Biomedical subjects

David I Stirling

Publications and source records attributed to David I Stirling.

25 records · Page 2Linked to original sources

PubMed2003

Neurobehavioral effects of racemic threo-methylphenidate and its D and L enantiomers in rats.

D,L-methylphenidate (Ritalin) is used to treat attention deficit hyperactivity disorder (ADHD) in children. The therapeutic effect is predominantly due to the d enantiomer. Dexmethylphenidate (D-MPH; Focalin) was therefore developed for its better therapeutic index. The present study determined and compared the acute behavioral toxicity of D,L-MPH, D-MPH and L-MPH in rats after oral dosing. Comprehensive functional observational battery (FOB) evaluations and rota-rod tests were performed 30, 60 and 120 min after dosing. Ten rats/sex/dose were administered a single dose of vehicle, 2, 20, 100 mg/kg D,L-MPH and 1, 10, 50 mg/kg D-MPH or 1, 100, 500 mg/kg L-MPH. There was no mortality. Certain FOB evaluations were statistically significant from vehicle control at any of the time points with most occurring at 60 and 120 min in the high D,L-MPH dose. These included increases in rearing, difficulty in removal from box, arousal, click, tail-pinch and decreases in hind-limb splay distance, hind-limb grip strength and handling reactivity. Behavioral responses were also present at the mid-dose D,L-MPH and high dose D- and L-MPH. Responses in female were significantly different from males in D,L- and L-MPH groups suggesting a sex difference in sensitivity. In the rota-rod test, mean latency to remain on the rod was significantly less for males compared to control given high dose D-MPH and D,L-MPH. In females, latency times were significantly less for high doses of all three compounds. In summary, fewer significant FOBs were seen with D- and L-MPH compared to equimolar doses of D,L-MPH. L-MPH was the least potent in producing FOBs. These results were supported by rota-rod studies.

Animals↗

PubMed2003

Potential new therapeutics for Waldenstrom's macroglobulinemia.

Thalidomide the first commercially available immune modulatory drug (IMiD), has activity in the treatment of Waldenstrom's macroglobulinemia (WM), as well as multiple myeloma, myelodysplastic syndrome, myelofibrosis with myeloid metaplasia, chronic lymphocytic leukemia (CLL), and B-cell lymphomas. Although its molecular mechanisms of action have not yet been elucidated, thalidomide and the IMiDs affect a variety of cytokines and inflammatory mediators including tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, interferon gamma (IFNgamma), IL-6, IL-10, IL-12, and COX-2 and angiogenesis factors such as vascular endothelial growth factor (VEGF) and its receptor. The IMiDs also affect adhesion molecules such as ICAM-1, ICAM-2, and L-CAM, in addition to preferentially stimulating CD8 cells and expanding natural killer (NK) cell populations. Since most IMiDs share these properties, it would be expected that the second-generation IMiDs (REVIMID, ACTIMID) would have activity similar to thalidomide in WM with an improved safety profile. TNFalpha and angiogenesis most likely play a role in promoting the growth and development of WM. The selective cytokine inhibitory drugs (SelCIDs) are potent phosphodiesterase 4 (PDE-4) inhibitors that inhibit TNFalpha production and are highly antiangiogenic. In addition, inhibition of PDE-4 induces apoptosis in human CLL lymphocytes. It is therefore expected that the SelCIDs might have activity in Waldenstrom's tumors. Jun N-terminal kinase (JNK) is a component of signaling cascades that modulate apoptosis, the induction of an inflammatory response via the AP-1 pathway, and modulation of cellular proliferation. In a variety of tumors, including multiple myeloma, JNK is induced as part of a protective mechanism. It is hypothesized that inhibition of JNK activity might allow other chemotherapeutic agents to be more effective in a similar manner to corticosteroids. Work is in progress to evaluate this. Inhibitors of the E3 subunit of ubiquitin ligase may also selectively modulate the expression of receptors, growth factors, and transcription factors essential to the growth, survival, and spread of tumors. We hypothesize that the IMiDs, SelCIDs, JNK inhibitors, and ligase inhibitors will be the basis for a new nonchemotherapeutic approach to the treatment of WM and other related diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2002

Protective antitumor immunity induced by a costimulatory thalidomide analog in conjunction with whole tumor cell vaccination is mediated by increased Th1-type immunity.

Thalidomide and its novel T cell costimulatory analogs (immunomodulatory drugs) are currently being assessed in the treatment of patients with advanced cancer. However, neither tumor-specific T cell costimulation nor effective antitumor activity has been demonstrated in vivo. In this study, we assessed the ability of an immunomodulatory drug (CC-4047/ACTIMID) to prime a tumor-specific immune response following tumor cell vaccination. We found that the presence of CC-4047 during the priming phase strongly enhanced antitumor immunity in the vaccinated group, and this correlated with protection from subsequent live tumor challenge. Protection was associated with tumor-specific production of IFN-gamma and was still observed following a second challenge with live tumor cells 60 days later. Furthermore, CD8(+) and CD4(+) splenocyte fractions from treated groups secreted increased IFN-gamma and IL-2 in response to tumor cells in vitro. Coculture of naive splenocytes with anti-CD3 mAb in the presence of CC-4047 directly costimulated T cells and increased Th1-type cytokines. Our results are the first to demonstrate that a costimulatory thalidomide analog can prime protective, long-lasting, tumor-specific, Th1-type responses in vivo and further support their ongoing clinical development as novel anti-cancer agents.

Adjuvants, Immunologic↗

PubMed2002

Sensitive and rapid method for the determination of thalidomide in human plasma and semen using solid-phase extraction and liquid chromatography-tandem mass spectrometry.

Liquid chromatography-tandem mass spectrometric assays were developed for the sensitive, rapid and high throughput bioanalyses of thalidomide in human plasma and semen. The matrices were first stabilized with 0.025 M Sorensen's citrate buffer at pH 1.5 to prevent spontaneous hydrolysis. Buffered thalidomide was stable when stored at room temperature for 24 h and for up to three freeze-thaw cycles. Samples were extracted using SPE cartridges. Extracts were then injected into the LC-MS-MS equipped with a reversed-phase column and an APCI interface in the negative ion mode. Calibration curves for both matrices were linear with r>0.99 from 2 to 250 ng/ml and ng/g. Inter-assay precision (RSD) of plasma and semen calibration standards were 2.6-11.6 and 1.9-12.4%, respectively. Recoveries from plasma and semen were greater than 69 and 78%, respectively. Batch sizes of 100 samples per matrix were analyzed with a total run time of 5 h. The methods successfully determined concentrations of thalidomide from a clinical study to levels as low as 7 ng/ml plasma and 8 ng/g semen, respectively.

Adult↗

PubMed2002

Thalidomide in the treatment of leprosy.

Leprosy is a chronic infection of the skin and nerves caused by Mycobacterium leprae. Erythema nodosum leprosum (ENL) is a reactive state in lepromatous leprosy. Thalidomide has been used to treat ENL since the 1960s. One of its mechanisms of action is anti-inflammatory through selective inhibition of the pro-inflammatory cytokine TNF-alpha produced by monocytes.

Drug Therapy, Combination↗

PubMedDate not supplied

The perinatal and postnatal toxicity of D-methylphenidate and D,L-methylphenidate in rats.

D-methylphenidate is an enantiomer of D,L-methylphenidate and was developed as an improved treatment for attention deficit hyperactivity disorder (ADHD) in children. The current study was performed to assess the potential perinatal and postnatal toxicity of both compounds in rats. About 125 presumed pregnant rats were assigned to five dose groups of 25 each. They were dosed with 2, 6, and 20 mg/kg/day D-methylphenidate and 40 mg/kg/day D,L-methylphenidate from gestation Day 7 to lactation Day 20. F1 generation rats were rebred to produce F2 fetuses. Various perinatal and postnatal measurements were made for the F0 and F1 rats. Among the significant findings were a reduction in maternal body weight gain for 20 mg/kg/day D-methylphenidate and D,L-methylphenidate and increased incidences of dilated pupil and vocalization for D,L-methylphenidate during the gestation period. Neither compound produced any other significant adverse findings in F0 and F1 generation rats at doses that were at least 25 times the maximum daily human therapeutic dose.

Animals↗

PubMedDate not supplied

A 90-day oral gavage toxicity study of d-methylphenidate and d,l-methylphenidate in beagle dogs.

d-Methylphenidate (d-MPH) was approved as a treatment for attention deficit hyperactivity disorder (ADHD) in children. The repeated-dose toxicity of the d enantiomer of d,l-methylphenidate (d,l-MPH) was assessed in male and female Beagle dogs. Dogs were orally dosed twice a day in equally divided doses 6 hours apart for total daily doses of 1, 3, and 10 mg/kg/day d-MPH or 20 mg/kg/day d,l-MPH for 90 days, followed by a 30-day recovery period. The top d-MPH dose of 10 mg/kg was equimolar to 20 mg/kg d,l-MPH in d-MPH content. The 10-mg/kg d-MPH and d,l-MPH doses were at least 13 times the maximum therapeutic dose giving rise to systemic exposures that were equivalent to or at least 2 times greater than those at the maximum therapeutic doses in children. The 10-mg/kg d-MPH and 20-mg/kg d,l-MPH doses had systemic exposures that were equivalent to or two to five times greater than the maximum therapeutic plasma levels in children respectively. There was no treatment-related mortality in all doses tested. Reversible salivation, hyperactivity, and diarrhea were seen in the high-dose d-MPH and d,l-MPH groups. Significant body weight loss and reduction in food consumption were observed in males for both high-dose groups with weights comparable to control values by the end of the recovery period. There were no abnormal clinical pathology or macroscopic or microscopic findings. Based on body weight changes, the no-observed-adverse-effect level (NOAEL) of d-MPH in beagle dogs was 3 mg/kg/day.

Administration, Oral↗