12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced increase in depressed white blood cell counts in patients treated with cytotoxic cancer chemotherapeutic drugs

Fifty-two patients with solid tumors had depressed white blood cell and neutrophil counts because of prior treatment with cytotoxic cancer chemotherapeutic drugs. These patients were given one or more i.v. infusions of 0.125–0.25 mg of 12-O-tetradecanoylphorbol-13-acetate (TPA), and this treatment increased the low white blood cell and neutrophil counts toward the normal range. The average white blood cell and neutrophil counts were 2.55 × 10⁹/liter and 1.76 × 10⁹/liter, respectively, before treatment with TPA. After one or more i.v. infusions of TPA, the white blood cell and neutrophil counts increased to peak values of 5.92 × 10⁹/liter and 4.76 × 10⁹/liter, respectively, within a few days. Most patients had increased levels of white blood cells and neutrophils by 24 hr after a single i.v. infusion of 0.25 mg TPA. Elevated levels were observed for at least 3 days. This study demonstrates that treatment with parenteral TPA is feasible with useful biological activity. Only mild and reversible side effects were observed.     

ACUTE EFFECTS OF ORAL GLIBENCLAMIDE ON BLOOD PRESSURE AND FOREARM VASCULAR RESISTANCE IN DIABETICS

1. To determine the effects of an acute oral dose of glibencla-mide on blood pressure (BP), basal forearm vascular resistance (FVR) and FVR responses to the K⁺_ATP channel activating vasodilator diazoxide, a placebo-controlled, double-blind cross-over study was performed in eight male volunteers with non-insulin-dependent diabetes mellitus. 2. Changes in vascular responses to progressively increasing concentrations of diazoxide (3.75–30 mg/kg per min) and noradrenaline (25–100 ng/kg per min) were measured by venous occlusion plethysmography. 3. Glibenclamide significantly lowered plasma glucose levels compared with placebo (P < 0.02) and attenuated the decrease in FVR (P < 0.05) and the decrease in systolic BP (P < 0.05) that followed a meal. However, vasodilator responses to diazoxide were potentiated by the administration of oral glibenclamide (P < 0.01). 4. Acute administration of oral glibenclamide attenuates the normal decrease in FVR and systolic BP that follows a meal and potentiates rather than inhibits forearm vasodilator responses to intra-arterial diazoxide, probably via indirect humoral effects. These results suggest that glibenclamide has direct or indirect vasoconstrictor effects that antagonize the normal increase in forearm blood flow that follows a meal and that the inhibition of vascular K⁺ATP channels following acute oral glibenclamide administration is clinically insignificant compared with other indirect vascular effects of the drug.     

Iopamidol and meglumine diatrizoate: comparison of effects on patient discomfort during aortofemoral arteriography

Iopamidol was compared with Renografin-60 (meglumine diatrizoate, Squibb) in a controlled, randomized double-blind study of 40 patients undergoing peripheral arteriography for arteriosclerotic occlusive disease to determine which agent caused less discomfort. Each patient was evaluated for objective signs of discomfort and subjective feelings of pain and heat. Monitoring was achieved by multiple physical examinations, chemical tests, electrocardiograms, and intra-arterial pressure recordings. It is concluded that iopamidol is safe and causes significantly less patient discomfort than Renografin-60.     

Comparison of the effect of sn-1,2-didecanoylglycerol and 12-O-tetradecanoylphorbol-13-acetate on cutaneous morphology, inflammation and tumor promotion in CD-1 mice

Since sn-1,2-didecanoylglycerol mimics 12-O-tetradecanoylphorbol-13-acetate(FPA) by inducing ornithine decarboxylase activity and stimulatingDNA synthesis in mouse epidermis [Smart,R.C., Huang,M.-T. andConney,A.H. Carcinogenesis, 7, 1865(1986)], we have investigatedmorphological changes induced by TPA and sn-1,2-didecanoylglycerolin the epidermis and we have also examined sn-1,2-didecanoylglycerolas a possible complete tumor promoter. It wasdetermined thattopical application of 2.5 or 10 µmol of sn-1,2-didecanoylglycerolinduced epidermal ornithine decarboxylase activity to aboutthe same extent as the application of 1 or 2 nmol of TPA respectively.Therefore, these doses of TPA and sn-1,2-didecanoylglycerolwere used in most of our studies. Single or multiple application(2 x /week for 4 weeks) of 1, 2 or 5 nmol of TPA to the skinof CD-1 mice produced a dose-dependent increase in the numberof epidermal non-cornified cell layers, epidermal thickness,leukocyte infiltration and intracellular edema. In contrast,neither single nor multiple application (2 x /week for 4 weeks)of 2.5 or 10 µmol sn-1,2-didecanoylglycerol produced anyof these responses. However, when 5 µmol sn-1,2-didecanoyl-glycerol was applied topically twice a day (10 µmol/day)for 5 days there was a significant increase in the number ofepidermal non-cornified cell layers and epidermal thickness.The effects of TPA and sn-1,2-didecanoylglycerol were comparedusing the mouse ear inflammation model. Application of TPA causededema, but sn-1,2-didecanoylglycerol had little or no effect.sn-1,2-Didecanoylglycerol was then evaluated as a complete tumorpromoter utilizing the mouse skin two-stage model. CD-1 micewere initiated with 200 nmol 7,12-dimethythenz[a]anthraceneand then treated wIth 1 nmol TPA or 2.5 µmol sn-1,2-didecanoylglyceroltwice a week for 28 weeks. A28 weeks, 28% of the mice treatedwith TPA had developed tumors, while none of the mice treatedwith 2.5 µmol sn-1,2-didecanoylglycerol developed tumors.The data indicate that topical application of 2.5 µmolsn-1,2-didecanoylglycerol induced ornithine decarboxylase activityto the same extent as a tumor-promoting dose of 1 nmol TPA,but it did not cause morphologial changes in the epidermis whenapplied once or when applied twice a week for 4 weeks and didnot function as a complete tumor promoter when applied twicea week for 28 weeks. Since more frequent applications of sn-1,2-didecanoylglycerol(5 µmol twice a day