Phenoxybenzamine is neuroprotective in a rat model of severe traumatic brain injury.

Phenoxybenzamine (PBZ) is an FDA approved α-1 adrenergic receptor antagonist that is currently used to treat symptoms of pheochromocytoma. However, it has not been studied as a neuroprotective agent for traumatic brain injury (TBI). While screening neuroprotective candidates, we found that phenoxybenzamine reduced neuronal death in rat hippocampal slice cultures following exposure to oxygen glucose deprivation (OGD). Using this system, we found that phenoxybenzamine reduced neuronal death over a broad dose range (0.1 µM-1 mM) and provided efficacy when delivered up to 16 h post-OGD. We further tested phenoxybenzamine in the rat lateral fluid percussion model of TBI. When administered 8 h after TBI, phenoxybenzamine improved neurological severity scoring and foot fault assessments. At 25 days post injury, phenoxybenzamine treated TBI animals also showed a significant improvement in both learning and memory compared to saline treated controls. We further examined gene expression changes within the cortex following TBI. At 32 h post-TBI phenoxybenzamine treated animals had significantly lower expression of pro-inflammatory signaling proteins CCL2, IL1ß, and MyD88, suggesting that phenoxybenzamine may exert a neuroprotective effect by reducing neuroinflammation after TBI. These data suggest that phenonxybenzamine may have application in the treatment of TBI.

Prevention of hypertensive crises in rats induced by acute and chronic norepinephrine excess.

Calcium Channel Blockers (CCBs), competitive α-adrenoceptor blockers, and phenoxybenzamine (POB) are used for preoperative treatment of pheochromocytomas. We analyzed the protection from hypertensive crisis provided by these drugs during acute and chronic norepinephrine excess. To ensure adaptive changes during chronic norepinephrine (NE) excess, we continuously exposed male Wistar rats to NE for 3 weeks (osmotic pumps). Afterwards, blood pressure (BP) was continuously measured while NE boli (0-1000 µg/kg, i. v.) were administered before and after antihypertensive treatment in anesthetized and catheterized rats. A single dose of urapidil (10 mg/kg), nitrendipine (600 µg/kg) and POB (10 mg/kg) lowered BP from 212 ± 12 mmHg by 52 ± 7%, 31 ± 9%, and 50 ± 6%, respectively. With NE boli a maximum BP of 235 ± 29, 240 ± 30 and 138 ± 3 mmHg was measured in urapidil, nitrendipine, and POB treated animals (p<0.05). The number of hypertensive episodes (delta BP >30 mmHg) was 3 (3), 1.5 (0-3), and 0 (0-1) (p<0.05). Because of inferiority, urapidil was excluded from further testing. Chronically NE exposed rats were treated with POB (10 mg/kg/d), nifedipine (10 mg/kg/d), or vehicle for 7 days. Marked BP elevations were observed at baseline (167 ± 7, 210 ± 7 , and 217 ± 7 mmHg, p<0.01) and maximum blood pressure was 220 ± 32, 282 ± 26, and 268 ± 40 mmHg (p<0.001) with NE boli. Further stabilization was achieved combining POB pretreatment with a continuous nifedipine infusion, which effectively prevented BP elevations during NE excess. POB was the most effective drug used in monotherapy, but BP stabilization was superior using a combination of POB pretreatment with a continuous nifedipine infusion in this model.

Complex regional pain syndrome (reflex sympathetic dystrophy and causalgia): management with the calcium channel blocker nifedipine and/or the alpha-sympathetic blocker phenoxybenzamine in 59 patients.

Complex Regional Pain Syndrome (CRPS) is the new name for entities formerly known mostly as Reflex Sympathetic Dystrophy and Causalgia. Treatment of CRPS with either the calcium channel blocker nifedipine or the alpha-sympathetic blocker phenoxybenzamine was assessed in 59 patients, 12 with early stages of CRPS, 47 with chronic stage CRPS. In the early stage CRPS patients, 3 of 5 were cured with nifedipine and 8 of 9 (2 of whom had earlier received nifedipine) with phenoxybenzamine, for a cure rate of 92% (11 out of 12). In the chronic stage CRPS patients, 10 of 30 were cured with nifedipine; phenoxybenzamine cured 7 of 17 patients when administered as a first choice and another 2 of 7 patients who received nifedipine earlier, for a total late stage success rate of 40% (19 out of 47). The most common side effects necessitating discontinuing the drug were headaches for nifedipine and orthostatic dizziness, nausea and diarrhoea for phenoxybenzamine. All male patients on phenoxybenzamine experienced impotence, but this did not lead to discontinuing this agent and immediately disappeared after stopping the drug. These results once again stress the importance of early recognition of CRPS, and treatment with either of these drugs could be considered as a first choice for early CRPS, especially because in this series this treatment was not combined with physical therapy making it very cost-effective. In the chronic stage of CRPS, treatment with these drugs was much less successful (40%), even though it was always combined with physical therapy, but it can still be considered, either as a first choice or when other types of treatment have failed.

[Clinical experience with alpha blockers and calcium antagonists in the perioperative treatment of pheochromocytoma]. / Esperienza clinica con alpha-bloccanti e calcioantagonisti nel trattamento perioperatorio del feocromocitoma.

This study aims to value the efficacy of the association between alpha-blockers and calcium channel-blockers, administered per os, in the reduction of preoperative preparation in patients with phaeochromocytoma and the calcium channel-blockers utility when are administered e.v. in the control of development of arterial paroxysmal hypertension during surgical manipulations. The trial had been conducted on 5 patients which have undergone the operation, before the operation we administered per os nifedipine and phonoxybenzamine for 8 days and during the operation we administered diltiazem e.v. The association between alpha-blockers and calcium-blockers per os, has reduced the preparation stage and has controlled the pressure parameters during the preoperative treatment. When we utilized diltiazem during the operation, we haven't note a good hemodynamic stability; these results are opposed to Tokioka's. Calcium channel-blockers and alpha-blockers seem to be a good therapy in the preoperative preparation of patients with phaeochromocytomas and they seem to be able to take fastly the standard of preoperative preparation.

Agonal hepatic arterial vasospasm.

The effect of donor pretreatment with Dibenzyline (phenoxybenzamine) on hepatic arterial vasospasm was studied in a porcine asphyxia model. Nine pigs underwent hepatectomy without pretreatment, while six were given 2 milligrams per kilogram of Dibenzyline prior to hepatic dissection. Hepatic arterial blood flow was monitored with an electromagnetic flow probe, and after cardiac arrest, arteriograms of the hepatic circulation were obtained. Hepatic arterial vasospasm occurred in seven of the pigs in group 1 and in only one of group 2 (p less than 0.05). Agonal hepatic arterial blood flow remained constant (415 +/- 30 milliliters per minute) in pretreated pigs during asphyxia, but was markedly reduced (98.6 +/- 63.3 milliliters per minute) in nonpretreated pigs (p less than 0.05). Results of this study demonstrate the agonal occurrence of hepatic arterial vasospasm and its prevention with Dibenzyline. Donor pretreatment with alpha-adrenergic antagonists may be indicated in clinical organ procurement to prevent agonal arterial vasospasm and its potentially adverse effect on early hepatic allograft function.

[Drug therapy of pheochromocytoma]. / Terapia medica del feocromocitoma.

The Authors briefly review the clinical findings, the diagnostic biochemical procedures and the management of pheochromocytoma. The most recent pharmacological approaches with calcium-channel blockers or angiotensin-converting enzyme inhibitors are particularly discussed.

Nifedipine and surgical removal of phaeochromocytoma.

The management of five patients with phaeochromocytoma undergoing surgical removal is described. Pre-operative preparation with phenoxybenzamine and nifedipine for 7 days before surgery prevented excessive fluctuations in cardiovascular parameters in the peri-operative period and resulted in an uneventful recovery.

[Decreased ethanol consumption by rats as affected by central alpha-adrenoblockaders: the role of liver aldehyde dehydrogenase isoenzymes]. / Snizhenie potrebleniia étanola krysami pod vliianiem tsentral'nykh al'fa-adrenoblokatorov: rol' izoferementov al'degiddegidrogenazy pecheni.

It has been shown in the experiments on rats that subcutaneous administration of central alpha-adrenoblockers IEM-611 (30 mg/kg and 15 mg/kg) and phenoxybenzamine (10 mg/kg) for one or two weeks brings about a decrease in voluntary ethanol consumption at early stages of experimental alcoholism (3-week alcoholization). In rats with chronic alcoholization for 6 months only IEM-611 had a remarkable inhibitory effect on alcohol consumption. Moreover, it has been stated that IEM-611 reduced threefold the activity of liver aldehyde dehydrogenase (AlDH) by the inhibition of AlDH isoenzymes with low and high Km for acetaldehyde. Phenoxybenzamine inhibited slightly only low Km AlDH. It is suggested that differences in IEM-611 and phenoxybenzamine effects may be associated with specific drug inhibition of AlDH isoenzymes.

Reflex sympathetic dystrophy. A review.

Reflex sympathetic dystrophy is a syndrome of burning pain, hyperesthesia, swelling, hyperhidrosis, and trophic changes in the skin and bone of the affected extremity. It is precipitated by a wide variety of factors in addition to nerve injury. It occurs outside of dermatomal distributions and can spread to involve other extremities without new injury. The diagnosis is primarily clinical, but roentgenography, scintigraphy, and sympathetic blockade can help to confirm the diagnosis. The most successful therapies are directed toward blocking the sympathetic innervation to the affected extremity, in conjunction with physical therapy. The theories proposed to explain the pathophysiology of reflex sympathetic dystrophy include "reverberating circuits" in the spinal cord that are triggered by intense pain, ephaptic transmission between sympathetic efferents and sensory afferents, and the presence of ectopic pacemakers in an injured nerve.

Raynaud's disease.

We report five children who presented with Raynaud's disease in whom we could find no clinical, haematological, or immunological evidence of a collagen disorder. Oral phenoxybenzamine proved useful for maintenance treatment in most, with infusions of prostacyclin, nitroprusside, and ketanserin during acute attacks.

A comparison of the efficacy of an alpha-I-adrenergic blocker in the slow calcium channel blocker in the control of autonomic dysreflexia.

Cystometry, using a portable CO2 cystometer, is a convenient method for detecting autonomic dysreflexia (A.D.) in response to bladder distention. Serial tracings on successive days were found to be consistent. This method was used to compare the effect of the antihypertensive drugs, phenoxybenzamine and nifedipine, in modifying the blood pressure responses of 12 tetraplegic patients. Given as regular medication twice daily, neither drug was effective in preventing A.D. responses to bladder filling, and a significant number of patients developed troublesome hypotension. Nifedipine by mouth was found to be a valuable drug for the treatment of attacks which developed, and capable of preventing an anticipated attack if given shortly before the stimulus. The condition of 'status dysreflexicus' and its appropriate management is described.

Pathophysiology and treatment of coronary arterial spasm.

Spasm of a large coronary artery occurs most often from midnight to early morning and least often in the afternoon, due to the circadian variation of the tone of the large coronary artery in most patients with variant angina. Alpha adrenergic stimulation induces coronary spasm most easily in the early morning and least easily in the afternoon. Coronary spasm is due to strong contraction of coronary vascular smooth muscle cells which is triggered by an increase of intracellular calcium ions; hyperventilation plus TRIS-buffer infusion induces coronary spasm by decreasing hydrogen ions which antagonize the action of calcium ions. Administration of nitroglycerin promptly relieves the acute attack of coronary spasm, and calcium antagonists such as diltiazem, nifedipine and verapamil, which block the entry of calcium ions into coronary vascular smooth muscle cells and dilate large coronary arteries, prevent the occurrence of coronary spasm.

What not to do in pheochromocytoma.

Use of a screening VMA procedure rather than a specific assay may yield false-positive results. Plasma catecholamine levels should be obtained in the unstressed, supine patient. Pharmacologic tests are less reliable than chemical tests. In the presence of a pheochromocytoma, phenoxybenzamine should be administered before any manipulative procedures, as well as prior to surgery. This agent should be given along initially; propranolol may be added preoperatively.

Haemodynamic effects of different corticosteroids in controlled haemorrhagic shock in the dog.

The haemodynamic effects of massive doses of hydrocortisone (80-320 mg.kg-1), methylprednisolone (4-32 mg.kg-1), betamethasone (1.6-12.8 mg.kg-1) and aldosterone (0.1-0.8 mg.kg-1) and the interaction with phenoxybenzamine and propranolol have been studied during controlled haemorrhagic shock in the anaesthetized dog. Hydrocortisone was the only steroid which showed any significant vasodilating ability when given alone. The alpha-receptor blocking agent phenoxybenzamine distinctly decreased the total peripheral resistance. The effect of the phenoxybenzamine was increased in combination with hydrocortisone or methylprednisolone, especially if the steroid was given as the first drug. The vasodilation found was efficiently abolished by the beta-receptor blocking agent propranolol. The ability of hydrocortisone or methylprednisolone to potentiate phenoxybenzamine was not shared by betamethasone or aldosterone. Thus, the haemodynamic effect of the steroid does not seem to be correlated to either a glucocorticoid nor a mineralocorticoid effect. It is suggested that the steroid effect studied is related to the ability of hydrocortisone or methylprednisolone to block the extra neuronal amine uptake which decreases the rate of elimination of the sympathetic transmitter from the vicinity of the adrenergic receptor of the vascular smooth muscle.