Individual variation in drug response is influenced by both genes and environment. We evaluated the potential of a metabolic phenotype to predict individual variation in the pharmacokinetics (PK) of tacrolimus. Liquid chromatography-mass spectroscopy (LC-MS)-based metabolic profiling was performed on 29 healthy volunteers by measuring the levels of 1,256 metabolite ions in their predose urine samples. After oral administration of tacrolimus, we monitored its plasma concentrations in these volunteers for up to 72 h and calculated the pharmacokinetic parameters. Partial least-squares (PLS) modeling was conducted with data relating to predose urine metabolites to predict the pharmacokinetic parameters of tacrolimus and to select the metabolites that substantially contributed to such prediction. The selection of these metabolites allowed us to understand their functional role and generate a clinically applicable index to predict individualized PK of tacrolimus. In conclusion, this integrative pharmacometabolomic approach, combining the metabolic profiling of predose urine with PLS modeling, can serve as a useful tool in "individualized drug therapy."

No abstract

Bowenoid papulosis (BP) of the genitalia, characterized by the histological findings of a squamous cell carcinoma, follows a largely benign clinical course. The detection of oncogenic human papilloma viruses (HPV) from BP points to an aetiological role of these viral infections. A 47-year-old man with multiple genital skin lesions was seen over a 10-year period with the diagnosis of BP. Recently, he attended again with a recurrent genital tumour that was diagnosed as squamous cell carcinoma. His genital lesions progressed and became polymorphic in appearance, from a wart-like tumour to a reddish invasive plaque. To screen for the presence of different HPV sequences from different skin lesions and to correlate each HPV type with distinct clinical manifestations, polymerase chain reaction and single-strand conformational polymorphism (PCR-SSCP) were performed. PCR-SSCP revealed the presence of several types of HPV from different genital lesions. Sequencing results disclosed that he had a mixed infection of HPV6b, HPV16, HPV18 and HPV33, respectively. Interestingly, the clinical findings were fairly well correlated with the oncogenic potential of HPV found from each lesion.

We consider a scheduling problem in a home healthcare system in which nurses visit patients regularly for relatively minor healthcare services. Intervals between the visits may differ for different patients. On each day in the planning horizon, a nurse must visit the patients assigned to her/him on that day, and then return to the hospital. For the problem of determining the visiting schedule with the objective of minimizing total travel time of the nurse over the planning horizon, we develop a two-phase heuristic algorithm. To evaluate performance of the proposed algorithm, a series of computational tests is performed on a number of randomly generated problem instances and a real instance. Results of the tests show that the heuristic algorithm gives near optimal solutions for problems of practical sizes in a reasonable time.

Impotence is one of the common complications after the radical prostatectomy. One of the main reasons of this complication is due to the dysfunction of the veins in corpus cavernosum. Recent studies have shown that the erectile function is improved after the long-term therapy of phosphodiesterase type 5 inhibitor among patients with post-prostatectomy erectile dysfunction. In this study, we evaluated the effects of mirodenafil on the penile erection and corpus cavernosum tissues in the rat model of cavernosal nerve injury. Rats were divided into four groups: (1) control group, (2) bilateral cavernosal nerve injury group, (3) mirodenafil 10 mg therapy group after the nerve injury and (4) mirodenafil 20 mg therapy group after the nerve injury. After we identified the nerve from the pelvic nerve complex on the lateral side of the prostate, the rats in the control group were sutured without causing any nerve injury and in other groups we damaged the nerve by compressing it with a vessel clamp. Then, 10 and 20 mg kg−1 of mirodenafil were orally administered to two experimental groups. After 8 weeks, the intracavernosal pressure (ICP) was recorded. The immunohistochemical staining and western blot were performed, and the effect of mirodenafil on the expression of cyclic guanosine monophosphate (cGMP) was evaluated through enzyme-linked immunosorbent assay. The ICP of nerve-injured group was decreased compared with the control group; however, the ICP of the mirodenafil-administered groups was improved compared with the nerve-injured group. The Masson's trichrome staining confirmed that the smooth muscle (SM) component was increased in the mirodenafil-administered groups. The nitric oxide synthase expression and cGMP of mirodenafil-administered groups was increased compared with the nerve-injured group. Long-term therapy of mirodenafil may improve the erectile function after the radical prostatectomy by preserving the SM content and inhibiting the fibrosis of the corpus cavernosum.