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.

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.

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.

Tc-99m-labeled polystyrene and cellulose macromolecules: agents for gastrointestinal scintigraphy.

Several polystyrene resin and cellulose derivatives were evaluated for potential use as Tc-99m-labeled particulate markers for studies of gastric emptying and intestinal transit time, and for imaging segments of the gastrointestinal tract. The polyamine and quaternary ammonium polystyrene resins bound pertechnetate (Tc--99m) anions effectively; the labeling efficiency was over 95% at physiological pH values. In-vitro stability studies of Tc-99m-labeled resins in simulated gastric and intestinal fluid showed that less than 8% of the label was released after 24 h. The commercial resins dowex 2-XB, AG 1-X2, and Bio-Rex 9, labeled with Tc-99m, may be used as particulate markers of solid digesta in external scintigraphic studies of the gastrointestinal tract. Dowex 2-X8 showed relatively more extensive uptake of pertechnetate and greater stability in simulated gastric and intestinal fluids.

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.

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.

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.

Rate and pattern of gastric emptying in humans using 99mTc-labeled triethylenetetraamine-polystyrene resin.

The preparation and application of a new radiopharmaceutical used in the investigation of the rate and pattern of gastric emptying by external scintigraphy are described. Triethylenetetraamine was bound covalently to cross-linked chloromethylated polystyrene. The triethylenetetraamine-polystyrene resin tenaciously and rapidly bound technetium 99m. The gastric emptying rate was evaluated in normal adult volunteers and patients by serially recording the gastric radioactivity after ingestion of a test meal mixed with 99mTc-labeled triethylenetetraamine-polystyrene resin. The data indicated that 99mTc-labeled triethylenetetraamine-polystyrene resin was an ideal agent for assessing the rate and pattern of gastric emptying in humans. The gastric emptying half-time (t 1/2 GE) in normal subjects ranged from 25 to 75 min.

Localization of technetium 99m-ethylenediamine-N,N'-bis(alpha-2-hydroxy-5-bromophenyl)acetic acid and technetium 99m-N-(2-mercapto-1-oxopropyl)glycine in hepatobiliary system.

Two radiopharmaceuticals, technetium 99m-N-(2-mercapto-1-oxopropyl)glycine (99mTc-I) and technetium 99m-ethylenediamine-N,N'-bis(alpha-2-hydroxy-5-bromophenyl)acetic acid (99MTc-II), were prepared and evaluated in dogs, rabbits, and rats. Both agents gave good scintigraphic images of the liver and gallbladder in dogs. The cumulative amount of 99mTc-I and 99mTc-II excreted in the bile of dogs and the physiological disposition data in rats revealed slight, inconclusive differences in their distributions. However, the scintigraphic images and physiological disposition data in rabbits revealed gross differences in the distribution pattern of the two agents. The observed similarities in the biliary excretion of both agents in dogs and rats were attributed to the fact that these species are relatively good biliary excretors, and both agents therefore were excreted extensively. However, rabbits, which are poor biliary excretors relative to dogs and rats, excreted 99mTc-II more extensively than 99mTc-I because of the favorable molecular characteristics of 99mTc-II.

Liver scintigraphy in ponies.

Six derivatives of ethylenediamine-N,N'-bis (alpha-2-hydroxy phenyl) acetic acid labeled with technetium 99m were prepared and their imaging qualities evaluated in ponies. The 6 agents produced good scintigraphic images of certain structures of the liver in the pony. For each agent, 13 different scans were taken. Dorsal views of the left lateral, right lateral, and quadrate lobe were obtained with dorsal scans. Left lateral and left lateral oblique (45 degrees) scans provided a left lateral view of the left lobe and a medial view of the right lateral lobe. Right lateral scans revealed the right lateral and quadrate lobes. Administration of 99mTc-labeled colloids which are commonly used in other species for liver scintigraphy resulted in extensive lung uptake in the pony.

Organ blood flow and distribution of cardiac output in nonanesthetized swine.

Organ blood flow and distribution of cardiac output (CO) were determined in awake resting swine, using radionuclide-labeled 15-micrometer diameter microspheres. Absolute values of blood flow (per 100-g basis) were determined for various organs and peripheral tissues. Internal organs of the swine, which constituted 8.25 +/- 0.79% of the total body mass, received 45.46 +/- 2.64% of the resting CO. The fraction of CO received by brain, heart, kidneys, liver (via hepatic artery), and gastrointestinal tract was 1.13%, 3.04%, 12.95%, 4.27%, and 18.71%, respectively.

External scintigraphy in measuring rate of gastric emptying in beagles.

The application of external scintigraphy and preparation of a new radiopharmaceutical agent for the investigation of the rate and pattern of gastric emptying in beagles and for the visualization of segments of the intestines have been described. 99mTc-labeled triethylenetetramine-polystyrene resin was mixed in a test meal and was administered to the animal. The gastric emptying rate of the beagle was evaluated by serially recording the gastric radioactivity by means of a scintillation camera, The experimental data indicate that the pattern of gastric emptying of beagles during the first 60 min was monoexponential and the gastric emptying half time was 1.3 h. The usefulness of external scintigraphy as a noninvasive method for determining the gastric emptying rates and for visualizing segments of GI tract in animals has been demonstrated.

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.