Actinomycin-D and dimethylamino-parthenolide synergism in treating human pancreatic cancer cells.

Preclinical Research & Development Pancreatic cancer is the third leading cause of death in the US with a poor 5-year survival rate of 8.5%. A novel anti-cancer drug, dimethylamino parthenolide (DMAPT), is the water-soluble analog of the natural sesquiterpene lactone, parthenolide. The putative modes of action of DMAPT are inhibition of the Nuclear chain factor kappa-light-chain enhancer of activated B cells (NFκB) pathway and depletion of glutathione levels; the latter causing cancer cells to be more susceptible to oxidative stress-induced cell death. Actinomycin-D (ActD) is a polypeptide antibiotic that binds to DNA, and inhibits RNA and protein synthesis by inhibiting RNA polymerase II. A phase 2 clinical trial indicated that ActD could be a potent drug against pancreatic cancer; however, it was not a favored drug due to toxicity issues. New drug entities and methods of drug delivery, used alone or in combination, are needed to treat pancreatic cancer more effectively. Thus, it was postulated that combining DMAPT and ActD would result in synergistic inhibition of Panc-1 pancreatic cancer cell growth because DMAPT's inhibition of NFκB would enhance induction of apoptosis by ActD, via phosphorylation of c-Jun, by minimizing NFκB inhibition of c-Jun phosphorylation. Combining these two drugs induced a higher level of cell death than each drug alone. A fixed drug ratio of DMAPT: ActD (1,200:1) was used. Data from metabolic (MTT) and colony formation assays were analyzed for synergism with CompuSyn software, which utilizes the Chou-Talalay equation. The analyses indicated synergism and moderate synergism at combination concentrations of DMAPT/ActD of 12/0.01 and 18/0.015 µM, respectively.

Eyelid skin as a potential site for drug delivery to conjunctiva and ocular tissues.

The feasibility of topical application onto the (lower) eyelid skin to deliver hydrophilic and lipophilic compounds into the conjunctiva and ocular tissues was evaluated by comparing with conventional eye drop application. Skin permeation and the concentration of several model compounds, and skin impedance were determined utilizing eyelid skin from hairless rats, as well as abdominal skin in the same animals for comparison. In vitro static diffusion cells were used to assess the skin permeation in order to provide key insights into the relationship between the skin sites and drugs. The obtained results revealed that drug permeation through the eyelid skin was much higher than that through abdominal skin regardless of the drug lipophilicity. Specifically, diclofenac sodium salt and tranilast exhibited approximately 6-fold and 11-fold higher permeability coefficients, respectively, through eyelid skin compared with abdominal skin. Histomorphological evaluation and in vivo distribution of model fluorescent dyes were also examined in the conjunctiva and skin after eyelid administration by conventional microscope and confocal laser scanning microscope analyses. The result revealed that eyelid skin has a thinner stratum corneum, thereby showing lower impedance, which could be the reason for the higher drug permeation through eyelid skin. Comparative evaluation of lipophilic and hydrophilic model compounds administered via the eyelid skin over 8h revealed stronger fluorescence intensity in the skin and surrounding tissues compared with eye drop administration. These results suggested that the (lower) eyelid skin is valuable as a prospective site for ophthalmic medicines.

[The comparative study of the of clinical effectiveness of the Candibiotic, Otipax, and Anauran ear drops for the treatment of acute external and middle ear otitis].

The objective of the present work was to study in vitro antimicrobial activity of the Candibiotic, ear drops used for the combined treatment of acute external ear otitis and acute otitis media Their anesthetic and anti-inflammatory action was compared with the effects of Otipax, and Anauran ear drops. The results of the study give a reason to recommend the application of Candibiotic ear drops as the highly effective medication for the endo-aural treatment of acute external ear otitis and acute otitis media.

[Clinical trial on the effect of buphenine, aminophenazone and diphenylpyraline hydrochloride in treating the common cold in children of 6 to 24 months of age]. / Ensayo clínico sobre el efecto de la bufenina, aminofenazona y el clorhidrato de difenilpiralina en el tratamiento del resfriado común en niños de seis a 24 meses de edad.

INTRODUCTION: Acute respiratory infections are the second leading cause of morbidity in children under 18 years. Several drugs have been used with variable efficacy and safety, trying to reduce the associated symptoms and improve quality of life. OBJECTIVE: To evaluate the efficacy and safety of buphenine, aminophenazone and diphenylpyraline hydrochloride when compared with placebo for the control of symptoms associated with common cold in children 6-24 months of age. MATERIAL AND METHODS: Randomized clinical trial, double blind, placebo controlled, in 100 children < 24 months of any gender, with symptoms associated to common cold. They received the drug under study vs. placebo for seven days. Both groups received acetaminophen. The change on common cold related symptoms were evaluated. Statistic analysis was made with STATA 11.0 for Mac. RESULTS: Fifty-three children were randomized to study drug and forty-seven to placebo. Age of children in each group was similar (12.2 +/- 5.8 months vs. 12.7 +/- 5.8 months, p NS). There were significant differences between groups in relation to rhinorrea and sneezing resolution, with better results in Flumil group and no adverse events observed. CONCLUSIONS: The results in this study indicates that Flumil is a safe and effective drug for control of symptoms present in the common cold in children aged 6-24 months.

Use of a 13C-aminopyrine blood test: first clinical impressions.

The purpose of this study was to collect initial data to determine the potential clinical usefulness of a 13C-aminopyrine demethylation blood test, and whether additional clinical investigation is warranted. Six dogs, initially suspected of having hepatic disease based on their history, physical examination, imaging studies, general laboratory parameters, or any combination of the above, were enrolled in the study. A baseline blood sample was collected, 2 mg/kg 13C-aminopyrine was administered intravenously, and another blood sample was collected 45 min afterwards. Carbon dioxide was extracted from the blood samples and analyzed using fractional mass spectrometry. Results from the 13C-aminopyrine demethylation blood test were compared to clinical data and histologic findings. Intravenous administration of 13C-aminopyrine leads to a decrease in the percent dose of 13C recovered from dogs with histologically confirmed liver disease. Based on our results, a full-scale investigation of the potential clinical usefulness of a 13C-aminopyrine demethylation blood test for assessment of hepatic function in dogs is warranted.

The pharmacologic stability of 35-year old theophylline.

The propensity to preserve and to hoard drugs over the years at home is a well-known phenomenon and offers the possibility for intentional and accidental drug poisoning in man. We report a case of acute theophylline poisoning in an 80-year old women after ingestion of 'Asthmo-Kranit', a 35-year old combined preparation containing theophylline and aminopyrine as the main ingredients. The patient developed the typical clinical picture of a symptomatic theophylline poisoning with flush, tremor, tachycardia, hyperventilation, hypotonia, and hyperglycaemia. The clinical course after treatment with beta-blockers was without complications. The determination of theophylline in tablets showed stability of 90% of the labelled amount of the drug 30 years beyond the expiration date. The case illustrates the prolonged shelf stability and pharmacological potency of some pharmaceuticals and points to the risk of long-outdated prescriptions. Physicians should primarily not underestimate drug toxicity in consequence of old-age pharmaceuticals.

Preliminary studies of a canine 13C-aminopyrine demethylation blood test.

The objectives of this study were to determine whether a 13C-aminopyrine demethylation blood test is technically feasible in clinically healthy dogs, whether oral administration of 13C-aminopyrine causes a detectable increase in percent dose/min (PCD) of 13C administered as 13C-aminopyrine and recovered in gas extracted from blood, and whether gas extraction efficiency has an impact on PCD. A dose of 2 mg/kg body weight of 13C-aminopyrine dissolved in deionized water was administered orally to 6 clinically healthy dogs. Blood samples were taken from each dog 0, 30, 60, and 120 min after administration of the 13C-aminopyrine. Carbon dioxide was extracted from blood samples by addition of acid and analyzed by fractional mass spectrometry. None of the 6 dogs showed any side effects after 13C-aminopyrine administration. All 6 dogs showed a measurable increase of the PCD in gas samples extracted from blood samples at 30 min, 60 min, and 120 min after 13C-aminopyrine administration. Coefficients of variation between the triplicate samples were statistically significantly higher for the %CO2, a measure of extraction efficiency, than for PCD values (P < 0.0001). The 13C-aminopyrine demethylation blood test described here is technically feasible. Oral administration of 13C-aminopyrine did not lead to gross side effects in the 6 dogs. Clinically healthy dogs show a measurable increase of PCD in gas extracted from blood samples after oral administration of 13C-aminopyrine. Efficiency of CO2 extraction from blood samples does not have an impact on PCD determined from these blood samples. This test may prove useful to evaluate hepatic function in dogs.

Microsomal function in hepatitis B surface antigen healthy carriers: assessment of cytochrome P450 1A2 activity by the 14C-caffeine breath test.

The hepatitis B surface antigen (HBsAg) carrier state is associated with changes in hepatocellular function involving the cytochrome P450 (CYP) system. Among this system, CYP1A2 enzyme plays an important role in chemical carcinogenesis and in the metabolism of several drugs. We have thus investigated CYP1A2 function using two 14C-caffeine breath tests (3-methyl-14C; C3BT and 7-methyl-14C caffeine; C7BT) in 12 HBsAg healthy carriers and 8 healthy volunteers matched for 14C-aminopyrine breath test values. HBsAg carriers exhibited lower C3- and C7BT values than normal controls. This difference, however, did not reach statistical significance except for C7BT values normalised for aminopyrine breath test values. Our data thus do not support the association between viral presence and CYP1A2 dysfunction.

Gaseous nitrogen dioxide increases the endogenous synthesis of carcinogenic N-nitrosodimethylamine in animals.

Inhalation of nitrogen dioxide (NO2) by mice administered orally amidopyrine (AP) and sodium nitrite resulted in increased biosynthesis of N-nitrosodimethylamine (NDMA), as determined by analysis using gas chromatography with thermal energy analyzer detector. These results were also confirmed indirectly in chronic experiments on rats using the system of biomarkers of NDMA formation (single-stranded DNA liver damages, alanine-aminotransferase, glutathione-S-transferase, and liver S9 fraction activity). The inhibition of NDMA metabolism by 4-methylpyrazol (4-MP) administration increases the sensitivity of NDMA biosynthesis assay in frozen whole-mouse powder. The results confirm that NO2 can serve as the precursor of nitrosamines.

A device for automatic measurement of writhing and its application to the assessment of analgesic agents.

A device was developed for automatically measuring writhing in mice so as to be applied to the assessment of analgesic agents. The device was composed of a specially designed container equipped with a detector, namely, a mechanoelectro transducer for writhing. The detector was made up of units of a string, two plates, and two strain gauges. In the unit, each end of the string was connected to either of the plates to which either of the strain gauges was attached. The change in tension of the string due to writhing was converted into the mechanical strain of the plates and then the resistance change of the strain gauges. The resistance change was amplified by a Wheatstone bridge circuit that was connected to a differential amplifier, a high-pass filter, comparator(s), and a monostable multivibrator to obtain the electrical signal for writhing. Using this device, writhing was continuously measured, and evaluation of various types of analgesic agents was performed. The result suggests that this device has sufficient accuracy both for the detection of writhing and the evaluation of analgesics. It has the advantage of automatic measurement of writhing in contrast to the conventional visual observation method.

[Effects of selenium on endogenous synthesis of N-nitrosamines and toxicity of nitrites in rats]. / Vliianie selena na éndogennyi sintez N-nitrozaminov i toksicheskoe deistvienitritov u krys.

Male Wistar rats were fed selenium (0.2, 2.9 or 5.5 mg/kg of dry feed) in the form of selenomethionine. They also received for 6 weeks amidopyrine (33 mg/kg b.w.) and/or sodium nitrite (20 mg/kg b.w.) administered intragastrically. The quantitation of endogenously synthetized volatile nitrosamines in the stomach, selenium in the serum, biochemically evaluated nitrite and nitrosamines toxicity revealed an inverse relationship between feed selenium concentrations and the amount of endogenously produced nitrosodimethylamine from equal precursor doses. A protective selenium effect on methemoglobin-producing action of nitrite ions was established. It is shown that introduction of precursors induces increased body need in selenium.

[Efficacy and tolerance of a local application of phenazone and chlorhydrate lidocaine (Otipax) in infants and children with congestive otitis]. / Efficacité et tolérance d'une application locale de phénazone et de chlorhydrate de lidocaïne (Otipax) dans les otites congestives du nourrisson et de l'enfant.

The efficacy and safety of ear drops containing phenazone and lidocaine hydrochloride (Otipax) for the treatment of congestive myringitis were evaluated in 18 infants and children aged 1 to 10 years. Relief of pain was evident 5 minutes after instillation and significant after 15 to 30 minutes. Serial photographs of the tympanic membrane demonstrated prompt improvement of inflammation. Congestion was significantly reduced after five minutes and overall ear drum color was significantly improved after 15 to 30 minutes. No adverse effects were recorded. These data suggest that Otipax is effective and safe for the treatment of painful congestive myringitis in infants and children.

[Ergotamine-induced rectal stenosis in a patient with long-term migraine]. / Ergotamin-induzierte Rektumstenose bei einer Patientin mit langjähriger Migräne.

A 36 year old woman was admitted to our hospital for treatment of a high-grade rectal stenosis of unknown origin. She had a history of migraine going back 10 years. On intensive questioning she admitted using up to 5 ergotamine-containing suppositories a day. On the basis of history and clinical investigations the rectal stenosis must be connected with the abuse of ergotamine-containing suppositories. This case demonstrates that patients with an unexplained rectal syndrome should be asked for analgetics-containing suppositories specifically. Only discontinuation of treatment in time can preserve the patient from development of a rectal stenosis. In case of a rectal stenosis surgical treatment can be avoided by means of endoscopic controlled dilatation.

Interaction between Ukrain and aminophenazone in analgesic tests in rodents.

The effect of Ukrain on the analgesic activity of aminophenazone was studied in mice and rats. Antinociceptive action induced by aminophenazone in doses of 50 or 100 mg/kg intraperitoneally (i.p.) was determined by using the writhing syndrome, hot-plate tests and tail-flick latency. The action of aminophenazone was significantly enhanced by Ukrain in the writhing syndrome test and in the tail-flick test. Antinociceptive action of aminophenazone was decreased by Ukrain in the hot-plate test in mice. These results suggest that Ukrain, given simultaneously with aminophenazone, changes susceptibility of animals to nociceptive reaction in the tests performed.

[A fatal thrombocytopenic hemorrhagiparous syndrome following aminophenazone in an infant]. / Sindrom hemoragipar trombocitopenic letal dupa aminofenazona la sugar.

A case of lethal thrombocytopenic purpura, with cutaneous and visceral haemorrhagic manifestations after the administration of aminophenazone suppositories in a suckling, without any intercurrent disease, is reported. General considerations regarding the action of some drugs, including aminophenazone, on blood platelets are made.

[Biopharmaceutical study of aminophenazone-containing suppositories. 2. Results of in vitro drug release and in vivo drug absorption]. / Aminofenazon-tartalmú kúpok biofarmáciai vizsgálata. II. Az in vitro gyógyszerleadás és az in vivo gyógyszerfelszívódás eredményei.

Ten kinds of surface active ingredients of Th. Goldschmidt AG. (Essen-FRG) in concentrations of 5% were mixed with Witepsol W 35 and Massa Estarinum 299 suppository masses of Hüls-Troisdorf AG. Werk (Witten-FRG) which are official in Hungary. According to the authors the above tensides, which have been used advantageously first of all in ointments, creams and cosmetic preparations, can also be applied in rectal preparations. In the publication of two parts it has been established that these ingredients influence physical parameters of suppositories beneficially. They always increase significantly in vitro diffusion values and in some cases with order of magnitude. Massa Estarinum 299 containing 5% of Emulgator BTO proved to be the best in case of chosen suppositories containing aminophenazone. Correlation between in vitro and in vivo investigations has shown the importance of correct selection of base and ingredient materials in biopharmaceutical work.