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Biomedical subjects

H Phillips

Publications and source records attributed to H Phillips.

At least 73 records · Page 4Linked to original sources
PubMed1987

Systematic preclinical study on the therapeutic properties of recombinant human interleukin 2 for the treatment of metastatic disease.

The availability of recombinant human interleukin 2 (rH IL 2) has resulted in its clinical utilization both as a single agent and in combination with lymphokine-activated killer cells. In this report, we discuss the effects of rH IL 2, administered by various routes, on effector cell function, pharmacokinetics and bioavailability, and therapeutic activity. Studies of the pharmacokinetics of in vitro natural killer (NK) cell augmentation by rH IL 2 revealed that a short exposure to high levels of rH IL 2 can augment NK cell activity; however, a prolonged exposure (greater than 12 h) was required to augment NK cell activity at lower doses of rH IL 2. These observations suggested that chronic administration of rH IL 2 might improve immunomodulatory and therapeutic activity. This hypothesis was supported by the results of studies in which we treated experimental and spontaneous metastasis, which revealed that the daily i.p. administration of rH IL 2 resulted in significantly greater therapeutic activity than administration three times/week. The therapeutic protocol for daily i.p. administration had a biphasic dosage optimum, such that low dose therapeutic activity was observed at approximately 100-1000 units/animal in the treatment of experimental metastases or 10 to 100 units/animal in the treatment of spontaneous metastases. There was a second dosage optimum at greater than or equal to 100,000 units/animal rH IL 2 delivered i.p. on a daily basis. Intermediate doses had no significant therapeutic activity. Additional studies revealed that low dose therapeutic activity was not observed in nude mice. In contrast, therapeutic activity was observed in nude mice at high doses of rH IL 2 suggesting that low dose activity was associated with a T-cell-mediated effect, whereas high dose activity may have been mediated by NK or lymphokine-activated killer-like cells. This observation was in agreement with the dose response for T-cell adjuvant activity supporting the hypothesis that low dose therapeutic activity was T-cell associated, because adjuvant activity was observed when rH IL 2 was given daily at approximately 100 units/animal for 3 days, and higher doses had no activity or had a suppressive effect. Because we were concerned about the pharmacological aspects of rH IL 2 treatment, we also examined its therapeutic properties after continuous administration i.p. by osmotic pumps. Under these conditions, therapeutic activity was observed after administration of 600 units/h, whereas lower or higher doses did not have significant therapeutic activity.

Adjuvants, Immunologic↗
PubMed1987

Immunomodulatory and immunotherapeutic properties of recombinant gamma-interferon and recombinant tumor necrosis factor in mice.

These studies were designed to examine the immunodulatory and immunotherapeutic properties of recombinant murine interferon gamma (rM IFN-gamma) and recombinant human tumor necrosis factor (rH TNF). We report that rM IFN-gamma activated murine natural killer cells and macrophages in a dose-dependent manner in vivo. The rM IFN-gamma, which demonstrated a bell-shaped therapeutic response curve, must be administered at specific doses and schedules to produce optimal therapeutic activity. Optimal activity was observed after i.v. administration of 50,000 U/animal rM IFN-gamma three times per week. In contrast, rH TNF produced its major therapeutic activity in the treatment of metastatic disease after i.v. but not i.p. administration. The therapeutic effects of rH TNF were as great in these in vivo systems as those of rM IFN-gamma. Furthermore, rH TNF had additive therapeutic activity when administered in conjunction with suboptimal doses of rM IFN-gamma. Unlike rM IFN-gamma, rH TNF did not activate natural killer cells in vivo or in vitro but did augment in vivo and in vitro macrophage tumoricidal activity. It also had synergistic cytostatic properties with rM IFN-gamma for some murine tumor cell lines in vitro. High levels of rH TNF were readily detected in the serum with a half-life of approximately 30 min after i.v. administration. In contrast, only minimal serum TNF activity occurred after i.p. administration, suggesting that i.v. administration may more efficiently facilitate systemic therapeutic activity. In summary, rH TNF and rM IFN-gamma have therapeutic activity for metastatic disease as individual agents and additive therapeutic activity when used in combination. Furthermore, it appears that in addition to therapeutic potential as cytostatic agents, the immunomodulatory properties of rH TNF have a role in its therapeutic properties.

Animals↗
PubMed1987

Immunomodulatory and therapeutic properties of alkyl lysophospholipids in mice.

This paper describes the immunomodulatory and therapeutic properties of the alkyl lysophospholipids [ALP; 1-O-octadecyl-2-O-rac-glycero-3-phosphocholine (ET-18-OCH3)]. ALP was able to activate macrophages both in vitro and in vivo as well as to act as an immunoadjuvant for syngeneic tumor vaccines. However, ALP appeared to be transferred, at least in part, to the macrophage membrane, and some of the tumoricidal macrophage-activating properties seem to be associated with the direct cytotoxic effect of membrane-released ALP. ALP also had some therapeutic activity for experimental and spontaneous metastases, requiring administration three but not two times weekly at near-toxic doses; this suggests that at least some of its therapeutic activity is due to direct cytotoxicity.

Animals↗
PubMed1987

Cervical myelopathy complicating multiple joint replacement in rheumatoid disease.

The incidence of cervical myelopathy and subluxation was investigated in 48 patients with rheumatoid disease who had three or more major lower limb joint replacements. Eight (17%) developed cervical myelopathy requiring cervical fusion. This was the subsequent cause of death in two. Four further patients demonstrated clinical features of myelopathy. Cervical subluxation was present in 29 of 44 (66%) in whom adequate radiographs were available. The development of cervical symptoms and signs could not have been predicted from the sex, age of onset, duration of disease or steroid therapy. Radiographic changes in the cervical spine were independent of major lower limb joint destruction and were often not present when planning a programme of joint replacement. Fifty-one control patients were studied. Cervical myelopathy occurred in 2 (4%) and subluxation in 24 (47%). The development of rheumatoid changes in the cervical spine was unrelated to involvement of the hip or knee joints in the control group. There was a significant (p less than 0.05) increase in the incidence of cervical myelopathy in patients with multiple lower limb joint replacements compared with the control population.

Adolescent↗
PubMed1987

Preclinical approaches to the treatment of metastatic disease: therapeutic properties of rH TNF, rM IFN-gamma, and rH IL-2.

The present studies were undertaken to examine the immunotherapeutic properties of recombinant murine interferon-gamma (rM IFN-gamma), recombinant human tumour necrosis factor (rH TNF), and recombinant human interleukin-2 (rH IL-2) in preclinical metastasis models. It was observed that these cytokines have disparate mechanisms of therapeutic activity as well as different optimal therapeutic protocols. Thus, not only is the dose important to the therapeutic activity of each of the agents; so also is the route of administration, schedule of administration, duration of administration, and sequence of administration. The rM IFN-gamma has a narrow window of activity, with a bell-shaped therapeutic response with a dosage optimum at 50,000 U/animal of rM IFN-gamma administered 3 times per week. In contrast, rH IL-2 has optimal therapeutic activity for the treatment of metastatic disease after i.p. as compared to i.v. administration. This appears to be associated with the serum pharmacokinetics, since longer serum concentrations are achieved following i.p. administration although lower serum levels are also achieved. RH IL-2 has a biphasic dose-response curve for therapeutic activity with optima from 100 to 1000 U/animal and at doses greater than 100,000 U/animal. The lower doses appear to be associated with T cell augmentation whereas the higher doses are associated with NK cell or LAK cell augmentation. RH TNF has therapeutic activity for the treatment of metastatic disease after i.v. but not i.p. administration. High levels of rH TNF are readily detected in the serum following i.v. administration, with a serum half-life of approximately 30 min. In contrast, only minimal serum TNF activity is observed after i.p. administration, suggesting that this may be the origin of the increased therapeutic activity following i.v. administration. Furthermore, rH TNF has additive therapeutic activity when administered in conjunction with suboptimal doses of rM IFN-gamma. Unfortunately, the additive therapeutic activity of rM IFN-gamma and rH TNF is also associated with increased toxicity. However, in preliminary experiments it was found that the b.i.d. administration of aspirin at 25 mg/kg resulted in decreased toxicity. In summary, the recombinant cytokines provide a challenge both preclinically and clinically to the development of optimal therapeutic protocols, and suggest that close attention must be paid to the dose, route, schedule, duration, and sequence of their administration.

Animals↗
PubMed1987

Modified posterior approach for right adrenalectomy.

I use this approach for all patients with primary hyperaldosteronism due to a right adenoma. In addition, the approach has been used for other functioning and nonfunctioning adrenal lesions less than 6 centimeters in size, if there is no anatomic or biochemical evidence of a malignant lesion. This approach is not recommended for patients with pheochromocytoma, carcinoma of the adrenal gland or lesions of the adrenal gland greater than 6 centimeters.

Adrenalectomy↗
PubMed1986

Immunomodulatory and therapeutic properties of bestatin in mice.

In this report, we describe the immunomodulatory properties and therapeutic efficacy of bestatin. Macrophage activation, but not natural killer cell augmentation, was observed both in vitro and in vivo. Immunostimulation of T-cell activity was observed in assays of allogeneic mixed lymphocyte response, but cytotoxic effector cells did not develop after an allogeneic mixed lymphocyte-tumor cell culture. Bestatin also had T-cell adjuvant activity when it was admixed with a suboptimal vaccine composed of irradiated tumor cells. We observed significant therapeutic activity against preexisting experimental and spontaneous metastases when bestatin was administered at high doses per animal for 4 weeks.

Adjuvants, Immunologic↗
PubMed1986

Isotretinoin and Staphylococcus aureus infection. A possible association.

The use of isotretinoin (13-cis-retinoic acid) in the treatment of numerous dermatologic disorders, as well as the side effects encountered with use of the drug, have increased remarkably since its release. We encountered a case of Staphylococcus aureus endocarditis in a patient with chronic stable aortic insufficiency undergoing therapy with isotretinoin for extensive actinic keratoses. Although significant dysfunction of the immune system has not been demonstrated with isotretinoin, nasal colonization with S aureus has been shown to occur. Changes in skin fragility caused by the drug may provide a portal of entry for the organism. Physicians should be alert for this potential complication in patients with an underlying cardiac valvular lesion; antibiotic prophylaxis may be indicated in this group during isotretinoin therapy.

Aortic Valve Insufficiency↗
PubMed1985

Immunomodulatory effects in mice of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose.

In this report, we describe the immunomodulatory characteristics of poly(I,C)-LC, a synthetic, double-stranded nucleic acid polymer, polyinosinic-polycytidylic acid, that is complexed with poly-L-lysine and solubilized by the addition of carboxymethylcellulose. We consistently observed, both in vitro and in vivo, stimulation of macrophage cytotoxicity and augmentation of natural killer-cell activity by poly(I,C)-LC. This immunomodulator also increased the allogeneic mixed-lymphocyte response, without any blastogenic effect on responder cells cultured in the absence of allogeneic stimulator cells. Further, the addition of poly(I,C)-LC to an allogeneic mixed-lymphocyte tumor reaction did not stimulate the development of cytotoxic effector T-cells. Poly(I,C)-LC did, however, have adjuvant activity when admixed with irradiated tumor cells in the immunization of syngeneic mice. Unlike classic adjuvants, poly(I,C)-LC also enhanced the development of specific cytotoxic T-lymphocytes when it was injected either i.v. or i.p. in conjunction with a vaccine delivered at an intradermal site. The results indicate that poly(I,C)-LC has considerable potential as an immunotherapeutic agent, with the ability not only to induce macrophage and NK cell activation but also to stimulate specific cytotoxic T-lymphocytes.

Adjuvants, Immunologic↗
PubMed1985

Immunotherapeutic potential in murine tumor models of polyinosinic-polycytidylic acid and poly-L-lysine solubilized by carboxymethylcellulose.

The systemic administration of multiple, nontoxic doses of polyinosinic-polycytidylic acid and poly-L-lysine solubilized by carboxymethylcellulose [poly(I,C)-LC] eradicated established experimental and spontaneous pulmonary metastases. Optimal immunotherapy was schedule dependent, requiring three to five injections of poly(I,C)-LC per week for a minimum of 4 weeks; in addition, therapeutic efficiency was partially dosage independent. Immunotherapy by poly(I,C)-LC was found to be limited by tumor burden, although when combined with chemotherapy as a debulking regimen it resulted in increased survival with protocols in which poly(I,C)-LC alone was insufficient. These data suggest that the systemic administration of poly(I,C)-LC may provide a successful adjuvant therapeutic modality against cancer metastasis.

Adjuvants, Immunologic↗
PubMed1985

Augmentation of NK cell activity in tissue specific sites by liposomes incorporating MTP-PE.

Liposomes incorporating a variety of immunomodulators have been shown to activate macrophages and monocytes for tumoricidal activity both in vivo and in vitro. We report that in addition to the activation of macrophages, the i.v. injection of liposomes (multilamellar vesicles) that have encapsulated muramyl tripeptide-phosphatidylethanolamine (MTP-PE) could also augment interstitial natural killer (NK) cell activity in the lung and the liver. In contrast, liposomes incorporating MTP-PE were unable to augment NK cell activity in the spleen, peripheral blood, or peritoneal cavity (after i.p. injection). In addition, liposomes did not augment splenic NK cell activity in vitro. This suggests that the augmentation of NK cell activity in the lungs and liver was not due to direct effects of the liposomes but may have been a secondary effect mediated by a monokine. The augmentation of pulmonary NK cell activity was paralleled by the nonspecific immunoprophylaxis of experimental pulmonary metastases. The augmented NK cell activity, as well as the enhanced nonspecific immunoprophylactic activity, was reduced by pretreatment of the mice with anti-asialo GM1 antiserum. Thus, the augmentation of organ-associated NK cell activity by liposomes incorporating MTP/PE plays a major role in the host's increased resistance to the formation of experimental metastases.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

Quantitative measurements of joint mobility in adolescents.

Six measurements of joint mobility were made in a group of 446 normal adolescents. A method of measuring hip and knee rotation is presented. All these data are normally distributed, and would suggest that joint hypermobility lies at the end of the normal spectrum. There was a weak but significant correlation between each of the different measures of joint mobility except elbow hyperextention. Criteria for joint laxity are discussed in this age group, and the importance of quantitative techniques of measuring joint mobility are emphasised.

Adolescent↗
PubMed1984

Mechanical factors in the incidence of knee pain in adolescents and young adults.

Mechanical abnormalities of the patellofemoral joint are among the many causes that have been suggested for adolescent knee pain. This study seeks to identify these factors. Measurements of joint mobility and lower limb morphology were made on 446 pupils at a comprehensive school, 136 of whom had suffered knee pain in the previous year. The pupils with symptoms enjoyed sporting activities significantly more than their symptom-free contemporaries. Joint mobility, the Q-angle, genu valgum and anteversion of the femoral neck were not significantly different between those pupils with and those without anterior knee pain. Data on lower limb morphology of normal adolescents are presented. Examination of 52 hospital outpatients aged 13 to 36 years with anterior knee pain produced results comparable with those for the pupils. It is concluded that chronic overloading, rather than faulty mechanics, is the dominant factor in the genesis of anterior knee pain in adolescent patients.

Adolescent↗