Perfluorochemical emulsions can increase tumor radiosensitivity.

An oxygen-carrying perfluorochemical emulsion enhanced the effectiveness of radiation therapy in two transplantable solid tumors in mice. The perfluorochemical emulsion had no effect on tumor growth after x-irradiation, but delayed tumor growth significantly when administered to oxygen-breathing mice before or during irradiation.

Addition of misonidazole, etanidazole, or hyperthermia to treatment with fluosol-DA/carbogen/radiation.

The antitumor efficacy of adding the nitroimidazole radiosensitizing drugs misonidazole and etanidazole or hyperthermia (43 degrees C for 30 min) to Fluosol-DA/carbogen (95% O2/5% CO2) and irradiation was tested in the FSaIIC tumor system. Both the nitroimidazole drugs and hyperthermia produced additional tumor growth delays and tumor cell cytotoxicity when given with Fluosol-DA/carbogen, either before or after irradiation. For each of the modalities tested, the dose-modifying effect was greater when that therapy preceded rather than followed irradiation (misonidazole 2.7 vs. 1.9, etanidazole 2.4 vs. 1.7, hyperthermia 4.0 vs. 1.7 relative to the effect of radiotherapy alone). Because the nitroimidazole drugs must be present before radiation is administered to exert their radiosensitizing effect, the increase in tumor growth delay observed when these drugs cytotoxic to hypoxic cells were administered following Fluosol-DA/carbogen and irradiation suggests that Fluosol-DA/carbogen could not fully oxygenate the tumors and that the nitroimidazole drugs were effectively toxic to residual hypoxic cells. The treatment Fluosol-DA/carbogen----hyperthermia----irradiation produced a marked increase in tumor growth delay not seen with the sequence Fluosol-DA/carbogen----irradiation----hyperthermia. The results indicate that a treatment combination of radiation sensitizers may be more effective than irradiation plus Fluosol-DA with oxygen breathing alone.

Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma.

In order to investigate the effect of environmentally determined conditions on the cytotoxicity of anticancer treatments, Hoechst 33342 dye selected tumor subpopulations were separated after in vivo treatment and plated for single cell colony survival. The 10% brightest cells were assayed as putative normally oxygenated cells and the 20% dimmest as putative hypoxic cells. At single therapeutic doses, cyclophosphamide treatment resulted in the largest differential killing between bright and dim cells (6.3-fold bright greater than dim); 1,3-bis(2-chloroethyl)-1-nitrosourea was 3.2-fold more cytotoxic toward bright cells and carboplatin was 2.4-fold more toxic toward bright cells. Both radiation (10 Gy) and melphalan were 2.2-fold more toxic to bright cells, while cis-diamminedichloroplatinum(II) was 1.8-fold, thiotepa was 1.2-fold and procarbazine was 1.3-fold more toxic to bright cells. Actinomycin D was 3.4-fold more toxic to bright cells. Adriamycin was 2.2-fold, vincristine was 2.1-fold, and etoposide was 1.6-fold more toxic to bright cells. Bleomycin and 5-fluorouracil were also tested and were 1.5- and 2.3-fold more toxic to bright cells, respectively. Only four treatments were more toxic to dim cells: mitomycin C (3.5-fold), misonidazole (1.5-fold), etanidazole (3.5-fold), and 43 degrees C, 30 min local hyperthermia (2.6-fold). In an attempt to shift the pattern of dim cell sparing, Fluosol-DA plus carbogen (95% O2/5% CO2) breathing was added to treatment with radiation (10 Gy), melphalan, cis-diamminedichloroplatinum(II), and etoposide. Although each of these treatments became significantly more toxic with the addition of Fluosol-DA/carbogen, only with melphalan did the combination overcome the sparing of dim cells. These results indicate that cells located distally from the tumor vasculature are significantly less affected by most anticancer drugs and suggest that successful therapeutic strategies against solid tumors will involve greater use of the few treatments which are more toxic toward this tumor subpopulation.

Co-trimoxazole prophylaxis during high-dose chemotherapy of small-cell lung cancer.

In 103 patients with small-cell lung cancer, we compared four courses of standard doses of Adriamycin (A) (Adria Laboratories, Columbus, Ohio), vincristine (V), and cyclophosphamide (C) with a regimen of increased doses of cyclophosphamide and to a lesser extent, Adriamycin. We found no significant difference in rate (22% v 21%) or median duration (seven v nine months) of complete remission. Patients not in complete remission after the four cycles of AVC received two courses of VP-16 (etoposide) and cisplatin: the complete remission rate increased to 49% and 48% respectively. Patients on the high-dose arm received co-trimoxazole prophylaxis; those on the standard arm did not. Patients on the high-dose arm had a higher incidence of neutropenia (nadir less than 500 cells/microL) but a lower incidence of infection for similar degrees of neutropenia. However, they also suffered more severe side effects of a different kind. Cotrimoxazole thus allowed for the administration of higher doses of chemotherapy to outpatients by protecting them from infection. However, the higher doses of cyclophosphamide and Adriamycin, did not improve treatment results, produced more severe side effects, and is not recommended.

Beneficial long-term effect of intracoronary perfluorochemical on infarct size and ventricular function in a canine reperfusion model.

The administration of a drug soon after reperfusion that could enhance myocardial salvage would have important clinical application. The aim of this study was to assess the long-term effect of the perfluorochemical, Fluosol DA 20%, on infarct size, infarct morphology, ventricular ectopic activity and serial regional ventricular function in a 2 week closed chest canine model. After 90 minutes of proximal left anterior descending artery occlusion, animals randomly received either oxygenated Fluosol DA (n = 9) or saline solution (n = 9) intracoronary at 15 ml/kg body weight over 20 to 30 minutes. Hemodynamic variables were similar in the two groups except for transient elevation of left ventricular filling pressure immediately after infusion in the treated group. Infarct size was markedly reduced in the perfluorochemical-treated animals when expressed as a percent of the risk region (10.8 +/- 1.8% versus 28.9 +/- 5.5%, p less than 0.02) or as a percent of the total left ventricle (3.7 +/- 1% versus 10.8 +/- 8%, p less than 0.006). This was associated with greater improvement in radial shortening in the jeopardized zone at 2 weeks after reperfusion (15.3 +/- 2.8% versus 5.2 +/- 2.1%, p less than 0.01). Histologic examination revealed adequate healing in the treated animals with an increased number of swollen mononuclear cells in the border zones. Holter electrocardiographic recordings demonstrated a low frequency of ventricular ectopic beats in both groups. This study suggests that the perfluorochemical, Fluosol DA, may be a potentially useful agent in enhancing myocardial salvage after successful reperfusion.

The search for the ideal thrombolytic agent.

Since streptokinase and urokinase became available for clinical use, numerous attempts have been made to improve these useful thrombolytic agents. To decrease its antigenicity, streptokinase has been fragmented or coupled to human plasminogen or polyethylene glycols. With a plasmin B chain-streptokinase complex a more potent agent was obtained. To prolong their half-life, streptokinase and urokinase were immobilized with water-soluble carriers. Coupling urokinase with fibrin-specific antibodies increases its thrombolytic efficacy, at least in vitro. The only thrombolytic agents with a relative fibrin specificity available for clinical purposes are tissue-type plasminogen activator and single chain urokinase-type plasminogen activator. Mutants and hybrids of these molecules are being constructed and may further improve their fibrin specificity and therapeutic potential.

Hyperkalemia in diabetes mellitus. Effect of a triamterene-hydrochlorothiazide combination.

Hyperkalemia is known to occur with increased frequency in the patient with diabetes mellitus and in the elderly when agents that interfere with renal potassium excretion are employed, but the precise frequency has not been established. We employed data from a post-marketing surveillance trial following the introduction of a triamterene-hydrochlorothiazide (Maxzide) combination to estimate the frequency. In patients normokalemic at baseline, hyperkalemia developed with a frequency of 0.59% in 20,809 nondiabetics and in 1.08% of 922 diabetics. Hyperkalemia was threefold to fivefold more likely in those more than 60 years of age, and all of the excess hyperkalemia in diabetics occurred in the elderly. The severity of hyperkalemia was not influenced by the diabetes mellitus. Hypokalemia occurred with a frequency of about 5% and was not influenced by either age or diabetes. In patients who were hypokalemic prior to treatment, hypokalemia was corrected in more than two thirds and hyperkalemia occurred less frequently. Although hyperkalemia indeed occurs with increased frequency in the elderly diabetic when a potassium-sparing combination is employed, the frequency is not so great that such agents should be avoided routinely when their use could be beneficial. Renal function and serum potassium concentration should be assessed prior to instituting treatment and repeated within a few days and a few weeks thereafter in the patient at risk, especially when renal function is suspected, and in the elderly.

Antihypertensive therapy with triamterene-hydrochlorothiazide vs amiloride-hydrochlorothiazide. Comparison of effects on urinary prostaglandin E2 excretion.

Amiloride hydrochloride has now been recognized as a safe and effective potassium-sparing diuretic alternative to triamterene with a similar mechanism of pharmacologic activity. Studies were undertaken to assess the difference between therapy with the triamterene-hydrochlorothiazide combination (Dyazide) and an amiloride hydrochloride-hydrochlorothiazide combination (Moduretic) on renal prostaglandin production, since an increase in renal prostaglandin synthesis has been shown to mediate or enhance the pharmacologic action of certain diuretic drugs. Eight subjects treated for four weeks with triamterene-hydrochlorothiazide were compared with nine patients similarly treated with amiloride-hydrochlorothiazide. A 24-hour urine sample for prostaglandin E2 (PGE2) assay was collected under control conditions and after six weeks of therapy with either diuretic in all patients. The PGE2 excretion increased in the amiloride-hydrochlorothiazide-treated group; in the other group PGE2 excretion actually declined. It is concluded from these studies that therapy with amiloride-hydrochlorothiazide enhanced renal PGE2 production, whereas that with triamterene-hydrochlorothiazide actually decreased renal PGE2 production. This difference is an important renal consequence of the use of either drug and should be considered in the choice between these diuretic combinations.

Sulfamethoxazole-trimethoprim therapy for Wegener's granulomatosis.

Cyclophosphamide has proved to be the most effective therapy for Wegener's granulomatosis, but mortality remains high at many medical centers, and the necessity for giving this toxic agent for many years to prevent relapses remains a major problem. Successful treatment of this disease with sulfamethoxazole-trimethoprim has been reported by DeRemee et al, and experience in a series of ten patients at Thomas Jefferson University Hospital, Philadelphia, confirms its effectiveness. Nine patients are in remission, and the condition of one patient improved. Relapses occurred in four patients after intervals of remission ranging from four to 30 months, but responded to increased doses of trimethoprim in two patients, while two patients required resumption of therapy with cytotoxic agents. Although the effects of sulfamethoxazole-trimethoprim are suppressive rather than curative, its use represents a major advance in treatment of Wegener's granulomatosis, permitting successful treatment of many patients without high toxic doses of cyclophosphamide and prednisone.

The treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.

Forty-four episodes of Pneumocystis carinii pneumonia (PCP) occurred in 36 of 70 patients with the acquired immunodeficiency syndrome. Thirty-four patients with 40 episodes of PCP were treated with trimethoprim-sulfamethoxazole. Therapy was successful in 18 episodes (45%), but was unsuccessful in 15 episodes (37.5%). In the latter cases, two patients died within 72 hours; 13, of whom nine died, had therapy changed to pentamidine. In seven additional episodes (17.5%), trimethoprim-sulfamethoxazole was changed to pentamidine due to adverse reactions; all patients survived. Seven patients (26% of survivors) developed recurrent PCP. Twenty-two patients (65%) developed adverse reactions to trimethoprim-sulfamethoxazole, including leukopenia (20), hepatotoxicity (12), fever (eight), rash (six), and immediate reactions (two). Reactions were most common during the second week of therapy. Patients with the acquired immunodeficiency syndrome who have PCP have a high trimethoprim-sulfamethoxazole failure rate, due either to adverse reactions or unresponsive infection. Late recurrence is common.

Wegener's granulomatosis treated with sulfamethoxazole-trimethoprim. Report of a case.

Wegener's granulomatosis has traditionally been treated with steroids and cyclophosphamide. However, sulfamethoxazole-trimethoprim has been shown to be effective. We used it to treat a patient with this disease who had pulmonary infiltrates, sinusitis, and evidence of renal disease manifested by hematuria and red cell casts. After two months of therapy with sulfamethoxazole-trimethoprim, his hematologic and radiologic values returned to normal.

Bacterial changes in the urine samples of patients with long-term indwelling catheters.

The bacterial flora in the urine samples of 15 nursing home patients with long-term, indwelling catheters were examined monthly for one year. There was a rapidly changing polymicrobial flora averaging 2.0 changes per month in species with colony counts greater than 100,000/mL, and 3.2 changes per month when changes in species, biogram, and quantity of bacteria were considered. The flora changed significantly more frequently, and cultures of Pseudomonas aeruginosa, Providencia stuartii, and Citrobacter diversus were significantly more frequent in those receiving sulfamethoxazole and trimethoprim prophylaxis than in those who did not. There was no difference in incidence of urinary tract infection (UTI) between those patients who received sulfamethoxazole and trimethoprim prophylaxis and those who did not. Ampicillin or gentamicin was effective against 99% of species cultured that are of established UTI pathogenicity. Owing to the rapidity of bacterial flora changes, routine monthly cultures are of little predictive value in patients with indwelling catheters. This study does not support the efficacy of sulfamethoxazole and trimethoprim prophylaxis in such patients.

Infection prophylaxis in acute leukemia. Comparative effectiveness of sulfamethoxazole and trimethoprim, ketoconazole, and a combination of the two.

In a comparative study of infection prophylaxis, patients with acute leukemia receiving remission induction therapy were assigned either no prophylaxis, sulfamethoxazole and trimethoprim, ketoconazole, or the combination of sulfamethoxazole and trimethoprim and ketoconazole. Both sulfamethoxazole and trimethoprim and the combination of sulfamethoxazole and trimethoprim and ketoconazole substantially reduced the overall incidence of infection consequent to a marked decrease in bacterial infection. However, sulfamethoxazole and trimethoprim were associated with an increased rate of fungal infection, while ketoconazole decreased this complication. No form of prophylaxis reduced infectious mortality or increased the complete remission rate. However, because of its effect in reducing infectious morbidity, we conclude that patients with acute leukemia receiving remission induction treatment should be given antibacterial and antifungal prophylaxis.

Cefoxitin resistance in community-acquired gram-negative bacillary bacteremia. Associated clinical risk factors.

Among 185 patients with nonneutropenic, community-acquired gram-negative bacillary bacteremias, clinical risk factors for cefoxitin resistance included any antibiotic taken within the last three weeks (25.6% cefoxitin resistance), long-term bladder catheterization or surgical urinary diversion (23.3%), hospitalization within the last 30 days (22.9%), and nursing home residence before admission (20.8%). Patients with none of these risk factors were less likely to have cefoxitin-resistant bacteremias (0.9%). When these risk factors were examined in the subgroups of urinary tract and non-urinary tract sources of community-acquired gram-negative bacillary bacteremia, they were also helpful in predicting sensitivity to trimethoprim-sulfamethoxazole and gentamicin. The presence of one or more of the risk factors identified may be a useful adjunct in determining initial empiric antimicrobial therapy for community-acquired gram-negative bacillary bacteremia.

AL721, a novel membrane fluidizer.

AL721, which is a novel lipid mixture extracted from egg yolks, is believed to be a therapeutic pharmacologic agent. AL721 interacts with membranes of various types of cells with a common mode of action. AL721 modifies cellular membrane composition and fluidity through passive extraction and/or exchange of cholesterol. Physiologically diminished cell function due to rigidification of its membrane is reversible both in vitro and in vivo by AL721. Fluidization of aged membranes with AL721 has been shown to restore brain serotonin receptor function both in vitro and in vivo. AL721 can also successfully restore deficient immune responsiveness of lymphocytes to mitogen stimulation in aged subjects. Drug tolerance to morphine and ethanol develops upon elevation of the viscosity of neuronal cell membranes in order to counteract the fluidization effect of the drug. Treatment of rigidified cellular membranes with AL721 in vivo can markedly reduce withdrawal symptoms. The virucidal effect of AL721 on the human immunodeficiency virus is believed to operate by lowering of viral membrane cholesterol thus interfering with the binding of the viral antigen to the host cell. Non-toxicity of AL721 is clearly demonstrated in animal and human safety studies.

Effect of dopamine agonist (Lergotrile mesylate) therapy on twenty-four hour secretion of prolactin in treated Parkinson's disease.

Plasma PRL was measured at 20-min intervals in six patients with Parkinson's disease under various treatment protocols. In addition, 24-h mean GH levels were measured. The results of these studies showed that two untreated patients with Parkinson's disease had normal 24-h mean PRL levels with the normal increase during sleep. During chronic treatment with L-dopa-carbidopa (Sinemet), the 24-h PRL level was 12.8 +/- 4.9 ng/ml (mean +/- SD) and there was persistence of augmented PRL secretion during sleep. The 24-h mean GH level ranged from 1.5-4.4 ng/ml, with a mean of 2.5 ng/ml. The addition of a dopamine agonist (Lergotrile mesylate) resulted in a significant (P less than 0.01) suppression of the 24-h mean PRL levels and abolition of the normal sleep augmentation after 2 weeks of therapy. This suppression was maintained in one patient who was restudied 4 months after the addition of dopamine agonist therapy to L-dopa-carbidopa. The 24-h mean GH levels did not change significantly after the addition of the dopamine agonist when compared to L-dopa-carbidopa alone. These results suggest a dichotomy between the PRL and GH responses to combined L-dopa-carbidopa and dopamine agonist therapy. In addition, the preservation of normal PRL regulation in the two untreated patients with Parkinson's disease suggests that dopaminergic neurons are not universally affected in this disorder.

Clinical evaluation of deprenyl (selegiline) in the treatment of Parkinson's disease.

The experiences of a seven-year study on deprenyl in the treatment of Parkinson's disease are summarized. It was found that the main advantage of deprenyl was that it permitted the reduction of the dose of levodopa in optimally treated patients. In the initial stage of Parkinson's disease deprenyl is only partially sufficient as monotherapy. Deprenyl can administered successfully for correcting the "wearing off" effect.

Selegiline in the treatment of Parkinson's disease--long term experience.

L-deprenyl (selegiline) has been reported as a safe effective adjunctive agent to levodopa in the control of Parkinson's symptoms, as well as a means of preventing the progressive nature of the disease process. In an ongoing study, now in its 12th year, L-deprenyl has been administered 1. as monotherapy or 2. in combination with levodopa, to previously untreated patients in the early phases of the disease; 3. added to an existing regimen of levodopa when optimal therapeutic results are not being obtained. This report reviews our experience in each of these three treatment categories. Results obtained to date, indicate that L-deprenyl administered alone does not prevent the occurrence of signs of Parkinson's disease. Its administration with levodopa, as initial therapy, allows for use of lower dosage and less side-effects of the latter agent. When L-deprenyl is added to sub-optimal responders to levodopa, it attenuates fluctuating responses, particularly those of the 'end-of-dose' variety.

Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain.

Ketorolac tromethamine, a nonnarcotic, prostaglandin synthesis-inhibiting analgesic, was compared with morphine sulfate for relief of moderate to severe postoperative pain. The 155 patient participants received single intramuscular doses of either ketorolac, 10, 30, or 90 mg, or morphine, 6 or 12 mg, administered in a double-blind, randomized fashion. Pain scores (verbal and visual analog) were recorded at baseline and assessed at 30 minutes and then hourly to 6 hours. Pain relief was rated at the same times. Ketorolac, 90 and 30 mg, was rated significantly better than morphine, 6 mg, at each assessment interval after 1 hour. Ketorolac, 90 and 30 mg, was rated similarly to morphine, 12 mg, for the first 3 hours and better than morphine, 12 mg, 4 hours after injection. There were no serious side effects reported. The only side effect reported in more than 3% of patients was 8% somnolence with morphine. This study shows ketorolac to be a safe and effective analgesic for relief of postoperative pain.

Evaluation of analgesic agents in recurring headache compared with other clinical pain models.

The efficacy of three preparations (placebo, analgesic agent, and analgesic plus antihistaminic agent) were compared in a double-blind crossover study in subjects with recurring headaches. It was confirmed that headache as a pain model does not show the usual return of pain with as the effects of a single analgesic dose wear off. Consequently, there is no "peak effect," and the rationale for comparing treatments by "area under the curve" calculations is weakened. Greater efficacy was demonstrated for the analgesic over the placebo and for the analgesic and antihistaminic combined over the analgesic alone in several parameters. Slopes of straight lines derived as a quadratic function of pain versus time data proved to be a more effective discriminator between treatments than area under the curve calculations from the same data.