Pharmacological interventions for preventing or delaying onset of type 2 diabetes mellitus.

Prevention or delay of onset of type 2 diabetes in individuals at varying risk across the dysglycaemia continuum before overt diabetes becomes clinically manifest constitutes a leading objective of global disease prevention schemes. Pharmacological intervention has been suggested as a means to help prevent diabetes and reduce the global burden of this chronic condition. However, there is no credible evidence that early pharmacological intervention leads to long-term benefit in reducing diabetes-related complications or preventing early mortality, compared to treating people with diagnosed diabetes who have crossed the glycaemic threshold. In this review, we examine published evidence from trials using pharmacological agents to delay or prevent progression to diabetes. We also explore the benefit/risk impact of such therapies, safety issues and relevant off-target effects. Current evidence suggests none of the drugs currently available sustainably lower cumulative diabetes incidence, none provides a durable delay in diabetes diagnosis and none provides a convincing concomitant excess benefit for microvascular or macrovascular risk.

Erythema multiforme following vaccination for human papillomavirus.

Erythema multiforme (EM) is an acute self-limited immune-mediated reaction manifested by target skin lesions with mucous membrane involvement. The most common causes are infections and drugs. Vaccinations have been reported as a triggering factor, and they may be a frequent cause of EM in childhood. A 19-year-old female developed several target lesions of the hands and feet 10 days after the second dose of human papillomavirus (HPV) vaccine. Clinico-histologically, a diagnosis of EM minor was made. Treatment with topical corticosteroids and oral antihistamines resulted in complete clearance of the rash. Four months later, she received the last booster dose of the vaccine. A few subtle lesions appeared and disappeared spontaneously after a few days. Gardasil is a non-infectious vaccine, developed for the prevention of cervical cancer, precancerous genital lesions and genital warts. It delivers the major capsid (L1) protein of HPV types 6, 11, 16 and 18. Mild local reactions are the main adverse events. The only serious events are very rare cases of anaphylaxis. In our patient, the temporal relationship between the development of EM and the vaccination suggests that the HPV vaccine probably was the causal agent. This is the first published case of EM following HPV vaccination.

Chitotriosidase in neonates with fungal and bacterial infections.

Increased plasma and/or urine chitotriosidase activity was found in neonates with fungal infection changing in parallel with their clinical condition. Increased levels were also found in neonates with bacterial infection. Chitotriosidase activity increase is not a response specific to fungi, but serial assays could monitor the course of neonatal fungal infection.

Quantification of pulmonary capillary endothelium-bound angiotensin converting enzyme inhibition in man.

Angiotensin converting enzyme (ACE, kininase II) is an endothelial luminal ectoenzyme expressed abundantly on the pulmonary capillary endothelium and recognized as the site for the conversion of circulating angiotensin I to II. In the present study, we have applied recently developed methodologies for assaying pulmonary capillary endothelium-bound (PCEB) ACE activity in man, to estimate the interaction of an ACE inhibitor (enalaprilat) with PCEB ACE in human subjects. Trace amounts of the specific ACE substrate, 3H-benzoyl-Phe-Ala-Pro (3H-BPAP; 40 Ci or 2 nmol), was injected as a bolus into the subclavian vein and immediately blood was withdrawn from a radial arterial catheter. Plasma concentrations of surviving substrate and product (3H-benzoyl-Phe) were estimated and BPAP utilization was calculated during a single transpulmonary passage, at baseline (T(0)) and at 15 min (T(15)) and 2 h (T(120)) after intravenous administration of 1.5 g/kg enalaprilat in 12 normotensive subjects. This treatment had no significant effect on mean arterial pressure (91+/- 6 vs. 84 +/- 7 vs. 88 +/- 6 mm Hg for T(0), T(15) and T(120), respectively), but significantly decreased serum and PCEB ACE activities. When normalized to predrug (T(0)) activity levels, enalaprilat inhibited PCEB and serum ACE activities at T(15) 74 +/- 6% and 68 +/- 6%, respectively. However, 2 h after enalaprilat (T(120)), PCEB ACE inhibition was maintained at 66 +/- 7%, whereas serum ACE inhibition was reduced to 46 +/- 8% (P<.01 from PCEB ACE), suggesting a preferential PCEB ACE inhibitory effect of enalaprilat.

Effect of nitrite on endothelial function in isolated lung.

Nitrated tyrosine, implicated in protein dysfunction, is increased in various tissues in association with diverse pathological processes. Angiotensin converting enzyme (ACE) is a luminal vascular endothelial enzyme whose dysfunction is an early sign of endothelial injury. ACE contains a tyrosine critical for its enzymatic activity. Others have shown that nitrite exacerbates the ACE dysfunction of cultured endothelial cells in contact with activated polymorphonuclear neutrophils (PMN). We hypothesized that exogenous nitrite would enhance endothelial ACE dysfunction associated with PMN activation in the isolated lung. Rats received lipopolysaccharide (LPS) 2 h prior to isolated lung perfusion with Ficoll containing buffer. Either formyl-Met-Leu-Phe (fMLP, 10(-7) M) or phorbol myristate acetate (PMA, 10(-7) M) was used to activate PMN in lungs treated or not treated with 300-microM nitrite. A first pass indicator dilution method and first order reaction kinetics were used to determine ACE activity, while lung Ficoll content served as an index of vascular permeability. Both fMLP and PMA decreased endothelial ACE activity and increased pulmonary artery pressure, edema and vascular permeability. Exogenous nitrate did not potentiate the decrease in ACE activity, the lung injury or nitrotyrosine immunoreactivity of lung homogenates. In contrast to observations in cultured endothelial cells, our findings in the whole lung are compatible with the speculation of others that the rat lung has an unidentified factor, which minimizes accumulation of nitrated proteins.

Microfilaremia from a Dirofilaria-like parasite in Greece. Case report.

In Europe, zoonotic filarial infections in humans are caused by two species, Dirofilaria immitis and Dirofilaria repens. These parasites are associated mainly with embolic infarcts of the pulmonary artery and subcutaneous nodules, respectively. An unusual dirofilarial infection in a Greek patient who showed marked eosinophilia and microfilaremia is presented. Although the identification of Dirofilaria species is not conclusive, this report is the first on a case of microfilaremia from a Dirofilaria infection in an immunocompetent patient.

Treatment of Langerhans cell histiocytosis with 2 chlorodeoxyadenosine.

Langerhans-cell histiocytosis (LCH) is a rare condition with a wide clinical spectrum and variable prognosis. Patients with multisystem LCH have been treated with a variety of agents but may develop resistant and progressive disease. Based on a preliminary encouraging report on the activity of 2 chlorodoxyadenosine in this disease, we administered this agent to a patient with LCH which was resistant to corticosteroids and etoposide. After 4 courses of treatment the patient achieved a complete remission which is currently ongoing for 12 months. 2 CdA appears to be effective in patients with resistant LCH and warrants investigation in previously untreated patients with poor risk disease.

Regulation of insulin-like growth factor (IGF)-I mRNA and peptide and IGF-binding proteins by interleukin-1.

The purpose of the present study was to determine whether interleukin (IL)-1 would alter the insulin-like growth factor (IGF) system in rats and whether this change was mediated by glucocorticoids. The IGF-I concentration was decreased in plasma (32%), liver (35%), skeletal muscle (40-50% depending on fiber type), pituitary (36%), and brain (52%), and increased in kidney (73%) 6 h after intravenous injection of IL-1 beta. IL-1 beta also decreased IGF-I mRNA levels in liver and muscle and increased expression in kidney. These changes were associated with a > 2.5-fold elevation in plasma corticosterone levels. Pretreatment of rats with the glucocorticoid receptor antagonist RU-486 prevented the IL-1 beta-induced decrease in plasma and liver IGF-I concentration and the reduction in hepatic IGF-I mRNA expression. In contrast, RU-486 did not significantly attenuate the fall in IGF-I content in skeletal muscle, heart, brain, or pituitary or the increase in IGF-I observed in kidney after IL-1 beta. Furthermore, pretreatment with RU-486 did not completely prevent the IL-1 beta-induced decrease in IGF-I mRNA in skeletal muscle. The concentration of both IGF-binding protein (BP)-1 and BP-2 was increased in plasma, liver, and muscle in response to IL-1 beta, and these changes were also not prevented by RU-486. These results indicate that the inflammatory cytokine IL-1 beta is capable of influencing multiple components of the IGF system. Whereas the enhanced endogenous production of glucocorticoids appears to mediate the IL-1 beta-induced decrease in IGF-I synthesis in liver, the changes in IGF-I content observed in other tissues and the increase in IGFBP-1 and IGFBP-2 appear to be largely glucocorticoid independent.

Rapid diminution of calcium in the myocardium by transfer to pericardial solutions. Myocardial dialysis.

A new method is described for the controlled and specific depletion of calcium from the vascularly perfused heart of experimental animals by means of dialysis, using a pericardial solution. A 30-40 ml isotonic phosphate buffer pH 7.3 with a low Ca2+ and high Mg2+ concentration (0.2 and 2.7 mM respectively) was inserted into the pericardial cavity of anaesthetized dogs and kept there for 10 or 60 min. The calcium content of the subendocardial and subepicardial halves of the left ventricular wall was similarly decreased to about 70% (P < 0.01) within 10 min and to 62% (P < 0.001) at 60 min, compared to that of hearts dialysed for 60 min in a standard solution of Ca2+ 1.2 mM and Mg2+ 1 mM. Calcium content of the myocardium dialysed with low Ca2+ and a standard Mg2+ solution decreased to only 75% (P < 0.01) at 60 min. Similar changes of calcium were measured in other parts of the heart. An increase in Ca2+ concentration in the pericardial solution was observed at the same time as a decrease in calcium in the myocardium. The increase in Ca2+ reached about 0.7 mM at 60 min, but decreased slightly, and finally, fell to 85% of pre-dialysis values at 60 min. It is concluded that this method of myocardial dialysis is effective in reducing myocardial calcium and is influenced by the duration of dialysis and the Mg2+ content of dialysate.

Distribution of lidocaine and digoxin in heart tissues and aorta following intrapericardial administration.

The distribution of lidocaine and digoxin in myocardial and aorta tissues of open chest anesthetized dogs was studied, following the administration of 30 ml phosphate buffer solution of the drugs in the pericardial cavity where it was kept for increasing time intervals. Transfer of lidocaine (15 or 30 mg) from the solution to myocardium was almost complete within 60 min, while only 50% of digoxin (2 or 50 micrograms) was removed, and this occurred during the first 30 min. Accordingly, the absorption rate of lidocaine by heart tissues increased with time up to 60 min while that of digoxin decreased with time. Absorption of digoxin by the atria and absorption of both drugs by intrapericardial aorta were higher than that of other heart tissues, between 20 and 60 min. At 30 and 60 min, lidocaine was evenly distributed across the LV wall while digoxin 50 micrograms was mainly concentrated subepicardially. On the contrary, i.v. administration of digoxin resulted in even distribution in the LV wall without preferential concentration in the atria. The uptake of both drugs by aorta was several times lower compared to heart tissues after i.v. administration. Drug concentrations in LV wall almost at therapeutic level, were derived from solution of low concentration of the drug in the pericardial cavity. It is concluded that intrapericardial administration of the drugs may be used when increased concentration of them is desired in specific areas of the heart and the aorta.

Thrombotic thrombocytopenic purpura: treatment with plasmapheresis.

Twenty-one episodes of thrombotic thrombocytopenic purpura (TTP) were treated with plasmapheresis. Adjunctive agents included corticosteroids, aspirin, dipyridamole, and vincristine. There were 17 patients; 12 were female. The median age was 41 years. Most patients presented with neurologic symptoms. Thrombocytopenia was profound with a mean initial platelet count of 14,900/mm3. The mean hematocrit on presentation was 26.7% and the mean LDH 1300 IU/L. Eighteen episodes responded completely following plasmapheresis/plasma exchange (86%). Response was prompt, the initial rise in platelet count occurred after a mean of four exchanges, and complete response (a platelet count over 150,000/mm3) was obtained after a mean of nine exchanges. Four of the episodes treated were relapses that occurred in three patients. All responders are alive with a median duration of follow-up of 20 months. The three patients who failed to respond have died. This report extends recent observations that the addition of plasmapheresis/plasma exchange to the therapy of TTP has significantly improved the outlook for patients with this disorder.

Amino acid derived latent isocyanates: irreversible inactivation of porcine pancreatic elastase and human leukocyte elastase.

Several amino acid derived azolides (I) have been synthesized and investigated for their inhibitory activity toward human leukocyte elastase and porcine pancreatic elastase. The inhibitory activity was found to be dependent on the nature of the precursor amino acid ester. Thus, compounds derived from L-valine methyl ester 3, L-norvaline methyl ester 5, DL-norleucine methyl ester 9, and L-methionine methyl ester 10 were found to inhibit irreversibly both enzymes. Compound 10 was found to be a specific and selective inhibitor of human leukocyte elastase. In contrast to these, inhibitors derived from glycine methyl ester 1, D-valine methyl ester 4, and D-norvaline methyl ester 6 were found to be inactive. The results of the present study show that latent isocyanates derived from appropriate amino acids can serve as selective inhibitors of serine proteases and are of potential pharmacological value.

Synthesis and antitumor activity of some aromatic seleno lactones.

Several aromatic seleno lactones have been synthesized and shown to possess significant inhibitory activity against human colon tumor-8r cells in culture at concentrations lower than 1 mM. Although all of the compounds tested were found to be active, 5-hydroxy-3-[(phenylseleno)methyl]hydrocoumarinoctanoate (3d) and 5-hydroxy-3-[(phenylseleno)methyl]hydrocoumarindecanoate (3e) were found to be the most effective in inhibiting cell growth. In situ formation of the corresponding alpha-methylene lactones is postulated to account for the cytotoxic activity in this class of compounds.

Comparison of in vitro and in vivo effects of vincristine and vindesine on leukemic cells from patients with chronic granulocytic leukemia in blast crisis.

We employed a liquid culture system to examine the in vitro effects of vincristine and vindesine on cellular incorporation of 35SO4 into leukemic cells obtained from 5 patients with chronic granulocytic leukemia in blast crisis. The per cent of 35SO4 into drug-treated as compared to saline-treated leukemic cells was compared to the clinical outcome of patients treated with these agents. A good or partial clinical response to vincristine or vindesine was seen in patients whose leukemic cells incorporated less than 50% 35SO4 when exposed to vincristine or vindesine in vitro, compared with control saline-treated cells. No clinical response was observed following treatment with vincristine or vindesine if the 35SO4 incorporation of drug treated leukemic cells was greater than 50% of saline-treated cells. These data suggest that the in vitro effects of vincristine or vindesine on 35SO4 incorporation into leukemic cells of patients in blast crisis may parallel the clinical outcome of patients treated with these agents in vivo.

Splenectomy for thrombocytopenia in chronic lymphocytic leukemia.

The role of peripheral platelet destruction as a reversible etiology of thrombocytopenia in chronic lymphocytic leukemia (CLL) was evaluated in nine patients with CLL and refractory thrombocytopenia who underwent splenectomy. The patients' ages ranged from 54 to 74 years. Progressive thrombocytopenia refractory to antineoplastic agents and corticosteroids had been present for a mean of 23.4 months. The platelet counts were 4,000-57,000/microliter, and were generally higher in those patients with larger spleens. The spleens ranged from 180 to 4050 gm. Seven patients responded completely to splenectomy, achieving platelet counts greater than 150,000/microliter, and in one other patient, the count rose to greater than 100,000/microliter. The platelet count of one patient failed to respond to surgery. Those patients with massive splenomegaly developed higher, more rapidly rising platelet counts postoperatively. No operative mortality was encountered. Median hospitalization was seven postoperative days. All patients experienced an increased sense of well-being. Median follow-up time is 9 months.

A rapid in vitro drug-sensitivity assay in acute nonlymphocytic leukemia.

Leukemic myeloid, myelomonocytic, and monocytic cells will incorporate radiolabeled sulfate into newly synthesized macromolecules. We developed a liquid culture technique to examine the in vitro effects of chemotherapeutic agents on the incorporation of radiolabeled sulfate into cells of patients with acute nonlymphocytic leukemia (ANLL). Cells recovered from bone marrow or peripheral blood of 25 patients with ANLL were incubated in vitro for one hour with saline (control) or a variety of chemotherapeutic agents. Cells were washed free of the drug and grown in liquid cultures containing nutrient medium and 35SO4. The percent of 35SO4 incorporated into the drug treated as compared with control cells was determined after one, three, and seven days of culture. Patients whose drug-treated cells incorporated less than 30% of 35SO4 when compared with the control after three or seven days of culture achieved a complete response to these agents in vivo (P less than .05). Thus, the in vitro effects of various chemotherapeutic agents on the incorporation of 35SO4 into cells obtained from patients with ANLL may help predict clinical response to these agents in vivo.

External scintigraphy in monitoring the behavior of pharmaceutical formulations in vivo I: technique for acquiring high-resolution images of tablets.

A new method for monitoring tablet disintegration in vivo was developed. In this method, the tablets were labeled with a short-lived radionuclide, technetium 99m, and monitored by a gamma camera. Several innovations were introduced with this method. First, computer reconstruction algorithms were used to enhance the scintigraphic images of the disintegrating tablet in vivo. Second, the use of a four-pinhole collimator to acquire multiple views of the tablet resulted in high count rates and reduced acquisition times of the scintigraphic images. Third, the magnification of the scintigraphic images achieved by pinhole collimation led to significant improvement in resolution. Fourth, the radioinuclide was incorporated into the granulation so that the whole mass of the tablet was uniformly labeled with high levels of activity. This technique allowed the continuous monitoring of the disintegration process of tablets in vivo in experimental animals. Multiple pinhole collimation and the labeling process permitted the acquisition of quality scintigraphic images of the labeled tablet every 30 sec. The resolution of the method was tested in vitro and in vivo.

Acute nonlymphocytic leukemia complicated by severe cytophagocytosis of formed blood elements by nonmalignant histiocytes: cause of significant clinical morbidity.

A 52-year-old female presented with Philadelphia chromosome-positive acute nonlymphocytic leukemia and a morphologically benign-appearing histiocytosis with intramedullary cytophagocytosis of formed blood elements. No cause of the reactive histiocytosis could be found. Despite initial successful therapy of the acute nonlymphocytic leukemia with induction of a cytological remission, pancytopenia with marked cytophagocytosis persisted. Therapy aimed at reducing the degree of cytophagocytosis by the histiocytes, in the form of vinblastine-treated platelets and, subsequently, prednisone, was instituted. There was no significant clinical response to either therapeutic maneuver. Cytophagocytosis persisted until leukemic relapse and death ensued.