ms (100% versus 44%, p less than 0.009) or ventricular fibrillation (100% versus 43%, p less than 0.009). Repeat programmed ventricular stimulation in Group II patients did not induce sustained ventricular arrhythmias in 31 of 35 patients (reproducibility 89%). Thus, in survivors of acute myocardial infarction, inducible slow sustained ventricular tachycardia was a highly reproducible finding, whereas inducibility of rapid sustained ventricular tachycardia and ventricular fibrillation showed a significant day to day variability.(ABSTRACT TRUNCATED AT 250 WORDS)

Doxorubicin encapsulated in sterically stabilized liposomes exhibits renal and biliary clearance properties that are independent of valspodar (PSC 833) under conditions that significantly inhibit nonencapsulated drug excretion.

Coadministration of anticancer drugs and multidrug resistance modulators directed against P-glycoprotein over-expressed in tumors also results in nonspecific blockade of this drug efflux pump in excretory tissues such as the liver and kidneys. These interactions often result in impaired renal and biliary clearance for anticancer agents such as doxorubicin (DOX). In the present investigation, we characterized the excretory processes associated with liposomal DOX administration to elucidate how liposome encapsulation may bypass adverse pharmacokinetic interactions between DOX and (3'-keto-Bmt1)-(Val2)-cyclosporin (Valspodar). Renal and biliary clearance properties of liposome-encapsulated DOX were compared with those for nonencapsulated DOX in the presence and absence of Valspodar using an instrumented rat model with implanted jugular vein and bile duct catheters for continuous sampling. Two types of liposomal DOX formulations were used, a drug-permeable egg phosphatidyl choline/cholesterol system and a sterically stabilized polyethylene glycol/1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol system to establish the relative roles of liposome-encapsulated and released drug on the pharmacokinetic and excretion alterations induced by Valspodar. DOX and its primary metabolites were quantitated using high-performance liquid chromatography. When Valspodar was coadministered with nonencapsulated DOX, 3.5- and 37.5-fold reductions in renal clearance (CLr) and biliary clearance (CLb), respectively, were observed, which resulted in increased plasma DOX concentrations and total exposure. However, Valspodar-induced alterations in CLr and CLb were less profound with egg phosphatidyl choline/cholesterol DOX (1.7- and 2.0-fold reductions, respectively) and negligible with the long-circulating polyethylene glycol-containing liposomal formulation. These results indicate that liposomes may circumvent Valspodar-induced DOX pharmacokinetic changes by reducing the rate of drug excretion in liver and kidney tissue to a level that is within the renal and biliary excretion capacity in the presence of P-glycoprotein blockade.

Molecular and pharmacokinetic properties associated with the therapeutics of bcl-2 antisense oligonucleotide G3139 combined with free and liposomal doxorubicin.

Bcl-2 is a key apoptosis-regulating protein that has been implicated in mechanisms of chemoresistance for a variety of malignancies by blocking programmed cell death. This study investigated the activity of the Bcl-2 antisense oligodeoxynucleotide (AS ODN) G3139 combined with free doxorubicin (F-DOX) or sterically stabilized liposomal doxorubicin (SL-DOX) to determine the role that drug pharmacodistribution properties may have on antitumor activity using a Bcl-2-expressing human breast solid tumor xenograft model. Administration of G3139 was able to delay the growth of MDA435/LCC6 cells compared with control ODN-treated animals; however, in all of the cases, tumors reestablished after AS ODN treatment. Western blot analyses of Bcl-2 levels of solid tumors showed a sequence-specific down-regulation of the Bcl-2 protein after four daily doses of G3139, which correlated with histological evidence of tumor cell death. Interestingly, the expression of Bcl-2 returned to pretreatment levels during the course of subsequent ODN administration, which suggested the development of resistance to continued Bcl-2 ODN treatment. The antitumor activity of ODN given in conjunction with either F-DOX or SL-DOX was also examined. The combination of G3139 and F-DOX was able to suppress the growth of MDA435/LCC6 cells beyond that obtained with either of the treatments given alone, indicative of synergistic action. Examination of the pharmacokinetics of F-DOX with systemic G3139 administration revealed that elevated tumor drug DOX levels were obtained compared with DOX treatment in the absence of G3139. This effect was sequence-specific and plasma DOX levels were unaffected by G3139 treatment, which indicated possible positive ODN-drug interactions at the tumor site. Combining G3139 with SL-DOX further increased the degree of antitumor activity. The improved efficacy of this combination was attributed to increased tumor drug levels that arise from the ability of SL-DOX to passively accumulate in solid tumors. These results suggest that additional benefits of Bcl-2 antisense ODN may be obtained when it is combined with liposomal formulations of anticancer drugs such as DOX.

Kupffer cells do not play a role in governing the efficacy of liposomal mitoxantrone used to treat a tumor model designed to assess drug delivery to liver.

A tumor model designed to assess liposome-mediated drug delivery to liver has been used in an attempt to better understand the mechanism of activity of liposomal mitoxantrone, a liposomal anticancer drug formulation that appears to be uniquely effective in treating this tumor model. Reductions in liposomal mitoxantrone accumulation in the liver were achieved either by use of poly(ethylene)glycol (PEG)-modified lipids or by methods designed to deplete liver phagocytes, a method referred to as hepatic mononuclear phagocytic system (MPS) blockade. A 2-fold reduction in mitoxantrone delivery to the liver was obtained using a mitoxantrone formulation with PEG-modified lipids, and a 3-fold reduction was obtained when liposomal mitoxantrone was given to animals pretreated to induce hepatic MPS blockade. Results demonstrate that the liposomal mitoxantrone formulation prepared with PEG-modified lipids was significantly less active than the formulations that did not contain PEG lipids, with median survival times of 17 days and 100% 60-day survival, respectively. In contrast, hepatic MPS blockade had no effect on the therapeutic activity of 1,2-dimyristoyl phosphatidylcholine/cholesterol (DMPC/Chol) mitoxantrone (100% 60-day survival). These data suggest that the hepatic MPS does not play a role in mediating the therapeutic activity of DMPC/Chol mitoxantrone in the treatment of liver localized disease. Results with formulations prepared with a PEG-stabilized surface, however, suggest that nonspecific methods to decrease liposome cell interactions inhibit the therapeutic activity of DMPC/Chol mitoxantrone.

The developmental pattern of somatostatin in the embryonic and fetal rat pancreas.

The ontogenesis of immunoreactive somatostatin in the embryonic and fetal rat pancreas has been measured by radioimmunoassay following acid extraction. Somatostatin (GIF) is detectable at 14 days gestation at a concentration of 1.6 X 10(-3) ng/pancreas. At term the content is 3.8 ng/pancreas, by 2 days neonatally, 8.3 ng/pancreas, and in the adult rat, 71 ng/pancreas through the concentration (expressed per microgram DNA) is constant from 14-19 days of gestation and reaches a level characteristic of the fully differentiated pancreas by birth. The detection of GIF in cultured pancreatic explants in the absence of innervation indicates that synthesis can occur independent of neural influence.

Pitfalls in the use of ELISA to screen for monoclonal antibodies raised against small peptides.

Small peptides are often conjugated to large carrier proteins such as thyroglobulin to increase their immunogenicity. Antibodies are raised against peptide, thyroglobulin and contaminants, such as immunoglobulins or BSA in the thyroglobulin preparation, but anti-contaminant antibodies will not be revealed if immune serum is diluted in buffer containing immunoglobulin-contaminated BSA. This may lead to the development of an inappropriate hybridoma-screening assay which detects more anti-contaminant than anti-peptide antibodies if ELISA plates are coated with a capture antibody or blocked with BSA. Dilution of culture supernatants in buffer containing BSA and Tween 20 minimises the risk of false positive results and makes plate-blocking unnecessary. The high affinity peptide-specific antibodies in immune serum, which are more readily detected than lower affinity monoclonal antibodies, may result in an inadequately sensitive hybridoma-screening ELISA.

A clinical trial of Fluosol DA 20% in advanced squamous cell carcinoma of the head and neck.

Fluosol DA 20% (Fluosol) enhances the response of several rodent tumors to radiation and oxygen. This is a Phase I/II study of Fluosol and oxygen breathing in the radiation treatment of advanced squamous cell carcinoma of the head and neck. Fifteen patients with Stage III/IV tumors entered and completed this trial. Patients received 1.8 Gy/fraction to 45 Gy, at which time the spinal cord was shielded and gross disease was carried to 68-72 Gy. 8 ml/kg (11 patients) or 9 ml/kg (4 patients) Fluosol was infused prior to the first fraction each week for the first 5 weeks. All patients inspired 100% oxygen before and during the initial 25 fractions. The infusions were well-tolerated. Four acute reactions that responded to diphenhydramine or steroids were observed in the 75 infusions. 8/15 patients exhibited liver function abnormalities of 2-3X normal which fell after therapy was discontinued. Normal mucosal reactions were enhanced despite the 1.8 Gy fraction size. 10/15 patients required at least one treatment break: the mean dose achieved before the break was 35 Gy. Tumor clearance was also accelerated. Thirteen patients had primary tumor clearance, but one had a local recurrence. Ten had primary and nodal clearance and 2/3 with nodal persistence had salvage surgery with fibrosis only at pathologic review. One patient, locally controlled, developed distant metastases. Thus, 10/15 patients are NED, but followup time is short.

Effects of intravenously infused Fluosol-DA 20% in rats.

Rats were injected with a fractionated 50 ml/kg dose of Fluosol-DA 20% with and without exposure to 100% oxygen. Animals were killed at 24, 43, 92, and 183 days post-treatment and samples taken for hematological, hepatic enzyme, histological, and perfluorochemical analyses. There were no significant differences in hemograms or hepatic enzyme findings between treatment and control groups. Differences in organ weights and histology were a result of perfluorochemical (PFC) accumulation in the tissues of treated animals. All changes were reversible. There were no effects from breathing high oxygen levels in either treatment or control animals.

Continuous monitoring of arterial oxygen tension using a catheter-tip polarographic electrode in infants.

An oxygen electrode mounted in the tip of an umbilical artery catheter was used in 36 newborn infants with severe respiratory illnesses, 28 of whom survived. Thirty-seven electrodes were used. The median age at insertion was 4 hours (range, 30 minutes to 122 hours). Three electrodes failed to work and they were removed or replaced, and two could not be properly evaluated. Thirty-two electrodes functioned satisfactorily for 10 to 190 hours (mean, 75 hours) after a one-point calibration against blood sampled through the catheter. Twenty-two did not need recalibrating before they were removed after 10 to 190 hours (mean, 88 hours. Four of the remaining ten electrodes were recalibrated once after 33 to 97 hours and then functioned until removed 15 to 55 hours later. The other six electrodes failed after 32 to 105 hours (mean, 49 hours). Complications were few. A total of 356 arterial blood samples, obtained after the initial calibration and before any recalibration was necessary, gave a correlation coefficient of 0.93 (P less than .0001) against an independent system for measuring arterial oxygen tension (Pao2) (Radiometer Type E.5046 oxygen electrode). We conclude that the catheter-tip electrode is a safe and reliable instrument for continuously recording Pao2 in newborn infants which much simplifies the management of serious respiratory illnesses.

A novel model of retinopathy of prematurity simulating preterm oxygen variability in the rat.

PURPOSE: To examine changes in the retinal vasculature of rat pups after 14 days of minute-by-minute small variations in oxygen. METHODS: Arterial oxygen data from a preterm infant who developed severe retinopathy of prematurity (ROP) was translated to equivalent values for the rat. Newborn rat pups were raised for 14 days in a cage in which a computer controlled the atmosphere to mimic the fluctuating oxygen profile (group V). Positive controls (P) of 12-hour cycles of 80% and 21% were run concurrently, as were room air controls (C). All were killed at day 14. RESULTS: Groups V and P had significantly larger avascular retinal areas than C [median, interquartile range (IQR) 1.7%, 0-7.9%; 10%, 8.1-13%; 0%, 0-0%, respectively; each group n = 30]. Group P had a higher capillary branch count than C (median, IQR: 310/mm(2); 253-311 mm(2); versus 277/mm(2), 272-364/mm(2), respectively), but this was not significant using a multilevel analysis. Group V had significantly reduced capillary counts compared with C (median, 261/mm(2); IQR, 215-290/mm(2); P < 0.05 multilevel analysis). No neovascularization was seen in any group, though abnormal terminal vessels were seen at the avascular/vascular retina interface in 73% of rats in group P and 21% of rats in group V. In situ hybridization on serial sections demonstrated VEGF in the inner nuclear layer of the retina in P and V, whereas C showed trace levels only. CONCLUSIONS: The vaso-obliterative stage of ROP can be induced in rats using clinically relevant oxygen levels.

Hemodynamic and volumetric effects of venodilation with nitroglycerin in chronic mitral regurgitation.

To evaluate the potential value of nitrate therapy in patients with chronic mitral regurgitation, the hemodynamic and angiographic effects of intravenous nitroglycerin were studied in 10 such patients. Nitroglycerin infusion, titrated to reduce mean pulmonary artery wedge pressure at least 20%, resulted in a significant reduction in mean blood pressure (from 91 +/- 12 to 77 +/- 13 mm Hg, p less than 0.0001), mean right atrial pressure (12 +/- 6 to 7 +/- 4 mm Hg, p less than 0.001), left ventricular end-diastolic pressure (22 +/- 7 to 13 +/- 5 mm Hg, p less than 0.0001) and peak V wave of indirect left atrial pressure (34 +/- 9 to 20 +/- 10 mm Hg, p less than 0.001). Changes in systemic vascular resistance (1,986 +/- 468 vs 1,582 +/- 534 dynes s cm-5) and forward stroke volume (39 +/- 14 vs 45 +/- 8 ml) were not statistically significant. Angiographic data showed a decrease in both end-diastolic and end-systolic left ventricular volumes (248 +/- 51 to 216 +/- 54 ml, p = 0.06 and 127 +/- 69 to 99 +/- 48 ml, p less than 0.05, respectively) and an improvement in ejection fraction, from 0.52 +/- 0.15 to 0.55 +/- 0.15 (p less than 0.05). There was no significant change in the group values for mitral regurgitant volume and fraction (from 85 +/- 32 to 72 +/- 32 ml and 67 +/- 10 to 64 +/- 5%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Central and renal hemodynamic effects and hormonal response to diltiazem in severe congestive heart failure.

The central and renal hemodynamic effects and the hormonal response to single doses of 60 mg and 90 mg of diltiazem were evaluated in 10 patients with severe chronic left ventricular (LV) systolic dysfunction (ejection fraction 0.22 +/- 0.08). Diltiazem administration resulted in only mild and mostly statistically insignificant changes. After 60 mg, only heart rate (from 86 +/- 10 beats/min at baseline to 79 +/- 14 beats/min at 4 hours) and pulmonary vascular resistance (from 231 +/- 108 to 165 +/- 74 dynes s cm-5 at 4 hours) changed significantly. Administration of 90 mg of diltiazem resulted in no significant change in any of the measured or calculated central hemodynamic variables. Individual data, however, revealed an increase stroke volume index in 3 patients but a decrease in 1 patient and a persistent increase in mean pulmonary artery wedge pressure in another patient. These hemodynamic changes were not associated with symptomatic deterioration in any of the patients. Both renal blood flow and glomerular filtration rate were impaired at baseline on both days and did not show a significant change 1, 2 and 4 hours after diltiazem administration. Similarly, no significant change was noted after either diltiazem dose in plasma catecholamine levels and renin concentration. In conclusion, administration of 60 to 90 mg of diltiazem in patients with severe chronic LV systolic dysfunction results in only mild and mostly insignificant acute effects on central and renal hemodynamics, plasma hormonal levels and patient clinical status.