Assessment of current hyperthermia technology.

The current state of the art in techniques for the production and control of whole-body and local hyperthermia is discussed. Techniques of radio-frequency, microwave, and ultrasonic local hyperthermia are considered and compared. Problems of thermometry and control system integration are defined, and requisite biophysical data requirements are established. A bibliography is provided to serve both as an introduction to the hyperthermia literature for researchers from other fields and as a convenient compendium of original sources for scientists currently engaged in hyperthermia research.

Parasympatholytic (anticholinergic) esters of the isomeric 2-tropanols. 2. Non-glycolates.

The 19 esters in Table I were prepared from (+)-2 alpha-tropanol, (-)-2 beta-tropanol, (+/-)-3-quinuclidinol, and a variety of non-glycolic acids in order to compare their central and peripheral activities with those of the glycolates reported in the previous paper. The results (Table II) showed that esters 6 and 17 were approximately equivalent to one another and to atropine, that 8 was equal in both central and peripheral activity to reference glycolates, that 9 and 19 were less active than 8 but 9 had a substantially reduced central activity, and that 10 and 11 were more active than the methoxy analogue reported earlier.

Emetic activity of N-substituted norapomorphines.

Norapomorphine and ten of its N-substituted derivatives were prepared by modifications of procedures described earlier. In a dog emesis test the N-ethyl and N-n-propyl compounds had minimum effective doses of 0.00025 and 0.0005 mg/kg, respectively, when administered iv, sc, or im. In a modified Irwin mouse profile screen the minimum effective iv dose was 0.013 mg/kg for the N-ethyl and 0.0024 mg/kg for the N-n-propyl compound; percutaneous absorption was also observed in mice. All compounds examined caused the stereotyped apomorphine behavior syndrome but hypotensive effects were not serious.

Parasympatholytic (anticholinergic) esters of the isomeric 2-tropanols. 1. Glycolates.

The 38 esters in Table I were prepared from the four isomeric 2-tropanols and a variety of racemic glycolic acids and their optical isomers. Anticholinergic activity in mice was measured in the peripheral nervous system (mydriasis) and in the central nervous system (anti-tremorine) and compared with that of atropine, scopolamine, and racemic 2-quinuclidinyl benzilate. The results (Table III) showed that several esters (such as 8, 12, 14, and 21) had significantly greater activity in both the peripheral and central nervous systems than did the reference compounds. Esters of (+)-2alpha-tropanol were more potent than those of either its epimer (-)-2beta-tropanol or its optical isomer(-)-2alpha-tropanol. Esters derived from (-)-glycolic acids were uniformly more potent than those from the (+)-glycolic acids. Esters of (+)-2alpha-notropanol and five of its N-substituted derivatives had markedly decreased activity. Peripheral/central activity ratios and time-activity profiles for five active compounds are discussed and compared with those of the reference compounds.

Synthesis, rodent biodistribution, dosimetry, metabolism, and monkey images of carbon-11-labeled (+)-2 alpha-tropanyl benzilate: a central muscarinic receptor imaging agent.

Muscarinic cholinergic receptors (mAChR) are abundant in the brain, and the mAChR system mediates many aspects of brain function. There is evidence of alterations in muscarinic binding in degenerative brain disorders. A muscarinic receptor radioligand, carbon-11-(+)-2 alpha-tropanyl benzilate ([11C]TRB), has been prepared through N-[11C]methylation of N-desmethyl TRB, and evaluated in rodents and primates. Full body biodistribution in rats has been determined and the expected human dosimetry calculated. Comparisons with [11C]scopolamine in rats showed 2-6 times greater brain uptake of [11C] TRB. Highly specific and saturable binding of [11C]TRB in the striatum and cortex was demonstrated by greater than 85% blockade of uptake following QNB or scopolamine pretreatment. Striatum/cerebellum ratios in mice at 60 min exceeded 12.6. TLC analysis of rat tissues showed the absence of 11C-metabolites in brain and heart, and a rapid solid phase C-18 Sep-Pak method found that unmetabolized plasma [11C]TRB in monkeys fell from 81% at 5 min to 48% at 80 min. Finally, brains of living primates have been imaged using PET and [11C]TRB; regional localization was consistent with muscarinic receptor distribution. These results represent intermediate steps in the development of [11C]TRB for quantification of central muscarinic receptors in man.

Antimalarials V: aminobenzothiazoles.

Four mono- and dialkylated 4-aminobenzothiazoles (VII-X) were prepared as analogs of potent causal prophylactic drugs in the 8-aminoquinoline series. Compounds VII and VIII were toxic at 80 mg/kg in the chick; IX was inactive at 640 mg/kg. In a sporozoite-induced mouse test system, X was inactive at 30 mg/kg and toxic at 480 mg/kg. None of the compounds was active as a suppressive drug.

Derivatives of apomorphine and of other N-substituted norapomorphines.

Derivatives of apomorphine and of N-n-propylnorapomorphine were prepared to obtain modified pharmacological activity and enhanced chemical stability. Mouse profile and dog emesis screens were performed, and the activity of various N-substituted derivatives and their esters was evaluated and compared to the parent compounds. The N-n-propyl diacetate derivative and N-methyl and N-n-propyl ascorbate salts were remarkably stable to air: apomorphine etherate was no more stable than the free base. The dimers, the major products formed during the acid-catalyzed rearrangement of morphines to apomorphines, were all potent emetics. Additionally, two showed a significant antagonism to morphine in mice and dogs.

The inhibition of bacterial cell growth by ketone bodies.

The effect of ketone bodies on the growth, in culture, of Escherichia coli was investigated. Both growth and glucose utilisation were inhibited in the presence of 20 mmol/l D-3-hydroxybutyrate. Lower concentrations of D-3-hydroxybutyrate caused proportionally less inhibition of growth. Acetoacetate also inhibited growth but other glycolytic inhibitors and chemical analogues of D-3-hydroxybutyrate either did not inhibit or proved to be too toxic for bacterial growth. Citrate enhanced the ketone body effect. D-3-hydroxybutyrate also inhibited the growth of Klebsiella pneumoniae, Enterobacter aerogenes, Citrobacter freundii and Salmonella typhimurium. The possible relationship between ketone body inhibition of cell growth and oxygen limitation is discussed.

An evaluation of liquid-crystal thermometry as a screening device for intraoperative hyperthermia.

Disposable liquid-crystal temperature-trend indicators were evaluated under clinical conditions that simulated the development of intraoperative hyperthermia during anesthesia. Comparison was made to forehead thermistors for rapidity, accuracy, and linearity of response as well as correlation with esophageal and rectal thermistor recordings. The liquid-crystal monitors were comparable to the forehead thermistors in both rapidity and linearity or response, but not in accuracy. A linear correlation existed with the esophageal thermistor temperatures. Correlation with the rectal temperatures was not as exact. It is concluded that liquid-crystal thermometers may adequately serve as screening devices for intraoperative hyperthermia.

Induced hyperthermia in sedated humans and the concept of critical thermal maximum.

The concept of critical thermal maximum (CTM) has been defined in the literature as the minimal high deep-body temperature that is lethal to an animal. In man the CTM has been estimated at 41.6--42.0 degrees C. Data are presented for sedated, unacclimatized, well-hydrated men heated 1 h at esophageal temperatures of 41.6--42.0 degrees C, without sequelae, except for modest elevation of serum enzymes in two of five patients. These data when combined with other observations in the literature suggest that CTM be redefined as the particular combination of exposure time at elevated body temperatures that results in either subclinical (CTM)s) or clinical (CTMc) injuries. Also presented is a mathematical technique, equivalent time at 42 degrees C (Teq 42 degrees), for expressing hyperthermia in terms of body temperature and exposure time.

Whole body hyperthermia: a phase-I trial of a potential adjuvant to chemotherapy.

Fourteen patients with a variety of neoplasms not responsive to standard forms of therapy underwent whole body hyperthermia for a maximum 4 h at 41.8 degrees C. This was a phase-I cancer trial designed to develop whole body hyperthermia as an adjuvant to systemic chemotherapy. Intravenous analgesia was used to sedate patients, obviating the need for general endotracheal anesthesia. Hyperthermia was induced by means of a high-flow water perfusion suit. Cardiovascular performance was evaluated using a flow-directed pulmonary artery catheter. Patients developed a twofold mean increase in cardiac index without evidence of cardiac damage by ECG or creatine phosphokinase (CPK) isoenzymes. An acute fall in serum magnesium and phosphate and an acute rise in arterial pH, serum CPK values, and granulocyte count occurred in all patients. There were no clotting abnormalities. Toxicity included fatigue, diarrhea, nausea, and transient elevations in liver enzymes. Four patients were febrile for 36 h after initial defervescence. Peripheral neuropathy developed in four. These results show that with carefully monitored conditions whole body hyperthermia is feasible.