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PubMed2001

Macromolecular therapeutics: emerging strategies for drug discovery in the postgenome era.

The postgenome era offers a plethora of potential therapeutic targets. Many of these targets will be addressable using small organic molecules as drug candidates. However, certain aspects of cell function, particularly those that rely on protein-protein or protein-nucleic acid interactions, will be difficult to influence using small molecules. Thus, the possibility of using highly specific macromolecules as potential therapeutic agents is an intriguing concept. Recent developments in several areas of research have brought this possibility closer to fruition. Peptide and nucleic acid combinatorial libraries allow the generation of novel molecules having exquisite selectivity. Structural information and molecular modeling also contribute to the design of new macromolecules with therapeutic potential. Perhaps most importantly, approaches for delivering macromolecules into the cell interior have been developed and applied with considerable success. Thus, the therapeutic use of macromolecules, including oligonucleotides, peptides, and proteins, may be an idea whose time has come.

Animals↗
PubMedDate not supplied

Evaluation of the therapeutic effect using MD-CT immediately after RFA for HCC.

BACKGROUND/AIMS: Radiofrequency ablation (RFA) is an effective modality for treatment of hepatocellular carcinoma (HCC), because it can induce large coagulation necrosis in a few sessions. The aim of this study is to evaluate whether we can assess the therapeutic effect of RFA immediately after RFA. METHODOLOGY: Twenty-one patients (25 nodules) with HCC undergoing RFA treatment were enrolled in this study. Fourteen patients were treated with combination therapy of lipiodol chemoembolization and RFA, while 7 patients were treated with RFA alone. Dynamic computed tomography (CT) using multidetector row helical CT (MD-CT) was performed before, immediately after and 1 week after RFA. Simultaneously, multiplanar reconstruction (MPR) images were also obtained for comparison. RESULTS: With or without chemoembolization, the size of coagulated necrosis was almost the same between the time immediately after and 1 week after RFA. The therapeutic effect was able to be evaluated by dynamic CT scans immediately after RFA in all patients. Moreover, MPR images facilitate the detailed evaluation of the therapeutic effect. CONCLUSIONS: Examination of dynamic CT using MD-CT immediately after RFA is useful to evaluate the therapeutic effect and may enable a shorter hospital stay.

Aged↗
PubMed1989

The intracapsular therapeutic modalities in conjunction with arthrography: case reports.

Manipulation and lavage of the temporomandibular joint has been shown to add an important therapeutic dimension to arthrography. These therapeutic modalities were prescribed by the primary treating practitioner in conjunction with diagnostic arthrography in a group of patients. The therapeutic modalities consisted of joint mobilization (Farrar manipulation or distraction) augmented by (1) increased hydraulic pressure in the superior compartment, or (2) with small amounts of contrast in both compartments, and/or (3) with lavage of the superior joint compartment. The therapeutic modalities were prescribed in association with the arthrography as a logical extension of the arthrographic technique. The result of the mobilization and lavage was an increase in the mandibular range of motion (ROM) and a decrease in pain in cases with adhesions as well as those with anteriorly displaced disks without reduction. Patients with anteriorly displaced disks with reduction, redundant tissue in the fossa, osteochondritis, and adhesive capsulitis also showed benefit, although patient populations treated with these conditions were small. There were no adverse sequelae. Manipulation and lavage should now be viewed as one more tool in the treatment of intracapsular pathology.

Adolescent↗
PubMed1978

[Socio-ecological study of the therapeutic milieu in a modern rehabilitation centre (author's transl)].

The article presents a data survey carried out by means of a questionnaire, the "ward atmosphere scale" described by Moos (1966--1974), U.S.A. In Austria, the effects of socio-ecological influences are examined for the first time at the rehabilitation centre in Hochegg. The data refer to autumn 1975. At that time attempts were made at Hochegg rehabilitation centre to develop a staff-centred guidance style and a client-centred therapeutic milieu in the sense of a therapeutic community. The patients were offered therapeutic programmes which were to the greatest possible degree tailored to their individual needs whilst not interferring with the patients' spontaneity and personal initiative. The analysis of the variables used in Hochegg are illustrated and compared with the mean values of the American results. It is pointed out that studies of existing conditions performed in an endeavour to create more human working conditions, are met with disapprouval. The first results of the survey are intended to be used as the basis for the improvement of the questionnaire and are helpful in decision-making regarding the development of therapeutic styles which meet the needs of the patient, regarding staff management and architectural influences.

Austria↗
PubMed1976

Peripheral dissemination of bacteria in contaminated wounds; role of devitalized tissue: evaluation of therapeutic measures.

The role of available therapeutic agents in the management of infection has long been a continuing source of debate. This study assessed the rapidity of lateral dissemination of three common pyogenic organisms from wounds. The Streptococcus spreads peripherally with greater speed than the Staphylococcus or E. coli. Appraisal of the role and effectiveness of jet wound irrigation, debridement, and penicillin provides firm evidence that, of these three therapeutic agents, the only one that can control bacterial proliferation in a contaminated wound is the antibiotic. The primary role of energized jet irrigation is to remove clots and wound debris. The specific function of debridement is removal of devitalized tissue, in which role it has no effective competitor. These studies demonstrate that devitalized tissue in a contaminated wound quickens the rapidity of peripheral spread of all three micro-organisms. Systemic penicillin plus saline irrigation is the most effective therapeutic measure at both the second and fourth postinoculation hours in nondevitalized contaminated wounds. Debridement proved to be the most effective therapeutic device at the second, fourth, and sixth postinoculation hours in devitalized wounds.

Animals↗
PubMed1998

[Significance of arterial infusion of SMANCS-dissolved Lipiodol in therapeutic strategies for hepatocellular carcinoma].

The arterial infusion of lipiodol (LPD) containing SMANCS (SMANCS/LPD) has been considered to be a tumor-targeting therapy for hepatocellular carcinoma (HCC). It is important to establish a role of this new therapy in systematic strategies for HCC. LPD has no embolic effect, and the lipophilic anti-cancer agent, SMANCS, suspended in LPD and delivered selectively in tumors, shows therapeutic effect. Accordingly, it is essential for therapeutic efficacy that HCC cells have a chemosensitivity to SMANCS. The maximum dose of SMANCS/LPD is 6 ml at one time, which is not sufficient for voluminous tumors. These are the disadvantages of SMANCS/LPD therapy. Furthermore, HCC tissues, in which lipiodol is retained, is limited to moderately differentiated, with large blood spaces. SMANCS/LPD is not effective for well- and poorly -differentiated HCCs, because blood spaces in these histological types are too small for SMANCS/LPD to be deposited. On the other hand, transcatheter arterial embolization therapy (TAE) is effective by occluding feeding artery with small pieces of gelatin sponge, and a much tumor necrosis is obtained by TAE at one time. However, HCC cells beneath and within the capsule, and invading outside the capsule, are viable, possibly due to backflow of blood via drainage vein. Tumor thrombi and tiny intrahepatic metastases also escape the TAE effect. Previously we reported the new therapy at the first time: the combination of arterial infusion of SMANCS/LPD and TAE (LpTAE). LpTAE has some therapeutic benefits of both therapies; SMANCS/LPD fills up a whole tumor, and part of the LPD flows out from the tumor, is trapped in the capsular invasion and microscopic metastatic foci with the necrotic change. LPD prevents regurgitation of blood flow in drainage vein, and promotes necrotic change. After LpTAE, Lipiodol CT shows 4 kinds of LPD-deposition pattern in HCC; the therapeutic effects of LpTAE are exactly evaluated by these patterns. For total necrosis, HCC nodule shows a complete type, in which the whole tumor shows a metallic density by lipiodol deposition. In other patterns, the LPD-deposited area in tumors generally shows necrosis, and non-LPD-deposited areas are viable. The second line of the therapies. PEIT or resection, can be selected by the LPD-deposition pattern. We consider that the intraarterial infusion of SMANCS/LPD reinforces TAE, and LpTAE is one of the most effective therapies.

Antineoplastic Agents↗
PubMed1998

The effects of therapeutic touch on patients with osteoarthritis of the knee.

BACKGROUND: The purpose of this study was to determine if therapeutic touch, an alternative medicine modality, is effective in the treatment of osteoarthritis of the knee. METHODS: A single-blinded randomized control trial was conducted in a family practice center of a community hospital family practice residency program in Pennsylvania. The patients were between the ages of 40 and 80, had been given a diagnosis of osteoarthritis of at least one knee, had not had knee replacement, and had no other connective tissue disease. The patients were randomized to therapeutic touch, mock therapeutic touch, or standard care. The main outcome measures were pain and its impact, general well-being, and health status measured by standardized, validated instruments, as well as the qualitative measurement of a Depth interview. RESULTS: Twenty-five patients completed the study. The treatment group had significantly decreased pain and improved function as compared with the placebo and control groups. The qualitative Depth interview confirmed this result. CONCLUSION: Despite the small numbers, significant differences were found in improvement in function and pain for patients receiving therapeutic touch. A larger study is needed to confirm these results. Alternative therapies can neither be accepted nor rejected without being subjected to the scientific method.

Activities of Daily Living↗
PubMed1998

Therapeutic touch: an extension of professional skills.

Therapeutic touch, developed 25 years ago by Dolores Krieger, RN, PhD, and Dora Kunz, continues to gain ever wider acceptance in the health care field for one reason--it works. In our high-tech dialysis world of invasive, often painful procedures, therapeutic touch offers a welcome reprieve for patients and staff alike. For patients it has decreased restlessness, anxiety, fear and the pain from cannulations and central venous catheter insertions. Besides helping the recipients, therapeutic touch also affects the practitioners, with most practitioners reporting a greater sense of calm and well-being, in addition to the personal satisfaction of being able to offer a treatment that brings such relief to stressed-out patients. This article will introduce therapeutic touch and its use in the clinical setting.

Clinical Competence↗
PubMedDate not supplied

Quality assessment of a collaborative approach for decreasing drug-related morbidity and achieving therapeutic goals.

BACKGROUND: Collaboration between physicians and pharmacists is one approach to address drug-related morbidity and achieve therapeutic goals. A collaborative practice of pharmaceutical care has been used in the Fairview Clinics System of Minneapolis-St Paul since 1999. METHODS: The quality of therapeutic determinations made by pharmacists within this collaborative practice of pharmaceutical care was studied by a 12-member panel of physicians and pharmacists who used randomly selected patient records. This was a quality improvement and care process validation component of a study evaluating the effects of drug therapy management in patients receiving prepaid medical assistance. An implicit review process was used to evaluate the clinical credibility of therapeutic determinations made by pharmaceutical care practitioners. RESULTS: A total of 5780 drug therapy problems were resolved for 2524 patients receiving pharmaceutical care. The rate of therapeutic goals achieved increased from 74% at the time of patients' initial pharmaceutical care encounters to 89% at patients' latest encounters. In this quality assessment analysis panel members performed a total of 4779 evaluations of clinical decisions. Panelists indicated agreement with the evaluations in 94.2% of cases, expressed a neutral opinion in 3.6% of cases, and disagreed in 2.2% of cases. Intraclass correlation coefficients ranged from 0.73 to 0.85. CONCLUSIONS: The decisions made by pharmaceutical care practitioners working in collaboration with physicians to provide drug therapy management services are clinically credible based on the evaluations and comments of a peer review panel. This study provides information on the quality of care provided by pharmacists when collaborating with physicians to provide drug therapy management services.

Cooperative Behavior↗
PubMed1976

Visual effects of pilocarpine in glaucoma comparative study of administration by eyedrops or by ocular therapeutic systems.

Eighteen glaucoma patients each received four pilocarpine regimens in random sequence: 1% and 4% eyedrops and 20mug/hr and 40mug/hr ocular therapeutic systems. Unimportant changes in refraction, near vision, and distance vision occurred during the use of either ocular therapeutic system. Miosis with ocular therapeutic systems was almost always less intense and variable than with eyedrops. Refractive changes occurred in 12 patients following 1% pilocarpine and in 16 patients following 4% pilocarpine drops; decreased distance vision occurred in nine patients after 1% drops and in 12 patients after 4% drops. Fewer patients showed decreases in near vision. In all cases, visual effects peaked one half hour after eyedrop instillations and returned gradually toward normal in the next two to three hours. Intraocular pressure levels were within comparable ranges during all four treatments, but the ocular therapeutic systems maintained pressure at a more constant level.

Adolescent↗
PubMed1978

A proposed pilocarpine therapeutic test.

For the pilocarpine therapeutic test that we have devised, one drop (0.1 ml) of 2% pilocarpine hydrochloride (an arbitrarily chosen concentration) is instilled in the glaucomatous eye to be treated, and the intraocular pressure is measured hourly for four hours. If the IOP does not fall below 24 mm Hg, which is our chosen pressure limit, the response is considered to be inadequate therapeutically. Our study showed that if an inadequate therapeutic response is obtained, initiation of treatment with 2% pilocarpine is not indicated, since in patients with such a response, continued treatment with 2% pilocarpine will be ineffective in controlling IOPs on subsequent clinical visits. In only those cases of patients with an adequate response to the pilocarpine therapeutic test (with a fall in pressure below 24 mm Hg) was there the likelihood of having the glaucoma controlled with continued 2% pilocarpine treatment.

Glaucoma↗
PubMed1997

Generation of therapeutic T cells from draining lymph nodes in a murine model of head and neck squamous cell carcinoma.

OBJECTIVES: To study immunotherapy for advanced head and neck squamous cell carcinoma using AT-84, a spontaneously arising murine tumor. We examined the draining lymph nodes (DLNs) for generation of potential therapeutic lymphocytes in head and neck squamous cell carcinoma. DESIGN: Experimental randomized control trial. INTERVENTION: Therapeutic T cells from DLNs were generated by the sequential activation of the in vivo-primed DLN cells with 2C11, and anti-CD3 antibody, and interleukin-2 (IL-2). Immunotherapy of mice bearing lung metastases was carried out in various experiments with low-dose systemic IL-2 and activated DLN cells. Using a 4-hour radioactive chromium Cr 51 release assay, in vitro cytotoxicity of these cells also was examined. RESULTS: Mice immunized with this tumor failed to reject the growth of a subsequent challenge with the tumor. Immunotherapy with low-dose systemic IL-2 resulted in a mean reduction of 79% in the number of lung metastases. Adoptive immunotherapy with activated DLN cells was effective in all experiments, with a mean reduction of 59% in the number of metastases in immunodeficient mice. However, DLN cells were not directly cytotoxic to the tumor cells in in vitro assays, unlike control lymphokine-activated killer cells. CONCLUSIONS: AT-84 is a nonimmunogenic tumor similar to many human malignant neoplasms, making this a suitable model for immunotherapy. Low-dose systemic IL-2 was effective in reduction of established metastasis in this model. Activated DLN cells show reproducible in vivo therapeutic efficacy despite lack of in vitro cytotoxicity. Use of DLN cells as sources of therapeutic T cells in patients with head and neck squamous cell carcinoma deserves exploration because they are readily obtainable and because conventional treatment is of limited benefit.

Animals↗
PubMed1998

A worse prognosis for men with testicular atrophy at therapeutic orchiectomy for prostate carcinoma.

BACKGROUND: The significance of testicular atrophy at the time of therapeutic orchiectomy for prostate carcinoma has not been examined even though pretreatment hypogonadism has been associated with poor prognosis during chemical androgen ablation for these tumors. METHODS: Survival after therapeutic orchiectomy was determined for 78 men with prostate carcinoma and related to the histologic severity of testicular atrophy. Included in analysis were the presence or absence of prior radiation therapy, tumor grade and stage at diagnosis, host age, obesity, and smoking habits. RESULTS: Among 35 men who underwent therapeutic orchiectomy for progressive disease after primary radiation therapy to the prostate bed, the 25 men with testicular atrophy had worse 5-year, tumor specific, postorchiectomy survival than the 10 men without testicular atrophy (30% vs. 89%) (P=0.02). These 25 men had tumors of more advanced stage and greater undifferentiation at the time of diagnosis an average of 45 months before orchiectomy, but neither characteristic was related to postorchiectomy survival. Among 25 men with Stage D2 disease (American Urologic Association staging system) with orchiectomy as the primary treatment, the 7 men with testicular atrophy more often had undifferentiated tumors and had lower 2-year tumor specific survival than the 18 men without atrophy (43% vs. 72% ) (P > 0.10). CONCLUSIONS: Testicular atrophy at the time of therapeutic orchiectomy for prostate carcinoma is associated with poor postorchiectomy prognosis in men with prior prostate bed radiation therapy and perhaps in men without prior radiation. The association may reflect a high frequency of inherently more aggressive tumors (often relatively nonandrogen-dependent) among those tumors that are progressing in hypogonadal men.

Aged↗
PubMed1999

Stage I (T1 N0 M0) squamous cell carcinoma of the laryngeal glottis: therapeutic results and voice preservation.

BACKGROUND: The therapeutic outcomes for voice preservation in Stage I (T1 N0 M0) glottic carcinoma, treated with conservation surgery, radiation therapy, and endoscopic resection, are controversial. METHODS: A retrospective tumor registry retrieval of data on patients treated with curative intent at Washington University Medical Center-Barnes Hospital between January 1971 and December 1990 for the surgical group, January 1971 to December 1985 for the low-dose radiation group, and January 1986 to January 1995 for the high-dose radiation group, was performed. RESULTS: The 659 patients with Stage I (T1 N0 M0) glottic carcinoma treated with curative intent were subdivided into four groups: (1) 90 patients received low-dose radiation (mean dose 58 Gy, range 55-65 Gy, daily fractionation 1.5-1.8 Gy); (2) 104 patients received high-dose radiation (mean dose 66.5 Gy, range 65-70 Gy, daily fractionation 2-2.25 Gy); (3) 404 patients underwent conservation surgery; and (4) 61 patients had endoscopic resection. T1A (85%) and T1B (15%) disease was equally distributed among the groups. The anterior commissure was involved in 38 patients in the radiation therapy groups and 56 patients in the surgical groups. The overall local control was 89%. The overall local salvage was 84%. The overall unaided laryngeal voice preservation was 90%. The overall 5-year disease specific and actuarial survival rates were 95% and 81%, respectively. Prevalence of 2% regional metastases, 1.2% distant metastases, and 14% second primary malignancies were documented. The cure rate was 69% for regional metastases, 13% for distant metastases, and 44% for second primary malignancies. There were 5 complication deaths (0.1%), and 38 (6%) patients died of intercurrent disease. The use and dose of tobacco products was significantly increased in patients who died of intercurrent disease (p = 0.004) or developed second primary malignancies (p = 0.024). No significant difference was observed among the four therapeutic groups in the 5-year cause-specific survival rate (p, 0.68). Actuarial survival was significantly decreased in the low-dose radiation therapy group as compared with the other three therapeutic groups (p = 0.04). Initial local control was poorer for the endoscopic (77%) and low-dose radiation (78%) groups as compared with the high-dose radiation (89%) and conservation surgery (92%) groups (p = 0.02) but significant differences were not found for ultimate local control following salvage treatment. Unaided laryngeal voice preservation was similar for high-dose radiation (89%), conservation surgery (93%) and endoscopic resection (90%), but significantly poorer for low-dose radiation (80%; p = 0.02). T1B disease (N = 94) had similar local control and voice preservation with conservation surgery (87%) and high-dose radiation (88%) but lower results with low-dose radiation and endoscopic resections (67% unaided laryngeal voice preservation; p = 0.02). CONCLUSION: (1)The four therapeutic groups achieved similar rates of disease specific survival and ultimate local control. (2) Low-dose radiation was associated with significantly lower overall actuarial survival and unaided laryngeal voice preservation. (3) Endoscopic resection was associated with a significantly lower initial local control rate, but following salvage therapy achieved equivalent results to the other treatment methods. (4) Patients with (T1 N0 M0) glottic carcinoma had similar survival, local control, and unaided laryngeal voice preservation rates with high-dose radiation, conservation surgery, and endoscopic resections, but not with low-dose radiation therapy. (c) 1999 John Wiley & Sons, Inc. Head Neck 21: 707-717, 1999.

Adult↗
PubMed2000

Troubles in the therapeutic relationship: a pluralistic perspective.

From a pluralist perspective, there is no universally correct therapeutic attitude and no set way to deal with troubled therapeutic relationships. A three-factor model of therapeutic impasse is presented in terms of hopeless narratives, failing strategies, and ineffective interactions. This triple mapping allows for the development of a working hypothesis and a critical intervention in order to set therapy back on track. Although a one-shot event, the critical intervention is not a single-session magical cure, but an attempt to restore a productive therapeutic routine based on a better working alliance. This article illustrates this approach in three separate cases.

Attitude↗
PubMed1997

Prediction of the therapeutic dose for benzodiazepine anxiolytics based on receptor occupancy theory.

Many benzodiazepines (BZPs) are now used as anxiolytics with nearly 200-fold variety of therapeutic doses. The variation of the doses of BZPs is due to differences both in their pharmacokinetics and in their receptor binding characteristics. The purpose of this study is to clarify the mechanism of the differences in therapeutic dose by retrospective analyses and to develop a system for the quantitative estimation of optimal doses of BZPs. The values of receptor dissociation constant (Kd), which indicates the binding affinity of each BZP at the receptor site, were obtained from a number of works based on in vitro binding experiments. The plasma unbound concentrations of the BZPs and their active metabolites were calculated using the reported values of their total plasma concentrations after average oral doses of the BZPs and the values of their plasma unbound fractions, which were also taken from the literature. There were log-linear relationships between the Kd values of BZPs and their average therapeutic doses or maximum plasma concentrations, but the correlation coefficients were relatively small (r < 0.77). In contrast, a good log-linearity (r = 0.96) was observed in the correlation between their Kd values and the effective plasma unbound concentrations considering the active metabolites. This finding indicates that the receptor occupancy after administration of therapeutic dose of BZPs is consistent (52.3 +/- 3.2%) among the BZPs. In this study, we also develop a possible system for estimating the appropriate doses of BZPs based on receptor occupancy theory.

Administration, Oral↗
PubMed2006

Polymer therapeutics: concepts and applications.

Polymer therapeutics encompass polymer-protein conjugates, drug-polymer conjugates, and supramolecular drug-delivery systems. Numerous polymer-protein conjugates with improved stability and pharmacokinetic properties have been developed, for example, by anchoring enzymes or biologically relevant proteins to polyethylene glycol components (PEGylation). Several polymer-protein conjugates have received market approval, for example the PEGylated form of adenosine deaminase. Coupling low-molecular-weight anticancer drugs to high-molecular-weight polymers through a cleavable linker is an effective method for improving the therapeutic index of clinically established agents, and the first candidates have been evaluated in clinical trials, including, N-(2-hydroxypropyl)methacrylamide conjugates of doxorubicin, camptothecin, paclitaxel, and platinum(II) complexes. Another class of polymer therapeutics are drug-delivery systems based on well-defined multivalent and dendritic polymers. These include polyanionic polymers for the inhibition of virus attachment, polycationic complexes with DNA or RNA (polyplexes), and dendritic core-shell architectures for the encapsulation of drugs. In this Review an overview of polymer therapeutics is presented with a focus on concepts and examples that characterize the salient features of the drug-delivery systems.

Amino Acid Sequence↗
PubMed2001

Engineering temperature-sensitive poly(N-isopropylacrylamide) polymers as carriers of therapeutic proteins.

This study was carried out to engineer N-isopropylacrylamide (NiPAM) polymers that contain protein-reactive N-acryloxysuccinimide (NASI) and hydrophobic alkylmethacrylates (AMAs). These thermoreversible, protein-conjugating polymers hold potential for retention of therapeutic proteins at an application site where tissue regeneration is desired. The lower critical solution temperatures (LCST) of the polymers were effectively controlled by the AMA mole content. The AMAs with longer side-chains were more effective in lowering the LCST. Polymers without NASI exhibited a stable LCST in phosphate buffer and in serum over a 10-day study period. The LCST of polymers containing NASI was found to increase over time in phosphate buffer, but not in serum-containing medium. The LCST increase in phosphate buffer was proportional to the AMA content. The feasibility of localizing a therapeutic protein, recombinant human bone morphogenetic protein-2 (rhBMP-2), to a site of application was explored in a rat intramuscular injection model. The results indicated that polymers capable of conjugating to rhBMP-2 were most effective in localizing the protein irrespective of the LCST (13-25 degrees C). For polymers with no NASI groups, a lower LCST resulted in a better rhBMP-2 localization. We conclude that thermosensitive polymers can be engineered for delivery of therapeutic proteins to improve their therapeutic efficacy.

Acrylic Resins↗