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Biomedical subjects

J Leonard

Publications and source records attributed to J Leonard.

At least 37 records · Page 2Linked to original sources
PubMed2001

Lamotrigine therapy of epilepsy in tuberous sclerosis.

PURPOSE: Lamotrigine (LTG), a newer antiepileptic drug (AED), has activity against both partial-onset and generalized seizures. Its reported benefits for behavior, and its effectiveness in Lennox-Gastaut syndrome and other forms of refractory epilepsy, make it a logical choice for treatment of epilepsy in tuberous sclerosis complex (TSC). We present our experience with LTG therapy of epilepsy in 57 patients with TSC. METHODS: Patients fulfilled the diagnostic criteria for clinically definite TSC. LTG was initiated and increased until improvement in seizure frequency was noted, intolerable side effects occurred, or maximal doses were reached. Seizure frequency and behavioral changes were recorded during LTG therapy and compared with those prior to the introduction of LTG. RESULTS: Twenty-four (42%) were seizure free, and 21 (37%) had a >50% reduction in seizure frequency. Eighteen (32%) had subjectively improved behavior and/or alertness with daily activities. Thirty-eight (67%) had no change in this regard, whereas one (2%) became worse. Responders were more likely to not have a history of infantile spasms, and to have experienced only partial seizures (p < 0.05). Otherwise no phenotypic correlations with response were apparent. CONCLUSIONS: Among patients with TSC and epilepsy, LTG was effective and well tolerated, including as initial monotherapy. Improved alertness and behavior were apparent in many patients. The incidence of side effects is similar to that reported for other pediatric populations with symptomatic partial epilepsy. The usefulness of LTG in TSC may relate to an underlying defect of glutamatergic neurotransmission in partial epilepsy.

Adolescent↗
PubMed2001

Malignant giant-cell tumor of the parietal bone: case report and review of the literature.

OBJECTIVE AND IMPORTANCE: Giant-cell tumors (GCTs) are primary bone tumors that involve long bones in 75 to 90% of patients. They seldom develop in the cranium and are very rare in patients older than 60 years of age. A GCT rarely occurs with Paget's disease; when it does, however, it is most commonly associated with the polyostotic form and tends to involve the craniofacial bones. Pagetic GCTs are less aggressive than GCTs that are not associated with Paget's disease. CLINICAL PRESENTATION: We report the case of an 81-year-old woman with a painless left parietal mass and asymptomatic monostotic parietal Paget's disease. INTERVENTION: Surgical resection was performed, and histological examination of the lesion demonstrated Paget's disease with a malignant GCT. An incidental, low-grade, small-cell lymphocytic lymphoma also was noted. The patient experienced local recurrence of the malignant GCT and eventually died after developing pulmonary metastases of the malignant GCT. CONCLUSION: This case is the first reported example of a patient with a malignant GCT of the cranium associated with monostotic Paget's disease. It provides evidence that not all pagetic GCTs in the cranium are benign, as has been reported.

Aged↗
PubMed2001

Monoclonal antibodies: a new era in the treatment of non-Hodgkin's lymphoma.

Monoclonal antibodies (MAbs) have been used as therapeutic agents for many years. In 1997, Rituxan (IDEC-C2B8, rituximab, MabThera) became the first MAb to be approved by the FDA for a cancer indication. Rituxan served to heighten interest in the therapeutic applications of MAbs. Herceptin (for patients with breast cancer) and Mylotarg (for patients with acute myeloid leukemia) were approved shortly thereafter. Literally dozens of antibodies are currently under investigation for a variety of malignant and non-neoplastic indications. Rituxan is effective in patients with low-grade or follicular, relapsed or refractory non-Hodgkin's lymphoma (NHL). The response rate and time to progression (responders) are in the 50% and 13 months range, respectively. It is also active in intermediate-grade NHL where a large randomized study, in combination with CHOP chemotherapy, has shown a statistically significant increase in complete response (CR) rate (75% vs. 60%), prolongation of 1 year event-free survival (69% vs. 49%) and of overall survival (83% vs. 68%) as compared to CHOP alone. This marks the first time that any agent has shown results superior to CHOP, the curative gold standard for this type of NHL. Other promising antibodies under clinical investigation include: Hu1D10; Anti CD19, 22, 52, and anti-Id antibodies. The safety profile, clinical activity, and mechanism of action of these MAbs make them ideal candidates for combination with chemotherapy or biologicals. Over the next few years, we will see very significant therapeutic advances emerge as this important research yields additional clinical results.

Antibodies, Monoclonal↗
PubMed2001

DICE (dexamethasone, ifosfamide, cisplatin, etoposide) infusional chemotherapy for refractory or relapsed non-Hodgkin's lymphoma (NHL).

Continuous exposure to naturally-derived chemotherapy agents such as etoposide may theoretically override drug resistance due to overexpression of the multidrug resistance gene product, p-glycoprotein. Dexamethasone in high dose may have a similar overriding effect. Data also suggest that ifosfamide both by continuous infusion and when combined with a platinum compound may be more effective. Forty-four chemotherapy-refractory/relapsed lymphoma patients received the DICE infusional regimen. The programme consisted of dexamethasone 40 mg i.v. daily for 4 days, ifosfamide 1500 mg mixed with equal dosing of mesna continuously infused i.v. daily for 4 days, cisplatin 25 mg i.v. each day for 4 days and etoposide 150 mg continuously infused i.v. daily for 4 days, all administered every 3 weeks. Doses of ifosfamide and etoposide were escalated by 250 mg and 25 mg, respectively, based on patient tolerance, usually lack of myelosuppression. Special hydration was not required. G-CSF support was provided to patients as required. All patients had disease that had relapsed from or was resistant to CHOP or a similar anthracycline-containing combination regimen. A majority had previously received at least two regimens and 27% had received three or more. Of 44 patients, 32 (73%) achieved a significant response consisting of 18 complete remissions (CR) (41%) and 14 (32%) partial remissions (PR). There were 81% objective responses in large cell lymphoma comprised of 50% CR and 31% PR. Previous response to chemotherapy predicted response to DICE: 83% (25/30) of prior responders vs 50% (7/14) of non-responders had a response to the treatment regimen (p = 0.031, Fisher's exact test). Patients not undergoing transplantation had a median time of 8 months on therapy and a mean of 10 months. Toxicity was haematological (36% developing grade III-IV toxicity) and neurological (9%). There were only three episodes of clinical cystitis or gross haematuria. Infusional DICE is an easily administered and well tolerated programme with significant activity in refractory or relapsed NHL and may be useful as a tumour-reductive therapy prior to high-dose chemotherapy and autologous stem cell transplantation.

Age Factors↗
PubMed2001

Odour emission rates from manure treatment/storage systems.

The effects of agitation, liquid-only manure, depth and time on odour emission rates were investigated. Manure storage tanks were filled to incremental depths every two weeks. At each depth odour samples were collected twice. The second sample was collected seven days after the first. Odour concentration was measured with an olfactometer. Three different pig-manure treatments were investigated. In one treatment, slurry manure in a storage tank was agitated before and during odour sampling. In a second treatment, the settlable solids in manure were removed gravimetrically over 24 hours and liquid manure was pumped to a storage tank. In the third treatment (control), odour samples were collected from unseparated and undisturbed slurry manure. Overall, the odour emission rates in the agitated manure treatment ranged between 0.39 and 1.02 ou s(-1) m(-2), increased with depth and decreased with time, i.e. after seven days at each depth. In the liquid-only manure treatment, the emission rates ranged between 0.09 and 0.69 ou s(-1) m(-2), increased with depth but the effect of time was not evident. In the control treatment, the emission rates ranged between 0.20 and 0.66 ou s(-1) m(-2) and increased with depth on the first odour sampling day but decreased with depth on the second sampling day.

Agriculture↗
PubMed2000

Characterization of Cyp2d22, a novel cytochrome P450 expressed in mouse mammary cells.

Endogenous steroids and numerous environmental agents have potent effects on mammary development and carcinogenesis. Locally produced cytochrome P450 enzymes that modify such molecules are therefore likely to be important regulators of these processes. Here we describe the characterization of a novel mouse gene, termed Cyp2d22, that is highly expressed in the mammary tumor derived cell line RIII/Prl. Cyp2d22 is expressed at intermediate levels in the weakly tumorigenic cell line RIII/MG, whereas expression is low or absent in all normal mouse mammary epithelial cell lines tested and three C3H mammary tumor derived cell lines. Immunoblot analysis of mouse tissues with highly specific antisera indicates that 2D22 protein levels are most abundant in liver, while intermediate levels of expression are seen in adrenal, ovary, and mammary gland. Immunohistochemical staining of liver sections with these antisera demonstrates that 2D22 is most abundant in the first layer or two of parenchymal cells surrounding the central vein, with virtually no expression detected in periportal cells. Interestingly, sequence similarity and functional data suggest that Cyp2d22 may be the mouse ortholog of human CYP2D6. These observations support the hypothesis that 2D22 mediates a distinct, biologically significant activity in relation to other mouse 2D family members.

Adenoviridae↗
PubMed2000

Naltrexone: effects on motor function, speech, and activities of daily living in a patient with traumatic brain injury.

Evidence from many studies has suggested that endogenous opioid peptides participate in a number of pathophysiological responses to brain injury. This provides the rationale for the use of opioid antagonists for the enhancement of neural recovery after brain injury. A case is presented of an 18-year-old male who had loss of consciousness for 1 month after a severe brain injury. Three months of intensive rehabilitative therapies did not change his functional status. A trial of naltrexone was given while his performance in mobility, speech and overall Functional Independence Measure (FIM) scores were monitored. Results indicate an accelerated improvement in functional status and statistically improved FIM score.

Activities of Daily Living↗
PubMed2000

Kawasaki disease: a diagnostic challenge.

Kawasaki disease (KD) is an acute, self-limited, febrile, multi-system vasculitis that predominantly affects the the pediatric population, and is the leading cause of acquired heart disease in children. No etiologic agent for the disease has been identified, there are no diagnostic tests available, and the diagnosis is established by fulfilling a defined set of clinical criteria. We report on a 9-year-old boy who presented initially with symptoms felt to represent a streptococcal infection. He was subsequently shown to meet the criteria for KD, developed cardiac complications of the disease and subsequently demonstrated recovery over a year's period of time. The diagnostic criteria for KD, differential diagnosis, pitfalls in diagnosis, therapeutic recommendations and outcomes are discussed with relevance to this case. Recent print and electronic information sources and references are provided.

Child↗
PubMed1999

Resources and estuarine health: perceptions of elected officials and recreational fishers.

It is important to understand the perceptions of user groups regarding both the health of our estuaries and environmental problems requiring management. Recreational fishers were interviewed to determine the perceptions of one of the traditional user groups of Barnegat Bay (New Jersey), and elected officials were interviewed to determine if the people charged with making decisions about environmental issues in the bay held similar perceptions. Although relative ratings were similar, there were significant differences in perceptions of the severity of environmental problems, and for the most part, public officials thought the problems were more severe than did the fishers. Personal watercraft (often called Jet Skis) were rated as the most severe problem, followed by chemical pollution, junk, overfishing, street runoff, and boat oil. Small boats, sailboats, wind surfers, and foraging birds were not considered environmental problems by either elected officials or fishermen. The disconnect between the perceptions of the recreational fishers and those of the locally elected public officials suggests that officials may be hearing from some of the more vocal people about problems, rather than from the typical fishers. Both groups felt there were decreases in some of the resources in the bay; over 50% felt the number of fish and crabs had declined, the size of fish and crabs had declined, and the number of turtles had declined. Among recreational fishers, there were almost no differences in perceptions of the severity of environmental problems or in changes in the bay. The problems that were rated the most severe were personal watercraft and overfishing by commercial fishers. Recreational fishers ranked sailboats, wind surfers, and fishing by birds as posing no problem for the bay. Most fishers felt there had been recent major changes in Barnegat Bay, with there now being fewer and smaller fish, fewer and smaller crabs, and fewer turtles. The results suggest that the views of a wide range of coastal users should be considered when making environmental health decisions.

Adult↗
PubMed1999

Sex hormone-binding globulin receptor signal transduction proceeds via a G protein.

The plasma protein, sex hormone-binding globulin (SHBG) binds to a receptor (R(SHBG)) on cell membranes to form an SHBG-R(SHBG) complex. When an appropriate steroid binds to this complex, there is a rapid rise in intracellular cyclic adenosine monophosphate (cAMP). Although the system is moderately well characterized, the molecular cloning of R(SHBG) has not been accomplished and there is a paucity of evidence regarding the mechanism of transmission of the R(SHBG) signal. In this communication, we offer two independent lines of evidence that a G protein is involved in R(SHBG) signal propagation. Exposure of cell membranes containing R(SHBG) to a non-hydrolyzable analog of guanosine triphosphate (guanylyl-5'-imidodiphosphate) caused a substantive decrease in the binding of SHBG to R(SHBG). This behavior is typical of membrane receptors coupled to G proteins and has been used by others as evidence to support that relationship. Another set of experiments involved the assumption that, if R(SHBG)-induced increases in cAMP were diminished when the wild-type alpha subunit of a G protein was replaced with mutants that were inefficient/ineffective in signal transduction, then the idea that G proteins were involved in that signal would be buttressed. Hence, we infected COS-1 cells with a construct containing such mutants, along with a cAMP response element reporter, and demonstrated a marked decrease in R(SHBG)-engendered reporter activity, e.g. cAMP generation.

Cyclic AMP↗
PubMed1998

Pharmacokinetic interaction between ritonavir and didanosine when administered concurrently to HIV-infected patients.

The effect of coadministration of ritonavir and didanosine (ddI) on the pharmacokinetics of these drugs was investigated in a single-center, three-period, crossover study. Eighteen asymptomatic, HIV-positive men were assigned randomly to 6 different sequences of 3 regimens: ddI (200 mg every 12 hours) alone for 4 days, ritonavir (600 mg every 12 hours) alone for 4 days, and 4 days of ddI with ritonavir under dose-staggering conditions. Although not statistically significant, ritonavir concentrations were slightly higher on average (<10%) with concurrent administration of ddI compared with those of ritonavir alone. In contrast, ddI concentrations were lower with concurrent administration compared with those of ddI alone; maximum concentration and area under the concentration-time curve were reduced by about 15% (p < .05). The ddI elimination rate constant was unaffected by ritonavir, suggesting no change in ddI's systemic metabolism. Adverse events were similar between regimens. The relatively minor changes in ritonavir and ddI pharmacokinetics are probably not clinically relevant; therefore, dosage adjustment of either compound appears unnecessary when administered concurrently. However, the combination regimen of ddI and ritonavir continue to be evaluated clinically.

Adult↗
PubMed1998

Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group.

BACKGROUND: Ritonavir is a potent, orally bioavailable inhibitor of HIV-1 protease. We undertook an international, multicentre, randomised, double-blind, placebo-controlled trial of ritonavir in patients with HIV-1 infection and CD4-lymphocyte counts of 100 cells/microL or less, who had previously been treated with antiretroviral drugs. METHODS: 1090 patients were randomly assigned twice-daily liquid oral ritonavir 600 mg (n = 543) or placebo (n = 547) while continuing treatment with up to two licensed nucleoside agents. The primary study outcome was any first new, or specified recurrent, AIDS-defining event or death. Open-label ritonavir was provided after 16 weeks in the study to any patient who had an AIDS defining event. FINDINGS: The baseline median CD4-lymphocyte count was 18 (IQR 10-43)/microL in the ritonavir group and 22 (10-47)/microL in the placebo group. Study medication was discontinued in 114 (21.1%) ritonavir-group patients and 45 (8.3%) placebo-group patients mainly because of initial adverse symptoms. Outcomes of AIDS-defining illness or death occurred in 119 (21.9%) ritonavir-group patients and 205 (37.5%) placebo-group patients (hazard ratio 0.53 [95% CI 0.42-0.66]; log-rank p < 0.0001) during median follow-up of 28.9 weeks, with loss to follow-up of 15 (1.4%) patients. Ritonavir was then offered to all patients; at median follow-up of 51 weeks, 87 (16%) ritonavir-group patients had died of any cause versus 126 (23%) placebo-group patients (hazard ratio 0.69 [95% CI 0.52-0.91], log-rank p = 0.0072). INTERPRETATION: Although earlier intervention with combination therapy may provide much more effective treatment, ritonavir in patients with advanced disease and extensive previous antiretroviral use is safe and effective, lowers the risk of AIDS complications, and prolongs survival.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Optimal scheduling of interleukin-12 and fractionated radiation therapy in the murine Lewis lung carcinoma.

Interleukin-12 (IL-12), a naturally occurring cytokine, has demonstrated antitumor activity in several murine solid tumors. The Lewis lung carcinoma was used to study the most effective scheduling of recombinant murine interleukin-12 (rmIL-12) administration with fractionated radiation therapy. The effect of the schedule of rmIL-12 administration alone or along with a 1- or 2-week fractionated radiation therapy regimen was examined. Beginning rmIL-12 prior to or at the same time as radiation therapy and extending rmIL-12 through the radiation regimen and beyond produced the longest tumor growth delays. Those treatment regimens which were most effective against the primary tumor were also most effective in decreasing the number of lung metastases on day 20. To further assess the immunotherapeutic effects from rmIL-12 administration, the efficacy of rmIL-12 with fractionated radiation therapy delivered to a right hind-limb tumor was measured as tumor growth delay in an unirradiated left hind-limb tumor. There was some difference in the tumor growth delay between the unirradiated tumor in the animals bearing an irradiated tumor in the contralateral leg, and the tumors in animals receiving rmIL-12 only. Recombinant murine granulocyte-macrophage-colony stimulating factor (rmGM-CSF) was also an antitumor agent active against the Lewis lung carcinoma and produced an additive effect in combination with fractionated radiation therapy in this tumor. rmIL-12 was a radiation sensitizer in the Lewis lung carcinoma. When rmIL-12 (45-microg/kg) and rmGM-CSF (45 microg/kg) were administered together with fractionated radiation therapy, a marked increase in tumor growth delay resulted. This treatment combination also nearly ablated lung metastases on day 20 in these animals. These results may serve as a useful guide in developing clinical protocols, including rmIL-12 and fractionated radiation therapy.

Animals↗
PubMed1998

The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin.

OBJECTIVE: To investigate the effects of ritonavir on the pharmacokinetics of rifabutin. METHODS: In a multiple-dose, randomized, parallel-group, double-blind study, subjects received 150 mg rifabutin daily for 24 days coadministered on days 15 to 24 with twice-daily doses of either placebo or ritonavir (300 mg on day 15, 400 mg on day 16, and 500 mg on days 17 to 24). Plasma concentrations of rifabutin and 25-O-desacetylrifabutin were measured by HPLC, and the pharmacokinetics were determined after the rifabutin doses on days 14 and 24. RESULTS: For subjects receiving rifabutin and placebo who completed the study (n = 11), there were small but statistically significant differences (< or = 32%) in several rifabutin and 25-O-desacetylrifabutin pharmacokinetic parameters between the regimens of rifabutin alone and rifabutin with placebo. In contrast, the effect of ritonavir on rifabutin pharmacokinetics of subjects completing the study (n = 5) was substantial. Rifabutin mean minimum observed concentration (Cmin), maximum observed concentration (Cmax), and area under the concentration-time curve [AUC(0-24)] increased by approximately sixfold, 2.5-fold, and fourfold, respectively, and 25-O-desacetylrifabutin mean Cmin, Cmax, and AUC(0-24) increased by approximately 200-, 16-, and 35-fold, respectively, when coadministered with ritonavir compared with rifabutin administered alone. The sum of the mean AUC(0-24) of rifabutin and 25-O-desacetylrifabutin increased nearly sevenfold when coadministered with ritonavir. CONCLUSIONS: Ritonavir inhibited the metabolism of rifabutin and 25-O-desacetylrifabutin, suggesting that both are metabolized at least in part by CYP3A. Ritonavir may have enhanced rifabutin bioavailability by reducing either intestinal of hepatic metabolism of both. Clarithromycin is an alternative to rifabutin for antimycobacterial therapy that may be administered concurrently with ritonavir. Administration of ritonavir with a reduced rifabutin dosage regimen (150 mg every Monday, Wednesday, and Friday) is being investigated.

Adult↗
PubMed1998

Multidose pharmacokinetics of ritonavir and zidovudine in human immunodeficiency virus-infected patients.

The effect of coadministration of ritonavir and zidovudine (ZDV) on the pharmacokinetics of these drugs was investigated in a three-period, multidose, crossover study. Eighteen asymptomatic, human immunodeficiency virus-positive men were assigned randomly to six different sequences of the following three regimens: ZDV (200 mg every 8 h [q8h] alone for 4 days, ritonavir (300 mg q6h) alone for 4 days, and ZDV with ritonavir for 4 days. Ritonavir pharmacokinetics were unaffected by coadministration with ZDV. However, ZDV exposure was reduced by about 26% (P < 0.05) in the presence of ritonavir. The maximum concentration in (Cmax) of ZDV plasma decreased from 748 +/- 375 (mean +/- standard deviation) to 546 +/- 296, and area under the concentration-time curve from 0 to 24 h (AUC0-24) decreased from 3,052 +/- 1,007 to 2,261 +/- 715 when coadministered with ritonavir. In contrast, the ZDV elimination rate constant was unaffected by ritonavir, suggesting that there was no change in ZDV systemic metabolism. Correspondingly, differences in ZDV-glucuronide Cmax and AUC were not statistically significantly different between regimens (P > 0.31). Also, there were no apparent differences in the formation of 3'-amino-3'-deoxythymidine or in the adverse event profiles between the regimens. The lack of change in ritonavir pharmacokinetics suggests that dosage adjustment of ritonavir is unnecessary when it is administered concurrently with ZDV. The clinical relevance of a 26% reduction in ZDV exposure when ZDV is administered with ritonavir is unknown. In addition to other multidrug regimens, the long-term safety and efficacy of coadministration of ritonavir and ZDV is being investigated.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Neurological outcome of methylmalonic acidaemia.

OBJECTIVE: To assess the long term outcome of patients with methylmalonic acidaemia in a cross sectional study. PATIENTS: All 35 patients with methylmalonic acidaemia seen at Great Ormond Street Hospital for Children in London, UK between 1970 and 1996 were studied. They were divided into cobalamin responsive (n = 6) and non-responsive (n = 29), and early and late onset groups. RESULTS: There was a significant difference between cobalamin responsive and non-responsive groups in severity, survival, and incidence of neurological sequelae. Cobalamin responsive patients had mild disease, irrespective of age at presentation, their neurological complications were less severe, and they are all alive. The cobalamin non-responsive group comprised 19 early and nine late onset patients. The early onset patients had more severe disease at presentation and 14 have died; all late onset patients are alive. There was no significant difference in abnormal neurological signs, although early onset patients had a significantly reduced full scale intelligence quotient and poor cognitive outcome. In both groups, abnormal neurological signs continue to increase with age. CONCLUSIONS: Cobalamin responsive patients have a better long term outcome. The outcome in the non-responsive patients, particularly the early onset group, remains poor and alternative treatments should therefore be considered early in this group.

Adolescent↗