Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function

Among the variable manifesting conditions of neuronal migration disorders, mental retardation, motor disturbance and epilepsy are the main features of developmental disabilities. We analyzed the relationship between clinical symptoms and magnetic resonance (MR) images, including surface anatomy scan (SAS). Thirty nine patients (23 males, 16 females; mean age 6.1 years) with neuronal migration disorders were studied. The diagnoses were cerebral palsy in 23 cases, mental retardation in 4. West syndrome in 4, Fukuyama type congenital muscular dystrophy (FCMD) in 6. Walker-Warburg syndrome in 1 and Dubowitz syndrome in 1. Cortical dysplasias were classified into the following 7 groups, mainly based on the SAS findings: complete agyria (AG 1), mixture of agyria and pachygyria (AG 2), bilateral complete pachygyria (BP 1), diffuse pachygyria with marked widening of the bilateral superior frontal gyrus (BP 2), unilateral pachygyria with hemispheric atrophy or hemimegalencephaly UP), focal cortical dysplasia (FP) and other findings such as solitary schizencephaly (Others). Most cases of AG 1 and AG 2 showed spastic quadriplegia (6/7) and symptomatic generalized epilepsy (5/7), whereas cases of BP1 showed spasticity only in 1/8 and epilepsy in 7/8. Hemiplegia was observed in 6/7 of UP, 2/8 of FP and 2/4 of Others. Partial epilepsy was observed in 2/7 of UP and 1/8 of FP. Intellectual level was variable in BP 1, UP, FP and Others, but all cases showed severe mental retardation in AG 1, AG 2 and BP 2. BP 2 was observed in all cases of typical FCMD (5/5). The birth weight was less than 2,500 g in 6/7 of UP. The structural findings well correlated with clinical symptoms and epileptic seizure types. The surface anatomy scan was a very useful technique for detecting cortical dysplasias.     

Pharmacokinetics of cefapirin in patients with normal and impaired renal functions

The pharmacokinetics of 3-hydroxymethyl-7-[2-(4-pyridyl-thio)acetamido]-2-cephem-2-carboxylic acid acetate (cefapirin) was evaluated after 1.0 g i.m. to 14 patients with different glomerular and tubular functions. Peaks in normal renal function ranged between 9--17 micrograms/ml and was 3--4 times higher in patients with glomerular filtration rates below 30 ml/min. The serum half-life in normal renal function was 0.8 h and was somewhat increased in renal impairment. The distribution volume was little influenced by renal capacity. Recommendations for dosage are given.     

Pharmacokinetics of glibenclamide and its metabolites in diabetic patients with impaired renal function

P-glycoprotein, a membrane-associated transport protein, has recently been recognised as an important element of the intestinal epithelium. This paper summarises the in vivo data on the pharmacological role of intestinal P-glycoprotein. These data show that P-glycoprotein contributes to the elimination of many drugs by mediating their direct secretion from the blood into the intestinal lumen. In addition, there is also evidence that this protein can limit oral drug absorption. Hence, inhibition of intestinal P-glycoprotein, e.g. by a reversal agent like cyclosporin A, may be a promising strategy for improving the oral bioavailability of P-glycoprotein substrate drugs. Indeed, several preclinical and clinical studies have shown that coadministration of drugs with a reversal agent can substantially increase oral drug absorption.     

Pharmacokinetics of single intravenous and oral doses of dolasetron mesylate in healthy elderly volunteers

Dolasetron mesylate (MDL 73,147EF, Anzemet; Hoechst Marion Roussel, Laval, Canada) is a 5-HT3 receptor antagonist undergoing clinical evaluation for use as an antiemetic agent. The pharmacokinetics of dolasetron and its reduced metabolite (MDL 74,156) were studied after administration of single intravenous and oral doses of dolasetron mesylate 2.4 mg/kg in 18 healthy elderly subjects. Expressed as the dolasetron base, this dose was 1.8 mg/kg. Dolasetron was rapidly metabolized to the reduced metabolite, which appeared in plasma within 10 minutes after intravenous or oral administration. The mean half-life (t1/2) of dolasetron was 0.24 hours after intravenous administration and 0.50 hours after oral administration. The pharmacokinetic parameters of the reduced metabolite were similar after intravenous and oral administration. The apparent absolute bioavailability of the reduced metabolite was 89%, and it had an elimination t1/2 of approximately 7 hours and an apparent volume of distribution (Vd beta) of 4.69 L/kg. Dolasetron was not detected in urine. Metabolites were excreted in urine almost completely within 24 hours of administration. The primary metabolite detected in urine was the (+)-enantiomer of the reduced metabolite, which accounted for 25.35% (+/- 7.79%) and 18.88% (+/- 7.65%) of the intravenous and oral doses, respectively. Hydroxylated metabolites accounted for 5% or less of the total dose via either route. The pharmacokinetics of the reduced metabolite after single intravenous or oral doses in elderly volunteers were consistent with pharmacokinetics observed in both young healthy men and cancer patients receiving high-dose cisplatin chemotherapy. Dosage adjustments of dolasetron mesylate on the basis of age do not appear to be necessary.     

Pharmacokinetics of oral and intravenous dolasetron mesylate in patients with renal impairment

In an open-label, randomized, two-way complete crossover study, the influence of renal impairment on the pharmacokinetics of dolasetron and its primary active metabolite, hydrodolasetron, were evaluated. Patients with renal impairment were stratified into three groups of 12 based on their 24-hour creatinine clearance (Cl(cr)): group 1, mild impairment (Cl(cr) between 41 and 80 mL/min); group 2, moderate impairment (Cl(cr) between 11 and 40 mL/min); and group 3, endstage renal impairment (Cl(cr) < or = 10 mL/min). Twenty-four healthy volunteers from a previous study served as the control group. Each participant received a single intravenous or oral 200-mg dose of dolasetron mesylate on separate occasions. Serial blood samples were collected up to 60 hours after dose for determination of dolasetron and hydrodolasetron, and urine samples were collected in intervals up to 72 hours for determination of dolasetron, hydrodolasetron, and the 5' and 6'-hydroxy metabolites of hydrodolasetron. Because plasma concentrations were low and sporadic, pharmacokinetic parameters of dolasetron were not calculated after oral administration. Although some significant differences in area under the concentration-time curve (AUC0-infinity), volume of distribution (Vd), systemic clearance (Cl), and elimination half-life (t1/2) of the parent drug were observed between control subjects and patients with renal impairment, there were no systematic findings related to degree of renal dysfunction. The elimination pathways of hydrodolasetron include both hepatic metabolism and renal excretion. Consistent increases in mean Cmax, AUC0-infinity, and t1/2 and decreases in renal and total apparent clearance of hydrodolasetron were seen with diminishing renal function after intravenous administration of dolasetron mesylate. No consistent changes were found after oral administration. Urinary excretion of hydrodolasetron and its metabolites decreased with decreasing renal function, but the profile of metabolites remained constant. Dolasetron was well tolerated in all three groups of patients. Based on these findings, no dosage adjustment for dolasetron is recommended in patients with renal impairment.     

Pharmacokinetics and safety of single intravenous and oral doses of dolasetron mesylate in healthy women

The protease thrombin seems to play a central role in events following neural injury, whereby the enzyme can act, in concert with other molecules as a hormone or as a growth factor. In cells derived from the nervous system, thrombin induces changes in morphology and proliferation. The signalling mechanisms involved in these thrombin-activated processes are still unclear. In the present study we investigated Ca2+ signals in fura-2 loaded rat astrocytes in primary culture. Brief stimulation of astrocytes with thrombin induced a dose-dependent transient elevation of [Ca2+]i, best fitted by a double-sigmoidal curve giving two EC50 values of 3 pM and 150 pM. Continuous superfusion of cells with thrombin induced Ca2+ responses with three different types of kinetics. In 48% of the cells tested a single transient rise superimposed with fast fluctuations of [Ca2+]i was seen. The following complex long-term changes of [Ca2+]i, dependent on the presence of the agonist thrombin, were observed: i) a biphasic [Ca2+]i elevation, characterized by an initial peak followed by a sustained plateau phase (in 43% of the cells) and ii) oscillations of [Ca2+]i (in 9% of the cells). The observed Ca2+ responses were inhibited by the phospholipase C (PLC) inhibitor U-73122 and the thrombin inhibitor protease nexin-1/glia-derived nexin. The synthetic thrombin receptor activating peptide could mimic the thrombin-induced changes of [Ca2+]i. In astrocytes in Ca2+-free medium, thrombin induced a sharp single transient Ca2+ rise, without superimposed fluctuations. After depletion of intracellular Ca2+ stores with thapsigargin the Ca2+ response to thrombin was diminished or completely suppressed indicating that thrombin induces the release of Ca2+ from intracellular stores. During long-term Ca2+ responses, omission of extracellular Ca2+ resulted in a reversible interruption of the signal. In conclusion our results demonstrate that thrombin by activation of its plasma membrane receptor induces through activation of PLC different types of Ca2+ responses. The complex Ca2+ signals are generated by an interplay of InsP3-mediated Ca2+ release from intracellular stores and Ca2+ entry across the plasma membrane.     

Bayesian calculation of methotrexate clearance after low dose intramuscular administration in patients with rheumatoid arthritis

OBJECTIVE: To determine a pharmacokinetic procedure (Bayesian method) for estimation of methotrexate (MTX) clearance, using only 2 blood samples, in outpatients with rheumatoid arthritis treated with low dose intramuscular (i.m.) MTX. METHODS: Population pharmacokinetic parameters were obtained by the weighted least squares (WLSQ) method in plasma samples from 14 patients with rheumatoid arthritis (RA). In each patient, 11 samples were measured by fluorescence polarization immunoassay, at Time 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, and 24 h after i.m. administration. These measures were validated by pharmacokinetic studies in 20 other patients with RA. Individual total body clearance of MTX was calculated using only 2 plasma samples (at 0.5 and 2 h after i.m. injection) by the Bayesian method using the population pharmacokinetic parameters. The clearance measures obtained by the Bayesian method were compared with those obtained by the WLSQ method. RESULTS: The pharmacokinetic variables (clearance, half-life, area under the curve) of 14 patients were determined, as well as the covariance and the mean values necessary to apply the Bayesian method. No significant difference was found between clearance values obtained by the Bayesian method compared to the WLSQ method, confirming the validity of the Bayesian values. CONCLUSION: The present population pharmacokinetic parameters allowed the determination of individual clearance of MTX with only 2 plasma samples (0.5 and 2 h after administration) in patients treated with low dose im MTX. Individual clearance is used to modulate MTX administration in patients presenting adverse reactions in spite of good clinical response. Individual determination of MTX pharmacokinetics in patients at risk for adverse MTX reactions could be useful for adjustment of the drug regimen.     

Ankle arthrodesis in patients with rheumatoid arthritis

The results of 26 ankle arthrodeses performed for rheumatoid arthritis on 21 patients were reviewed. Tibiotalar arthrodesis was performed in 14 ankles, and tibiotalocalcaneal arthrodesis was performed in 12. External fixation was used in 20 ankles, and internal fixation was used in six. Followup was available in 24 of 26 ankles (19 patients), and averaged 5 years (range, 2-8 years). There was no pain experienced in 19 ankles; mild, occasional pain was experienced in four ankles; and moderate, daily pain was experienced in one ankle. Daily activities were limited in five patients and recreational activities were limited in 11. All patients reported some difficulty walking on uneven terrain. Nearly all patients were satisfied; two were satisfied with reservations and two were dissatisfied. Union was achieved in 25 of 26 (96%) ankles. Ankle arthrodesis is an effective operation in patients with rheumatoid arthritis. Unlike previous reports, union and complication rates in this series were comparable with rates for arthrodesis for posttraumatic and degenerative arthritis.     

Chloroquine retinopathy in patients with rheumatoid arthritis

The paper presents data on the differential fertility of schizophrenics and controls, and the fertility of their siblings. This study used several methodological procedures in the study of schizophrenia reproduction, which strengthens the validity of the findings. Firstly, both male and female rates were examined. Secondly, the method of selection of a control avoided the biases introduced by using census data or other non-matched controls. Third, a diagnostic criterion was used which minimizes the possibility of the inclusion of other psychiatric illnesses. The results obtained support prior reports of the lowered reproductive rates of schizophrenics. Further, the siblings of schizophrenics were found not to have a reproductive advantage when contrasted to control siblings. The failure to find a reproductive advantage conflicts with a hypothesis of a balanced polymorphism as the mechanism maintaining an apparent constant rate of schizophrenia.     

HLA-DM polymorphisms in patients with rheumatoid arthritis

OBJECTIVE: To investigate the contribution of HLA-DMA and DMB genes, which play a crucial role in the HLA class II restricted antigen presentation pathway, in susceptibility to rheumatoid arthritis (RA). METHODS: The distribution of DMA and DMB alleles was examined in patients with RA and in healthy subjects by oligotyping of PCR amplified genomic DNA with sequence specific oligonucleotide probes. RESULTS: There were no significant differences in the prevalence of DMA and DMB alleles in patients with RA as compared to healthy controls. In addition, no significant differences in frequencies of DMA and DMB alleles were observed in RA susceptibility epitope positive RA patients and controls. CONCLUSION: DMA and DMB genes do not appear to play a role in susceptibility to RA.     

Family physician consultation by patients with rheumatoid arthritis or gonarthrosis/coxarthrosis

OBJECTIVE: To determine how often patients with rheumatic joint disease consult their general practitioner (GP), and if there are disease and patient characteristics that influence GP consultation of gonarthrosis/coxarthrosis patients. DESIGN: Prospective record investigation. SETTING: Seven GP centres in the southeast of the Netherlands. METHOD: All patient contacts were registered prospectively in the seven GP centres: 46 concerned patients with rheumatoid arthritis (RA), 122 patients with gonarthrosis/ coxarthrosis. Patient and disease characteristics were collected on intake sheets. RESULTS: Three-quarters of the RA patients were periodically seen (mostly by a specialist), and 47% of the gonarthrosis/coxarthrosis patients (as often by their GP as by a specialist). Of the RA patients and of the gonarthrosis/coxarthrosis patients 74% and 89% respectively consulted their GPs in one year (the average numbers of contacts were 4.7 and 5.0); 50% and 57% did so because of the chronic joint disease (with 2.2 and 1.6 contacts respectively). No disease characteristics and only a few patient characteristics (arthroplasty, chronic use of medication) of patients with gonarthrosis/coxarthrosis influenced GP consultation. CONCLUSION: Patients with rheumatic joint disease often consult their GP, but not always because of this illness. If they consult their GP, they usually do so more than once a year.     

Lymphocyte depletion in patients with rheumatoid arthritis

Sixteen patients with severe rheumatoid arthritis, marked inflammation of the synonvial membrane and high rheumatoid titer were cannulated by the thoracic duct for a period rangin between 82 up to 100 days. The patients being not under any medication during that time. Quantitative and qualitative analysis of the lymphocytes were performed, as well as responses to mitogens, rheumatoid factor, circulating antibodies and delayed hypersensitivity. By the 14th day nearly all the patients had a partial or almost complete remission of their disease. No complications were observed. These results will be discussed.     

膝关节骨性关节炎关节镜清理术手术时机的选择

目的:探讨关节镜清理术对不同分期膝关节骨性关节炎(OA)的临床疗效,为膝关节OA患者关节镜清理术手术时机的选择提供依据.方法:根据Kellgren-Lawrence X线及Outerbridge关节镜分级标准将134例膝关节OA患者分为早期(58例)、中期(28例)和晚期(48例),并对不同时期的膝关节OA患者进行相应清理术治疗.术后平均随访18.6 个月,对早、中、晚期膝关节OA患者的主观满意度、VAS和HSS评分进行术前与术后比较及不同组间的比较.结果:患者主观评定,早期患者满意40例(68.9%),中期患者满意16例(57.1%),晚期患者满意6例(12.5%),即满意患者所占构成比早期及中期患者高于晚期患者( P<0.05),早期患者高于中期患者( P<0.05);早、中和晚期OA患者膝关节VAS评分术后较术前均明显降低( P<0.05),HSS评分术后则较术前明显升高( P<0.05);术后中期和晚期OA患者VAS评分高于早期组( P<0.05),HSS评分低于早期组( P<0.05);术后晚期OA患者VAS评分低于中期组( P<0.05),HSS评分高于晚期组( P<0.05).结论:关节镜清理术对早期及部分中期OA患者术后患者满意度较高,VAS和HSS评分疗效好,提示OA患者应在患病早期及时行关节镜手术治疗.     

Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment

Although long-term clinical studies have shown no excessive risk of lymphoma in rheumatoid arthritis (RA) patients treated with methotrexate (MTX), an increasing number of reports of this association continue to appear. We describe two cases, review the cases in the world's literature, and summarize their important characteristics. Possible oncogenic mechanisms are discussed. Most lymphoproliferation cases presented here have features of immunosuppression-associated lymphoma. The immunosuppressed state is attributable to a combination of factors, such as RA itself and the actions of MTX. The risk factors for RA patients to develop lymphoma while on MTX include severe disease, intense immunosuppression, genetic predisposition, and an increased frequency of latent infection with prooncogenic viruses such as Epstein-Barr virus (EBV). The spontaneous remission of lymphomas in eight RA patients after MTX was stopped highlights the likely causative role of the drug in the development of these malignancies. If the clinical situation permits, a period of observation for spontaneous remission after MTX is stopped is advisable. The physicians caring for RA patients on MTX should maintain a high surveillance for signs and symptoms suggestive of lymphoma.     

Hypothalamo-pituitary-thyroid system in patients with rheumatoid arthritis]

OBJECTIVE: To determine the effect on the uptake of breast screening of a personalized letter from the general practitioner recommending mammography, sent to coincide with an invitation from the NHS breast screening programme. DESIGN: Randomised control trial with stratification of prognostic variables. SETTING: A group practice in Hackney, east London. SUBJECTS: 473 women invited for breast screening by the City and East London Breast Screening Service. OUTCOME MEASURE: Attendance for mammography. RESULTS: All women in the randomised trial were followed up; 134 of 236 (57%) randomly allocated to receive the prompting letter attended for mammography compared with 120 of 234 (51%) controls This difference was not significant (chi 2 = 1.43, p = 0.23) CONCLUSION: Personal recommendation by a letter prompting attendance for mammography from the general practitioner known best to women due to be screened did not improve uptake of breast screening in this east London practice. Other strategies are needed to increase uptake of mammography in inner cities.     

Cementless hip prosthesis in patients with rheumatoid arthritis

A recent study conducted in Sweden reported that 1) leukemia risk in children who lived near 220 or 400 kV electric-power transmission lines was associated with calculated historical magnetic field levels; 2) children living within a distance of 50 m of transmission lines had an elevated risk of leukemia; and 3) there was no association between leukemia and residential magnetic fields measured many years after diagnosis. Subsequently, these investigators found through logistic regression analysis that disease was more strongly associated with calculated historical fields than with distance. Since the calculated historical fields in that study depended predominantly on distance and transmission-line load current, the logistic regression results suggest that historical load current plays an important role in the epidemiological results. Thus, we studied hourly 1974 load-current data for six transmission lines, and we examined 1958-1985 annual load-current data for 112 transmission lines. Most lines exhibited marked diurnal load-current rhythms during 1974, and all six showed systematic weekday-weekend differences. During 1958-1985, average loadings of Swedish 220 and 400 kV lines increased by about 1.3% year. Predictive-value and kappa-statistic analyses indicated that Swedish transmission-line load currents were not stable over long periods, so that contemporaneous load current (or a contemporary magnetic field measurement) was not a good surrogate for historical load current (or historical magnetic fields). The results provide a potential explanation of the failure of the Swedish Study to find an association between leukemia and contemporaneous magnetic field levels measured many years after the etiologic period, and suggest that the inclusion of load-current data could significantly improve the quality of historical field calculations.     

Endogenous opioid tone in patients with rheumatoid arthritis

A monoclonal antibody giving a dominant reaction with the group-specific polysaccharide of streptococcus group B in an ELISA test has been developed. The purified polysaccharide exhibited a high positivity with reference anti B streptococcal antiserum in the ELISA test. Cross-tests of antibodies with other groups of streptococci provided a minimum cross-reaction only in the case of G streptococci. Monoclonal antibodies were prepared using Streptococcus agalactiae S 589 MT strain isolated from a case of bovine mastitis which does not express Ia, Ib, II, III, IV and V type antigens, nor C, R and X protein antigens.     

Delayed type hypersensitivity in patients with rheumatoid arthritis

This study was performed to verify and further characterize the role of neuroendocrine factors in the regulation of fetal adipose metabolism. On day 72 to 74 of gestation, pig fetuses in one uterine horn were hypophysectomized (hypoxed) by micro-cauterization, fetuses in the other horn served as sham controls. Fetuses were removed by laparotomy on day 110 of gestation. Slices of subcutaneous adipose tissue from control fetuses responded to lipolytic stimulation by norepinephrine alone (NE; 1 microgram/ml), NE plus adenosine deaminase (160 mUnits/ml) or dibutyryl cyclic AMP (5 mM). Adipose tissue from hypoxed fetuses, however, responded to lipolytic stimulation by only dibutyryl cyclic AMP, not NE. Lipogenesis in adipose tissue slices, as quantitated by 3H2O incorporation into triglyceride fatty acids, was increased 2.6 fold by hypophysectomy. These results demonstrate the necessity of a functioning pituitary in the normal regulation of fatty acid synthesis and receptor-mediated lipolytic response in developing fetal adipose tissue.