Mobilization of iron by chiral and achiral anionic 3-hydroxypyrid-4-ones.

In the search for 3-hydroxypyrid-4-ones with enhanced iron-mobilizing ability, seven chiral, anionic amino acid derivatives of maltol (3-hydroxy-2-methyl-4-pyrone) have been synthesized, utilizing L-methionine, L-serine, L-leucine, L-phenylalanine, L-glutamic acid, and the D- and L-isomers of alanine. Two achiral, aromatic compounds were also synthesized and compared with the phenylalanine derivative. The biliary iron excretion following iv injection and the urinary iron excretion following po administration were measured using female Sprague-Dawley rats and compared to that of the standard, 1,2-dimethyl-3-hydroxypyrid-4-one (L1). While none of the compounds was as effective as L1 in enhancing the urinary excretion of iron, all monoanionic chelators increased excretion relative to the controls. All monoanionic compounds were at least equivalent to L1 in enhancing the biliary excretion of iron, with the methionine, leucine, and benzoate derivatives surpassing the standard and the other aromatic compounds also showing strong activity. The dianionic glutamate derivative showed low activity relative to the controls for both urinary and biliary iron excretion. No significant difference in iron excretion was observed due to variation in chirality; molecular weight and the number of negative charges appeared to have the greatest influence on the ability of the various derivatives to enhance iron excretion. In order to evaluate the relative purity of the stereoisomers, the alanine derivatives were analyzed by circular dichroism. Further characterization was provided by UV/vis spectroscopy for all compounds and X-ray crystallography for the novel dianionic derivative.

Neuropathologic findings in patients receiving long-term vigabatrin therapy for chronic intractable epilepsy.

Vigabatrin is a new antiepileptic drug that acts by the irreversible inhibition of gamma-aminobutyric acid (GABA) aminotransferase. During animal safety testing, vigabatrin was found to cause reversible intramyelinic edema in the brains of rodents and dogs but not in primates. In humans, the drug is well tolerated, and extensive clinical, neurophysiologic, neurochemical, and psychometric testing has failed to demonstrate any evidence of neurotoxicity. Neuropathologic examination has now been carried out on 62 patients with refractory epilepsy, who were on vigabatrin therapy either prior to undergoing neurosurgery for their epilepsy or before death. A further ten similar cases have been included in the study from age-matched patients with refractory epilepsy who had not been treated with vigabatrin prior to surgery or death. None of the neuropathologic changes seen in the preclinical animals studies have been observed in the human cases. In no case was there considered to be any evidence of myelin microvacuolation or myelin sheath splitting that could be attributed to vigabatrin treatment. Demyelination has never been observed in either the animal or human material. These findings support the clinical tolerability seen in long-term treatment.

Combination and individual antitumor effects of hyperthermia, cisplatin, and selected dithiocarbamates.

The antitumor effects produced by combinations of cisplatin (Pt), substituted dithiocarbamates (dimethyldithiocarbamate [DmDTC] and sodium N-methyl-D-glucamine dithiocarbamate [NMGDTC]) and hyperthermia (H) were measured and compared to those produced by single agents alone in C3H/HeN mice bearing the transplantable radiation-induced fibrosarcoma, RIF-1, in one or both hind feet. The average tumor volumes of control and treatment groups were compared periodically after treatment with H. Combinations of H and Pt completely resolved established foot tumors in 10/13 mice. However, evidence of long-term nephrotoxicity and gastrointestinal (GI) toxicity became evident causing death of these mice within 120 to 122 days after tumor inoculation. Hyperthermia plus DmDTC resolved tumors in heated and non-heated feet in 3/8 mice, thus demonstrating both ipsilateral and contralateral anti-tumor activity. Furthermore, H-Pt-NMGDTC produced complete tumor resolution in 7/13 mice; these mice survived and were tumor-free 180 days post inoculation and autopsies revealed no appreciable nephro- or GI toxicity. In addition, 4/8 mice underwent complete tumor resolution in heated left feet plus dramatic retarding of tumor growth in unheated right feet (ipsilateral and contralateral anti-tumor effects). Five heat-treated left foot tumors resolved in the H-Pt-DmDTC group with one mouse demonstrating resolution of tumor in both feet. Advanced foot tumors were treated with H-DmDTC and H-Pt-DmDTC. Hyperthermia and Pt were administered on day 0 of the experiment and DmDTC on days 0 through 3; dramatic tumor shrinkage continued through day 6 for a total of 75 to 80 percent reduction of tumor volume in both groups. The concurrent administration of DmDTC or NMGDTC with H and Pt prevented or greatly reduced nephrotoxicity and GI toxicity in all experiments without retarding anti-tumor efficacy.

Mechanical induction of osteogenesis: the importance of pin rigidity.

Eight dogs, divided into two groups of four by varying pin rigidity, underwent 15% left tibial lengthening by the Ilizarov method. In group I, "tensioned" 1.6-mm wires maintained a rigidity approaching that of 4.0-mm pins. In group II, the wires, maintained at half the tension, averaged 45% of the rigidity measured in group I. All dogs in group I filled the experimental gap with de novo osteogenesis, whereas all of the dogs in group II prematurely bridged the gap, arresting the process of osteogenesis. From these experimental results, clinical trials have been started using commercially available external fixation devices utilizing pins with equivalent rigidity.

Abdominal aortic aneurysm, Leriche's syndrome, inguinal herniation, and smoking.

We previously found an increase in serum proteolytic activity in smokers with direct inguinal herniation and a similar imbalance in smokers with abdominal aortic aneurysm (AAA), but not in smokers with Leriche's syndrome (LS). If the protease imbalance in the blood of smokers with AAA or herniation is a causal factor, these conditions should be associated. Therefore, we determined whether this is true using patients with LS as control subjects. The frequency of inguinal herniation was significantly higher in the AAA population (N = 341; 25.8%) than in patients with LS (N = 417; 14.6%). In addition, patients with AAA had more severe herniation (direct, bilateral, recurrent, or earlier onset) and had more pronounced leukocytosis (9,000/cu mm v 8,190/cu mm). These data suggest that increased blood proteolytic activity may play a role in the development of both AAA and adult inguinal herniation but not LS. Men who smoke manifest different systemic effects.

Serum proteolytic and antiproteolytic activity in acute pancreatitis.

This study has demonstrated an imbalance between the blood proteolytic and antiproteolytic system in acute pancreatitis. Serum elastase activity is markedly increased and elastase inhibitory capacity is decreased in this disease as compared with those in chronic pancreatitis and the control values. We have found that a return to normal values represents better evidence of resolution than amylase determinations. These results offer the clinician a biochemical guideline for the medical management of acute pancreatitis.

The effects of preoperative radiation on healing of rat colonic anastomoses.

The effect of delaying surgery, after a nominal standard dose of 4500 rad was administered to the abdomen of rats, on the healing of colonic anastomoses was evaluated. Healing, as determined by bursting pressure of colonic segments, was significantly depressed (p less than 0.05) at five days after surgery in groups irradiated five or 15 days prior to surgery as compared with groups receiving either no radiotherapy or irradiation ten days prior to surgery. Five-day healing was not significantly depressed in the group irradiated ten days prior to operation as compared with the group receiving no irradiation. No significant (p less than 0.05) differences were noted at ten or 15 days after surgery between groups that were and were not irradiated. At ten days after surgery all groups had higher bursting pressures than the control group at five days after surgery. Thus, there appears to be an optimal time interval between radiation and surgery to ensure maximal colonic healing.

Blood elastolytic activity in patients with aortic aneurysm.

The question of why obstruction of the aorta (Leriche's syndrome) develops in some patients with severe atherosclerosis of the abdominal aorta while an abdominal aortic aneurysm occurs in others was examined. Significant differences in age, height, weight, mortality, and subsequent operative treatment were found between 335 patients with Leriche's syndrome and 103 patients with abdominal aortic aneurysm. Almost all in both groups smoked and demonstrated leukocytosis. In smokers with aneurysm, circulating serum elastolytic activity and leukocytic granular elastolytic activity were significantly increased, whereas serum antiproteolytic capacity was reduced. These results indicate that the development of abdominal aortic aneurysm in patients who smoke correlates with an abnormal homeostasis between proteolytic and antiproteolytic activity.

Metastatic emphysema: a mechanism for acquiring inguinal herniation.

Since our previous work had indicated that veterans with inguinal herniation demonstrated qualitative and quantitative changes in connective tissue, we tested the hypothesis that a possible mechanism for the defect was chronic exposure to circulating proteases generated in the lung by cigarette smoke. We investigated 59 men (average age: 60 years) with eigher primary direct of indirect hernias. Most of the patients smoked. Circulating serum elastolytic activity was significantly greater in patients with direct hernias who smoked when compared with controls (p less than 0.001). In addition, the serum alpha-1-antitrypsin inhibitory capacity was significantly lower in this category than controls (p less than 0.001). Patients with indirect defects who smoked also had significantly higher elastolytic values but to a lesser degree (p less than 0.01). Serum antiprotease and protein concentrations were within the normal range in all categories. Our results indicate that an imbalance between blood protease and antiproteases, resulting from chronic smoking can damage connective tissue in the groin as well as the lung.