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Introduction/aims: Lipid peroxidation is thought to play a biologically important role in motor neuron death in amyotrophic lateral sclerosis (ALS). 11,11 Di-deuterated linoleic ethyl ester (RT001) prevents lipid peroxidation in cellular and mitochondrial membranes. Herein we report on the use of RT001 under expanded access (EA)., Methods: We provided RT001 to patients with ALS via EA at a single site. The starting dose was 2.88 g/day, which was increased to to 8.64 g/day as tolerated. Participants were not eligible for alternative clinical trials. Participants were followed for adverse events and pharmacokinetic (PK) parameters were measured approximately 3 months after RT001 initiation., Results: Sixteen participants received RT001 (5.6 ± 1.6 g/day; dose range, 1.92 to 8.64 g/day) for a mean period of 10.8 ± 7.1 months. After 3 months of treatment, PK studies showed that RT001 was absorbed, metabolized, and incorporated into red blood cell membranes at concentrations expected to be therapeutic based on in vitro models. The most common adverse events were gastrointestinal, including diarrhea, which occurred in 25% of the participants, and were considered possibly related to RT001. One participant (6%) discontinued due to an adverse event. Ten serious adverse events occurred: these events were recognized complications of ALS and none were attributed to treatment with RT001., Discussion: RT001 was administered safely to a small group of people living with ALS in the context of an EA protocol. Currently, there is an ongoing randomized, double-blind, controlled study of RT001 in ALS., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Chronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis ( n  = 13) were matched to healthy volunteers (HVs) ( n  = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life ( t 1/2 ) increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin's inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Schattauer GmbH Stuttgart.)

Tecarfarin is a vitamin K antagonist (VKA) with reduced propensity for drug interactions. To evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety of tecarfarin, we performed single ascending dose (SAD) (n=66), multiple ascending dose (MAD) (n=43), and tecarfarin versus warfarin (n=28) studies in human volunteers. In the SAD, tecarfarin was administered to 5 of 6 subjects (1 received placebo) in each of 11 cohorts. AUC 0-∞ exhibited linearity and dose proportionality. Elimination T 1/2 ranged from 87-136 hours (h) across all doses. In the MAD, tecarfarin was administered to 5 of 6 volunteers in each of 7 cohorts. The starting dose was continued until the subject's INR reached the target range (TR) of 1.7 to 2.0. Dosing was down-titrated if the TR was achieved. Elimination T 1/2 ranged from 107-140 h. Doses <10 mg had insignificant effect on INR. Higher doses raised INRs and required down-titration to maintain the TR. Steady state INR dosing was 10-20 mg. INR declined promptly after discontinuation. In the comparative study, subjects received tecarfarin or warfarin and dose titrated to a TR of 1.5-2.0. Mean dose after TR was achieved was 13.9 mg (range 10.0-25.5 mg) for tecarfarin and 5.3 mg (range 2.5-9.0 mg) for warfarin. At similar INR levels, the concentration of coagulation factors II, VII, IX, and X were similar for tecarfarin and warfarin. Tecarfarin was tolerated well without serious adverse events in all three studies.

Tecarfarin is a novel vitamin K antagonist that is metabolised by carboxyl estererase, thereby eliminating the variability associated with cytochrome-mediated metabolism. EmbraceAC was designed to compare the quality of anticoagulation with tecarfarin and warfarin as determined by time in therapeutic range (TTR). In this phase 2/3 randomised and blinded trial, 607 patients with indications for chronic anticoagulation were assigned to warfarin (n=304) or tecarfarin (n=303). Dosing of study drugs was managed by a centralised dose control centre, which had access to genotyping. The primary analysis tested superiority of tecarfarin over warfarin for TTR. Patients were recruited between May 12, 2008 and May 12, 2009. TTR with tecarfarin and warfarin were similar (72.3 % and 71.5 %, respectively; p=0.51). In those taking CYP2C9 interacting drugs, the TTR on tecarfarin (n=92) was similar to that on warfarin (n=87, 72.2 % and 69.9 %, respectively; p=0.15). In patients with mechanical heart valves, the TTR of tecarfarin (n=42) was similar to that of warfarin (n=42, 68.4 % and 66.3 %, respectively; p=0.51). The same was true for the TTR in patients with any CYP2C9 variant allele and on CYP2C9-interacting drugs (tecarfarin, n=24, 76.5 % vs warfarin, n=31, 69.5 %; p=0.09). There was no difference in thromboembolic or bleeding events. In conclusion, superiority of tecarfarin over warfarin for TTR was not demonstrated. The TTR with tecarfarin was similar to that with well-controlled warfarin and tecarfarin appeared to be safe and well tolerated with few major bleeding and no thrombotic events. Favourable trends in certain subpopulations make tecarfarin a promising oral anticoagulant that deserves further study.

Objective: The aim of this study was to investigate the preliminary safety and efficacy of three doses of budiodarone in patients with paroxysmal atrial fibrillation., Background: Budiodarone is a chemical analogue of amiodarone and shares its mixed ion channel electrophysiological properties. It has a shorter half-life than amiodarone., Methods: Patients with paroxysmal atrial fibrillation and a previously implanted dual-chamber pacemaker capable of storing electrograms for at least 4 weeks were enrolled. Pacemaker memories were used to quantify atrial tachycardia/atrial fibrillation burden (AT/AFB). All antiarrhythmic drugs were stopped for greater than five half-lives and amiodarone greater than 3 months prior to enrollment. Following a 4-week baseline period to assess AT/AFB off antiarrhythmic drugs, patients with AT/AFB between 3% and 70% were blindly randomized to placebo, 200, 400, or 600 mg BID of budiodarone for 12 weeks followed by a 4-week washout period. Pacemakers were interrogated and safety assessed every 4 weeks. Pacemaker-derived electrograms were adjudicated blinded to treatment assignment. The primary study endpoint was percent change from baseline AT/AFB over 12 weeks of treatment compared to placebo., Results: Of 72 randomized patients, 61 completed the study. The median reduction of AT/AFB for the 400 and 600 mg BID groups vs. placebo was 54% and 74% (p = 0.01 and 0.001), respectively. The budiodarone dose-response was statistically significant (p < 0.001). Number and duration of AT/AF episodes were reduced., Conclusions: In this preliminary study, budiodarone at both higher doses significantly reduced AT/AFB. The study is novel because dual-chamber pacemakers, previously placed for standard clinical indications, were successfully used to monitor AT/AFB.

Comparative pharmacokinetics of vitamin K epoxide reductase antagonists tecarfarin and warfarin were assessed before and after coadministration for 21 days of the CYP450 inhibitor fluconazole in a randomized, open-label, single-center drug interaction study. Twenty healthy adult participants were randomized 1:1 to receive approximately equipotent single oral doses of tecarfarin (50 mg) or warfarin (17.5 mg). Following 7 days of baseline serial blood level collections, each participant received oral fluconazole 400 mg daily for 21 days. A second identical single oral dose of tecarfarin or warfarin was given 14 days after starting fluconazole with serial pharmacokinetic sampling. Key pharmacokinetic parameters C(max), t(max), AUC(0-168), apparent clearance, and t(1/2) demonstrated no tecarfarin-fluconazole interaction but a strong warfarin-fluconazole interaction. The ratio of log-transformed mean AUC(0-168) with versus without fluconazole for tecarfarin was 91.2% (90% confidence interval [CI]: 83.3-99.8) and for racemic warfarin was 213% (90% CI: 202-226). The 90% CI was entirely within the standard 80% to 125% bioequivalence interval for tecarfarin but well outside the bioequivalence interval for warfarin, confirming a clinically significant pharmacokinetic interaction between warfarin and fluconazole. In contrast, tecarfarin pharmacokinetics were apparently unchanged by fluconazole.

A site-specific 1:1 dynorphin A-(1-13)-NH(2) derivative conjugated specifically to Cys 34 on human serum albumin (CCI-1035) was shown to be an opioid receptor agonist in vitro and to be a long lasting antinociceptive agent when administered intravenously to mice as assessed by an acetic acid writhing assay. When 10 micromol/kg of CCI-1035 was administered to mice, rapid antinociception was observed within 5 min following intravenous bolus injection and was sustained beyond 8 h. Antinociceptive activity was absent in a heat induced pain model using a mouse tail-flick assay. This finding represents the first report of a 1:1 albumin opioid conjugate retaining potent in vivo activity equal to or greater than dynorphin A, accompanied by a dramatic extension in duration of action. This novel site-specific bioconjugation technology produces an agent that may be useful for peripheral pain therapy.

Localized delivery of antisense oligonucleotides directed against cell cycle regulatory proteins has been proposed as a means to prevent restenosis after angioplasty. To test whether single endoluminal delivery of a combination of proliferating cell nuclear antigen (PCNA) and cell-division cycle 2 kinase (cdc2) antisense might affect restenosis, we delivered 2 ml of lipid-complexed PCNA/cdc2 antisense oligomers (1.35 mg) to the coronary arteries of pigs after balloon overstretch angioplasty (AS group) and performed planimetric histomorphometry on arterial sections of the tissue, harvested at 4 wk. Compared with controls receiving 3'-5' reversed sequence oligomers (REV group), there were no differences in absolute intimal area (AS 1.36 +/- 0.08 mm2, REV 1.23 +/- 0.10 mm2, P = NS), intimal area normalized to extent of injury (AS 0.67 +/- 0.03, REV 0.77 +/- 0.10, P = NS), or vessel perimeter (AS 7.72 +/- 0.19 mm, REV 7.36 +/- 0.22 mm, P = NS). We conclude that single endoluminal delivery of antisense against key cell cycle regulatory proteins does not affect neointima formation or vessel size in this model of restenosis.

When delivered locally to the arterial wall by passive fluid transfer systems such as perforated balloons, water-soluble compounds in aqueous solution are not readily taken up by tissue, show low levels of cellular localization, and are quickly lost by wash-out. One approach to improve delivery is addition of an "active" component to the catheter system to change the nature of the drug-to-tissue interaction. Using an iontophoretic balloon catheter to deliver antisense oligonucleotide (ODN) to pig coronary arteries after balloon angioplasty, we determined the quantity and localization of ODN in the tissue. By radiolabeling, 7.3 +/- 2.4 micrograms ODN was present at 30 min, 1.5 +/- 0.6 at 2 h, 0.52 +/- 0.35 at 24 h, and 0.26 +/- 0.11 at 7 d. By fluorescent labeling, circumferential medial uptake and adventitial delivery at the site of medial injury was observed, with primarily cellular localization. The iontophoretic catheter thus appears to be a useful device for ODN delivery to arterial tissue.

Cyclin-dependent kinase 2 is a serine/threonine protein kinase essential for progression of the mammalian cell cycle from G1 to S phase. CDK2 mRNA has been shown to be induced by serum in several cultured cell types. Therefore, we set out to identify elements that regulate the transcription of the human CDK2 gene and to characterize its structure. This paper describes the cloning of approximately 2.4-kilobase pair genomic DNA fragment from the upstream region of the human CDK2 gene. This fragment contains five transcription initiation sites within a 72-nucleotide stretch. A 200-base pair sub-fragment that confers 70% of maximal basal promoter activity was shown to contain two synergistically acting Sp1 sites. However, a much larger DNA fragment containing approximately 1.7 kilobase pairs of upstream sequence is required for induction of promoter activity following serum stimulation. The intron exon boundaries of seven exons in this gene were also identified, and this information will be useful for analyzing genomic abnormalities associated with CDK2.

The D-type cyclins promote progression through the G1 phase of the cell cycle and may provide a link between growth factors and the cell cycle machinery. We determined the nucleotide sequence of the 5'-flanking region of the human cyclin D2 and cyclin D3 genes and identified the transcription start sites. Analysis of the upstream sequences required for transcription of the cyclin D2 and cyclin D3 genes in continuously dividing cells revealed marked differences in their regulatory elements. In the cyclin D2 gene positive elements were localized between positions -306 and -114 relative to the ATG codon at +1. Additional positive elements were localized between -444 and -345, whereas sequences that reduced transcription were identified between nucleotides -1624 and -892. In the cyclin D3 gene all of the positive elements required for maximal transcription were localized between nucleotides -366 and -167, and no negative elements were found. The activities of a reporter gene linked to the upstream regulatory sequences of the cyclin D2 gene but not the cyclin D3 gene were induced when starved cells were serum stimulated. This suggests that although the abundance of both the cyclin D2 and cyclin D3 mRNAs is increased by serum stimulation, only the cyclin D2 gene is up-regulated at the transcriptional level. Sequences between nucleotides -306 and -1624 of the cyclin D2 gene were necessary for serum inducibility.

Background: Some growth factors may promote tumor growth by affecting tumor angiogenesis. The angiogenic growth factor, pleiotrophin, was demonstrated previously in human breast carcinoma tissues; however, the pattern of pleiotrophin expression in normal breast tissues has not been established., Methods: The expression of pleiotrophin and the related growth factor, midkine, was examined by polymerase chain reaction amplification of reverse transcriptase copies of RNA transcripts (RT-PCR) from freshly resected normal and malignant human breast tissues. Northern blot analysis of midkine expression was performed on a limited number of the specimens and on human and canine breast carcinoma cell lines. Clinicopathologic variables from the breast cancer patients were examined in relation to the growth factor expression patterns., Results: The majority of both malignant and normal breast tissues expressed pleiotrophin. In contrast, midkine was expressed frequently in the malignant breast tissues but in only one of the normal specimens. Northern blot analysis of the breast carcinoma cells lines showed that they commonly expressed midkine transcripts. The only correlation of the growth factor expression patterns with the other clinical variables was the finding that the three midkine-negative breast carcinoma specimens also had low estrogen receptor levels., Conclusions: By this analysis, the expression of pleiotrophin was equivalent in both malignant and normal human breast tissues. Midkine, on the other hand, exhibited increased expression in the breast carcinomas but showed much lower expression in the normal breast tissue. Although the cellular source of the midkine expression was not determined by the RT-PCR assay, the Northern blot analysis showed that isolated populations of breast cancer cells commonly express this growth factor. This is the first example of a tissue simultaneously expressing high amounts of both pleiotrophin and midkine, a finding of unclear pathophysiologic significance.

The heparin-releasable proteins are a group of proteins that are targeted to the endothelial surface by attachment to glycosaminoglycans and may have functions specific to the endothelium-blood interface. In this study, heparin-affinity chromatography of human postheparin plasma was used as a method to identify and study novel heparin-releasable proteins. Six proteins seen on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels have increased levels in plasma after intravenous heparin. The six proteins are platelet factor 4, midkine, pleiotrophin, and several novel proteins. Midkine and pleiotrophin are related cytokines that are developmentally regulated, neurotrophic, and mitogenic. Additional studies show that levels of midkine and pleiotrophin peak at 10 to 30 minutes after injection of heparin. Heparin-releasable midkine and pleiotrophin do not originate from blood cells or the kidney. Heparin-releasable midkine may originate from endothelial cells. Soft agar culture of an adenocarcinoma cell line (SW-13) demonstrates growth-stimulating activity similar to that described for pleiotrophin in the heparin-agarose eluate of postheparin plasma but not in the heparin-agarose eluate of preheparin plasma. It is concluded there are more heparin-releasable proteins than previously identified, including midkine and pleiotrophin, and that heparin-affinity chromatography of postheparin plasma is a useful technique for identifying novel heparin-releasable proteins.

Abundant evidence suggests that growth factors are important mediators of non-small cell lung cancer (NSCLC) growth. Although multiple growth factors have been found to be produced by NSCLC tissues, little is known about possible differences in growth factor expression between malignant and adjacent normal lung tissues. Variation in growth factor expression between normal and malignant lung tissues could be potentially useful diagnostically and therapeutically. In studies reported here, the expression of the angiogenic growth factor pleiotrophin (PTN) and homolog midkine (MK) was assessed in resected normal and malignant lung tissues. Primers specific for the two growth factors were used to amplify reverse transcriptase-produced DNA copies of RNA transcripts harvested from the tissues. This analysis revealed that all normal lung tissues examined (n = 17) expressed PTN but only two expressed MK. Conversely, all of the resected lung cancers (n = 20) expressed MK but only one expressed PTN. These results demonstrated a striking reciprocal expression pattern of MK and PTN in normal versus malignant lung tissue.

Pleiotrophin (PTN), midkine (MK), and retinoic acid-induced heparin-binding (RI-HB) protein are members of a recently discovered family of developmentally regulated cytokines. We report here the cloning, sequencing, chromosomal localization, and structural organization of the genomic version of the human PTN gene and its comparison to the mouse MK gene. The PTN gene was found to be arranged in five exons and four introns, in a fashion similar to that of the mouse MK gene. Exon 1, as for MK, does not appear to encode amino acid sequence. As in the case of the MK gene, exon 2 encodes the hydrophobic leader sequence of PTN, which constitutes the beginning of gene translation. The signal peptide cleavage site of both genes lies toward the 3' end of exon 2. Exons 3 and 4 of PTN were most closely related to exons 3 and 4 of the MK gene; in particular, six of the ten cysteine residues were coded for in exon 3 and the remaining 4 in exon 4. The intron-exon splice junctions of both genes occurred through the same residues. The two genes were found to be less closely related in the fifth exon which encodes the highly basic C-terminal domains, the translation termination codon, and the polyadenylation signal of both cDNAs. We also report approximately 2000 bp of the 5' untranslated sequence of the PTN gene and the site of initiation of transcription in human placenta. PTN was localized to human chromosome 7q33-34 by fluorescence in situ hybridization. These data confirm the existence of a new gene family of developmentally regulated cytokines.

Transformation of normal rat kidney fibroblasts (NRK) by the simian sarcoma virus (SSV) occurs as a result of expression of p28v-sis, a homologue of platelet-derived growth factor-B chain. Chromatographic separation revealed that the bulk (85%) of the mitogenic activity in SSV-transformed NRK cells was not due to p28v-sis but rather two distinct endothelial cell growth factors that eluted off heparin-Sepharose between 1 and 2 M NaCl. Protein purification and Northern blot analysis revealed that one of these growth factors was the 18 kd form of bFGF, the expression of which was found to increase 15-fold with SSV-transformation of NRK cells. The pure 18 Kd bFGF had no effect on NRK cell growth but was a potent neurotrophic agent for fetal rat cortical neurones and a potent growth factor for fetal bovine heart endothelial cells, suggesting a paracrine but not autocrine role for this protein. The second endothelial cell growth factor activity in SSV-transformed NRK cells was due to an 18 Kd protein which could be distinguished immunologically, biochemically, and mitogenically from bFGF.

A heparin binding mitogenic protein isolated from bovine uterus shares NH2-terminal amino acid sequence with a protein isolated from newborn rat brain. The cDNA's of the bovine, human, and rat genes have been isolated and encode extraordinarily conserved proteins unrelated to known growth or neurotrophic factors, although identity of nearly 50 percent has been found with the predicted sequence of a retinoic acid induced transcript in differentiating mouse embryonal carcinoma cells. Lysates of COS-7 cells transiently expressing this protein were mitogenic for NRK cells and initiated neurite outgrowth from mixed cultures of embryonic rat brain cells. RNA transcripts encoding this protein were widely distributed in tissues and were developmentally regulated. This protein, previously designated as heparin binding growth factor (HBGF)-8, is now renamed pleiotrophin (PTN) to reflect its diverse activities. PTN may be the first member of a family of developmentally regulated cytokines.

The relation between arrhythmias at cardiac arrest and the outcome of arrest is poorly understood. The Holter monitor tracings of 13 patients were reviewed after they sustained an in-hospital cardiac arrest during ambulatory electrocardiographic monitoring. All had a prior cardiac arrest or cardiac syncope. Twelve patients had ventricular tachycardia (VT) as their initial arrest arrhythmia and 1 patient had bradycardia followed by ventricular fibrillation (VF). VT degenerated to VF in 10 of 12 patients after a mean interval of 96 +/- 31 seconds (+/- standard error of the mean). The number of VT runs increased significantly during the hour immediately preceding arrest (p = 0.004). Despite prompt resuscitation efforts in 12 patients, only 6 survived. The 6 survivors and 6 nonsurvivors were not different with regard to age, ejection fraction, extent of coronary artery narrowing and time to first defibrillation. However, degeneration to VF within 30 seconds of arrest (5 of 6 nonsurvivors and 1 of 6 survivors, p = 0.04) and a slower rate of VT at the onset of arrest (166 beats/min in nonsurvivors and 227 beats/min in survivors, p = 0.02) were associated with unsuccessful resuscitation.

Endothelium-dependent relaxation is mediated by the release from vascular endothelium of an endothelium-derived relaxing factor (EDRF). It is not clear what role arachidonic acid has in this process. Inhibition of phospholipase A2, and diacylglycerol lipase in cultured bovine aortic endothelial cells caused a marked reduction in agonist-induced arachidonic acid release from membrane phospholipid pools, and complete inhibition of prostacyclin production. EDRF release, assayed by measuring endothelium-dependent cGMP changes in mixed endothelial-smooth muscle cell cultures, was not inhibited under these conditions. In fact, EDRF release in response to two agonists, melittin and ATP, was actually increased in cells treated with phospholipase A2 inhibitors. In addition, pretreatment of rats with high-dose dexamethasone, an inhibitor of PLA2, did not attenuate endothelium-dependent relaxation in intact aortic rings removed from the animals, or depressor responses in anesthetized animals induced by endothelium-dependent vasodilators. In summary, inhibition of arachidonic acid release from membrane phospholipid pools does not attenuate endothelium-dependent relaxation in rats, or the release and/or response to EDRF in cultured cells.

We have purified to near homogeneity a novel 17 kD growth factor from bovine uterus which we designated heparin-binding growth factor-8 (HBGF-8). The growth factor binds tightly to cation exchange resins and to Heparin-Sepharose and is stable to acetone precipitation and labile in acid. Based upon total activity in acetone extracts of bovine uterus stimulating 3H-thymidine incorporation into DNA of serum-starved NIH 313 cells, a 6940 fold purification was achieved with an overall yield of HBGF-8 activity of 0.4%, using extraction of acetone powders and chromatographic separations at neutral pH. Approximately 18 micrograms protein was obtained from 1.2 kg wet weight of tissue. HBGF-8 was clearly separated from 17.5 kD bovine uterus basic fibroblast growth factor (bFGF) by purification and its N-terminal amino acid sequence analyzed. A polypeptide with a unique 25 N-terminal amino acid sequence was found. HBGF-8 was as active as acidic fibroblast growth factor (aFGF) and slightly less active than bFGF in the mouse NIH 3T3 fibroblast mitogenic assay system with an intrinsic specific activity of 5000 dpm/ng under standard assay conditions.

Sustained ventricular tachyarrhythmias and sudden death are particularly prevalent in patients with idiopathic dilated cardiomyopathy (IDC). In contrast to patients with ischemic heart disease, the value of electrophysiological stimulation (EPS) in patients with IDC has not yet been established. To clarify the role of EPS in these patients, we studied 19 patients (58 +/- 11 years) with IDC who had symptomatic ventricular tachycardia (VT) or ventricular fibrillation (VF). The mean left ventricular ejection fraction was 26 +/- 9%. Ten patients had survived out-of-hospital cardiac arrest, eight had documented sustained monomorphic VT and one patient had non-sustained VT associated with syncope. Thirteen of the 19 patients (68%) had their clinical ventricular tachyarrhythmias induced at EPS (12 VT, 1 VF). In nine of 13 patients (69%), the arrhythmias were subsequently suppressed during serial electrophysiological drug testing. During 17 +/- 11 months of follow-up, 10/19 (53%) patients experienced recurrence of their arrhythmias and nine out of 19 (47%) patients died; six died suddenly and three secondary to heart failure. There was no difference in arrhythmia recurrence between patients with and without inducible ventricular tachyarrhythmias at initial study. Furthermore, suppression of arrhythmia during serial testing did not predict outcome; recurrences were observed in five out of nine patients whose arrhythmias were suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet-derived growth factor (PDGF) is the major growth factor in serum and a potent mitogen for cells mesenchymal origin. It is a highly basic heterodimeric protein with a molecular mass of approximately 30 kDa and binds to a cell surface receptor with high affinity. The amino acid sequence of PDGF revealed sequence homology to the v-sis gene product of simian sarcoma virus (SSV), a transforming retrovirus. Characterization of cells transformed by SSV has revealed PDGF-related proteins in subcellular organelles and in conditioned media consistent with the autocrine stimulation of cell growth through cell surface receptors and perhaps through an internal autocrine mechanism as the growth factor and its receptor are processed. PDGF is also a potent chemotactic agent for inflammatory and other mesenchymal cells and has been implicated in normal tissue repair processes such as wound healing, as well as in aberrant proliferative processes like atherogenesis.

The platelet-derived growth factor (PDGF) is a potent mitogen for cells derived from mesenchyme and is highly related to the transforming protein of the simian sarcoma virus (SSV), p28v-sis. Both PDGF and p28v-sis appear to initiate DNA synthesis and cell proliferation through an interaction with PDGF cell surface receptors but the identity of the PDGF induced signals which are recognized within the nucleus is unknown. It has been suggested that PDGF is directly transported to the nucleus although conflicting data have been obtained when nuclear fractions have been analysed for PDGF-like proteins. Specific antisera recognizing PDGF and p28v-sis were used to isolate and partially characterize proteins from nuclei of SSV-transformed NRK fibroblasts. Nuclear proteins of 66, 65, and 44 kD were identified in immunoprecipitates. These proteins were displaced competitively from binding to anti-PDGF antisera by either PDGF or by mitogenically active recombinant v-sis protein homodimers and the proteins were not recognized by non-immune sera. Proteins of 66, 65, and 44 kD also were partially purified from nuclear extracts with anti-PDGF immunoaffinity chromatography and were identified in silver stained PAGE gels. The data establish the presence of proteins antigenically related to PDGF within the nuclei of SSV-transformed cells and suggest possible roles of nuclear proteins related antigenically to PDGF and p28v-sis in cell growth and transformation.