Herbert E. Spiegel

Interferon kinetics and adverse reactions after intravenous, intramuscular, and subcutaneous injection

Three groups of six subjects each received a single 36 × 106 U dose of recombinant leukocyte A interferon (rIFN‐αA) as a 40‐min infusion, an intramuscular injection, or a subcutaneous injection. Blood samples were collected at specific times after dosing for analysis of rIFN‐αA serum concentrations by an enzyme immunoassay method, ELISA. The rIFN‐αA was rapidly distributed and moderately eliminated (t½ =5.1 hr) after intravenous infusion. The maximum concentrations at the end of intravenous infusion were tenfold the maximum concentrations after intramuscular and subcutaneous injections. Renal tubular secretion or extrarenal elimination was suggested by clearance values of 1.8 times the glomerular filtration rate. After intramuscular and subcutaneous injection, rIFN‐αA was absorbed slowly (time to reach maximum concentration ranged from 4 to 8 hr), which resulted in prolonged serum concentrations. Estimated bioavailability was more than 80% for both intramuscular and subcutaneous injection shares qualitatively the same adverse reactions, the reactions differ in severity and duration. The adverse effects appear to be related to route of administration, of herpes labialis were also noted. There were no significant clinical laboratory abnormalities of medical concern. Although rIFN‐αA injected by intravenous infusion or intramuscular or subcutaneous injection shares qualitatively the same adverse reactions, the reactions differ in severity and duration. The adverse effects appear to be related to route of administration.

Serum glycoproteins in cancer patients: First report of correlations with in vitro and in vivo parameters of cellular immunity

Serum levels of proteins previously shown to be elevated [acute‐phase proteins (APP)—haptoglobin, α1‐acid glycoprotein, α1‐antitrypsin] or depressed (α2HS‐glycoprotein, prealbumin, albumin) in cancer patients were correlated with tumor extent, in vitro lymphocyte reactivity (LR) to phytohemagglutinin (PHA), and quantitative delayed hypersensitivity (DH) to dinitrochlorobenzene (DNCB) in 147 pre‐operative patients with operable solid malignancies either confined to the primary site or with regional spread only. Compared to 58 normal controls, levels of the APP were significantly elevated, α2HS‐glycoprotein and prealbumin depressed, and albumin levels unchanged in patients with either local or regional tumors. In patients with normal DH to DNCB, the APP were higher and prealbumin was lower than in controls; in patients with impaired DH to DNCB, haptoglobin and α1‐acid glycoprotein were higher and α2HS‐glycoprotein and prealbumin lower than in patients with normal DH to DNCB. Albumin levels did not differ from normals in any of the groups. Serum protein levels appeared to be more related to the immune status of the patient than to tumor extent. The levels of the three APP correlated directly with each other but inversely with α2HS‐glycoprotein and prealbumin; levels of α2HS‐glycoprotein and prealbumin correlated directly with each other. Levels of haptoglobin and α1‐acid glycoprotein correlated inversely with LR to PHA; however, levels of α2HS‐glycoprotein correlated directly with LR to PHA, and uniquely the levels of α2HS‐glycoprotein and LR to PHA both showed similar changes for each of the four quantitative levels of DH to DNCB measured in the cancer patients. The data show that the proteins studied, except for albumin, correlate inversely (APP) or directly (α2HS‐glycoprotein and prealbumin) with in vitro and in vivo parameters of cellular immunity. The results provide a rationale for attempts to improve depressed cellular immunity by lowering circulating levels of APP, as is being attempted in ongoing trials using plasmapheresis, and assessing the effect of exogenous α2HS‐glycoprotein or prealbumin in patients with low levels of these glycoproteins and depressed cellular immunity. The correlations between serum glycoprotein levels and in vitro and in vivo parameters of cellular immunity lend rationale to investigations of the interactions of serum glycoproteins and blood cells having immunologic function that determine the level of cellular immunity expressed in vivo.

Serum glycoproteins in head and neck squamous carcinoma: Correlations with tumor extent, clinical tumor stage, and T-cell levels during chemotherapy

Abstract In patients with solid malignancies, serum levels of specific acute phase proteins (haptoglobin, α 1 -acid glycoprotein, and α 1 -antitrypsin) have been correlated with parameters of both tumor extent and cellular immunity, while α 2 HS-glycoprotein and prealbumin have been correlated with parameters of cellular immunity. To determine the relation of the glycoproteins to these parameters in head and neck squamous carcinoma, serum levels were measured in 90 untreated patients, 51 cured patients, 11 patients with recurrent carcinoma, and 20 patients during preoperative chemotherapy. The control patients were 139 chronic cigarette smokers. Haptoglobin levels were significantly increased in patients with stage I through IV tumors (AJC-1977), but levels were similar for each stage. Serum levels of α 1 -antitrypsin and α 1 -acid glycoprotein increased progressively with increasing tumor stage. Serum α 2 HS-glycoprotein, prealbumin, and albumin levels were decreased in all patients, and α 1 HS-glycoprotein levels decreased progressively with increasing tumor stage. When patients were classified into those with local tumors only and those with regional metastases, and further subclassified by extent of local or regional tumor, the acute phase proteins generally increased with increasing local or regional tumor extent and α 2 HS-glycoprotein levels tended to decrease in the same groups. In cured patients, haptoglobin and α 1 -acid glycoprotein levels were significantly lower and α 2 HS-glycoprotein and prealbumin significantly higher than in untreated patients. Protein levels in patients with recurrent tumors were similar to levels in untreated patients. During acute immunosuppressive chemotherapy, levels of T-cells and α 2 HS-glycoprotein decreased significantly and similarly, and after completion of chemotherapy, rebounded to pretreatment levels, while α 1 -antitrypsin levels increased and haptoglobin and α 1 -acid glycoprotein levels did not change. The data show that α 1 -antitrypsin and α 1 -acid glycoprotein correlate better with AJC tumor stage than cellular immune parameters previously studied and that α 2 HS-glycoprotein levels may be as useful as T-cell levels for monitoring immune reactivity in patients with squamous cancer of the head and neck. These results suggest the potential of these biologic parameters as adjuncts in the derivation of improved staging systems and as indicators of tumor status and immune reactivity in patients with squamous carcinoma of the head and neck.

Debrisoquin, a selective inhibitor of intraneuronal monoamine oxidase in man

Indices of MAO activity were monitored during administration of debrisoquin to 4 patients with hypertension. That there was no inhibition of MAO was indicated by unaltered urinary tryptamine and tyramine excretion, no depression of intestinal mucosal MAO activity, and no decrease of intestinal inactivation of orally ingested tyramine. Inhibition of sympathetic neuronal MAO is suggested by increased sensitivity to intravenous tyramine with a slight increase in norepinephrine sensitivity, decreased urinary VMA, and increased NMN excretion. It is suggested that anatomic selectivity of enzyme inhibition is related to drug‐concentrating mechanisms in sympathetic neurons.

An analytical method for measuring dopa and some metabolites in urine and plasma of parkinsonian patients

A method is presented for the separation and analysis of Dopa, dopamine, norepinephrine and epinephrine which is suitable for analyzing plasma and urine specimens from patients receiving levodopa.

Serum glycoproteins and immunoglobulins in nasopharyngeal carcinoma: correlations with Epstein-Barr virus associated antibodies and clinical tumor stage.

The consistent association of elevated antibody titers to the Epstein-Barr virus associated antigens in patients with nasopharyngeal carcinoma has led to correlations of antibody titers with tumor presence and extent. Recently, serum levels of specific glycoproteins and immunoglobulins have been correlated with tumor presence and extent in patients with head and neck squamous carcinomas, and elevation of the immunoglobulin IgA has been described in patients with nasopharyngeal carcinoma. These correlations prompted a study of 69 untreated patients with nasopharyngeal carcinoma and 53 healthy normal subjects in Taiwan to determine the relations among specific proteins (haptoglobin, α1-acid glycoprotein, α1-antitrypsin, α2-HS-glycoprotein, prealbumin, and albumin), immunoglobulin levels (IgA, IgG, IgM), anti-EBV associated antibody titers, and clinical tumor stage. Elevated antibody titers to EBV-associated antigens (EBV-associated nuclear antigen, viral capsid antigen, and early antigen) were related to tumor presence but not significantly related to clinical tumor stage. Compared with the levels in normal subjects, serum levels of acute-phase proteins (haptoglobin, α1-acid glycoprotein, α1-antitrypsin) were significantly increased (p < 0.001) in patients with nasopharyngeal carcinoma, and levels of α2HS-glycoprotein were significantly decreased (p < 0.001). Uniquely, serum levels of acute-phase proteins, particularly haptoglobin, were directly related to clinical tumor stage (p < 0.05 − 0.001). Furthermore, serum haptoglobin levels correlated directly with anti-EBNA antibody titers (p < 0.03) and serum levels of IgA (p < 0.01). Serum levels of α2HS-glycoprotein correlated inversely with titers of IgA antibodies to early antigen (p < 0.03). The findings demonstrate that measurement of specific serum glycoprotein and immunoglobulin levels may be useful adjuncts to anti-EBV antibody titers in the serodiagnosis and monitoring of response to treatment of nasopharyngeal carcinoma and aid in the derivation of improved staging systems for these tumors.

Pyridoxine and oral contraceptives.

Tryptophan loading tests were performed to determine how much pyridoxine hydrochloride must be given to women taking oral contraceptives to correct their heightened excretion of xanthurenic acid. 43 women 33 of whom took the pill participated for 3 months. 2 gm of tryptophan was administered orally on 3 occasions per cycle and an 8 hour urine sample was analyzed for xanthurenic acid. Pyridoxine was administered during cycles 1 and 3 at doses of 2 5 10 or 20 mg. Placebo was given in the second cycle and 5 women in each group took no medication. Xanthurenic acid excretion ranged from 0 to 32 micromoles/8 hours in those not on the pill after tryptophan load but averaged 167.5 micromole/8 hours in pill users after tryptophan. The pyridoxine doses of 10 mg daily corrected some women and 20 mg corrected most womens excess xanthurenic acid excretion. The authors recommended that 30 mg pyridoxine be given to women on the pill. This is far in excess of the daily allowance of 2 mg/day recommended by the United Kingdom Department of Health.

Continuous Intravenous Infusion Pharmacokinetics of Interferon to Patients With Leukemia

R ecombinant human alpha A interferon (rIFN-aA), a single protein moiety derived by recombinant DNA techniques,1 is being evaluated in disseminated cancers and viral diseases. In a recent report involving healthy volunteers,2 it was shown that a single dose of rIFN-aA given by intravenous infusion was much better tolerated than by either intramuscular or subcutaneous injections. Therefore, the route of administration may be an important factor in determining tolerance. In addition, early clinical studies suggested that patients with acute leukemia were responsive to interferon when administered by intravenous bolus3 or infusion.4 This study assessed the pharmacokinetics of rIFNaA in patients with relapsed and/or refractory acute leukemia or blast crisis myelogenous leukemia following a 14-day continuous intravenous infusion. Thirteen patients (eight men and five women) having relapsed and/or refractory acute leukemia or blast crisis chronic myelogenous leukemia were entered into this study after giving written informed consent. Study approval was obtained from the Baltimore Cancer Research Center, University of Maryland Hospital, Institutional Review Board. Dr. R.D. Leavitt conducted the study. The entrance criteria included those patients who were previously treated with chemotherapy, immunotherapy, or radiation therapy, had an evaluable disease, and an expected survival of eight weeks. Entry criteria did not require palliative radiation therapy at the time of entry into the study, chemotherapy, immunotherapy, or hormonal therapy, other than the treatment regimen prescribed by this protocol. Patients did not suffer from any severe heart disease, intercurrent infections, impaired renal or hepat-

A Semi-Automated Colorimetric Method for the Analysis of Dihydroxyphenylacetic Acid (DOPAC) in Urine of Parkinsonian Patients Receiving L-Dopa

Abstract An analytical system is presented which permits the separation and analysis of urinary dihydroxyphenylacetic acid (DOPAC). This method is suitable for analyzing the urine from both normal and Parkinsonian patients receiving L-Dopa.