This paper investigates how to estimate the likelihood of a customer accepting a loan offer as a function of the offer parameters and how to choose the optimal set of parameters for the offer to the applicant in real time. There is no publicly available data set on whether customers accept the offer of a financial product, whose features are changing from offer to offer. Thus, we develop our own data set using a fantasy student current account. In this paper, we suggest three approaches to determine the probability that an applicant with characteristics will accept offer characteristics using the fantasy student current account data. Firstly, a logistic regression model is applied to obtain the acceptance probability. Secondly, linear programming is adapted to obtain the acceptance probability model in the case where there is a dominant offer characteristic, whose attractiveness increases (or decreases) monotonically as the characteristic's value increases. Finally, an accelerated life model is applied to obtain the probability of acceptance in the case where there is a dominant offer characteristic.

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions is being investigated.

Clinical Pharmacology & Therapeutics (2003) 73, P36–P36; doi:

Clinical Pharmacology & Therapeutics (2003) 73, P36–P36; doi:

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.

Thalidomide is a TNF-α inhibitor that is used experimentally in a number of HIV-associated disorders, including aphthous ulcers, diarrhoea and cachexia [1–4]. Its use in HIV patients with aphthous ulcers has been associated with a two- to threefold increase in plasma HIV-1 viral load, suggesting a stimulatory production of HIV, which has raised concerns about its use in immunocompromised states [2]. In the present study, we investigated the effects of thalidomide administered at 100 mg once a day over 8 weeks on the viral load and body weight of six male and one female HIV-infected patients. They ranged in age from 35 to 49 years old and were on highly active antiretroviral therapy. The patients had median CD4 cell counts of 405 cells/ml (range 142–693). They were counselled on the use of contraceptives and the fecundity status of the female patient was monitored. The plasma viral load was determined using a Roche Ultrasensitive Kit (Roche Diagnostics, Lewes, East Sussex, UK) with a detection limit of 50 HIV-1 copies/ml. The majority of the patients had a baseline plasma HIV-1 viral load of less than 50 copies/ml with one patient (P.W.) having more than 1000 copies/ml (Table 1). They were evaluated at baseline (−4 weeks), 1, 2, 4, 6 and 8 weeks of thalidomide and at week 4 of a drug-free follow-up period. Plasma thalidomide levels were determined [5] and correlated with the viral load at weeks 4 and 8 and at the follow-up visit. For statistical analysis, viral loads below the detection limit were taken as 50 copies/ml, and when necessary, data were log-transformed before applying a paired t-test.Table 1: Plasma HIV-1 viral load and plasma thalidomide concentrations in patients receiving 100 mg thalidomide orally for 8 weeks.Thalidomide was generally well tolerated, but two patients failed to complete the study after complaining of excessive fatigue (patient L.H.) at week 1 and a ‘spaced out’ feeling (patient S.A.) at week 6. Viral load was variable but a general trend was discernible. An approximately twofold increase (range 1.0–4.3; P < 0.05) in the plasma HIV-1 viral load was seen at week 2, which returned to baseline by week 4 on continued thalidomide treatment (Table 1). One subject (M.F.) showed an additional late increase in viral load at week 8 before declining at the follow-up visit. The median plasma concentrations of thalidomide were 313 ng/ml at week 4 and 162 ng/ml at week 8 in samples taken nominally at more than 10 h post-dose. Bodyweight increased by (mean with range) 1.9 kg (0.6–3.2, week 1; P < 0.05); 1.9 kg (1.0–3.1, week 2, P < 0.05); 1.3 kg (−1.8–3.4, week 4); 2.1 kg (−1.0–4.2, week 6) and 3.1 kg (1.6–5.2, week 8; P < 0.05) compared with baseline. Five out of the seven subjects continued to show a net weight gain, ranging from 0.7 to 3.3 kg whereas the remaining two subjects showed net weight losses of 0.1 and 1.6 kg at the follow-up visit. Subsequent expanded studies using 64 patients confirmed our finding of significant weight gains [6]. The beneficial effects of thalidomide in promoting weight gain in HIV-associated cachexia have been tempered by concerns about the accompanying increase in viral load [2–4]. In the present study, consistent weight gain was apparent after one week and a temporary increase in the plasma HIV-1 viral load after 2 weeks of thalidomide treatment, even with highly active antiretroviral therapy. The weight gain was maintained but the viral load declined to baseline levels on continued treatment with thalidomide. One subject (M.F.), however, had an additional late increase in plasma viral load at week 8. The thalidomide concentration was found to be 7 ng/ml, a level more consistent with plasma sampling more than 24 h post-dose, suggesting non-compliance before the week 8 visit [7]. An association between a high viral load and circulating TNF-α concentrations has been reported, although the nature of this relationship is not fully understood [8,9]. The paradoxical increase in the plasma viral load in the presence of a TNF-α inhibitor could be caused by escape mechanisms that evade the apoptotic and pro-inflammatory effects of the host immune response. An example is the expression of proteins that mimic TNF-α receptors or disrupt the coupling between receptor and signal transduction pathways, subsequently neutralizing the cytopathic effects of TNF-α [10,11]. This, coupled with a thalidomide-induced decrease in tissue levels of TNF-α, might provide the virus with an opportunity to replicate before the host can mount effective alternative immune responses. The potential of the increased transmissibility of the HIV virus early in therapy reinforces the need for strict adherence to the antiretroviral regimen. Our finding that a thalidomide-induced increase in the plasma viral load was transient is reassuring and suggests that any deleterious effect on the course of HIV infection is unlikely.

d-methylphenidate is an enantiomer of d,l-methylphenidate and was developed as an improved treatment for attention deficit hyperactivity disorder in children. The current study was performed to determine and compare the toxicity of 2–50 mg/kg per day d-MPH and 100 mg/kg per day d,l-MPH for 90 days in rats with the top d-MPH dose being equimolar to 100 mg/kg d,l-MPH. The top d-MPH and d,l-MPH doses were at least 67 times that of the human dose and produced systemic exposures that were over 10 times higher than those typically achieved in children. During the course of the study, one male each from the 50 mg/kg per day and d,l-MPH groups and one female from the 50 mg/kg group died. Incidences of material around nose/eyes, scabbing, foot swelling, alopecia and abrasions were evident at 50 mg/kg per day d-MPH and 100 mg/kg per day d,l-MPH doses. Body weight and its changes decreased in a dose-dependent manner for d-MPH males. There were significant changes in some clinical chemistry measurements at the terminal bleed in the high dose groups of both sexes although most of these changes were resolved by the recovery bleed. Differences in absolute and relative body and certain organ weights for high dose d-MPH and d,l-MPH groups were seen at terminal necropsy with the differences no longer present after the recovery period. No abnormal or gross histopathological changes were associated with any of these organ weight changes reported for the terminal and recovery periods. Based on body weight changes, the no observed adverse effect level for d-MPH in rats was 20 mg/kg. Overall, the toxicity profile observed in rats with 50 mg/kg per day d-MPH was comparable to that of an equimolar dose of d,l-MPH (100 mg/kg per day) when given repeatedly for 90 days using a twice a day dosing regimen.

A double-blind, placebo-controlled trial of efficacy and safety of thalidomide in AIDS-associated wasting was carried out. Ninety-nine of 103 male patients had at least one on-study measurement (intent-to-treat [ITT] cohort). Patients were randomized to thalidomide at 100 mg/day (T100) or 200 mg/day (T200), or placebo for 8 weeks. By ITT analysis, the mean change in body weight of the placebo, T100, and T200 treatment groups was 0.3 kg (0.4%), 2.0 kg (3.0%), and 0.9 kg (1.4%), respectively (p = 0.021 for T100 versus placebo; p = 0.53 for T200 versus placebo). Of the 64 patients who completed the 8 weeks of study treatment, significant weight gain was observed in both the T100 group (2.2 kg, [33%]; p = 0.008 versus placebo) and the T200 group (1.5 kg [2.5%]; p = 0.019 versus placebo). Approximately half the weight gain was fat-free mass (bioimpedance analysis). Patients in the T100 or T200 groups had no significant change in CD4+ cell counts, neutrophil counts, or TNF-alpha levels, compared with placebo. HIV viral load measured as log10 copies/ml decreased by a median of 0.07 in the placebo group, and increased by a median of 0.29 (T100 group) and 0.23 (T200 group) (p = 0.024 andp = 0.018 versus placebo, respectively). Thalidomide therapy was associated with mild to moderate rashes and fevers, but not peripheral neuropathy. Although the anabolic benefits of high-dose thalidomide are limited by drug intolerance, 8 weeks of low-dose thalidomide results in significant weight gain in patients with AIDS-associated wasting.

Thalomid is the FDA-approved commercial formulation of thalidomide currently used in the US to treat erythema nodosum leprosum, a complication of leprosy. The genotoxicity of Thalomid thalidomide was assessed in the Ames reverse mutation, AS52/XPRT mammalian cell forward gene mutation, and mouse bone marrow micronucleus assays. The Ames and AS52 assays were performed with and without S9. In the Ames, Salmonella typhimurium strains TA1535, 1537, 98, 100, and 102 and Escherichia coli strain WP2 uvrA were used. Assays were performed by using plate incorporation and liquid pre-incubation systems at thalidomide doses of 50-10,000 microg/plate. In the AS52 assay, Chinese hamster ovary cells were plated with fortified Ham's F12 medium and incubated overnight. The medium was then incubated with 1-1000 microg/ml thalidomide. After a series of aspirations, washings, reconstitutions, and incubations, mutant AS52 cells were fixed and stained. Colonies were then counted and the relative survival frequencies compared to negative controls. In the mouse micronucleus assay, Crl:CD-1 albino mice were dosed with 500, 2,500, and 5,000 mg/kg thalidomide and sacrificed over 72 h. Femurs were flushed with fetal bovine serum and the suspensions centrifuged. The supernatant was aspirated and the cell pellet resuspended and stained. Polychromatic erythrocytes were scored for micronucleated polychromatic and normochromatic erythrocytes. Thalidomide did not increase revertant frequencies in all bacterial strains. It also did not produce any significant increase in the average mutant frequencies of AS52 cells and mouse micronucleated polychromatic erythrocytes. We conclude that Celgene's Thalomid thalidomide is non-genotoxic.