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PubMed1993

Antifungal triazole alcohols: a comparative analysis of structure-activity, structure-teratogenicity and structure-therapeutic index relationships using the Multiple Computer-Automated Structure Evaluation (Multi-CASE) methodology.

An increase in the opportunistic fungal infections necessitates a design of new more effective and safer antifungal agents. Triazole alcohols are effective antifungals, but have a risk of teratogenicity associated with them. Therefore, successful design of drugs from this class depends on understanding the structure-activity and structure-teratogenicity relationships in conjunction. To this end, we applied the Multiple Computer-Automated Structure Evaluation (Multi-CASE) methodology to a study of the relationships between the structures of 71 triazole alcohols and their in vitro antifungal activity, teratogenicity, and therapeutic index. For each end point, several relevant structural descriptors were identified. A comparative analysis of the Multi-CASE results indicates that cyano, methoxy groups, and ortho-difluorination on the aromatic ring decrease antifungal activity, but not the therapeutic index because of the concomitant negative contribution to teratogenicity. Metabolically deactivating para-substitution in the benzene ring is beneficial for the therapeutic index in agreement with the idea of metabolically induced teratogenicity. Fluorinated para-alkyl substituents are most preferable. The pattern of ortho-substitution in the benzene ring affects both antifungal and teratogenic activity. This suggests that the relative orientation of the benzene ring with respect to the rest of the molecule may play a modulating role. The Multi-CASE model could correctly predict, a priori, the teratogenicity and antifungal potency of SCH 39304 and ICI 156,066 and be used to optimize the structure and therapeutic index of the latter.

Animals↗
PubMed1996

Therapeutic pars plana vitrectomy for chronic uveitis: a retrospective study of the long-term results.

BACKGROUND: Pars plana vitrectomy has both diagnostic and therapeutic potential in chronic uveitis. In this paper the therapeutic value of vitrectomy is investigated. METHODS: This is a retrospective study on 25 eyes that underwent pars plana vitrectomy with therapeutic intent. Surgery was considered in patients with severe vitreous clouding or macular pucker and in those who responded poorly or not at all to conventional treatment for uveitis. The mean period of follow up was 4.5 years, varying from 2 to 12 years. RESULTS: Improved vision was observed in 56% of the eyes (14/25). Twenty-four percent of the eyes (6/25) had stable vision. Macular edema disappeared in 40% (10/25) of cases and persisted in 60% (15/25). Two of the nine eyes with persistent macular oedema progressed to a macular hole. Four of the six eyes with macular pucker suffered recurrence, one ended in phythisis, while the pucker was cured in only one patient. Twelve percent of the eyes (3/25) subsequently experienced a recrudescence of uveitis, making systemic treatment necessary. One patient presented, after vitrectomy, a traction retinal detachment with proliferating vitreoretinopathy. No complications or recurrences were seen in 44% of the eyes (11/25). CONCLUSION: Vitrectomy has a definite place in the treatment of chronic uveitis, both on the functional level, with improvement or stabilisation of visual acuity and on the therapeutic level, with possible reduction or cessation of systemic treatment.

Adolescent↗
PubMed1984

The influence of the protector thiol L-cystein on the toxic and therapeutic responses of stabilized "activated" cyclophosphamide (4-(S-ethanol)-sulfido-cyclophosphamide).

The influence of L-cystein on the toxic and therapeutic responses of 4-(S-ethanol)-sulfido-cyclophosphamide (P1), a stabilized "activated" cyclophosphamide, was investigated. Stabilized "activated" cyclophosphamides hydrolyze under physiological conditions to 4-hydroxycyclophosphamide (4-OH-CP). The antitumor activity of P1 was investigated on a heterotransplanted human bladder sarcoma in nude mice and in perfusion experiments carried out on the isolated tumor bearing limb in rats. Due to its rapid hydrolysis to 4-OH-CP, P1 exhibits severe local toxicity which is decreased by the protector thiol L-cystein. Simultaneous application of double molar amounts of L-cystein reduces toxicity in nude mice to approximately one-third. Therapeutic activity is not affected by this ratio of L-cystein so that the protector thiol increases the therapeutic efficacy of P1. Higher amounts of L-cystein reduce both the acute toxicity in nude mice and the therapeutic efficacy against the human xenograft. The perfusion experiments demonstrate that a P1 concentration necessary to cure rats with tumor bearing limb is only tolerated in combination with L-cystein.

Animals↗
PubMed1984

Therapeutic approach to acute pulmonary embolism.

Many therapeutic aspects of venous thromboembolism continue to generate controversy so that the general therapeutic guidelines given below are only indicative. The first step is the diagnosis of venous thromboembolism; this is done in the vast majority of patients by visualization of blood clots using either pulmonary angiography or phlebography. The second step is to arrest the thrombotic process; the best means of doing this is to administer IV heparin. In the case of contra-indication or documented inefficacy of heparin therapy, the only therapeutic solution is to interrupt the inferior vena cava either with a clip, an umbrella or a filter. The blood clot lysis, which represents the third step, is effected by the natural fibrinolytic system. Thrombolytics , administered as a bolus of urokinase (15000 CTA U/kg), are indicated in cases of life-threatening pulmonary emboli, i.e. those with a pulmonary vascular obstruction of more than 50% and with hypotension, shock, or acute right ventricular failure. The use of thrombolytics is more questionable when they are administered to improve the quality of vascular patency. The only indication for pulmonary embolectomy is a contra-indication or inefficacy of thrombolytics . Due to the diagnostic and therapeutic difficulties, the first and most important part of the treatment of pulmonary emboli must be the broad application of prophylaxis treatment in patients with a high risk of venous thromboembolism.

Acute Disease↗
PubMed1986

Therapeutic drug monitoring of digoxin: help or hindrance?

A major role of therapeutic drug monitoring services is to advise on the dose of a drug which would be required to bring the concentration in the blood to within specific 'therapeutic' limits. Monitoring digoxin usage constitutes a substantial part of the work load. We have examined the potential variability in recommendations for digoxin dosages based on a series of serum digoxin measurements in each of 80 out-patients. In over a third of cases a dose, which seemed to be optimal on the basis of the first assay result, would have produced concentrations outside the conventional therapeutic range when the measurement was repeated. This was despite careful supervision of medication and the timing of the blood sample in relation to its administration. In routine practice the apparent variability in dose requirements would be far greater. Objectives of therapeutic drug monitoring services remain the same, the way forward would seem to lie in their taking on a heavy commitment to counsel and supervise patients before repeated blood sampling. However, effort and resources might be better channelled into producing simple prescribing aids relating the risk of cardiotoxicity directly to the size of the maintenance dose and the individual's renal function.

Aged↗
PubMed1991

Positive therapeutic interaction between thiopurines and alkylating drugs in human glioma xenografts.

We used human anaplastic glioma xenografts to evaluate the therapeutic efficacy of combinations of alkylating drugs, either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-(2,5-dioxo-3-piperidyl)-1-nitrosourea (PCNU), or procarbazine, and thiopurines, either 6-mercaptopurine (6MP) or 6-thioguanine (6TG). Using growth delay as the endpoint in subcutaneous (s.c.) tumors and increased life span as the endpoint in intracranial (i.c.) tumors, we found that combinations of chloroethylnitrosoureas (CENUs) and thiopurines were significantly more active than either type of agent alone. In contrast, combinations of procarbazine and thiopurines were not significantly more active than procarbazine alone. The therapeutic potentiation of the CENU was greater when the latter was given on the 4th day of the thiopurine treatment cycle than when it was given on the 1st day. Characterization of the interaction between CENUs and thiopurines also revealed a supraadditive therapeutic response at higher BCNU doses in combination with 6TG. Interaction between the nitrosoureas and the thiopurines probably occurs in the guanine base of tumor DNA and has important therapeutic implications.

Alkylating Agents↗
PubMed1991

Comparisons of tetrachloro(d,l-trans)1,2-diaminocyclohexane-platinum(IV) biotransformations in the plasma of Fischer 344 rats at therapeutic and toxic doses.

Plasma biotransformations of tetrachloro(d,l-trans)1,2-diaminocyclohexaneplatinum(IV) (tetraplatin) were determined in vivo at both therapeutic (3 mg/kg) and toxic (12 mg/kg) doses in Fischer 344 rats. Tetraplatin was rapidly converted to dichloro(d,l-trans)1,2-diaminocyclohexaneplatinum(II) [PtCl2(dach)]. This conversion was complete at the earliest time measured (7.5 min) at the therapeutic dose, but some unreacted tetraplatin was detectable in the circulation at the toxic dose. Three other major biotransformation products were observed in plasma: (d,l-trans)1,2-diaminocyclohexaneaquachloroplatinum(II) [Pt(H2O)(Cl)(dach)]+, the Pt-methionine complex, and another biotransformation product tentatively identified as either the Pt-cysteine or Pt-ornithine complex. Several other minor plasma biotransformation products were detected. Two of these were most likely formed intracellulary from tetraplatin. Two or more other platinum complexes appeared to lack the diaminocyclohexane carrier ligand and were most likely formed intracellulary by trans-labilization of the carrier ligand. Tetraplatin, PtCl2(dach), and [Pt(H2O)(Cl)(dach)]+ all rapidly disappeared from the circulation. The other biotransformation products were persistent through at least 3 h and could be responsible for the delayed toxicity of tetraplatin. Although some minor differences were observed between tetraplatin biotransformations at the toxic vs therapeutic doses, most biotransformation products were simply present at much greater concentrations at the toxic dose than at the therapeutic dose. Thus, our data suggest that dose-dependent differences in tetraplatin toxicity are probably attributable to the amount, rather than the type, of biotransformation products present in the plasma.

Animals↗
PubMed1990

The therapeutic effect of OK-432-combined adoptive immunotherapy against liver metastases from breast cancer.

We studied the therapeutic effect of OK-432 combined with adoptive immunotherapy in 19 cases of liver metastases from breast cancer. Of the 14 patients who received intraarterial OK-432 injection and transfer of cultured lymphocytes, 9 responded to this therapy, whereas no patients responded to intravenous administration. The minimum cell number for a therapeutic response was 8 x 10(8) cells. Metastatic lesions other than those in the liver regressed after therapy in 4 patients. The serum carcinoembryonic antigen level paralleled the therapeutic effect. There were no severe side-effects accompanying this therapy. These results indicate that intraarterial adoptive immunotherapy combined with OK-432 is effective as a new therapeutic approach against liver metastases from breast cancer.

Adult↗
PubMed1978

Retinoids, a new class of compounds with prophylactic and therapeutic activities in oncology and dermatology.

A review of recent investigations in the retinoid field is presented. Retinoic acid exerts a prophylactic and a therapeutic effect on chemically induced benign and malignant epithelial tumors in mice. In clinical studies positive therapeutic results have been obtained in patients with preneoplastic and neoplastic epithelial lesions. However, treatment with retinoic acid is limited by serious side effects (hypervitaminosis A syndrome). Therefore, the synthesis of analogs of retinoic acid (retinoids) possessing a more favorable therapeutic ratio has been initiated. Among a large series of synthesized compounds, certain aromatic analogs proved to have a particularly favorable therapeutic ratio. The structure-activity relationship of the most active retinoids is discussed including some biological data concerning prophylaxis and therapy of epithelial tumors. The total synthesis of retinoids according to various building schemes is discussed in detail. Methods for the synthesis of the cyclic end group, of the polyene chain component, and of the full retinoid skeleton are described. Metabolic studies of retinoic acid and of the most active retinoid, as well as the synthesis of some isolated metabolites are outlined. Suggestions concerning the mechanism of action of retinoids are made. Some clinical results on the treatment of acne, psoriasis and precancerous conditions are reported.

Animals↗
PubMed1985

Correlation plasma levels, NSAID and therapeutic response.

A regular control of nonsteroidal anti-inflammatory drug (NSAID) plasma levels may be useful to avoid undesirable side-effects to monitor therapeutic progress to see if patients are complying with their prescription. Trying to establish a relationship between the plasma concentration of a drug and its clinical effects requires a few prerequisites which may or may not be fulfilled according to the NSAID (e.g. a drug acting by itself, a reversible action, no tolerance to the drug, a highly specific and sensitive enough analytical method of the drug, similar free drug concentrations in the plasma and at the receptor sites,...), the most important of them-which is also probably the most difficult to fulfil in the case of rheumatic diseases-being that the clinical effect of the drug must be easily measured. In fact, the evidence for a good correlation between clinical effects and drug plasma levels are very scarce in the field of NSAID. The best correlation was obtained with salicylates for which ranges of plasma concentrations needed for observing therapeutic effects in rheumatoid arthritis as well as in juvenile rheumatoid arthritis have been established. Similar correlations have been made for side effects such as tinnitus or headaches as well as for toxic manifestations of salicylism. However, many individual variations have been described and there is considerable overlap between therapeutic and toxic concentrations. According to different authors there are or there are no correlations between phenylbutazone plasma levels and either is therapeutic or its side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Inflammatory Agents↗
PubMedDate not supplied

Preventive and therapeutic vaccines for human papillomavirus-associated cervical cancers.

'High risk' genotypes of the human papillomavirus (HPV), particularly HPV type 16, are the primary etiologic agent of cervical cancer. Thus, HPV-associated cervical malignancies might be prevented or treated by induction of the appropriate virus-specific immune responses in patients. Sexual transmission of HPV may be prevented by the generation of neutralizing antibodies that are specific for the virus capsid. In ongoing clinical trials, HPV virus-like particles (VLPs) show great promise as prophylactic HPV vaccines. Since the capsid proteins are not expressed at detectable levels by basal keratinocytes, therapeutic vaccines generally target other nonstructural viral antigens. Two HPV oncogenic proteins, E6 and E7, are important in the induction and maintenance of cellular transformation and are coexpressed in the majority of HPV-containing carcinomas. Therefore, therapeutic vaccines targeting these proteins may provide an opportunity to control HPV-associated malignancies. Various candidate therapeutic HPV vaccines are currently being tested whereby E6 and/or E7 are administered in live vectors, in peptides or protein, in nucleic acid form, as components of chimeric VLPs, or in cell-based vaccines. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials. Should they fulfill their promise, these vaccines may prevent HPV infection or control its potentially life-threatening consequences in humans.

Dendritic Cells↗
PubMed1998

Therapeutic node dissections in malignant melanoma.

BACKGROUND: Therapeutic lymphadenectomies involve the dissection and removal of clinically enlarged, histologically positive nodes at the regional nodal basin, in the absence of detectable distant disease. METHODS: The literature dealing with therapeutic lymphadenectomies in malignant melanoma was reviewed. RESULTS: The rate of wound complications varies with the particular nodal basin. The 5-year survival varies from 19% to 38%, with an average of 26%. Survival is affected primarily by the number of histologically positive nodes and extracapsular spread, and secondarily by the extent of disease at the various levels of the nodal basin, fixation of the nodes, and, probably, the preceding disease-free interval. Prognostic parameters of the primary lesion, e.g., thickness, ulceration, and location, also may have an effect on survival. The rate of local recurrence at the nodal basin after lymphadenectomy has varied from 0.8% to 52%. Adjuvant therapy with interferon alfa-2b has improved the 5-year disease-free survival from 26% to 37%. CONCLUSIONS: Therapeutic node dissections in melanoma provide an appreciable 5-year survival rate, which is further augmented by adjuvant therapy. Many series report a significant rate of local recurrence at the nodal basin following therapeutic dissection. Complete lymphadenectomy reduces the rate of local failure with its attendant morbidity.

Algorithms↗
PubMedDate not supplied

Therapeutic gastrointestinal endoscopy.

The safety, efficacy and utility of various therapeutic gastrointestinal (GI) endoscopic procedures performed on children (January 1992 to July 1995) at a tertiary referral centre in India were studied. A total of 1,030 sessions (upper GI 972 and lower GI 58) of therapeutic GI endoscopy were performed in 162 children (mean age 7.4 +/- 4 years; upper GI 115, lower GI 47). Various upper GI endoscopic procedures done were injection sclerotherapy (EIS), endoscopic variceal ligation (EVL), bougie dilatation of oesophageal strictures, balloon dilatations of oesophageal stricture/pyloric obstruction and retrieval of foreign bodies in 75%, 6%, 9%, 4% and 12% of children respectively. Therapy for bleeding from oesophageal varices constituted the major group (75%). Repeated EIS (sessions total--876, mean 8, range 5-15) performed on 86 children resulted in control of bleeding in all and eradication of oesophageal varices in 85% of cases. Minor complications (oesophageal ulcers and oesophageal strictures) due to EIS were observed in 9% of children. EVL (10 sessions in 7 children) was effective in controlling bleeding and substantial decrease of varices in all without any complication. Oesophageal dilation either by bougie (61 sessions in 10 children) or balloon (6 sessions in 3 children) were performed for benign strictures. Balloon dilatation of pyloric obstruction was successfully done in 2 children. Foreign bodies (retained or sharp) were retrieved from upper GI tract in 14 children. No complications were observed with stricture dilatation/foreign body retrieval. Therapeutic lower GI endoscopies were performed in 47 children (colonoscopic polypectomy in 92%, anal dilatation and piles banding in 4% each). One child with juvenile polyposis coli developed sigmoid colon performation following colonoscopic polypectomy which required surgical correction. We conclude that upper and lower GI endoscopic therapeutic procedures in children are highly effective and safe. The risk of major complication is very small in experienced hands and occasional minor complications, can be managed conservatively.

Adolescent↗
PubMed1997

[The therapeutic management of radiogenic oral mucositis].

BACKGROUND: Acute reactions of oral mucosa are a frequent side effect of radiotherapy, which often necessitates interruption of the treatment. Marked proliferation of tumor stem cells during treatment interruptions may occur in squamous cell carcinomata, which represent the majority of tumors in the head and neck area. Hence a fatal consequence of treatment breaks may be a significant decrease in tumor cure rates. Furthermore, marked acute responses frequently result in increased late sequelae ("consequential damage"). Therefore, amelioration of the mucosal response aiming at avoiding treatment breaks and at reduction of late reactions could definitely increase the therapeutic success of radiation treatment. PATIENTS AND METHOD: Various possibilities for the therapeutic management of radiation-induced oral mucositis with a symptomatic or radio- and epithelial biological background are summarized and presented systematically. RESULTS: A variety of prophylactic and therapeutic methods have been proposed for the management of acute radiation reactions of the oral mucosa. Frequently, their efficacy has been established for chemotherapy or in combination with other immunosuppressive treatments. Hence, systematical rather than local effects have to be considered. CONCLUSIONS: In general, prophylaxis of oral mucositis is mainly based on dental restoration or edentation, in combination with frequent oral hygienic measures after the meals and with antiseptic mouthwashes. Intensive personal care is recommended. The necessity of a percutaneous endoscopic gastrostoma is dependent on the status of the patient and on size and localization of the treatment area, i.e. the impairment of food uptake which is to be expected. Therapeutic intervention is restricted to local or systemic treatment of pain and local application of antimycotics and antibiotics.

Acute Disease↗
PubMed2002

A novel therapeutic approach for hematological malignancies based on cellular differentiation and apoptosis.

Hematological malignancies including acute leukemia, and multiple myeloma are disorders characterized by the accumulation of neoplastic hematopoietic cells, resulting in aggressive clinical manifestations with poor prognosis. The therapeutic approach to these disorders is basically chemotherapy for achieving complete remission based on the concept of total cell kill. However, severe side effects and complications such as serious infection and bleeding due to anti-cancer drugs are major problems in the clinical setting. In addition, repeated episodes of relapse of the disease may lead to refractory or chemotherapy-resistant disorders. These problems are occurred because anti-cancer agents have effects on both cancer cells and normal hematopoietic cells. The clinical evidences thus suggest the limitations of the chemotherapy for hematological malignancies: novel effective therapeutic approaches with less toxicity are therefore actively being sought. Differentiation-inducing therapy employing a physiologically active derivative of vitamin A, all-trans retinoic acid (ATRA), brought remarkably advances in the therapeutic outcome of APL at the end of last century. More recently, the clinical success of imatinib mesylate (STI571), potent competitive inhibitor of the Bcr/Abl protein tyrosine kinase, in the treatment of CML has focused enthusiasm toward molecular targeted therapy for the hematological malignancies. The therapeutic activity of these agents can be explained by their abilities to modify cellular growth, differentiation, and apoptosis in cells by activating unknown gene programs that molecular cellular proliferation. We have actively sought out new agents among natural products and cytokines with the ability to induce cellular differentiation and apoptosis. In this symposium, I will present our recent data of these novel compounds and their molecular mechanisms for inducing differentiation and apoptosis of hematological malignant cells.

Animals↗
PubMedDate not supplied

Diagnostic and therapeutic ERCP: a large single centre's experience.

BACKGROUND: Most large published series on endoscopic retrograde cholangiopancreatography (ERCP) are multicentre-based and consequently reflect varying experience. AIMS: To assess morbidity and mortality rates of ERCP in a single tertiary referral centre. METHODS: A series of 1,758 consecutive ERCPs performed in 1,148 patients between 1991 and 1994 were reviewed to evaluate indications, findings, procedures, success, complication and mortality rates. RESULTS: There were 1,108 (63%) successful initial ERCPs, 11% failed cannulation attempts and 26% follow-up ERCPs. The desired duct was successfully cannulated in 96.5% of cases. Initial cannulation failure rate was 8.8%. Twenty-seven per cent had normal ERCPs, 30% had choledocholithiasis and 22% had strictures. Fifty-five per cent had therapeutic ERCPs. Major complications occurred in 3.5% with four ERCP-related deaths (0.35%). Therapeutic ERCP had a higher incidence of major complications compared to diagnostic ERCP: 4.6% vs 2.1%, (p=0.02); and mortality rate was 0.5% vs 0.2%, (p=0.4). Significant haemorrhage secondary to biliary sphincterotomy, pre-cut papillotomy and snare papillectomy accounted for most of the difference (1.6%). CONCLUSIONS: The majority of ERCPs were performed in elderly patients, over half of whom required therapeutic ERCP. Therapeutic ERCP carried significantly higher complication rate compared with diagnostic ERCP. Unsuccessful cannulation and follow-up ERCP accounted for 11% and 26% of ERCP workload, respectively.

Adolescent↗
PubMed2005

Tin foil as bolus material for therapeutic electron beams from the Varian Clinac 2100C/D.

Tin foils of sub-millimetre thickness have been investigated as bolus material for therapeutic electron beams from the Varian Clinac 2100C/D linear accelerator. Measurements with ionisation chamber and radiographic film in Plastic Water or water were performed under tin foil bolus to determine surface dose, therapeutic ranges, output factor correction, penumbra and dose outside the field edge. Appropriate thicknesses of tin foil for 90% dose at the surface were found to be approximately 0.3 mm for 6 MeV, and 0.4 mm for 9 MeV and 12 MeV. Enhanced therapeutic interval with tin foil bolus over water-equivalent bolus has previously been reported, but was found not to be evident for 12 MeV and for a small (4 x 4 cm2) 9 MeV field. The penumbra width of fields with tin foil and water-equivalent bolus were found to be within 2 mm, while the doses at 1 cm outside the field edge were within 1.5% of peak dose. Output factor corrections for fields with tin foil were measured as within 2% of unity. Air gaps between the tin foil and phantom surface up to 5 mm were observed to have minimal effect on output correction factor, relative surface dose, and therapeutic range.

Dose-Response Relationship, Radiation↗
PubMed1995

Therapeutic drama activity for the cognitively impaired elderly in a nursing home.

The use of drama as a nightly activity for the cognitively impaired elderly patients at the Sakubara skilled nursing home commenced in 1989. Although it was started for the pleasure of the patients, and not for a therapeutic purpose, positive behavioral changes were observed. The therapeutic effects of the activity were measured and reported. Based on our 7-year experience and research, the definition, goals, structure, and conceptual framework of therapeutic drama activity were developed; the skills used in this activity and its cultural background are discussed. Finally, the philosophical background of the nursing home that promotes the therapeutic effects is presented.

Aged↗