Bakgrund: De preventivmedel som finns idag riktas främst till kvinnor. Bristen på antikonceptionsmetoder för män har lett till att kvinnan har ett större ansvar i familjeplaneringen och riskerar att drabbas av de biverkningar som ett preventivmedel kan ha. Om det fanns fler metoder att välja på skulle troligtvis även antalet oönskade graviditeter och dess konsekvenser samt antalet aborter minska. Verkningsmekanismen för hormonella preventivmedel riktade mot män som är under utveckling baseras på att hämma spermatogenesen genom att minska sekretion och produktion av de två gonadotropinerna FSH och LH. Ett stort fokus för utvecklingen har varit administrering av androgener och injektioner av testosteron har visats ge en hämning av spermatogenesen. När exogent testosteron tillförs till kroppen binder det till androgenreceptorer i hypotalamus som leder till att sekretionen av GnRH från hypotalamus minskar, vilket leder till en minskad frisättning av FSH och LH. Detta leder i sin tur till att produktionen av endogent testosteron i testiklarna minskar och att spermatogenesen hämmas. Världshälsoorganisationen har fastställt att en mans spermiekoncentration bör reduceras till £3 miljoner spermier/ml sädesvätska för att ett hormonellt preventivmedel ska vara effektivt. Syfte: Syftet med detta arbete var att undersöka effekten av hormonella preventivmedel för manligt bruk, samt vilken effekt de undersökta preparaten uppvisat. Metod: Detta arbete är en litteraturstudie baserat på sju randomiserade kontrollerade vetenskapliga studier där effekten av administrering av testosteron utvärderas, antingen i kombination med en progestin eller som monoterapi. Studierna hämtades från databasen PubMed. Resultat: Samtliga studier visade att spermatogenesen hämmas mer effektivt av en kombinationsbehandling av en progestin och testosteron än av testosteron som monoterapi, dock med biverkningar såsom viktuppgång och akne. Slutsats: Samtliga sju studier har visat ett gott resultat med få allvarliga biverkningar, vilket tyder på att det första hormonella preventivmedlet för män kommer vara en kombination av testosteron och en progestin. Administreringssättet av testosteron kommer antagligen vara intramuskulärt på grund av att oralt snabbt bryts ned och im har visats hämma spermatogenesen mer än vad en administrering av testosteron i gelform gjort. Det behövs dock att fler studier utförs på större populationer och under en längre tid innan ett manligt hormonellt preventivmedel kommer att komma ut på marknaden. / Even though there are many contraceptive methods available for females, almost half of all pregnancies worldwide are unintended. Compared with female contraceptive methods, male alternatives are few. The only contraceptive methods that are available for men are condoms and vasectomy. The mechanism of action of hormonal contraceptives that are under development for men is based on a suppression of spermatogenesis. Effective suppression of the spermatogenesis can be achieved by the co-administration of exogenous androgens and progestogens. Exogenous testosterone binds to androgen receptors in the hypothalamus which reduces the secretion of GnRH from the hypothalamus. That leads to a decreased secretion of the gonadotropin hormones, FSH and LH, from the pituitary and thereby consequently suppressing intra-testicular testosterone synthesis and spermatogenesis. The World Health Organization (WHO) has determined that a man's sperm concentration should be reduced to below three million spermatozoa/mL of ejaculate to provide effective contraception. If men had more contraceptive options, it would lead to shared contraceptive responsibility and equal responsibility for family planning. It would also hopefully lead to fewer unintended pregnancies and abortions. The aim of this study was to determine the effect of hormonal preventive agents on male use, as well as the effect of the investigated preparations. This study is a literature review based on seven randomized controlled trials evaluating the effect of testosterone administration, either in combination with a progestin or as a monotherapy. The studies were found in the database PubMed. All seven studies on which this worked were based on showed that spermatogenesis is more effectively inhibited by a combination therapy of a progestin and testosterone than of testosterone as monotherapy, however, with side effects such as weight gain and acne. All studies showed good results with few serious side effects, suggesting that the first hormonal male contraception for men will be a combination of testosterone and a progestin. Before a male hormonal contraceptive will be available, more studies need to be concluded.

7,8-dihydroxyflavone (7,8-DHF), which is a member of the flavonoid family, is a selective tyrosine kinase receptor B (TrkB) agonist that has neurotrophic effects in various neurological diseases such as ischemic stroke and Parkinson’s disease [3]. In this study, we assessed the angiogeneic effect of 7,8-DHF in endothelial cells derived from resistance vessel of the brain. Angiogenesis by 7,8-DHF is an important factor that helps prevent and treat various ischemic diseases. In this study, we found that rat RV cells used in the experiment possess the TrkB receptor. Our data also demonstrates that 7,8-DHF is able to stimulate cell proliferation in RV cells, suggesting that 7,8-DHF is capable of inducing angiogenesis. The 7,8-DHF activates the TrkB receptor which then leads to cell proliferation. In our study we also showed the effects of 7,8-DHF in the presence of the TrkB inhibitor cyclotraxin-B. Addition of cyclotraxin-B blocked the TrkB receptor and counteracted the effects of 7,8-DHF. Cell proliferation occurs in RV cells with the addition of 7,8-DHF, but this proliferation is inhibited by cyclotraxin-B.

Flavonoids are ubiquitous to all terrestrial plants and many are known to have anti-tumor activities. In this research project we studied the differential cytotoxic effects of two flavone isomers on human breast cancer cells (BT-474, SKBR-3, and MCF-7) and normal breast cells as a control (MCF-10A). The basis of the relationships between chemical structures, type and position of substituent groups and the effects these compounds exert specifically on cancer cells are not completely elucidated. These flavones are derived from plants native of Colombia, South America. These plants of the family Asteraceae, genera Gnaphalium and Achyrocline are reputed to have anti-cancer properties. The flavones are non-toxic to normal human cells. Our studies indicate that 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone, flavone B) is highly cytotoxic to poorly differentiated carcinomas of the breast such as SK-BR3, with minimal activity against more differentiated carcinomas of the same organs such BT-474. Immunoblot analysis suggests that the anti-tumor effects of flavone B in SKBR-3 may be mediated through the down regulation of the ERK pathway. ERK activation promotes cell proliferation, differentiation and survival. Additionally, flavone B down regulates PS6 in SKBR-3. PS6 controls protein translation by phosphorylating the S6 protein of the 40S ribosomal subunit. On the other hand, neither flavone A or B has a significant inhibitory effect on breast cancer cell line BT-474. The flavones were tested in the human fibrocystic mammary tissue MFC-10A, defined as a normal breast cell line, to demonstrate their lack of toxicity against normal cells.

Abstract available in the Journal of Oncology Pharmacy Practice.

Oral antineoplastics (OAs) have become an emerging and rapidly growing field in cancer treatment. As with any chemotherapeutic agent, clinicians must be aware of potential drug interactions. Drug information databases are a common resource utilized to check for interactions between OAs and patient’s home medications. A major concern with OAs is that they are usually taken at home as well as picked up at a pharmacy by the patient themselves. The objective of this study was to determine the reliability of these databases for identifying potential interactions with OAs in a real-world setting. Hospital records were used to identify patients with common malignancies (leukemia, sarcoma, colon, lung, thyroid, prostate, kidney and liver cancers) treated with OAs from 2013 to 2014. To be included patients must have started an OA during the study period and have adequate records to evaluate OA use as well as home medications. The patient’s regimen is then entered into Drugs.com and Lexicomp™ interaction databases. In addition to documenting the number of interactions flagged by both databases, the severity of the interaction and disagreements between databases were analyzed. A major interaction was defined as either a “D” or “X” by Lexicomp™ and “major” by Drugs.com. As of this preliminary analysis, 407 of 876 subjects have been screened. Of the 407 screened, 9 patients (one patient with 3 different OAs) have been enrolled. Lexicomp™ flagged 34 interactions, of which 10 were major interactions. Drugs.com flagged 34 interactions, of which 6 were major interactions. Between the 2 databases there was only 60% agreement in flagging major interactions. These discrepancies are of concern in that clinicians hope resources they utilize are congruent with one another and allow them to practice in the safest manner in terms to avoid clinically significant drug interactions OA.

No description available.

The pharmacokinetics of ethanol and (-)-trans-isomer of 9-tetrahydrocannabinol (THC), and the pharmacokinetic interaction between them were characterized using statistical models in this thesis. In chapter II, a semi-mechanistic absorption rate dependent hepatic extraction model was developed to characterize ethanol pharmacokinetics. The statistical analysis conducted based on this model indicated no association between ethanol disposition and subject age or sex, and a 23% higher typical Vmax value, a 12.5% lower typical Km value for heavy drinkers compared with moderate drinkers. In chapter III, a parent-metabolite pharmacokinetic model was developed to simultaneously describe the concentration time profile of THC and its active metabolite 11-OH-THC. A parent-metabolite model with 3-compartment pharmacokinetic model for THC and a 2-compartment model for 11-OH-THC was found to best describe the pharmacokinetics of THC and 11-OH-THC simultaneously. In chapter IV, the pharmacokinetic interactions of ethanol on THC, 11-OH-THC and 11-nor-COOH-THC were evaluated using linear mixed effects models. The results suggested that co-administration of ethanol caused an increase in THC and 11-OH-THC systemic exposure, failed to influence the terminal elimination processes of THC and 11-OH-THC, and did not affect the pharmacokinetics of 11-nor-9-COOH-THC.

Fluoroquinolones are broad spectrum antibiotics that have been in use for nearly 50 years. These agents are used to treat a variety of bacterial infections from simple urinary tract infections to tuberculosis. The protein targets of fluoroquinolones are bacterial type II topoisomerases. Fluoroquinolones inhibit the function of these topoisomerases by intercalating in the nick site of the DNA and forming an interaction with helix-4 of the enzyme through a magnesium-water bridge. The binding of a fluoroquinolone stabilizes the DNA-topoisomerase-fluoroquinolone ternary complex. Helix-4 is where some of the most important fluoroquinolone resistance mutations occur. While the fluoroquinolone class of antibiotics has been successful at treating a variety of infections over the past few decades, a number of problems exist. These problems include the inability of many fluoroquinolones to kill non-growing cells, the emergence of fluoroquinolone resistant mutants, and adverse side effects of this antibiotic class. Thus, various aspects of fluoroquinolone structure and activity are explored in this study. The first topic explored is the question of what structural features are necessary for a fluoroquinolone to be able to kill bacteria in the presence and absence of the protein synthesis inhibitor, chloramphenicol (to mimic a dormant, non-growing state of the bacteria). Previous studies have shown that steric bulk at the C-8 position (especially a methoxy group) is necessary to support the ability of a fluoroquinolone to kill non-growing cells. In this study, the N-1 position of a series of C-8 methoxy fluoroquinolones was explored to gain an understanding of what substituents at the N-1 position of C-8 methoxy fluoroquinolones support the ability to rapidly kill bacteria in the presence of a protein synthesis inhibitor. In a second study the N-1 position is further explored, but with different goals. A recent crystal structure of a fluoroquinolone bound in the ternary complex with topoisomerase IV and DNA has revealed that the N-1 position of the fluoroquinolone is near in space to the catalytic tyrosine residue. It was reasoned that new interactions can be made with active site tyrosine residue through the N-1 position of the fluoroquinolone core. A number of N-1 fluoroquinolone derivatives were designed, synthesized, and evaluated for their ability to inhibit the DNA supercoiling activity of DNA gyrase, as well as the poisoning ability of the fluoroquinolones. The advantages of targeting the catalytic tyrosine residue are that this amino acid cannot be mutated without loss of enzyme function, and that by forming a new binding contact to the enzyme, activity can be maintained against helix-4 mutants. Finally, in a step toward the goal of mitigating the tendon related side effects of fluoroquinolones (thought to be due to Ca2+ coordination), the metal binding domain of the fluoroquinolone was altered. These fluoroquinolones were tested for their ability to inhibit and poison DNA gyrase. From the studies described, we have learned that the N-1 position is very sensitive to modification, that novel binding contacts to bacterial topoisomerases can be made through the N-1 position, and that modifying the metal binding domain of fluoroquinolones can lead to retention of activity against DNA gyrase. These accomplishments all push the fluoroquinolone field ahead by introducing a novel binding interaction to optimize (with the goal of creating a fluoroquinolone that is active against current fluoroquinolone resistant mutants) and by showing that fluoroquinolone activity can be retained even when the metal binding domain is altered, thus moving us closer to the goal of reducing tendon-related side effects.

Sulfonamide- and sulfone-induced hypersensitivity reactions are thought to be mediated through bioactivation of parent drug molecule(s) to their respective reactive metabolite(s). In order to explain the cutaneous drug reactions caused by sulfonamides and sulfone, a mechanism can be proposed by which the bioactivation of these drugs in keratinocytes of the skin forms reactive hydroxylamine metabolites that can covalently bind to cellular proteins, which in turn act as antigens leading to the cascade of immune reactions resulting in a cutaneous drug reaction. In order to probe the proposed mechanism, we determined the enzymes responsible for the bioactivation of these parent drugs to their hydroxylamine metabolites in cultured human keratinocytes. It was found that flavin containing monooxygenases and peroxidases play an important role in the bioactivation of these drugs in keratinocytes. We also confirmed the presence of these enzymes in keratinocytes. Interestingly, though cytochrome P450s are important in the oxidation of parent arylamine xenobiotics to their hydroxylamine metabolites in the liver, they do not appear to play a significant role in the bioactivation of these drugs in keratinocytes. The hydroxylamine metabolites of sulfamethoxazole and dapsone can undergo autooxidation, generating reactive free radicals. Our studies showed that both of these metabolites elevate oxidative stress in keratinocytes by forming reactive oxygen species. Though the cytotoxicity induced by these metabolites is not correlated with the extent of oxidative stress, the generation of reactive oxygen species may be important finding as these species can act as danger signals that activate antigen presenting cells in the skin. As a possible explanation for the idiosyncratic nature of these reactions, folate deficiency was studied as a potential risk factor. However, the results of these studies suggested that deficiency of folic acid in keratinocytes does not predispose such cells to the toxicity associated with the parent drugs or their metabolites. Unexplored is the potential role of such deficiency on the immune response itself.

Cationic antimicrobial peptides (CAPs) are an important component of the innate immune system and are instrumental in the elimination of bacteria, viruses, protozoa, yeast, fungi and cancerous cells from the body. CAPs are comprised of less than 100 amino acids and have a net positive charge due to a multitude of basic residues in their primary sequences. CAPs exert their antimicrobial activity primarily through the formation of pores in microbial membranes, but also play important immunostimulatory roles in the body. Glycosaminoglycans (GAGs) are negatively charged, polydisperse linear polysaccharides found at cellular surfaces. Although many protein-binding interactions of the GAG family, including heparin and heparan sulfate, have been well-characterized, it is not known to what extent endogenous GAGs affect the innate immune system. In the studies here the modulatory activities of GAGs and other polyanionic polysaccharides (PPSs) on CAPs were probed. Initial studies focused on interactions between a short peptide derived from bovine lactoferricin and GAGs. GAGs and other PPSs were then tested for their ability to modulate the antimicrobial activities of a number of CAPs against Gram-positive and -negative organisms. GAGs were also tested for the ability to modulate CAPs binding to bacterial lipopolysaccharide. CAP affinities for the GAGs were determined from lipopolysaccharide competition binding assays. Finally GAGs were evaluated for the ability to protect CAPs from proteolytic degradation. The modulatory activities of GAGs and other PPSs are largely dependent upon all components of the test system and, to a lesser extent, the charge of the molecule.