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PubMed1995

Effects of prolonged L-arginine administration on blood pressure in patients with essential hypertension (EH).

L-arginine (L-Arg) was administered intravenously through 4 consecutive days to 20 males (40-63 years old) with essential hypertension (EH). Significant decrease (p < 0.02) of systolic blood pressure (SBP) was observed only during the first day of the therapy and tachyphylaxis against L-Arg was noticed. The reduction of diastolic blood pressure (DBP) was more marked (p < 0.001). Significant changes in cGMP plasma level and the nitrite/nitrate urine concentration were not observed. L-Arg caused a significant activation of fibrinolysis (p < 0.005). The decrease of platelet activity, measured by the ADP-induced aggregation, after L-Arg administration was not statistically significant. Therefore, L-Arg may play only a secondary role in the treatment of EH.

Adult↗
PubMed1997

Nicotine and sympathetic neurotransmission.

Nicotine increases heart rate, myocardial contractility, and blood pressure. These nicotine-induced cardiovascular effects are mainly due to stimulation of sympathetic neurotransmission, as nicotine stimulates catecholamine release by an activation of nicotine acetylcholine receptors localized on peripheral postganglionic sympathetic nerve endings and the adrenal medulla. The nicotinic acetylcholine receptor is a ligand-gated cation channel with a pentameric structure and a central pore with a cation gate, which is essential for ion selectivity and permeability. Binding of nicotine to its extracellular binding site leads to a conformational change of the central pore, which results in the influx of sodium and calcium ions. The resulting depolarization of the sympathetic nerve ending stimulates calcium influx through voltage-dependent N-type calcium channels, which triggers the nicotine-evoked exocytotic catecholamine release. In the isolated perfused guinea-pig heart, cardiac energy depletion sensitizes cardiac sympathetic nerves to the norepinephrine-releasing effect of nicotine, as indicated by a leftward shift of the concentration-response curve, a potentiation of maximum transmitter release, and a delay of the tachyphylaxis of nicotine-evoked catecholamine release. This sensitization was also shown to occur in the human heart under in vitro conditions. Through the intracardiac release of norepinephrine, nicotine induces a beta-adrenoceptor-mediated increase in heart rate and contractility, and an alpha-adrenoceptor-mediated increase in coronary vasomotor tone. The resulting simultaneous increase in oxygen demand and coronary resistance has a detrimental effect on the oxygen balance of the heart, especially in patients with coronary artery disease. Sensitization of the ischemic heart to the norepinephrine-releasing effect of nicotine may be a trigger for acute cardiovascular events in humans, such as acute myocardial infarction and/or life-threatening ventricular tachyarrhythmias.

Animals↗
PubMed1987

The role of calcium channel in the effect of nicotine on contractility in isolated toad ventricle.

The mechanism of the positive inotropic effect produced by nicotine (6.2 X 10(-5) mol/l to 4.9 X 10(-4) mol/l) on electrically driven toad ventricles was investigated. The response to nicotine was not affected by 6-hydroxydopamine pretreatment, bretylium (2.4 X 10(-4) mol/l) exposure or tyramine tachyphylaxis. Following desensitisation by isoprenaline (4.2 X 10(-6) mol/l) of the beta-adrenoceptor in the ventricles, the response to nicotine was no affected. However, the response was antagonised by ethylene diamine tetraethyl acetate (2.3 X 10(-4) mol/l), verapamil (0.4 X 10(-5) mol/l) or calcium-free Ringer. Nicotine prolonged the action potential duration and enhanced the force of contraction. Nicotine induced slow action potentials in partially depolarized (in high potassium solution) ventricles and this was antagonised by verapamil (0.4 X 10(-5) mol/l). These results suggest that the effects of nicotine are mediated by a direct interaction with the Ca2+ channels at the cell surface.

Action Potentials↗
PubMed1988

The depolarizing action of 5-hydroxytryptamine on rabbit isolated preganglionic cervical sympathetic nerves.

This study describes a depolarizing action of 5-hydroxytryptamine (5-HT) on rabbit isolated preganglionic cervical sympathetic nerves using an extracellular recording technique. From cumulative concentration-response curves for 5-HT (1 mumol/l-1 mmol/l), the mean maximal depolarization was shown to be 277 +/- 32 microV and EC50 was 9.4 mumol/l (6.5-13.6 mumol/l, geometric mean, 95% confidence limits, n = 42). The responses to 5-HT displayed marked tachyphylaxis. When cumulative concentration-response curves to 5-HT and 2-methyl-5-HT were determined in the same preparations (n = 4), the mean maximal response to 5-HT was 519 +/- 167 microV, EC50 32.2 mumol/l (8.8-118 mumol/l) and the mean maximal response to 2-methyl-5-HT was 317 +/- 63 microV, EC50 35.1 mumol/l (12.9-95.5 mumol/l, geometric means, 95% confidence limits). The action of selective 5-HT antagonists was tested on repeated cumulative concentration-response curves to 5-HT. Neither methiothepin (0.1-1 mumol/l, n = 3) nor ketanserin (0.1-1 mumol/l, n = 3) had an action on 5-HT responses. The selective 5-HT3 antagonists MDL 72222, ICS 205-930 and SDZ 206-830 were all potent antagonists of the 5-HT depolarizations. The action of these antagonists was quantified by determining the apparent pA2 from the dose ratios and a Schild plot.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Interaction of adenine nucleotides, UTP and suramin in mouse vas deferens: suramin-sensitive and suramin-insensitive components in the contractile effect of ATP.

Effects of various nucleotides, nucleosides and noradrenaline on smooth muscle tension were studied in the isolated mouse vas deferens. alpha, beta-Methylene-ATP, ATP gamma S, noradrenaline, ATP and UTP elicited contraction, with potency decreasing in that order; there was no contractile response to adenosine or uridine (up to 100 mumol/l). Prolonged incubation with alpha, beta-methylene-ATP (concentration increased stepwise from 0 to 15 mumol/l) selectively reduced contractions induced by ATP and UTP but not those induced by noradrenaline, and there was cross-tachyphylaxis between ATP and UTP. Suramin (10-300 mumol/l) did not alter the response to noradrenaline but shifted the concentration-response curves for alpha, beta-methylene-ATP, ATP gamma S, UTP and lower concentrations of ATP (0.1-1 mumol/l) to the right. The pA2-values of suramin were 5.2 against alpha, beta-methylene-ATP, 4.8 against ATP gamma S, 5.1 against UTP and 5.4 against lower concentrations of ATP. The effects of higher concentrations of ATP were largely resistant to suramin. The results indicate that the mouse vas deferens possesses contraction-mediating smooth muscle P2x-receptors. UTP also acts at this receptor, and there is no evidence for a separate UTP receptor. The selective inhibition of nucleotide- but not noradrenaline-induced contractions by suramin confirms the view that suramin is a selective P2-antagonist. The resistance against suramin of part of the effect of ATP suggests that ATP activates a suramin-insensitive site in addition to the P2x-receptor.

Adenine Nucleotides↗
PubMed1989

Prostaglandins and CGRP release from cardiac sensory nerves.

(1) The possible influence of prostaglandins (PG) E1 and I2 as well as ischaemia, ouabain and bradykinin on the outflow of calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-like immunoreactivity (LI) from the guinea-pig heart was studied in vitro. (2) Exposure to PGE1 (10(-5) M), but not PGI2 (10(-5) M), induced an increased outflow, suggesting release of CGRP-LI. PGE1 simultaneously increased the contractile force and heart rate while no effects were observed on perfusate volume or outflow of NPY-LI. PGI2 had no effect on contractile parameters or coronary flow. In separate experiments on capsaicin-pretreated animals, the stimulatory effects of PGE1 on heart rate and contractile force remained unchanged while no increased CGRP-LI outflow was detectable. (3) Ouabain, bradykinin and reperfusion after total stop-flow ischaemia was associated with an indomethacin-resistant increase in perfusate levels of CGRP-LI but not of NPY-LI. While ouabain markedly increased the contractile force, exposure to bradykinin or ischaemia did not induce any clear-cut changes in contractile force or heart rate. (4) Capsaicin-exposure evoked a markedly increased outflow of CGRP-LI but not of NPY-LI in combination with an increase in heart rate and a decrease in contractile force. Repeated administration of capsaicin induced tachyphylaxis. The stimulatory effects of capsaicin on CGRP-LI outflow and heart rate, but not the negative inotropic effect, did not occur in capsaicin-pretreated animals. (5) It is concluded that PGE1, but not PGI2, can activate cardiac capsaicin-sensitive fibres as revealed by increased outflow of CGRP-LI.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗
PubMed1989

The vasodilator action of parathyroid hormone fragments on isolated perfused rat kidney.

The renal vasodilator responses to various fragments of PTH were quantified on a model of isolated perfused rat kidney (IPK), under non-filtering conditions. The 1-34 fragment of bovine PTH, its Nle analogue and rat PTH, injected in sequential cumulative doses, caused concentration-dependent vasodilatation in the vasculature of the IPK which was preconstricted with prostaglandin F2 alpha. The EC50 of PTH for renal vasodilatation ranged from 1 to 2 nM for all PTH fragments and maximum vasodilatation ranged from 33 to 41% of the maximum vasodilatation induced by papaverine. Renal vasodilation was not related to prostaglandin release since similar vasodilatation occurred after the inhibition of prostaglandin synthesis with indomethacin. When PTH was administered in single bolus injections, using a separate kidney for each hormone concentration, rather than repeated injections into the same kidney, higher maximum vasodilatations were obtained (64%). These results most likely reflected tachyphylaxis of the renal vasculature to PTH occurring after repeated exposure of a single kidney to the hormone. The antagonist analogue [Nle8,18, Tyr34]-bPTH-(3-34)A shifted the concentration-related response curve to the right, indicating that the renal vasodilator response to rPTH-(1-34) involved specific vascular receptors.

Animals↗
PubMed1994

Nicotine-induced activation of locus coeruleus neurons--an analysis of peripheral versus central induction.

Previous electrophysiological experiments have shown that the marked but short-lasting excitation of locus coeruleus (LC) neurons seen after systemic administration of low doses of nicotine is of a peripheral origin. In addition, nicotine induces a weak but more long-lasting activation of LC neurons which is preferentially observed following administration of high doses of the drug. In the present study this latter activation was pharmacologically analysed. Whereas low intravenous doses of nicotine caused a marked but short-lasting excitation of most LC cells recorded from, higher doses of nicotine were associated with a moderate but durable (> 20 min) activation. In contrast to the short-lasting activation of the LC, the long-lasting effect of the drug was not counteracted by chlorisondamine (0.3 mg/kg, i.v.; n = 5). On the other hand, administration of mecamylamine (4 mg/kg, i.v.; n = 5) rapidly and effectively decreased the elevated spontaneous firing rate of LC neurons (as observed following repeated nicotine injections) to the original baseline firing rate. Intravenous administration of tetramethylammonium (TMA, 50-800 mg/kg, i.v.), activated most LC neurons in a manner resembling that of nicotine at low doses, i.e. a marked but short-lasting excitation with no tachyphylaxis. However, in contrast to nicotine, TMA administered in higher doses did not affect the baseline firing rate of LC neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1990

Capsaicin-like activity of some natural pungent substances on peripheral endings of visceral primary afferents.

1. The effects of some naturally occurring pungent substances, piperine, mustard oil, eugenol and curcumin, were compared to those of capsaicin in the rat isolated urinary bladder. 2. All test compounds dose-dependently contracted the rat bladder and produced desensitization toward capsaicin (1 mumol/l). Development of cross-tachyphylaxis among the natural pungent substances on one hand and capsaicin on the other, suggested a common site of action on visceral primary afferents. 3. Contractile responses to piperine, mustard oil and eugenol were partially tetrodotoxin and ruthenium red-sensitive, suggesting that activation of sensory terminals by these agents takes place indirectly, as well as by a direct action on sensory receptors. 4. The presence of the secondary acrylamide linkage (present in the backbone of capsaicin, but not in that of test compounds) does not appear to be essential to produce desensitization of sensory nerve terminals.

Alkaloids↗
PubMed1990

Sensory nerves, vascular endothelium and neurogenic relaxation of the guinea-pig isolated pulmonary artery.

1. In the presence of atropine and guanethidine (3 mumol/l each), electrical field stimulation (1-20 Hz) produced frequency-dependent relaxations of the histamine- (3 mumol/l) induced vascular tone in isolated rings from the guinea-pig pulmonary artery. The electrically-evoked relaxations were abolished by tetrodotoxin (1 mumol/l). The amplitude of these nerve-mediated, non-adrenergic non-cholinergic (NANC) relaxations was unaffected by removal of the vascular endothelium produced through rubbing of the internal surface. 2. Capsaicin (1 mumol/l) produced a prompt and sustained relaxation of the histamine-induced tone which was unaffected by removal of the endothelium. A second application of capsaicin 60-120 min later had no further relaxant effect, indicating desensitization. After in vitro capsaicin desensitization, the electrically-evoked NANC relaxations were abolished, both in the presence or absence of the vascular endothelium. 3. Substance P evoked a prompt and transient relaxation in precontracted arterial rings with intact endothelium and a transient small contraction in rings in which the endothelium had been mechanically removed. The selective NK-1 receptor agonist, [Pro9]-substance P sulfone closely mimicked the relaxation produced by substance P while the selective NK-2 or NK-3 receptor agonists had no relaxant effect. Tachyphylaxis to substance P did not modify the amplitude of the capsaicin-induced relaxation. 4. Human alpha calcitonin gene-related peptide (CGRP) produced a prompt and sustained relaxation both in the presence and absence of the vascular endothelium. 5. Ruthenium red (10 mumol/l) blocked the relaxation to capsaicin while leaving unaffected the relaxation to electrical field stimulation or CGRP (0.1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Capsaicin-induced local effector responses, autonomic reflexes and sensory neuropeptide depletion in the pig.

Systemic capsaicin pretreatment (total cumulative dose 50 mg/kg administered s.c. over 2h) was performed in pigs under pentobarbitone anaesthesia and the effects on sensory and sympatho-adrenal mechanisms were examined acutely and 2 days after treatment. During pretreatment with capsaicin, pronounced sensory and sympatho-adrenal activation were noticed. This resulted in a several-fold increase in the systemic arterial plasma levels of calcitonin gene-related peptide (CGRP), neurokinin A (NKA), noradrenaline (NA), adrenaline (Adr) and neuropeptide Y (NPY), and a slight increase (39%) in plasma cortisol. Simultaneously, there was marked tachycardia, an increase in blood pressure, total skin erythema and some bronchoconstriction, all lasting for about 30 min. Upon repeated injections tachyphylaxis was observed. 2 days after capsaicin pretreatment, basal plasma levels of the neuropeptides, catecholamines and cortisol as well as basal cardiovascular and pulmonary parameters were similar in control and capsaicin-treated pigs. The tissue content of CGRP and NKA was reduced by 50-65% in the airways and by 80-90% in the skin 2 days after capsaicin pretreatment. In contrast, the CGRP content was unchanged or increased (by 195%) in the nodose and spinal ganglia, respectively. The corresponding tissue levels of vasoactive intestinal polypeptide (VIP) and NPY were basically unchanged in capsaicin-treated pigs. A bolus injection of capsaicin (1 mg/kg i.v.) in control animals resulted in a marked increase in plasma catecholamines and NPY, concomitant with elevation in blood pressure and heart rate. These effects were preceded by an initial bradycardia and decrease in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Glycine-evoked release of [3H]acetylcholine from rat striatal slices is independent of the NMDA receptor.

KCl-, NMDA-, and glycine-evoked release of [3H]acetylcholine was studied in superfused rat striatal slices. KCl-evoked release of [3H]acetylcholine was inhibited by 1.2 mM MgCl2 and 100 microM lidocaine. Similarly, NMDA-evoked release was inhibited by MgCl2 and lidocaine as well as 10 microM CGS 19755, a competitive antagonist at NMDA receptors, and 10 nM MK-801, a noncompetitive antagonist of NMDA-induced responses. Glycine-evoked release was calcium-dependent and was inhibited by 0.1 microM strychnine whereas KCl- and NMDA-evoked release were resistant to strychnine. In addition, lidocaine inhibited the glycine-induced response. Cross-tachyphylaxis was not observed between NMDA- and glycine-evoked release. These results indicate that the strychnine-sensitive, glycine-evoked release of [3H]acetylcholine is independent of the NMDA receptor.

Acetylcholine↗
PubMed1989

Phase I study of recombinant human tumor necrosis factor alpha in advanced malignant disease.

A phase I study with recombinant human tumor necrosis factor alpha (rhuTNF-alpha; Knoll AG, Ludwigshafen, FRG) in patients with advanced malignant disease was undertaken to evaluate drug toxicity (organ specificity, time course, predictability, reversibility, maximal tolerated dose), effectiveness, antigenicity and pharmacokinetics. TNF was administered as a test dose followed by daily i.v. infusions for 5 days, every 3 weeks (single i.v. infusion lasting 10 min, TNF dissolved in 50 ml 5% human albumin). Dosage was increased in groups of 3 or 4 patients from 0.04 mg/m2 to 0.28 mg/m2. A total of 19 patients with different cancers, including seven large-bowel carcinomas, three chronic myelogenous leukemias, three hypernephromas, two small-cell lung cancers, one malignant melanoma, one malignant lymphoma, one rhabdomyosarcoma and one fibrosarcoma were treated. Major side-effects were chills and fever (maximum 40.4 degrees C, median 38.7 degrees C, 19/19), headache (12/19), nausea and vomiting (12/19) and pronounced (greater than 20%) hypotension (4/19). Acute side-effects could be diminished by paracetamol or indomethacin pretreatment, and with one possible exception no tachyphylaxis to TNF was noted. Mild renal toxicity was seen during TNF treatment. Pharmacokinetic studies showed a serum half-life (t1/2) ranging from 11 min to 17 min for doses from 0.04 mg/m2 to 0.16 mg/m2 and prolonged clearance with t1/2 ranging from 54 min to 70 min in the 0.20-0.28 mg/m2 dose range. No objective antitumor effects were observed in this phase I study.

Adenocarcinoma↗
PubMed1982

Endotoxin-induced release of tumour necrosis factor and interferon in vivo is inhibited by prior adrenoceptor blockade.

The effect of alpha- and beta-adrenoceptor blocking agents on endotoxin-induced release of tumour necrosis factor (TNF), and of interferon in the circulation of Corynebacterium parvum-treated mice was the subject of this study. TNF was quantified after injection of TNF containing heated serum (TNS) into Meth A sarcoma-bearing mice by determining colour, extent, and incidence of haemorrhagic necrosis. The release of TNF was weakly inhibited by the competitive alpha-blocker phentolamine and the beta-blocker propranolol. The non-competitive alpha-blocker phenoxybenzamine inhibited to a higher degree. Endotoxin-induced elicitation of growth-inhibiting principles into TNS was antagonized by propranolol and phenoxybenzamine. Administration of adrenaline before endotoxin inhibited the elicitation of TNF and growth-inhibitory activities, which indicates tachyphylaxis. The release of interferon was effectively inhibited by both alpha-adrenoceptor blockers but not by propranolol. The interferon was heat-labile. The results indicate that endotoxin-induced TNF and interferon are separate factors, elicited in different ways. As both alpha-blockers do not only inhibit reactions at the alpha-adrenergic receptor but also reactions at the serotonin receptor and in the case of phenoxybenzamine also at the choline receptor, it is suggested that endotoxin-induced release of the anti-tumour factors is controlled by reactions mediated by one or more of these receptors. It is suggested that the inhibition of TNF release by propranolol may be due to the membrane-stabilizing activity of this agent.

Animals↗
PubMed1992

Excitation of cutaneous afferent nerve endings in vitro by a combination of inflammatory mediators and conditioning effect of substance P.

A broad mixture of inflammatory mediators ("inflammatory soup") was used to investigate the responsiveness of primary afferents from rat hairy skin in an in vitro skin-saphenous nerve preparation. In addition, a conditioning effect of the tachykinin substance P on chemosensitivity of nociceptors was examined. Inflammatory soup (IS) was made up in synthetic interstitial fluid from bradykinin, serotonin, histamin and prostaglandin E2 (all 10(-5) M). In addition, the potassium and the hydrogen ion concentration (7 mM, pH 7.0) and the temperature (39.5 degrees C) were elevated. The latter agents, in a control solution, did not excite nociceptors (n = 5). IS was repeatedly superfused over the receptive fields for 5 min at 10 min intervals; substance P (SP 10(-6) and 10(-5) M) was applied during the last 5 min of the interval and during the subsequent IS stimulation. IS excited more than 80% of the mechano-heat sensitive ("polymodal") afferents with slowly conducting nerve fibres (n = 72), but none of the low-threshold mechanoreceptive slow and fast conducting units (n = 17). Slow conducting afferents with high mechanical threshold (n = 35) were weakly, and less frequently (< 20%), driven by IS. A majority, but not all, of the responsive units showed tachyphylaxis upon repeated IS application. None, however, lost its responsiveness completely. Conditioning heat stimulation (32-46.5 degrees C in 20 s) did not enhance the subsequent IS response, which may indicate that sensitizing substances normally released by a noxious heat stimulus were already contained in IS. No sensitization to mechanical (von Frey) or heat stimulation could be established in the period after the IS response had subsided and after the washout was completed, respectively. A short-lived sensitization may have been overlooked under these temporal restrictions. Conditioning SP in 10(-5) M but not in 10(-6) M concentration significantly increased the IS response of polymodal C fibres, by 58% on average (n = 14). SP did not excite the units. Comparing with previous data, we conclude that there is a significant synergism between inflammatory mediators, acting to induce more intense and more sustained discharge via many nociceptors than single mediators alone could achieve. Conditioning substance P can further enhance this algogenic action. Mechanisms of interaction and relative contributions of single substances remain to be elucidated.

Animals↗
PubMed1992

Non-cholinergic effects of acetylcholinesterase in the substantia nigra: a possible role for an ATP-sensitive potassium channel.

Within the substantia nigra acetylcholinesterase has non-cholinergic actions that can be demonstrated at both behavioural and cellular levels: the aim of this study was, thus, to explore, in the in vitro guinea pig substantia nigra, the ionic mechanisms which mediate these non-classical phenomena. Acetylcholinesterase had a reversible hyperpolarizing action, via an opening of potassium channels, on a selective population of nigral neurons. These neurons could be identified by an ability to generate bursts of action potentials and by a sensitivity to either amphetamine or to a reduction of glucose in the perfusing medium. The acetylcholinesterase-induced hyperpolarization could not be attributed to a contaminant in the exogenous solution, since a highly purified preparation was even more potent. Furthermore, enzymatic action of any kind could be eliminated as boiled acetylcholinesterase was equally efficacious. The effect of acetylcholinesterase was not subject to tachyphylaxis and was resistant to blockade of potassium channels with tetraethylammonium: since both these phenomena are features of the D2 autoreceptor for dopamine within the substantia nigra, it seems unlikely that acetylcholinesterase is operating on the same target as dendritically released local dopamine. On the other hand, the actions of acetylcholinesterase were enhanced by low glucose and blocked by the sulfonylurea, tolbutamide. These results strongly suggest that acetylcholinesterase can exert a nonenzymatic action and that this action, in the substantia nigra, is mediated by an ATP-sensitive potassium channel.

Acetylcholinesterase↗
PubMed1988

Do nigro-striatal neurones possess a discrete dendritic modulatory mechanism? Electrophysiological evidence from the actions of amphetamine in brain slices.

Dopamine released from dendrites of nigrostriatal neurones in the substantia nigra exerts an inhibitory action on these cells. However, the spatio-temporal characteristics of the action of dendritic dopamine is still unclear. The aim of the present study was to investigate the responses of these neurones in the guinea-pig to amphetamine, applied locally in the region of the distal dendrites in pars reticulata. During intracellular recording in vitro it was found that amphetamine hyperpolarizes the membrane and causes a decrease in the input resistance, probably by increasing a potassium conductance. This response was resistant to blockade of sodium channels but sensitive to dopamine depletion by reserpine and alpha-methyl-p-tyrosine. The response showed tachyphylaxis and proved to be highly dependent on the site of administration of amphetamine. It is concluded that the release and action of dopamine occurs locally, in a heterogeneous pattern, within the dendritic field of nigrostriatal neurones. The possibility is discussed that this phenomenon underlies a modulatory mechanism, localized in dendrites.

Action Potentials↗
PubMed1984

A phase I toxicity study of human rDNA interferon in patients with solid tumours.

This study was designed to evaluate the clinical tolerance to multiple IM injections of rDNA-produced human alpha-2 interferon (IFN) (Schering-Plough 30500) in patients with solid tumours. IFN was administered in escalating IM doses in separate groups of patients daily for 14 days and then twice weekly for a further 10 weeks. The dosage levels were 1, 3, 10, and 30 million U/injection. Subjective toxicity could be divided into two types, acute and chronic. The acute reactions took the form of an influenza-like syndrome consisting in chills, rigors, headache, tremor, nausea, vomiting, and myalgia. These symptoms were dose-related but tachyphylaxis developed with continued dosing. The chronic toxicity consisted of malaise, lethargy, fatigue, anorexia, and confusion. These symptoms were not so dose-dependent and tended to become more severe with prolonged treatment. Objective toxicity consisted of myelosuppression and liver dysfunction. Granulocyte counts below 1.0 X 10(9)/l were seen in three patients at the 30-million-U level, with platelet counts less than 100 X 10(9)/l in two of these. Elevation of the liver enzymes were seen in all five patients treated at 30 million U, but returned to normal after 1 week without IFN in all but one patient. A tolerable dose (IM) for phase II/III studies lies between 3 and 10 million U for daily scheduling and between 10 and 30 million U for twice-weekly injections.

Blood↗