Depot medroxyprogesterone acetate (DMPA) is a long acting progesterone only contraceptive agent. Side effects such as irregular bleeding patterns and weight gain are attributed to discontinuation. The purpose of this study was to describe depot medroxyprogesterone acetate discontinuation after weight gain in 17 to 19 year-old adolescent girls.

Two subjects exhibiting drug-induced hand tremor received EMG feedback from electrode sites above the forearm extensor muscles . EMG feedback resulted in reductions in muscle potentials for both subjects. However, self-report measures of tremor severity showed only general improvement in Subject l and little or no improvement in Subject 2. Behavioral measures of hand steadiness taken immediately after each treatment session showed slight changes across treatment conditions for both subjects. As indicated by a rapid increase in EMG measures during reversal, treatment effects appear transitory.

No description available.

Chemotherapy in childhood cancer patients is associated with reduced bone density that can result in osteoporotic fracture in survivors. A significant proportion of paediatric patients experience a reduction in plasma 25 - hydroxyvitamin D3 [ 25 ( OH ) D3 ] and 1,25 - dihydroxyvitamin D3 [ 1,25 ( OH ) 2D3 ] levels during treatment, the basis of which is unknown. A balance between the bioactivation and degradation of 1,25 ( OH ) 2D3 is responsible for maintaining homoeostatic levels of 1,25 ( OH ) 2D3 at the correct set - point. Whereas the cytochrome P450 enzyme, CYP27B1 ( 25 - hydroxyvitamin D3 1 α - hydroxylase ), catalyses the hydroxylation of the precursor 25 ( OH ) D3 to generate 1,25 ( OH ) 2D3, catabolic inactivation and cleavage of 1,25 ( OH ) 2D3 is achieved by the mitochondrial cytochrome P450 enzyme, 25 - hydroxyvitamin D3 24 - hydroxylase ( CYP24 ), which is highly expressed in bone and kidney cells. Since many of the signalling pathways which regulate the expression of CYP24 are also activated by chemotherapeutic drugs, we hypothesised that the drugs could cause the degradation of plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3 by increasing CYP24 expression, the principal means of facilitating the bio - inactivation and degradation of plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3. Using the kidney cell - lines, COS - 1 and HEK293T cells, we now report that chemotherapeutic drugs, represented by daunorubicin hydrochloride ( an anthracycline antibiotics ), etoposide and vincristine sulphate ( vinca alkaloids and related compounds ) and cisplatin ( an alkylating agent ), were able to enhance CYP24 promoter activity in kidney cell lines transfected with a CYP24 promoter - luciferase construct, either by themselves or in the presencedaunorubicin hydrochloride and etoposide, two of the strongest inducers of CYP24 promoter activation under our experimental conditions, demonstrate that these drugs acted in a concentration - dependent manner. In addition to stimulating promoter activity on their own, the drugs also amplified the induction of the CYP24 promoter by 1,25 ( OH ) 2D3. Synergistic increases were generally observed when the cells were treated simultaneously with 1,25 ( OH ) 2D3 and a drug. The two kidney cell lines generally responded in a similar manner when challenged with the drugs, either in the presence or absence of 1,25 ( OH ) 2D3. Interestingly, the hydroxylated derivative of daunorubicin hydrochloride, doxorubicin hydrochloride which is also a commonly used chemotherapeutic drug, had no effect of promoter activity. Further studies with daunorubicin hydrochloride demonstrated that the effects of the drug per se were not mediated by oxidative stress and the vitamin D receptor was not required for daunorubicin hydrochloride per se to stimulate CYP24 promoter activity. However, daunorubicin hydrochloride caused a modest increase in the expression of the vitamin D receptor and this could contribute to its synergistic activity with 1,25 ( OH ) 2D3. In the presence of etoposide, there was also a tendency for the kidney cells to express higher levels of the vitamin D receptor. A key role for the extracellular signal - regulated protein kinase ( ERK ) 1, ERK2 and ERK5 mitogen - activated protein ( MAP ) kinases was demonstrated for the inductive action of daunorubicin hydrochloride and etoposide, with CYP24 promoter - specific transcription factors located in the first - 298bp being likely targets of the ERK activity. Studies with a dominant negative mutant of MKK4, one of the two immediate upstream activators of the c - jun N - terminal kinase isoforms, demonstrated that this MAP kinase also played a crucial role in inductive actions of the of 1,25 ( OH ) 2D3. Dose - response studies with drugs. Consistent with their use in anti - cancer therapy, all of the above drugs killed the human promyelocytic HL60 leukaemic cells at very low concentrations but had no effect on the viability of kidney or liver cells, either at concentrations used in our experiments or at higher levels. Our data provide novel biochemical evidence that some of the commonly used chemotherapeutic drugs could cause an increase in the transcriptional activation of the promoter, most likely via the MAP kinases activating the transcription factors which bind to the CYP24 promoter. Such an effect could contribute to the reduction in plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3 in some of the patients undergoing chemotherapy. / Thesis (Ph.D.)--School of Paediatrics and Reproductive Health, 2005.

Pharmacovigilance is “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem”. To date, no comprehensive study has been performed to evaluate the pharmacovigilance system in the public health sector in South Africa. The primary aim of this study was to evaluate the current status of pharmacovigilance systems within the public healthcare sector in South Africa, and the level of functioning of these systems, in order to provide relevant recommendations, where necessary, for improvement, using the Indicator-based Pharmacogivilance Assessment Tool (IPAT). National and provincial entities were deemed compulsory (n=14), while facilities were selected via random, stratified sampling to obtain a representation at each facility level (n=101). The IPAT was amended for relevance at each level of data collection. Indicators are classified as core and supplementary and compliance with core indicators shows the level of functioning National entities obtained an IPAT score of 36 out of a maximum of 72, achieving 50% compliance. Province D and Province G obtained overall IPAT scores of 29 and 12 respectively out of a maximum of 40, achieving an overall 72.5% and 30% compliance respectively Results at provincial and facility levels were not fully representative due to a limited response rate of 22.2% and 65.3% respectively. Regional/tertiary facilities and district facilities displayed increased awareness and implementation of pharmacovigilance activity than the lower levels of Community Health Centres (CHCs) and Primary Health Centres (PHCs). South Africa”s public healthcare system possesses the infrastructure for a well functioning pharmacovigilance system. However there are gaps in level of functioning at a national, provincial and facility level. Addressing these gaps would show a marked improvement in the system and go a long way towards the contribution of medicine safety information not only locally, but to aid other developing nations.

Post-marketing surveillance refers to any non-experimental or observational study, method, or monitoring strategy that is applied to obtain information on drug experience (primarily adverse) after a drug has been approved for clinical use. One of the major problems in post-marketing surveillance studies is the lack or under-reporting of drug experiences by health care professionals. This study was developed to describe the impact of three different prescription event monitoring programmes on the reporting of adverse drug reactions (ADR's) in the hospital situation. The intensive ADR monitoring programme and two voluntary ADR monitoring programmes which followed were conducted in the medical wards of an urban teaching and referral hospital. All patients admitted to the designated wards were monitored by a dedicated pharmacist in the intensive programme, ward pharmacists in the first voluntary programme and by medical and nursing staff in the second voluntary programme. The pharmacist monitored a cohort of patients prospectively in two medical wards for a period of three months. The patient's record was linked with any suspected ADR. All details, i.e. patient drug orders, characteristics and ADR description, were recorded and then reported. From 228 patients monitored, 25 cases have been reported. The impact of the intensive ADR monitoring programme was a reporting rate of 11 percent. Reports were received on ADR's of a particularly mild, common and pharmacologically predictable (type A) nature. The first voluntary ADR monitoring programme comprised the reporting of suspected AD R's and the recording of drug orders for the patients and the patient characteristics. The ward pharmacists monitored for suspected AD R's in all patients during their regular ward rounds. Six cases were reported in a population of 1506 patients monitored during the three months. The reports were mainly on moderate to severe suspected AD R's of pharmacologically unpredictable (type B) nature. The rate of reports received by the surveillance unit in this study was 4 reports per ward pharmacist per annum. The second voluntary ADR monitoring programme comprised the prospective monitoring of 1555 patients by medical and nursing staff during their stay at the designated medical wards during the three month period. Patients were monitored for any ADR and when an ADR was suspected, the patient characteristics and drug orders were recorded and reported to the surveillance unit. Ten cases were reported represented by six reports from doctors and four by sisters. The reporting rate was 2 reports per doctor in four years and 3 reports for each member of the nursing team in 5 years. Reports were mainly received on moderate to severe suspected ADR's of a pharmacologically unpredictable (type B) nature.

There is a significant current need to elucidate the molecular mechanisms of the side-effects caused by widely-used pharmaceuticals. Examples include the acute nephrotoxicity and irreversible ototoxicity promoted by the cationic drugs gentamicin and cisplatin. Gentamicin is an aminoglycoside antibiotic used for the prevention and treatment of life-threatening gram-negative bacterial infections, such as tuberculosis and meningitis. Cisplatin is used to treat a broad spectrum of cancers including head and neck, ovarian, cervical, stomach, bladder, sarcoma, lymphoma, testicular cancer and others. The objective of this study is to design and synthesize rhodamine derivatives that can be used for the construction of geometrically well-defined cationic drug conjugates. The long-term goal is to use the conjugates as tools to aid in elucidating the properties and identities of ion channels involved in the uptake of cationic pharmaceuticals into kidney and cochlear hair cells. This will shed light on the origin and potential prevention of unwanted side effects such as nephrotoxicity and ototoxicity associated with specific cationic drugs. A series of extended rhodamine analogs with reactive groups for biomolecule conjugation has been synthesized. These fluorophores show similar spectral properties to their prototype, Texas Red succinimidyl ester (TR-SE). However, they contain rigid linkers between the fluorophore and amine-reactive moiety. The resultant gentamicin conjugates of these materials are rigidified enabling one to assess channel pore dimensions without the confounding issue of conjugate folding. Preliminary cell studies are promising, as one observes reduced gentamicin uptake in both kidney and sensory hair cell upon systematically increasing the dimension of the fluorophore. This work has enabled us to tentatively assign the maximum dilated MET channel pore size as between 1.44 nm to 1.56 nm. However, this preliminary finding, though encouraging, needs further validation via ongoing studies with larger diameter fluorophore conjugates, A cisplatin-Texas Red conjugate has also been synthesized to enable studies of cellular uptake mechanisms. This conjugate preserves not only the spectral properties of Texas Red after conjugation, but also the cytotoxicity of cisplatin. This has been validated in zebrafish. The series of rhodamine probes that have been conjugated to gentamicin should be similarly useful for cisplatin studies. These studies are planned. Additional future work includes the synthesis of semi-flexible (glycol) and flexible (alkyl) linkers to evaluate structure-activity relationships.

University of Macau / Institute of Chinese Medical Sciences

Despite a rise in breast cancer incidence, mortality rates have fallen. This improvement in mortality is due to the success of anti-cancer treatments such as chemotherapy and radiotherapy. Such treatments, however, are known to be associated with a range of symptoms. A number of studies exploring patients’ chemotherapy-related symptom experiences have shown that patients consistently rate nausea and fatigue highly, not only in relation to severity, but also in relation to the associated distress they experience. The subjective and non-observable nature of both nausea and fatigue complicates their assessment. While a range of assessment tools exists to evaluate patients’ experiences of these two symptoms, there is currently no gold standard assessment tool for assessing either symptom. Moreover, while a range of pharmacological and non-pharmacological interventions have been developed for both symptoms, further evaluation is often needed to provide the level of evidence required to recommend their implementation in real life clinical environments. The SNA↔P (structured nursing assessment into practice) study arose in response to this clinical situation. The SNA↔P study was a longitudinal study that evaluated the impact of a complex evidence-based intervention, incorporating structured multidimensional symptom assessment and multiple symptom management techniques, on patients’ experiences of nausea and fatigue during a course of chemotherapy for breast cancer. Using complementary quantitative and qualitative research methods not only allowed in-depth understanding of patients’ experiences and patterns of nausea and fatigue during a course of chemotherapy, but also facilitated a rounded evaluation of the intervention, incorporating both statistical elements and those of personal significance. The use of these methods showed that the implementation of the SNA↔P intervention in routine clinical practice has significant potential for improving patients’ symptom experiences during a course of chemotherapy. In so doing, it also highlighted a number of areas in which clinical practice can be influenced, and research conducted, to further improve patients’ symptom experiences.

Indiana University-Purdue University (IUPUI) / Most pancreatic cancer patients receiving gemcitabine chemotherapy eventually develop resistance to gemcitabine. To improve survival and prognosis of pancreatic cancer patients, better understanding the mechanisms of gemcitabine resistance and discovery of new therapeutic targets are required. In this study, I investigated the molecular mechanisms of acquired gemcitabine resistance using a stepwise gemcitabine-selected pancreatic cancer cell line in comparison to the parental cell line. I found that 14-3-3σ is up-regulated in the drug resistant cell line due to demethylation in its first exon, and the up-regulation of 14-3-3σ gene expression, in turn, contributes to gemcitabine resistance. Intriguingly, I found that demethylation of the 14-3-3σ gene in gemcitabine resistant cells is reversibly regulated by DNMT1 and UHRF1. Furthermore, I found that 14-3-3σ over-expression causes gemcitabine resistance by inhibiting gemcitabine-induced apoptosis and caspase-8 activation possibly via binding to YAP1. The finding of demethylation of the 14-3-3σ gene in gemcitabine resistant cells led to a hypothesis that other genes may also be changed epigenetically following gemcitabine selection. By RRBS (Reduced Representation Bisulfite Sequencing) analysis, 845 genes were found to have altered methylation. One of these genes, PDGFD, was further investigated and found to have reversible demethylation at its promoter region in the drug resistant cells and contribute to gemcitabine resistance possibly via autocrine activation of the STAT3 signaling pathway. Together, these findings not only provide evidence that 14-3-3σ and PDGFD over-expression contribute to acquired gemcitabine resistance and that reversible epigenetic changes may play an important role in acquired gemcitabine resistance, but also demonstrate that the molecular mechanisms of acquired gemcitabine resistance in pancreatic cancer cells are complex and multifaceted.