Two series of diphenhydramine analogues have been prepared. In the first series, one phenyl ring in the benzhydryl nucleus has been substituted with a cycloalkyl ring containing three to seven carbon atoms inclusive. In the second series both phenyl rings have been replaced by two rings containing three, five and six carbon atoms. The following amines have been prepared: 2-(α -cyclopropylbenzyloxy)-N,N-dimethylethylamine, 2-(α -cyclobutylbenzyloxy) -N,N-dimethylethylamine, 2-(α-cyclopentylbenzyloxy)-N,N-dimethylethylamine, 2- (α -cyclohexylbenzyloxy) -N, N-dimethylethylamine, 2-(α-cycloheptylbenzyloxy)-N,N-dimethylethylamine, 2-(dicyclopropylmethoxy)-N,N-dimethylethylamine, 2-(dicyclopentylmethoxy)-N,N-dimethylethylamine and 2-(dicyclohexylraethoxy)-N,N,-dimethylethylamine. These compounds have been characterized by their infrared spectra and, where possible, by elemental analyses of the chloroplatinates. The reaction scheme involved a Grignard reaction of the cycloalkylbromide on benzaldehyde to yield the cycloalkyl-phenylcarbinol for the first series, and reaction on ethyl formate to yield the dicycloalkylcarbinol for the second series. Cyclobutylphenylcarbinol was obtained through a Friedel-Crafts reaction of cyclobutanecarboxyl chloride on benzene using aluminum chloride as the catalyst and subsequent reduction of the cyclobutylphenylketone with lithium aluminum hydride. These secondary carbinols were then condensed with 2-dimethylaminoethylbromide hydrobromide in the presence of sodium amide. An alternate condensation reaction in the second series involved reaction of the dicycloalkylmethylbromide with 2-dimethylaminoethanol using sodamide as the condensing agent. The major problems in the syntheses of the carbinols are the presence of carbonyl contaminants in some of the products, particularly in the cycloheptyl and cyclooctyl compounds, and the low yields of addition products obtained. It appears that better results would be achieved if the amount of Grignard reagent in the solution is estimated by a standard method to determine the amount of aldehyde or ester required for the reaction. In the condensation reactions, difficulty was encountered in formation of the sodium derivative. This reaction required a finely-divided form of the condensing agent and sufficient warming time for the reaction to proceed. However, too lengthy a period of heating appears to alter the carbinol molecule so that no product could be obtained. The second phase of the condensation reaction also proceeds slowly, and a sufficient period of refluxing is necessary for the reaction to go to completion. The alternate procedure which was also employed in the second series of compounds did not appear to improve the yields of products. Signature of Examiners / Pharmaceutical Sciences, Faculty of / Graduate

Class of 2015 Abstract / Objectives: To assess the solubility and stability of tetracycline in compounded miracle mouthwash solutions over time, and at different temperatures (room temperature versus refrigerated) and pH (unaltered versus pH 7). Methods: Miracle mouthwash (MMW) solutions were compounded using tetracycline HCl capsules and 1:1 pseudo-dexamethasone elixir and diphenhydramine. High-performance liquid chromatography (HPLC) was used to measure the tetracycline concentrations in the MMW samples tested. Data on tetracycline crystal composition over time were also collected using powder x-ray diffraction, differential scanning calorimetry (DSC), and thermal gravimetric analysis (TGA). Results: For the tetracycline MMW solutions stored at room temperature, only 16% of the original tetracycline remained in solution after 24 hours, stabilizing at 65-81 mcg/mL on day 5 then decreasing further down to 45 mcg/mL by day 15. Similar results were obtained for the refrigerated tetracycline MMW solution (11% of original concentration after 5 days, with a decrease from 31-54 mcg/mL on day 5 to 22 mcg/mL on day 15). Tetracycline concentrations appeared to undergo a steeper decline in MMW solutions of pH 7 than in unadjusted MMW solutions (pH 4.68). All MMW samples exhibited a conversion from tetracycline HCl to tetracycline hexahydrate. Conclusions: Tetracycline solubility decreases rapidity in MMW within 24 hours of compounding regardless of temperature. MMW solutions at pH 7 may have further reduced solubility. Stability decreases at a stable rate from tetracycline HCl to tetracycline hexahydrate.

No description available.

A diverse cocktail of pharmaceuticals is spreading via water treatment plants’ effluent to surface water with known and unknown consequences of individual organisms and the ecosystem. In prior research on what consequences the pharmaceutical discharge can have, the antihistamine diphenhydramine has been found in surface waters and has been linked to alteration in organisms’ behaviours. In this study, Dytiscidae larvae were filmed before and after being exposed to diphenhydramin with a concentration of 1 µg/l. The exposure was done using four different treatments: no diphenhydramine, diphenhydramine in water, in their food or in both water and food. This was done to observe whether the behaviour, specifically activity and boldness, of Dytiscidae larvae would change with the exposure of the antihistamine and therefore potentially be a problem in aquatic ecosystems exposed to effluent. The experiment showed a significant difference (P = 0.015) between larvae in the control group and larvae only exposed to diphenhydramine through water, where exposed larvae were less active than the control group. Also, a trend pointed to a potential difference in exploration between the same groups, where the group exposed to diphenhydramine explored more than the control group. No behavioural change was found when larvae was exposed via food or food and water. The changed behaviour found here could influence fitness of the larvae and potentially also other parts of the ecosystem through cascading effects. Further research is required to confirm the dangers and consequences of diphenhydramine in surface waters, but my results suggest that it can alter the organism’s behaviour in aquatic ecosystems.

Although an iontophoretic trans-dermal drug delivery is known as an effective means for drug transportation through the human skin, it is not widely used because of the various side effects that come to life due to a high applied voltage of up to 80V. This study introduces an alternative means of drug transportation through the skin by means of sweat gland activation and reduction of an applied voltage to ensure that the iontophoresis is safe. The skin conductance studies performed on the pulmar area using 50mM of NaCl showed that the activation of sweat glands led to the increase of the skin conductance up to 8-10 times which enabled us to use a lower voltage of 2V in order to achieve noticeable results during the actual drug delivery experiment performed in the points of low ionic resistance that are located on a human biceps, also the application of Vaseline on the experimental surface does not allow the decrease of a skin conductance for as long as 11 hours which enables us to do the drug delivery over a long period of time. Finally, the drug delivery was performed and tested by means of HPLC method.

A common practice amongst street drug manufacturers and dealers is to combine the illicit drug of abuse they intend to distribute with additional substances. Substances added in an attempt to mimic or enhance the desired effect of the drug of abuse are known as adulterants as opposed to diluents, which are added simply to increase the weight of the product. By definition, an adulterant has a physiological effect on the body and as physiologically active compounds these adulterants may have side effects apart from the drug it is added to. They can be minimal, treatable, or otherwise manageable while others can be worse than those incurred from the drug of abuse itself. Due to varying trends in street drug purity, an effort must be made to understand the effects adulterants and diluents, as well as mixtures thereof, may have on forensic drug analysis. Colorimetric spot test analysis is typically performed using a representative sample of the raw, suspected drug material. These tests are often employed in the lab prior to any attempt to isolate a specific compound or at the scene before an arrest is made. This being the case, the reagents will be exposed to and have the potential to react with anything present in the sample with the drug of abuse. While much work has been done regarding the specificity and cross reactivity of colorimetric spot tests, limited information is available about how mixtures of adulterants may affect the results. This research consists of two parts which approach the common theme of adulterants differently. The first part is a literature based investigation into the pathological side effects of several common drug adulterants. The specific compounds discussed are: levamisole, phenacetin, atropine, and several topical anesthetics (benzocaine, lidocaine, prilocaine, and procaine). A review of articles from the scientific literature was conducted in order to convey what is known in the medical field regarding the effects these compounds can have on the body. The second part of this research was a laboratory based investigation which analyzed the effects of twenty-three common adulterants on two colorimetric spot tests: the Marquis reagent for the presumptive identification of heroin, morphine, amphetamine, methamphetamine, and 3,4-methylenedioxy-N-methamphetamine (MDMA) and the modified Scott test for the presumptive identification of cocaine. This was performed in order to observe the reactivity of these compounds so that a better understanding of the effect their presence can have on the analysis of seized drug samples using these tests could be obtained. The literature review portion of this research revealed that the adulterants levamisole, atropine, phenacetin, and the topical anesthetic adulterants lidocaine, prilocaine, benzocaine, and procaine, can be toxic and have severe, deleterious effects on the body in both chronic and acute exposures. Levamisole stimulates the immune system resulting in the production of self-reactive antibodies that attack neutrophils. This causes an autoimmune disorder that weakens the immune system and causes leukocyte agglutination leading to necrotizing vasculitis. Atropine functions to decrease the parasympathetic tone and increase the sympathetic tone in the body. An overdose can cause anticholinergic toxicity, a syndrome very similar to sympathomimetic toxidrome caused by cocaine overdose. Both are characterized by hypertension, hyperthermia, tachycardia, ataxia, disorientation, and mydriasis. However, they can be distinguished as anticholinergic toxicity causes dry and flush skin and mydriasis which is unreactive to light while sympathomimetic toxidrome causes profuse sweating and mydriasis which is reactive to light. Phenacetin is metabolized to O-ethyl-N-acetyl-p-benzoquinone imine (O-Et-NAPQI), a highly reactive and unstable electrophile. It is capable of covalently binding with proteins and other cellular components, including deoxyribonucleic acid (DNA). This leads to mutagenesis and subsequent tumor generation as well as apoptosis and necrosis of various tissues in the bladder and kidneys. The topical anesthetics have each been associated with the development of methemoglobinemia. This is a condition caused by an increase in the concentration of methemoglobin in the blood. Methemoglobin binds more strongly to oxygen so that it cannot be released to the tissues resulting in oxygen starvation. This was found to be caused by the metabolism of prilocaine and lidocaine to the oxidative compounds O-toluidine and 2,6-xylidine respectively. The cause has not been previously reported for benzocaine or procaine. The laboratory portion of this research revealed the impact several adulterants and their mixtures can have on colorimetric spot tests. Testing with approximately 1 mg of sample material revealed that eight out of the twenty-three adulterants reacted with the Marquis reagent to cause a color change within 15 minutes. Of the ten 3-component mixtures tested, eight resulted in a color change. Of the six five-component mixtures, four resulted in a color change; of the six eight-component mixtures, three resulted in a color change; and of the six ten-component mixtures, five resulted in a color change. Of the color changes observed, none were consistent with the "expected" color change for a presumptively positive result of the Marquis test. Testing with the adulterant diphenhydramine revealed that this compound had a unique and intense reaction with the Marquis reagent. This compound initially reacted by turning the liquid a vibrant yellow-green upon contact with the sample. Prior to 2 minutes, solid red-brown aggregates formed in the liquid and proceeded to increase in size while the reagent solution darkened to a red-black color over the 15 minutes of observation. Mixtures containing diphenhydramine each reacted differently. Solid material did not form in the mixture tests and the color changes observed ranged from light orange to a dark red-orange. In addition, one 3-component mixture containing adulterants which did not cause a color change when tested individually (diltiazem, acetaminophen, and quinine) was observed to cause a light brown color to develop, which darkened over the 15 minutes of observation. The results for the modified Scott test showed that the complexity of this test has made it highly specific for cocaine. None of the individual components or mixtures tested reacted in a manner consistent with a presumptively positive identification for cocaine hydrochloride (HCl) or cocaine base for all three steps. Of the twenty-three adulterants tested, eight of the twenty-three gave a similar result to cocaine base in step 1, however, of these eight, only one (quinine) gave a similar result to cocaine base in step 2, and this adulterant did not react consistently to cocaine base in step 3. The research using the adulterant mixtures revealed that the compounds present in these samples tended to react individually with the modified Scott test reagents. In other words, the results for each mixture appeared as a combination of the individual results for each component. While the results observed for the adulterants and mixtures tested were not consistent with the expected presumptively positive results for the drugs these tests are used to detect, it was concluded that the presence of adulterants in a sample has the potential to affect the results of a colorimetric spot test in a variety of ways. Given that these tests are typically employed on samples of raw suspected drug material, it is important that analysts understand the impact adulterants can have on the interpretation of presumptive drug tests.

Das Ovarialkarzinom ist eine maligne Entartung der Eierstöcke und die achthäufigste Krebserkrankung in Deutschland. Aufgrund einer initialen langen symptomfreien Zeit und einer raschen Dynamik wird die Erkrankung meist erst im fortgeschrittenen Stadium, d.h. im Stadium III oder IV diagnostiziert, welches mit einer geringen 5-Jahres-Überlebenswahrscheinlichkeit von ca. 43 % einhergeht. Aktuell beruht die Standard-therapie auf einer radikalen Operation mit dem Ziel der makroskopischen Komplettresektion gefolgt von einer Platin/Paclitaxel-basierten Chemotherapie, welche im fortgeschrittenen Stadium mit dem Antikörper Bevacizumab kombiniert wird. Doch bis zu 85 % der Patientinnen mit fortgeschrittenem Ovarialkarzinom erleiden ein Rezidiv, und dabei stellt vor allem die Platin-Resistenz ein großes Problem dar. Im Rahmen dieser Arbeit wurde die Wirkung des zugelassenen H1-Antihistaminikums Diphenhydramin (DIPH) auf die platin-basierte Chemotherapie in Ovarialkarzinomzellen in vitro und in vivo untersucht. Während frühere Arbeiten eher eine schützende Wirkung von DIPH vor den Nebenwirkungen (z.B. Nephrotoxizität, Ototoxizität) der Platin-Therapie berichtet haben, wird in dieser Arbeit gezeigt, dass DIPH außerdem überraschenderweise in platin-resistenten Ovarialkarzinomzellen als „Platin-Sensitizer“ fungieren kann, da in der Kombinationstherapie Cisplatin mit DIPH eine Erhöhung der intrazellulären DNA-Platinierung, sowie der Apoptoseinduktion beobachtet wurde. Nachfolgende Experimente belegen, dass DIPH, neben seiner bekannten Funktion als H1-Antagonist, die Transportkapazitäten der Effluxpumpen MRP2, MRP3 und MRP5 inhibiert, welche bereits mit der Platin-Resistenz im Ovarialkarzinom in Verbindung gebracht wurden. Diese Erkenntnis unterstützt die Hypothese, dass DIPH Tumorzellen für die Cisplatin-Behandlung sensitiviert, indem der MRP-vermittelte Cisplatin-Efflux inhibiert wird. Darüber hinaus wurde in dieser Arbeit erfolgreich ein intraperitoneales Mausmodell für das platin-resistente Ovarialkarzinom mit Hilfe von Biolumineszenzimaging etabliert, um den Effekt von DIPH als möglichen „Platin-Sensitizer“ auch in vivo zu untersuchen. Es zeigte sich, dass mit Cisplatin und DIPH behandelte Versuchstiere tendenziell ein geringeres intraperitoneales Tumorwachstum aufwiesen als die mit Cisplatin behandelten Versuchstiere, was für eine mögliche Rolle von DIPH als Platin-Sensitizer spricht. Jedoch konnte eine statistische Signifikanz dieses Effektes auf Grund einiger technischer Limitationen des etablierten Mausmodells bislang noch nicht gezeigt werden. Ziel der vorliegenden Arbeit ist es, den Effekt von DIPH auf die platin-basierte Chemotherapie in einem umfassenden experimentellen in vitro Ansatz zu erforschen. In diesem Kontext wurde eine pharmakologische Strategie zur DIPH-vermittelten Sensitivierung des platin-resistenten Ovarialkarzinoms entwickelt, die anschließend in einem in vivo System präliminär getestet wurde. Die Ergebnisse liefern insgesamt eine vielversprechende Basis für weiterführende präklinische in vivo Versuche mit DIPH im Rahmen eines „Drug repositioning“ Ansatzes. / Ovarian cancer is a malignancy of the ovaries and the eighth most common cancer in Germany. Due to an initial long symptom-free period and rapid dynamics, the disease is usually diagnosed only at an advanced stage, i.e. stage III or IV, which is associated with a low 5-year survival probability of about 43 %. Currently, standard therapy is based on radical surgery with the goal of complete macroscopic resection followed by platinum/paclitaxel-based chemotherapy, which is combined with the antibody bevacizumab in advanced stages. However, up to 85 % of patients with advanced ovarian cancer experience recurrence, and platinum resistance in particular is a major problem. In this dissertation, the effect of the approved H1 antihistamine diphenhydramine (DIPH) on platinum-based chemotherapy was investigated in ovarian cancer cells in vitro and in vivo. While previous work has tended to report a protective effect of DIPH against the side effects (e.g., nephrotoxicity, ototoxicity) of platinum therapy, this work demonstrates that DIPH can also, surprisingly, act as a 'platinum sensitizer' in platinum-resistant ovarian cancer cells, as an increase in intracellular DNA platinization, as well as apoptosis induction, was observed in combination therapy with cisplatin and DIPH. Subsequent experiments indicate that DIPH, in addition to its known function as an H1 antagonist, inhibits the transport capacities of the efflux pumps MRP2, MRP3, and MRP5, which have previously been associated to platinum resistance in ovarian cancer. This finding supports the hypothesis that DIPH sensitizes tumor cells to cisplatin treatment by inhibiting MRP-mediated cisplatin efflux. In addition, this work successfully established an intraperitoneal mouse model for platinum-resistant ovarian cancer using bioluminescence imaging to investigate the effect of DIPH as a potential 'platinum sensitizer' in vivo as well. It was found that experimental animals treated with cisplatin and DIPH tended to have lower intraperitoneal tumor growth than those treated with cisplatin, suggesting a possible role of DIPH as a platinum sensitizer. However, statistical significance of this effect has not yet been demonstrated due to some technical limitations of the established mouse model. The aim of the present work is to explore the effect of DIPH on platinum-based chemotherapy in a comprehensive experimental in vitro approach. In this context, a pharmacological strategy for DIPH-mediated sensitization of platinum-resistant ovarian cancer was developed and subsequently preliminarily tested in an in vivo system. Overall, the results provide a promising basis for further preclinical in vivo trials with DIPH in the context of a 'drug repositioning' approach.

Purpose: To establish a tool, termed as antimuscarinic activity (AMA), to predict the incidence of antimuscarinic adverse events (AMAEs).Methods: A literature review, focused on drugs having off-target interaction with muscarinic receptors, was performed. Prototypical drugs olanzapine, diphenhydramine, paroxetine were selected for the analysis. Scopolamine and darifenacin were included as positive and negative controls, respectively. Physiochemical properties, pharmacokinetic data, and clinical incidence of AMAEs for the selected drugs were collected from reported literature. Extrapolation of literature data was carried-out to obtain exposure data. To determine the drugs muscarinic affinity (Ki values), experiments were performed using 3H-QNB and membrane suspensions of M1, M2, and M3. Cmax, values were combined with Ki values to generate the relevant AMA. Validation of the AMA biomarker was carried-out against the reported AMAEs incidence. Results: With the exclusion of scopolamine and olanzapine for CNS and peripheral AMAEs, respectively, AMA ranking was related to the drugs AMAEs.

No description available.