SEARCH · Search PubMed

Results for “THERAPEUTICS”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 775 records · Page 43Linked to original sources

PubMed1991

Overview and evolution of therapeutic systems.

Therapeutic systems were born of the recognition that the actions and safety of hormones depend not solely on chemical structure but also on their precisely controlled endogenous delivery. In contrast, conventional drug dosage forms exert no control, permitting the familiar peak-and-trough concentration cycle, often resulting in side effects or suboptimal therapy or both. Therapeutic systems were conceived to optimize treatment by delivering drug according to a therapeutically rational program that would select desired actions from a spectrum of concentration-dependent actions. The systems' design concept incorporated a reservoir isolating drug from the body, a rate controller, an energy source, and a platform. Because the program is the systems' raison d'etre, we considered them not devices but rate- and duration-controlled drug products requiring Food and Drug Administration approval. Our decision to create these products, rather than licensing the technology to others, reflected our own commitment to advancing therapy, not simply creating "hardware" for delivering drugs. Milestones in systems development were discussed, including the uncovering of therapeutic values and optimal delivery patterns along the way. Finally, future challenges for therapeutic systems development in the biotherapeutic era were briefly sketched.

Administration, Cutaneous↗

PubMedDate not supplied

Small computer algorithms for comparing therapeutic performances of single-plane iridium implants.

We present a uniform method for selecting an optimum implant geometry by presenting techniques for evaluating the therapeutically significant maximum dose rate (herein referred to as the "maximum dose rate"), the reference isodose (85% of the maximum dose rate), and the area enclosed by the reference isodose contour. The therapeutic performances of planar iridium implants may be compared by evaluating their respective maximum dose rates, reference isodoses , and areas within the reference isodose contours. Because these parameters are mathematically defined, they reproducibly describe each implant geometry. We chose a small microcomputer to develop these comparison algorithms so that the radiotherapist need not have large, expensive computer facilities available to conduct his own studies. The development of these algorithms led to some significant conclusions and recommendations regarding the placement of interstitial implants. Using seeds that are centrally located in the array to evaluate the maximum dose contour avoids underestimating the array's maximum dose rate. This could occur if edge or corner seeds were used. Underestimating the maximum dose rate (and hence the reference isodose contour area) may have a serious therapeutic outcome, because the actual total treatment dosage may be excessive. As ribbon spacing is increased, there is a point beyond which the reference isodose contours become decoupled. At this point, a single relatively uniform reference isodose contour separates into several contours. This effect not only complicates the planimetry calculations, but it also adversely affects the therapeutic efficacy of the implant by producing therapeutically "cold" regions.

Brachytherapy↗

PubMed2003

Multiple injections of pegylated liposomal Doxorubicin: pharmacokinetics and therapeutic activity.

Effects of multiple injections of liposomal doxorubicin on pharmacokinetics, therapeutic outcome, and toxicity were studied in mice using different dosing schedules and dose intensities. Biodistribution of doxorubicin to the cutaneous tissues of mice (skin and paws) and to orthotopically implanted mammary tumors (4T1) was examined. Weekly intravenous administration of pegylated (STEALTH) liposomal doxorubicin (SL-DXR) at a dose of 9 mg/kg (every week x 4 doses) resulted in accumulation of doxorubicin in cutaneous tissues of mice and development of lesions resembling palmar-plantar erythrodysesthesia (PPE). Lengthening the dose interval to every 2 weeks x 4 doses reduced the accumulation of doxorubicin and lowered the incidence of PPE-like lesions. A dose interval of every 4 weeks x 4 resulted in complete clearance of doxorubicin from tissues between subsequent doses and a negligible incidence of PPE-like lesions. Doses of 9 mg/kg SL-DXR given at every week x 2 or every 2 weeks x 2 had similar therapeutic activities, whereas prolonging the dose interval to every 4 weeks x 2 reduced therapeutic activity. Pharmacokinetics, biodistribution, and therapeutic activity were studied in tumor-bearing mice for three dose schedules having the same dose intensity (4.5 mg/kg every 3 days x 4, 9 mg/kg every week x 2, or 18 mg/kg every 2 weeks x 1). For these schedules, larger doses administered less often tended to be superior therapeutically to smaller doses given more often. These data provide the first pharmacokinetic measurements of doxorubicin concentrations in cutaneous tissues and tumors with repeat administration of liposomal formulations, and they provide a useful model for the study of factors leading to PPE in humans.

Animals↗

PubMed2006

Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse.

Accumulation of amyloid beta-peptide (Abeta) is considered a key step in the etiology of Alzheimer's disease. Abeta is produced by sequential cleavage of the amyloid precursor protein by beta- and gamma-secretase enzymes. Consequently, inhibition of gamma-secretase provides a promising therapeutic approach to treat Alzheimer's disease. Preclinically, several gamma-secretase inhibitors have been shown to reduce plasma and brain Abeta, although they also produce mechanism-based side effects, including thymus atrophy and intestinal goblet cell hyperplasia. The present studies sought to establish an efficient screen for determining the therapeutic window of gamma-secretase inhibitors and to test various means of maximizing this window. Six-day oral administration of the gamma-secretase inhibitor N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411,575) reduced cortical Abeta(40) in young (preplaque) transgenic CRND8 mice (ED(50) approximately 0.6 mg/kg) and produced significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). The therapeutic window was similar after oral and subcutaneous administration and in young and aged CRND8 mice. Both the thymus and intestinal side effects were reversible after a 2-week washout period. Three-week treatment with 1 mg/kg LY411,575 reduced cortical Abeta(40) by 69% without inducing intestinal effects, although a previously unreported change in coat color was observed. These studies demonstrate that the 3- to 5-fold therapeutic window for LY411,575 can be exploited to obtain reduction in Abeta levels without induction of intestinal side effects, that intermittent treatment could be used to mitigate side effects, and that a 6-day dosing paradigm can be used to rapidly determine the therapeutic window of novel gamma-secretase inhibitors.

Administration, Oral↗

PubMed1964

TOXICITY, THE THERAPEUTIC INDEX, AND THE RANKING OF DRUGS.

The therapeutic index is often used to rank the net effectiveness of drugs and to provide a guide for choosing the best among several drugs. This can be a misleading guide since we show that drugs with the same therapeutic index can have unequal "worth." A substitute ranking measure for the therapeutic index is proposed that would be based on minimizing the losses from the failure to cure plus the losses due to toxicity. This measure would specify a "best" dose over a wide range of conditions, which the therapeutic index does not do. An example is given in which the minimum loss approach produces a ranking of drugs different from that produced by the therapeutic index. In this example the different rankings hold, with minor shifts, over a wide range.

Drug Therapy↗

PubMed2005

Fluconazole MIC and the fluconazole dose/MIC ratio correlate with therapeutic response among patients with candidemia.

We tested 32 Candida isolates recovered in the early 1990s from the bloodstreams of patients with candidemia for in vitro susceptibility to fluconazole and determined if MIC and/or the daily dose of fluconazole/MIC ratio correlated with the response to therapy. This is a unique data set since 87.5% (28/32) of patients were treated with fluconazole doses now considered to be inadequate (</=200 mg), which contributed to high therapeutic failure rates (53% [17/32]). The geometric mean MIC and dose/MIC ratio for isolates associated with therapeutic failure (11.55 mug/ml and 14.3, respectively) differed significantly from values associated with therapeutic success (0.95 mug/ml and 219.36 [P = 0.0009 and 0.0004, respectively]). The therapeutic success rates among patients infected with susceptible (MIC </= 8 mug/ml), susceptible-dose dependent (S-DD) (MIC = 16 or 32 mug/ml), and resistant (MIC >/= 64 mug/ml) isolates were 67% (14/21), 20% (1/5), and 0% (0/6), respectively. A dose/MIC ratio >50 was associated with a success rate of 74% (14/19), compared to 8% (1/13) for a dose/MIC ratio </=50 (P = 0.0003). Our data suggest that both fluconazole MIC and dose/MIC ratio correlate with the therapeutic response to fluconazole among patients with candidemia. In clinical practice, dose/MIC ratio might prove easier to interpret than breakpoint MICs, since it quantitates the effects of increasing fluconazole doses that are alluded to in the S-DD designation.

Adolescent↗

PubMed2025

Identification of a novel phage depolymerase against ST11 K64 carbapenem-resistant Klebsiella pneumoniae and its therapeutic potential.

UNLABELLED: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a clinical pathogen with a high mortality rate, and its clinical management and infection control have become a serious challenge. Phage-encoded depolymerase cleaves the capsular polysaccharide, a major virulence factor of K. pneumoniae. This study aimed to identify a phage depolymerase targeting ST11 K64 CRKP, evaluate its antimicrobial activity and therapeutic efficacy, and provide new alternative therapeutic strategies for K64 CRKP. Phages were screened from untreated hospital sewage using clinically isolated CRKP as the host bacterium. The host range, efficiency of plaque formation, optimal multiplicity of infection, adsorption efficiency, and one-step growth curve of phage vB_KpnP_IME1309 were determined by the double-layer agar plate culture method. The morphology of the phage was observed by transmission electron microscopy. Phage nucleic acids were extracted for whole-genome sequencing, and the phage-encoded depolymerase gene ORF37 was amplified by polymerase chain reaction. Next, a recombinant plasmid was constructed to induce depolymerase expression, which was verified using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In vitro bactericidal activity was determined using a combined serum assay, and the anti-K. pneumoniae biofilm effect of depolymerase was determined by crystal violet staining. Finally, a Galleria mellonella larvae infection model was established to investigate the therapeutic effect of depolymerase on larvae in vivo. Here, we isolated and characterized a phage vB_KpnP_IME1309 targeting ST11 K64 CRKP, which featured a latent period of 20 min and a burst size of approximately 290 plaque-forming units/cell. It contained 41 predicted open reading frames, of which ORF37 encoded depolymerase. The expressed and purified depolymerase Dep37 cleaved only ST11 K64 CRKP and formed a translucent halo on the agar plate. Dep37 increased the susceptibility of K. pneumoniae B1 to serum killing, inhibited CRKP biofilm formation, and degraded mature biofilms. The combination of Dep37 and kanamycin was significantly more effective in treating CRKP biofilms compared to either Dep37 or kanamycin alone. An injection of Dep37 at 5 min and 2 h after the CRKP infection of Galleria mellonella larvae increased their survival rates by up to 73% and 53%, respectively. Depolymerase Dep37 may be used as a potential method for capsule typing of K. pneumoniae, showing great promise for the development of novel alternative therapeutic strategies against ST11 K64 CRKP. IMPORTANCE: A novel phage vB_KpnP_IME1309 targeting ST11 K64 carbapenem-resistant Klebsiella pneumoniae (CRKP) was isolated and characterized. The ORF37 encoding depolymerase gene of phage vB_KpnP_IME1309 was successfully expressed and purified. Depolymerase increases the susceptibility of CRKP to serum killing, inhibits CRKP biofilm formation, and degrades mature biofilms. The combination of depolymerase and kanamycin is significantly more effective than either depolymerase or kanamycin alone in the treatment of CRKP biofilm. Depolymerase injection at 5 min and 2 h after CRKP infection of Galleria mellonella larvae increased the survival rate of larvae by up to 73% and 53%, respectively. Depolymerase Dep37 may be used as a method for the development of novel alternative therapeutic strategies against ST11 K64 CRKP.

Klebsiella pneumoniae↗

PubMed1995

Specific therapeutic group age-sex related prescribing units (STAR-PUs): weightings for analysing general practices' prescribing in England.

OBJECTIVES: To derive cost comparators for prescribing by English general practitioners in eight specific therapeutic groups, based on age-sex related weightings, and to confirm, from a new dataset, earlier age-sex weightings for overall prescribing (ASTRO-PUs). DESIGN: Calculations based on one year's prescribing data from selected practices using AAH Meditel software, held on MediPlus by Intercontinental Medical Statistics (IMS, UK and Ireland), and research practices using VAMP software, held on the General Practice Research Database. SETTING: 112 English practices with 739,672 patients and 510 British practices with 3,126,570 patients. MAIN OUTCOME MEASURES: Cost based weightings for 18 age-sex groups and for temporary residents for eight leading specific therapeutic groups and for prescribing overall. RESULTS: The two datasets were similar in age distribution and in the way that prescription numbers were distributed by age-sex band in each therapeutic group. The cost based weightings for specific therapeutic groups showed great variation in the use of these groups for patients in different age-sex groups. When these weightings were applied to the prescribing of practices in two family health services authorities they differed in their power to predict prescribing costs: for cardiovascular and gastrointestinal drugs predictive power was particularly high; for drugs for infections it was particularly low, since these are widely used at all ages and for both sexes. Cost based weightings for overall prescribing derived from the IMS data were similar to those of the ASTRO-PU system even though they were derived by different methods from different datasets. CONCLUSIONS: The weightings (STAR-PUs) offer a sound basis for cost comparisons at the therapeutic group level. Cost-based weightings for overall prescribing derived from the IMS data were reassuringly similar to those of the existing ASTRO-PU system.

Adolescent↗

PubMed2006

Therapeutic effect of urocortin and adrenomedullin in a murine model of Crohn's disease.

BACKGROUND AND AIMS: Urocortin 1 (UCN) and adrenomedullin (AM) are two recently discovered neuropeptides that, due to their distribution and binding to receptors in immune cells, have emerged as potential endogenous anti-inflammatory factors. Crohn's disease is a chronic debilitating disease characterised by a Th1 driven severe inflammation of the gastrointestinal tract. This study investigated the therapeutic effect of UCN and AM in a murine model of colitis. METHODS AND RESULTS: Treatment with UCN or AM ameliorated significantly the clinical and histopathological severity of the inflammatory colitis, abrogating body weight loss, diarrhoea, and inflammation, and increased the survival rate of colitic mice. The therapeutic effect was associated with downregulation of both inflammatory and Th1 driven autoimmune responses, including regulation of a wide spectrum of inflammatory mediators. In addition, partial involvement of interleukin 10 secreting regulatory cells in this therapeutic effect was demonstrated. Importantly, UCN or AM treatments were therapeutically effective in established colitis and avoided recurrence of the disease. CONCLUSIONS: This work identifies UCN and AM as two potent anti-inflammatory factors with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels. Consequently, both peptides represent novel multistep therapeutic approaches for the treatment of Crohn's disease and other Th1 mediated inflammatory diseases.

Adrenomedullin↗

PubMed2006

A questionnaire on factors influencing children's assent and dissent to non-therapeutic research.

BACKGROUND: Knowledge about assent or dissent of children to non-therapeutic research is poor. OBJECTIVES: To assess sociodemographic characteristics in healthy children and adolescents who were invited to participate in non-therapeutic research, to evaluate their motives for assent or dissent and their understanding of the information given. METHODS: A total of 1281 healthy children and adolescents six to sixteen years of age were invited to participate in a non-therapeutic study and a questionnaire. RESULTS: Assenting children were motivated by a desire to help sick children (n = 638, 98%) and to gain experience with participating in a research study (n = 503, 82%). Dissenting children made their decision because of worries about having a blood (n = 193, 46%) or a urine sample (n = 94, 26%) taken or because of worries about a doctor's examination (n = 136, 33%). Fewer children in the assent group (n = 166, 25%) than in the dissent group (136, 33%) worried about the doctor's examination (p = 0.01). In the assent and dissent group, 568 (86%) and 343 (85%) children, respectively, said they were able to understand some or all of the written information (p = 0.42), and 650 (97%) and 330 (98%), respectively, were able to understand some or all of the verbal information (p = 0.07). CONCLUSIONS: Sociodemographic characteristics may not influence healthy children's decision to volunteer for non-therapeutic research. Assenting children have altruistic and educational motives, whereas worries about procedures may cause children to dissent. A great majority of school children and adolescents feel capable of understanding and giving assent or dissent to non-therapeutic research.

Adolescent↗

PubMed2000

Randomised prospective parallel trial of therapeutic versus subtherapeutic nasal continuous positive airway pressure on simulated steering performance in patients with obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) impairs vigilance and may lead to an increased rate of driving accidents. In uncontrolled studies accident rates and simulated steering performance improve following treatment with nasal continuous positive airway pressure (NCPAP). This study seeks to confirm the improvement in steering performance in a randomised controlled trial using subtherapeutic NCPAP as a control treatment. METHODS: Fifty nine men with OSA (Epworth Sleepiness Score (ESS) of > or =10, and > or =10/h dips in SaO(2) of >4% due to OSA) received therapeutic or subtherapeutic NCPAP ( approximately 1 cm H(2)O) for one month. Simulated steering performance over three 30-minute "drives" was quantified as: standard deviation (SD) of road position, deterioration in SD across the drive, length of drive before "crashing", and number of off-road events. The reaction times to peripheral target stimuli during the drive were also measured. RESULTS: Subtherapeutic NCPAP did not improve overnight >4% SaO(2) dips/h compared with baseline values, thus acting as a control. The SD of the steering position improved from 0.36 to 0.21 on therapeutic NCPAP, and from 0.35 to 0.30 on subtherapeutic NCPAP (p = 0.03). Deterioration in SD of the steering position improved from 0.18 to 0.06 SD/h with therapeutic NCPAP and worsened from 0.18 to 0.24 with subtherapeutic NCPAP (p = 0.04). The reaction time to target stimuli was quicker after therapeutic than after subtherapeutic NCPAP (2.3 versus 2.7 seconds, p = 0.04). CONCLUSIONS: Therapeutic NCPAP improves steering performance and reaction time to target stimuli in patients with OSA, lending further support to the hypothesis that OSA impairs driving, increases driving accident rates, and that these improve following treatment with NCPAP.

Accidents, Traffic↗

PubMed2003

Therapeutic effect of anti-OX40L and anti-TNF-alpha MAbs in a murine model of chronic colitis.

Interaction of OX40 (CD134) on T cells with its ligand (OX40L) on antigen-presenting cells has been implicated in pathogenic T cell activation. This study was performed to explore the involvement of OX40/OX40L in the development of T cell-mediated chronic colitis. We evaluated both the preventive and therapeutic effects of neutralizing anti-OX40L MAb on the development of chronic colitis in SCID mice induced by adoptive transfer of CD4(+)CD45RB(high) T cells as an animal model of Crohn's disease. We also assessed the combination of anti-OX40L and anti-TNF-alpha MAbs to improve the therapeutic effect. Administration of anti-OX40L MAb markedly ameliorated the clinical and histopathological disease in preventive and therapeutic protocols. In vivo treatment with anti-OX40L MAb decreased CD4(+) T cell infiltration in the colon and suppressed IFN-gamma, IL-2, and TNF-alpha production by lamina propria CD4(+) T cells. The combination with anti-TNF-alpha MAb further improved the therapeutic effect by abolishing IFN-gamma, IL-2, and TNF-alpha production by lamina propria CD4(+) T cells. Our present results suggested a pivotal role of OX40/OX40L in the pathogenesis of T cell-mediated chronic colitis. The OX40L blockade, especially in combination with the TNF-alpha blockade, may be a promising strategy for therapeutic intervention of Crohn's disease.

Animals↗

PubMed2006

Therapeutic effect of imatinib in gastrointestinal stromal tumors: AKT signaling dependent and independent mechanisms.

Most gastrointestinal stromal tumors (GISTs) possess a gain-of-function mutation in c-KIT. Imatinib mesylate, a small-molecule inhibitor against several receptor tyrosine kinases, including KIT, platelet-derived growth factor receptor-alpha, and BCR-ABL, has therapeutic benefit for GISTs both via KIT and via unknown mechanisms. Clinical evidence suggests that a potential therapeutic benefit of imatinib might result from decreased glucose uptake as measured by positron emission tomography using 18-fluoro-2-deoxy-d-glucose. We sought to determine the mechanism of and correlation to altered metabolism and cell survival in response to imatinib. Glucose uptake, cell viability, and apoptosis in GIST cells were measured following imatinib treatment. Lentivirus constructs were used to stably express constitutively active AKT1 or AKT2 in GIST cells to study the role of AKT signaling in metabolism and cell survival. Immunoblots and immunofluorescent staining were used to determine the levels of plasma membrane-bound glucose transporter Glut4. We show that oncogenic activation of KIT maximizes glucose uptake in an AKT-dependent manner. Imatinib treatment markedly reduces glucose uptake via decreased levels of plasma membrane-bound Glut4 and induces apoptosis or growth arrest by inhibiting KIT activity. Importantly, expression of constitutively active AKT1 or AKT2 does not rescue cells from the imatinib-mediated apoptosis although glucose uptake was not blocked, suggesting that the potential therapeutic effect of imatinib is independent of AKT activity and glucose deprivation. Overall, these findings contribute to a clearer understanding of the molecular mechanisms involved in the therapeutic benefit of imatinib in GIST and suggest that a drug-mediated decrease in tumor metabolism observed clinically may not entirely reflect therapeutic efficacy of treatment.

Apoptosis↗

PubMed2004

Curtailing the high rate of late-stage attrition of investigational therapeutics against unprecedented targets in patients with lung and other malignancies.

A greater understanding of the pathogenesis and biology of cancer coupled with major advances in biotechnology has resulted in the identification of rationally designed, target-based (RDTB) anticancer therapeutics, ushering in new therapeutic opportunities and high expectations for the future as well as developmental challenges. Because these agents appear to principally target malignant cells, it is expected that they will produce less toxicity at clinically effective doses than nonspecific cytotoxic agents, but their target requirements are likely to be much more stringent. The innate complexity of the networks that contain elements targeted by these agents also decreases the probability that any single therapeutic manipulation will result in robust clinical activity and success when used alone, particularly in patients with solid malignancies that have multiple relevant signaling aberrations. In contrast, proof of principle and robust antitumor activity may be most efficiently demonstrated in nonrandomized evaluations involving tumors that are principally driven by aberrations of the specific target. The predominant therapeutic manifestation of RDTB agents in preclinical studies is due to decreased tumor growth rates and will likely be similar in the clinic; however, such manifestations are not readily detectable and quantifiable using nonrandomized clinical evaluations. To curtail the increasing rate of late-stage attrition of RDTB agents, which, if maintained, will stymie progress in cancer therapy, the design of initial nonrandomized evaluations, particularly the selection of tumors and patients, must be guided by the principal biological features of the agents. Next, evaluations, some of which must be randomized, can be performed in a wide range of tumor types, depending on the presence and relevance of the target. To validate the concept of RDTB therapeutics and to realize their full potential, radically different development, evaluation, and regulatory paradigms must be adopted.

Antineoplastic Agents↗

PubMed2006

Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression.

PURPOSE: Medulloblastoma, a malignant pediatric brain tumor, is incurable in about one third of patients despite multimodal treatments. In addition, current therapies can lead to long-term disabilities. Based on studies of the extensive tropism of neural stem cells (NSC) toward malignant gliomas and the secretion of growth factors common to glioma and medulloblastoma, we hypothesized that NSCs could target medulloblastoma and be used as a cellular therapeutic delivery system. EXPERIMENTAL DESIGN: The migratory ability of HB1.F3 cells (an immortalized, clonal human NSC line) to medulloblastoma was studied both in vitro and in vivo. As proof-of-concept, we used HB1.F3 cells engineered to secrete the prodrug activating enzyme cytosine deaminase. We investigated the potential of human NSCs to deliver a therapeutic gene and reduce tumor growth. RESULTS: The migratory capacity of HB1.F3 cells was confirmed by an in vitro migration assay, and corroborated in vivo by injecting chloromethylbenzamido-Dil-labeled HB1.F3 cells into the hemisphere contralateral to established medulloblastoma in nude mice. In vitro studies showed the therapeutic efficacy of HB1.F3-CD on Daoy cells in coculture experiments. In vitro therapeutic studies were conducted in which animals bearing intracranial medulloblastoma were injected ipsilaterally with HB1.F3-CD cells followed by systemic 5-flourocytosine treatment. Histologic analyses showed that human NSCs migrate to the tumor bed and its boundary, resulting in a 76% reduction of tumor volume in the treatment group (P<0.01). CONCLUSION: These studies show for the first time the potential of human NSCs as an effective delivery system to target and disseminate therapeutic agents to medulloblastoma.

Animals↗

PubMed2007

Modifying dendritic cells via protein transfer for antitumor therapeutics.

PURPOSE: The modification of therapeutic dendritic cells (DC) with various immunostimulatory molecules represents a useful means for improving the antitumor efficacy of DC transfer-based immunotherapy. We have evaluated the feasibility of modifying therapeutic DCs with multiple immunostimulatory molecules using a time-efficient, protein transfer (or protein "painting")-based method. EXPERIMENTAL DESIGN: Bone marrow-derived DCs were painted with either control protein human IgG (hIgG) or three immunostimulatory molecules, SLC, 4-1BBL, and TRANCE (the triad protein). Painted DCs were injected intratumorally into mice bearing established tumors. Subsequently, the capacities of painted DCs to migrate to the draining lymph nodes, recruit the host T cells, promote Th1 cytokine responses, and elicit therapeutic antitumor responses were evaluated. RESULTS: The triad protein transfer yields a uniform population of DCs that coexpress all three of the proteins. Compared with the hIgG-painted DCs, the triad protein-painted DCs migrate more efficiently to the draining lymph nodes and show enhanced capabilities to induce T cell infiltration of tumors and to promote Th1 cytokine responses in vivo. Furthermore, in both the EG.7 and TRAMP-C2 tumor models, compared with the DCs painted with hIgG or only one of the three proteins, the triad protein-painted DCs, upon adoptive transfer, elicit stronger therapeutic responses against established tumors. Importantly, the antitumor responses of the triad protein-painted DCs are mediated by systemic antitumor immunity. CONCLUSIONS: This study establishes, for the first time, the feasibility of optimizing DC transfer-based immunotherapy via combinatorial protein transfer of therapeutic DCs with an array of immunostimulatory molecules.

Animals↗

PubMedDate not supplied

Ethical questions raised by in utero therapeutics with stem cells and gene therapy.

The plasticity of living beings is limitless and our guidelines are constantly upset. Several ethical questions arise with this new in utero therapeutic approach: (1) The possibility of a mother giving truly informed consent when she is divided between a proposal to terminate her pregnancy and resignation to the birth of an abnormal child. How can she choose between three therapeutic proposals, when two of them are unbearable and only one carries some hope? (2) If a dead fetus is used as a donor of hepatic or hematologic stem cells, should this be based on the mother's consent? If so, what status is given to this fetus? Is it possible to take into consideration at the same time the growing demand to recognize the fetus as a person and his gift? (3) It is important to separate the services that receive dead fetuses from those that perform the injection of fetal stem cells so that the fetus does not become a mere therapeutic tool. (4) Even if the technique is not very difficult, can ex vivo transduction of mesenchymatous cells be performed as a kind of gene therapy without causing great anxiety over the embryo's germinal future? The main question is that even though surgery and medical therapeutics for the fetus have made great progress and become commonplace, the use of stem cell transplantations and eventually gene therapy privileges experimental medicine and research that are more and more difficult to conceive on an ethical level. If indeed fetal therapeutics seems to hold out promise for the future, the very speed with which we pass from conception to its experimental realization with a child must necessarily challenge our thinking.

Abortion, Eugenic↗

PubMed2005

Patient-Practitioner-Remedy (PPR) entanglement, Part 8: 'Laser-like' action of the homeopathic therapeutic encounter as predicted by a gyroscopic metaphor for the vital force.

BACKGROUND: A preliminary mathematical model for the Vital Force had been developed based on the idea of a metaphorical gyroscope, combined with earlier notions derived from Weak Quantum Theory (WQT) and Patient-Practitioner-Remedy (PPR) Entanglement. This combination generates a hypothetical 'wave function' as a description of the state of the Vital Force that is intimately related to the secondary symptom picture of the therapeutic remedy, and is capable of illustrating certain empirical observations of the homeopathic process, including the bi-phasal action of remedies and some of the results gained from provings. OBJECTIVE: The goal of this present study was to further develop the idea of a Vital Force 'wave function' by generating insights into its mode of reaction to therapeutic intervention by a practitioner. METHODS: In orthodox quantum theory, the time-dependent Schrödinger equation, in which a particle's wave function is operated upon by the Hamiltonian total energy operator, provides information concerning the temporal evolution of the wave function. By analogy, a secondary-symptom-dependent Vital Force equation is postulated in which the Vital Force 'wave function' is operated upon by a so-called 'homeopathic operator'. RESULTS: By inserting the previously developed wave function for the Vital Force into the secondary-symptom-dependent Vital Force equation, another equation is generated mathematically reminiscent of longitudinal mode standing waves set up in the resonant cavity of a laser. CONCLUSION: In the language of therapeutics, it is often said an essential part of the curative process is that practitioners act as 'mirrors' for their patients. Previous papers in this series have shown that this reflective practitioner activity is more than a poetic analogy. Borrowing from the mathematical formalism of quantum theory, with its ideas of entangled, coherent wave-functions as metaphors for the homeopathic process, this mirror-like activity can be seen to be an integral part of the curative therapeutic encounter. The preliminary theoretical investigation reported here develops the metaphor further by suggesting that the effect of this practitioner mirror-like activity on a patient's Vital Force during the therapeutic encounter, might be likened to the sequence of operations by which lasers function. The analogy seems compelling, as an essential feature of laser operation is the arrangement of parallel mirrors placed at both ends of the laser's resonant cavity.

Empiricism↗