Phase I/II trial of dexverapamil, epirubicin and granulocyte/macrophage-colony-stimulating factor in patients with advanced pancreatic adenocarcinoma

A group of 28 previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas were entered in this phase I/II study. Treatment consisted of oral dexverapamil 1000–1200 mg/day for 3 days, epirubicin given as an intravenous bolus injection on day 2 with a starting dose of 90 mg/m², and 400 μg granulocyte/macrophage-colony-stimulating factor (GM-CSF) administered subcutaneously from day 5 through 14. Epirubicin dose escalation levels were 90, 105, 120 and 135 mg/m². Consecutive cohorts of 4–8 patients were planned at each dose level. Treatment cycles were repeated every 3 weeks. Haematological toxicity, specifically granulocytopenia constituted the dose-limiting toxicity with a maximum tolerated dose of 120 mg/m² for epirubicin. Despite routine supportive therapy with GM-CSF, 4, 2, and 5 patients experienced grade 4 granulocytopenia during their first two treatment courses at levels of 105, 120, and 135 mg/m² respectively. Non-haematological toxicity was uncommon, generally modest, and did not demonstrate a clear relationship with the anthracycline dose. Dexverapamil-related cardiovascular symptoms occurred frequently, but they never resulted in serious toxicity requiring active medical intervention or permanent discontinuation of therapy. Of the 28 patients, 9 achieved partial responses to this therapy. The recommended dose of epirubicin for this regimen with dexverapamil and GM-CSF is 120 mg/m² every 3 weeks. Therapeutic results suggest this regimen to be an effective and tolerable treatment strategy in pancreatic cancer, which should be evaluated further.     

Polyarteritis nodosa and myocardial infarction

A 35-year-old man with a history of polyarteritis nodosa is presented. The patient presented with acute anterolateral myocardial infarction that was complicated by diffuse coronary artery aneurysms found during cardiac catheterization. The complication of acute myocardial infarction in a patient with diffuse coronary artery aneurysms associated with polyarteritis nodosa is rare.     

Prediction of early-onset asthma in genetically at-risk children

The W.T. Grant Foundation Asthma Risk Study was designed to prospectively examine children who were considered at a genetically increased risk for the development of asthma. The respective contributions of 11 potential risk factors, both environmental and biological, were assessed in order to determine their relative roles in affecting the early onset of asthma. This is a report of an inception cohort of children born to asthmatic mothers and followed for a 3-year period. All 150 families were recruited from the general community and living within 2 h of the National Jewish Center for Immunology and Respiratory Medicine (Denver, CO). Mothers in the index risk sample had been previously diagnosed with asthma and were recruited during their pregnancy through physician referrals and media solicitation. The index sample of 150 families was 92% Caucasian and predominantly middle class. The mean age of mothers was 29.3 years, and of fathers, 31.1 years. The main outcome was the determination of the early onset of asthma and its association with quantified risk factors. By age 3 years, 14 of the 150 children had developed asthma. Frequent illness, IgE levels at age 6 months, parenting difficulties, and early eczema were significantly associated with the onset of asthma (P = 0.003, P = 0.006, P = 0.01, and P = 0.03, respectively). Only frequent illness, elevated serum IgE levels, and parenting difficulties entered a predictive model where they were independently related to the development of asthma.     

Comparative in vitro activity of -ofloxacin and FK037 to other agents against 10,040 fresh clinical isolates

Fresh clinical isolates collected from November 1, 1992 through November 1, 1993, were tested by agar dilution against 26 different antimicrobial agents including FK037 and -ofloxacin. Among the 10 040 organisms tested were Staphylococcus aureus (n = 1222), methicillin-resistant Staphylococcus aureus (MRSA, n = 455), Staphylococcus epidermidis (n = 533), Staphylococcus hominis (n = 90), Staphylococcus hemolyticus (n = 89), Streptococcus pneumoniae (n = 144), Escherichia coli (n = 2326), Klebsiella pneumoniae (n = 745), Enterobacter cloacae (n = 258), Proteus mirabilis (n = 445), Pseudomonas aeruginosa (n = 998), and Stenotrophomonas (Xanthomonas) maltophilia (n = 102). Both -ofloxacin and FK037 inhibited 98% of S. aureus strains at 4 μg/ml. FK037 was at least 4 times more effective than the third generation cephalosporins against MRSA, inhibiting 79% of the strains at 16 μg/ml. While the potency of these agents looks promising, their clinical utility will depend in part upon the maximal dosage that can be safely administered.     

Pituitary adenylate cyclase activating peptides relax human pulmonary arteries by opening of KATP and KCa channels

BACKGROUND—Pituitaryadenylate cyclase activating peptides (PACAPs) are potent endotheliumindependent dilators of human coronary arteries; however, their effectson human pulmonary arteries are unknown.
Methods—Thevasorelaxant effects of PACAP27 on human pulmonary segmental arterieswere studied and the specific potassium (K⁺) channelregulatory mechanisms in the vasorelaxant effects were tested by meansof isometric contraction experiments.
RESULTS—PACAP27produced dose dependent relaxations of 10 µM rings preconstrictedwith prostaglandin F_2α (PGF_2α ) with half maximal relaxation (IC₅₀) at 17 nM. Pretreatment of thevessels with the ATP sensitive K⁺ (K_ATP)channel blocker glibenclamide (1 µM) or with the Ca²⁺activated K⁺ (K_Ca) channel blockeriberiotoxin (100 nM) inhibited the PACAP27 induced relaxation.
Conclusions—Theseresults provide evidence that PACAPs are potent vasodilators of humanpulmonary arteries and that this relaxation might be mediated byopening of K_ATP and K_Ca channels.

     

Differentiation of substantia gelatinosa-like regions in intraspinal and intracerebral transplants of embryonic spinal cord tissue in the rat

The differentiation of intracerebral and intraspinal transplants of fetal (E14-E15) rat spinal cord was studied to determine the extent to which myelin-free zones in these embryonic grafts exhibit cytological features and immunocytochemical characteristics of the substantia gelatinosa (SG) of the normal spinal cord. Immunocytochemical staining with antiserum to myelin basic protein (MBP) revealed myelin-free areas of varying proportions within fetal spinal cord grafts. These regions were identified in both newborn and adult recipients regardless of whether donor tissue was grafted to heterotopic (intracerebral) or homotopic (intraspinal) sites. As in the SG of the intact spinal cord, the myelin-free regions consisted mainly of small (7-15 microns) diameter neurons. At the ultrastructural level, these cells were surrounded by a neuropil composed of numerous small caliber, unmyelinated axons and intermediate-sized dendrites. Synaptic terminals in these areas were primarily characterized by the presence of clear, round vesicles, although granular vesicles were occasionally found within these terminals. Immunocytochemical staining demonstrated met- and leu-enkephalin-, neurotensin-, substance P-, and somatostatin-like immunoreactive elements within these myelin-free areas. Thus, regions within embryonic spinal cord grafts undergo some topographical differentiation which parallels that of the normal superficial dorsal horn. The presence of SG-like regions illustrates the potential capacity of fetal spinal cord transplants for replacing some intraspinal neuronal populations at the site of a spinal cord injury in neonatal and adult animals. These graft regions may serve as a source of intersegmental projection neurons or establish an extensive intrinsic circuitry similar to that seen in the normal SG. In addition, the definition of these areas provides a useful model to study the innervation patterns of host axons that typically project to the substantia gelatinosa of the normal spinal cord.