Dopamine-like renal and mesenteric vasodilation caused by apomorphine 6-propylnorapomorphine and 2-amino-6, 7-dihydroxy-1,2,3,4-tetrahydronaphthalene.
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Biomedical subjects
Publications and source records attributed to R M Pinder.
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Several derivatives of tetrahydroisoquinoline were injected bilaterally into the nucleus accumbens of rat 2 h after a nialamide pretreatment and activity recorded in cages fitted with photocells. 1,2,3,4-Tetrahydroisoquinoline, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydro-6,7-dihydroxy-1-(3,4-dihydroxybenzyl)-isoquinoline (tetrahydropapaveroline) and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused virtually no change in locomotor activity and 2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused only modest hyperactivity responses. However, 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both shown to markedly increase activity in a dose-dependent manner. Of these two compounds, the 3-methyl-6,7-methylenedioxyderivatives was most active and equalled the effectiveness of dopamine. The responses to dopamine and to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both threshold at 3.125 mug and maximum at 50 mug. Both effects developed within 1-2 h and persisted for at least 6 h. The hyperactivity induced by dopamine was antagonised in a dose-dependent manner by haloperidol: propranolol and aceperone were without effect. Similar results were obtained for these blocking agents against the responses to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydroisoquinoline but aceperone and propranolol, in addition to haloperidol, were shown to inhibit the hyperactivity induced by 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline.
Carbenoxolone sodium has been shown to accelerate the rate of healing of both gastric and duodenal ulcers, but its overall value in duodenal ulcer is probably less because of the high rate of natural remission of duodenal ulcers. Further studies are required to decide whether it should be used prophylactically to delay ulcer recurrence. Carbenoxolone may act by affecting both the proliferative activity of gastric epithelium and the differentiation of the epithelial cells to produce mucus (as well as favourably altering the physicochemical properties of mucus and by reducing peptic activity), factors which may be relevant ot the prevention of acute gastric ulcers. Some studies suggest that carbenoxolone adds to the effect of hospitalisation and bed rest on ulcer healing. Whether bed rest confers additional benefit to the drug's ulcer healing effect in outpatients is also uncertain. There is no evidence that accelerated healing by carbenoxolone is associated with improved overall prognosis. Carbenoxolone is of greatest benefit in accelerating the healing of gastric ulcers in patients for whom hospitalisation is not possible or desirable, but it should only be used in the ambulatory patient when careful and regular observation of serum electrolytes (particularly potassium), blood pressure and weight is possible and when it is known that the patient will attend regular follow-up. Patient must be educated in the proper use of the drug. If severe mineralocorticoid-like toxic effects such as sodium and water retention and hypokalaemia appear, as they do in a variable proportion of patients but most frequently in those receiving excessive doses, carbenoxolone should be stopped and the complication treated; they respond to thiazide diuretics and potassium supplements, and probably to amiloride given in conjunction with a low dose of a thiazide diuretic. Treatment with carbenoxolone can continue with concurrent diuretic therapy in patients with less severe side-effects. Optimum therapeutic effect in gastric ulcer with the least side-effects is achieved with a dosage of 100mg carbenoxolone tablets 3 times daily for the first week followed by 50mg 3 times daily thereafter, best taken before meals. A lower dosage is desirable in the elderly and in those with liver, cardiac or renal disease. Barium meal or preferably endoscopic examinations should be performed regularly and therapy continued until the ulcer is healed. Dosage for duodenal ulcer is 50mg 4 times daily, in special positioned-release capsules. These are best taken about 20 minutes before meals.
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Tinidazole, a synthetic imidazole derivative, has been used in the oral treatment of several protozoal infections - trichomoniasis, giardiasis and amoebiasis. Among the protozoal organisms inhibited by tinidazole are Trichomonas vaginalis, Trichomonas foetus, and Entamoeba histolytica. In vitro, tinidazole has been shown to possess antiprotozoal activity at least comparable to, and in some cases greater than, metronidazole. Tinidazole also has activity against some Gram-negative anaerobic bacilli, including Bacteroides spp. Following oral administration of a 2g dose, like metronidazole serum levels peak in about 2 hours but persist for longer. Any clinical significance of the longer plasma half-life (tinidazole 12.5h; metronidazole 7.3h) has yet to be demonstrated. Tinidazole is approximately 20% bound to plasma proteins. Only unchanged drug has been found in the plasma and urine of tinidazole-treated subjects, although metabolites have been detected in animal studies. A single 2g dose of tinidazole has been shown to be effective therapy in vaginal trichomoniasis and in urogenital trichomoniasis in males. Single-dose therapy in general offers advantages in regard to convenience, and in the treatment of a sexually transmissible disease such as trichomoniasis, single-dose therapy facilitates compliance of patient and sexual partner. In comparative studies, tinidazole, in both single-dose and traditional multiple-dose regimens, has been shown to be equivalent and often superior to other antitrichomonal agents, including metronidazole. In intestinal amoebiasis, tinidazole has been evaluated after both once-a-day and multiple daily dose regimens, with the former giving slightly better results. When both metronidazole and tinidazole were administered in multiple daily dose regimens, the two agents yielded similar cure rates; in one study fewer tinidazole-treated patients required a second course. Tinidazole has also been successful in some cases of amoebic liver abscess, but an advantage over metronidazole has not been demonstrated. Results in the treatment of giardiasis, especially with the single-dose regimen, are promising, and in one study, tinidazole proved effective in infections resistant to metronidazole. Even in large doses, tinidazole has been well tolerated, although rarely vomiting may occur and the patient may need to be re-treated with a multiple dose regimen.
Pimozide 1-(1-[4,4-bis(4-fluorophenyl)butyl]-4-peperidinyl)-2-benzimidazolone, is the first of a new series of psychotropic drugs, the kiphenylbutylpiperidines. It is advocated for once-daily use as maintenance therapy in chronic schizophrenia and for the treatment of psychic and functional disorders induced by personality traits. Published data suggest that in chronic schizophrenia, pimozide 4 to 6mg daily is indistinguishable from maintenance doses of chlorpromazine, fluphenazine, flupenthixol, perphenazine, or thioidazine. Patient groups have usually been to small to allow statistically significant differences to be apparent, but in some trials pimozide was significantly superior to trifluoperzine and to haloperidol. On present evidence, pimozide has no place in the hyperactive, aggressive type of patient or in treating the acute phase of schizophrenia, probably because of its relative lack of sedative properties compared with many antipsychotic drugs. The incidence and severity of extrapyramidal reactions with pimozide are low, but suitably designed controlled studies are needed to determine whether its use leads to a reduction in the requirement for antiparkinsonian medication. In anxious patients, pimozide seems to offer no advantages over currently available anxiolytic agents, either in terms of efficacy or incidence of side-effects. Claims for a specific effect against anxiety associated with psychosis or disturbed personality traits remain unproven.
Metoclopramide, 4-amino-5-chloro-2-methoxy-N-(2-diethyl-aminoethyl) benzamide, is advocated for use in gastro-intestinal diagnostics, and in treating various types of vomiting and a variety of functional and organic gastro-intestinal disorders. Published data have indicated that metoclopramide assists radiological identification of lesions in the small intestine, facilitates duodenal intubation and small intestine biopsy, and eases emergency endoscopy in upper gastro-intestinal haemorrhage. Metoclopramide reduces post-operative vomiting and radiation sickness, and ameliorates some types of drug-induced vomiting. It may provide symptomatic relief in dyspepsia and possibly in vertigo, reflux oesophagitis and hiccups, but further controlled trials are needed to confirm the efficacy of metoclopramide in these proposed areas of use. It promotes gastric emptying prior to anaesthesia. Its effects in healing gastric ulcer and preventing relapse of duodenal ulcer remain unproven. Side-effects are few and transient, though alarming extrapyramidal reactions can occur in a small proportion of patients receiving therapeutic doses but more usually following excessive doses in young subjects. They respond rapidly to withdrawal of the drug.
SYNOPSIS: Tobramycin is a new aminoglycoside antibiotic with a broad antibacterial spectrum in vitro, and pharmacokinetic properties similar to those for gentamicin. Tobramycin is more active than gentamicin against Pseudomonas aeruginosa and active against many gentamicin resistant strains, but is not active against enterobacteriaceae resistant to gentamicin. Theoretically, tobramycin has an advantage over gentamicin against infections caused by P. aeruginosa, but any advantage in clinical practice has yet to be adequately demonstrated. Clinical experience with tobramycin is considerably less than with gentamicin. Whilst tobramycin appears to offer no clear advantages over gentamicin against sensitive organisms it is indicated in infection caused by strains of P. aeruginosa which are resistant to gentamicin, but sensitive to tobramycin. Like gentamicin, tobramycin acts synergistically with corbenicillin and the cephalosporins. The efficacy of the tobramycin-carbenicillin combination has been shown in endocarditis caused by P. aeruginosa which was unresponsive to gentamicin plus carbenicillin. Ototoxicity and nephrotoxicity similar to that seen with other animoglycosides have been encountered in therapeutic trials with tobramycin and wider clinical experience is necessary to determine the relative incidence of these side-effects with gentamicin and tobramycin used under similar conditions. Antimicrobial activity: In comparative studies, in vitro, tobramycin is more active than gentamicin against clinical isolates of Pseudomonas aeruginosa. Similarly, the inhibitory index, which is the ratio between the serum concentration attained at usual therapuetic doses and the minimum inhibitory concentration, for Pseudomonas aeruginosa is higher for tobramycin than for gentamicin. Against Gram-negative bacteria other than Pseudomonas spp. the spectrum of activity of tobramycin is similar to that of gentamicin. For most species the activity of tobramycin is slightly less than that of gentamicin. Gentamicin is consistently more active than tobramycin against Serratia marcescens. Like other aminoglycoside antibiotics, tobramycin is active in vitro in low concentrations against Staphylococcus aureus. Tobramycin is essentially inactive against Streptococcus pyogenes, Streptococcus faecalis and Streptococcus pneumoniae (pneumococci). Maner aminoglycosides and of other antibiotics against various bacteria in vitro, but comparisons between studies cannot always be interpreted literally because the activity of many antibiotics in vitro, including tobramycin, is influenced by the nature of the culture media and the presence of certain salts. The sensitivity of P. aeruginosa to tobramycin is influenced by the magnesium, and calcium content of the culture media whilst that of all species is reduced by sodium ions. Wide variations in the concentration of these ions may result in divergent MIC values and an inappropriate choice of antibacterial agent to treat pseudomonas infection...
Hydrocortisone 17-butyrate is a new non-fluorinated topical corticosteroid for use in psoriasis, eczema and other inflammatory dermatoses. In double-blind paired comparisons with other topical corticosteroids, the efficacy of hydrocortisone 17-butyrate 0.1% has generally been indistinguishable from that of triamcinolone acetonide 0.1%, fluocinolone acetonide 0.025% or betamethasone 17-valerate 0.1% in patients with eczema or psoriasis. When applied to the face of patients with atrophy superimposed on rosacea and perioral dermatitis resulting from prolonged use of fluorinated topical corticosteroids, hydrocortisone 17-butyrate 0.1% did not prevent the beneficial effect of systemic tetracycline nor the disappearance of telangiectasis, and tended to be more effective than hydrocortisone 1%. This result suggests that hydrocortisone 17-butyrate may be suitable for long-term use on facial lesions, although the occurrence of moderate rebound eruption in about 10% of patients indicates the need for caution. The findings suggest that hydrocortisone 17-butyrate may be less liable to cause skin atrophy and adrenal suppression than some other potent topical corticosteroids, but trials to date have been too short to allow definite conclusions regarding possible long-term effects and have not involved infants or children.
Clonazepam or 5-(2-chlorphenyl)-1, 3-dihydro-7-nitro-2H-1,4benzodiazepin-2-one, is a close structural and pharmacological relative of nitrazepam. It has a broad spectrum of activity against the various types of epilepsy, and is effective in many patients whose condition has proved resistant to other antiepileptic drugs. Its chief uses are in status epilepticus, in which intravenous clonazepam may replace diazepam as the drug of first choice, and in the minor motor seizures of childhood, particularly petit mal absences, the Lennox-Gastaut syndrome and infantile spasms. Clonazepam is also at least as effective as current treatment in psychomotor and myoclonic epilepsies, but seems unlikely to replace phenytoin and the barbiturates in the treatment of grand mal or focal motor seizures except in patients resistant to standard therapy. Initial success with clonazepam can be followed by loss of effect, but benefit can often be restored, at least initially, by temporary interruption and re-institution of treatment. Side-effects are common with clonazepam. Most patients experience drowsiness and fatigue, which are frequent causes of withdrawal, together with lesser incidences of ataxia, dystonia, hypotonia, and hyperactivity. These effects usually disappear with continued therapy, and are minimised by gradual introduction of the drug over 2-4 weeks. Hypersalivation and excessive bronchial secretion may be a problem in children and infants.
Tri-potassium di-citrato bismuthate is a complex bismuth salt stable in colloidal form advocated for the treatment of peptic ulcer. Preliminary placebo-controlled trials in small numbers of ambulant patients with endoscopically proven peptic ulcer, strongly suggest that the compound accelerates the rate of healing of gastric and duodenal ulcer within 4 weeks of treatment. However, trials involving larger numbers of patients followed-up for longer periods are required before a clear verdict on the efficacy of tripotassium di-citrato bismuthate in gastric and duodenal ulcer can be given. There are no reliable data on the effect of the drug on ulcer recurrence rate. Side-effects are negligible and the drug could become an important therapeutic agent in peptic ulcer therapy if results of further study are conclusive. The drug causes dark discolouration of the stools and this should be borne in mind when considering the possibility of the presence of intestinal bleeding.
The intrastriatal injection of dopamine-like compounds in the guinea pig caused the development of abnormal involuntary movements (dyskinesias) which were observed as facial grimacing, biting/gnawing/licking, severe hear and neck twisting, limb movements, whole body rocking, head and neck rocking and marked locomotor hyperactivity. With the exception of the whole body and head and neck rocking movements the dyskinesias were specifically induced by dopamine-like agents. The most conspicuous dyskinesias which followed the administration of phenylethylamine derivatives were the movements of biting/gnawing/licking and the development of marked locomotor hyperactivity. This effect was shown to be highly specific for dopamine. Tetrahydroisoquinohydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) caused locomotor hyperactivity and gnawing/biting/licking dyskinesias. Of all compounds investigated 1-(3,4-dihydroxyphenyl)pierazine (DHPP) induced the most marked dyskinetic disturbances upon intrastriatal injection: intense facial grimacing, biting/gnawing/licking, head and neck twisting and limb movements were observed although the locomotor hyperactivity was absent. Of the 1-phenylpiperazine derivatives examined, dyskinetic activity was only demonstrated using compounds with a hydroxyphenyl substitution. Results are discussed in terms of the structure--activity relationships for the stimulation of different types of dopamine receptive structures within the neostriatum.
Naproxen2, (+)-6-methoxy-alpha-methyl-2-naphthalene acetic acid, is a new non-steroidal anti=inflammatory agent advocated for use in rheumatiod arthritis, degenerative joint disease and ankylosing spondylitis. Published data suggest that in rheumatiod arthritis, naproxen 500mg daily comparable in efficacy with moderate doses of aspirin (3.6 to 4g daily) or 150mg daily of indomethacin, but generally causes fewer and milder side-effects than these drugs at the dosages used and can be given less frequently (12-hourly). Encouraging intial results have been reproted from its use in other inflammatory joint disorders, including acute gout and juvenile rheumatiod arthritis. It has compared favourably with indomethacin in ostioarthrosis of the hip of knee. Its exact place in the management of ankylosing spondylitis remains to be determined.
Miconazole2, a synthetic imidazole derivative, is a new topical antifungal agent for use in the local treatment of vaginal, and skin and nail infections due to yeasts and dermatophytes. It is particularly active against Candida spp., Trichophyton spp., Epidermophyton spp., Microsporum spp. and Pityrosporon orbiculare (Malassezia furfur), but also possesses some activity against Gram-positive bacteria. In vaginal candidiasis, miconazole vaginal cream has produced higher cure rates than conventional nystatin vaginal tablets or amphotericin B vaginal cream. There have been no published comparisons with nystatin vaginal cream or foaming vaginal tablets - the nystatin dosage form preferred by some clinicians. The vaginal cream has also achieved a cure where previous nystatin or natamycin therapy had failed. Miconazole has proved equally effective in both Candida and dermatophyte infections of the skin, but as yet there have been no published comparisons with other antifungal agents. However, it has been successfully used in chronic skin infections which had not responded satisfactorily to other agents such as natamycin and pecilocin. Preliminary experience with oral and intravenous miconazole therapy in systemic candidiasis is promising. Miconazole preparations are well accepted and tolerated.
Clotrimazole 2, a synthetic imidazole derivative, is primarily used locally in the treatment of vaginal and skin infections due to yeasts and dermatophytes. In vitro, it is most active against Candida spp., Trichophyton spp., Microsporum spp. and Malazzesia fuffur (Pityrosporon orbiculare). In addition, it has some in vitro activity against certain Gram-positive bacteria, and at very high concentrations has activity against Trichomonas spp. In the treatment of vaginal candidiasis, clotrimazole vaginal tablets have produced cure rates comparable with those of conventional nystatin vaginal tablets. There have been no published comparisons with nystatin vaginal cream or foaming vaginal tablets - nystatin dosage forms preferred by some clinicians. Cootrimazole has also been successful in patients who had failed to respond to other antifungal agents such as nystatin and amphotericin B. Results in trichomonal vaginitis are not impressive. Skin infections caused by Candida or dermatophytes have been effectively treated with topical application of clotrimazole. In comparative trials, clotrimazole cream has been as effective as Whitfield's ointment and tolnaftate in the treatment of dermatophytoses, and as effective as nystatin in cutaneous candidiasis. Clotrimazole topical preparations are generally well tolerated, but local irritation has necessitated withdrawal of therapy in a few cases. Candidal septicemia and urinary and pulmonary candidiasis have been cured with oral clotrimazole therapy. Results in other types of serious fungal infections, including pulmonary aspergillosis, have been disappointing. A limiting factor in oral clotrimazole therapy is the high incidence of gastro-intestinal disturbances and neurological reactions.
Beclomethasone dipropionate is a topically active corticosteroid used as an adjuvant in the control of chronic asthma when given by inhalation as an aerosol. It is not intended for treatment of acute attacks. It appears that the main difference between beclomethasone dipropionate and other corticosteroids previously used by inhalation is its high topical activity together with a lower systemic activity due to metabolic inactivation of the swallowed portion of the dose. Clinical experience has shown that at doses of 200 to 600mug daily, beclomethasone dipropionate inhaler is preferable to oral corticosteroids, because of lack of side-effects, when adult patients and children who are inadequately controlled by full doses of sodium cromoglycate and bronchodilators, are first considered to need maintenance corticosteroids. Inhaled beclomethasone dipropionate can allow a worthwhile reduction in maintenance doses of systemic corticosteroids in many patients already receiving these drugs and can replace systemic steroids entirely in some patients, particularly when their initial dose of steroids is less than 10mg daily of prednisone or its equivalent. Substitution should be attempted when the patient's asthma is well controlled on their usual doses of systemic steroids and full doses of other adjuvant therapy. Withdrawal of systemic corticosteroids should be performed slowly and carefully. Because recovery from impaired adrenocortical function caused by prolonged systemic steroid therapy is usually slow, special care is necessary for 9 to 12 months after transfer to beclomethasone dipropionate aerosol until the hypothalamo-pituitary-adrenal axis has sufficiently recovered to cope with emergencies such as trauma, surgery, severe infections or an acute attack of asthma. It is essential that additional therapy including high doses of systemic corticosteroids be used immediately to control any acute exacerbation of asthma which occurs during maintenance therapy with beclomethasone dipropionate aerosol. Tests of adrenal function suggest that beclomethasone dipropionate at dosages of 400 to 800 mug daily has little or no adverse effect. The most common side-effect associated with the continuous use of beclomethasone dipropionate inhaler has been oropharyngeal candidiasis, which appears to be dose-related and more common in women than in men. Systemic steroid withdrawal effects, like being generally unwell, and exacerbation of underlying allergic diseases such as allergic rhinitis, have been reported after substitution of beclomethasone dipropionate inhaler for systemic steroids. However, systemic withdrawal effects seldom occur if systemic steroids are withdrawn slowly.
At doses similar to those used in the treatment of chronic bronchial asthma, intranasal beclomethasone dipropionate is effective in alleviating nasal symptoms of seasonal allergic and perennial rhinitis in about three-quarters of patients. Eye symptoms are not relieved. The carry-over effect of the evening dose is useful in preventing early morning attacks of sneezing. Intranasal beclomethasone dipropionate is useful in controlling symptoms persisting after polypectomy and may possibly delay or eliminate the need for the surgical removal of nasal polyps, which may shrink after several weeks or months of treatment.
Fenfluramine has been used for a number of years as a short-term adjunct to diet in the management of obesity. Controlled studies and clinical experience have shown that it possesses anorectic activity at least as good as that of other therapeutically useful drugs of its type, but like these drugs it has only a limited role in the overall management of obesity. Tolerance to the anorectic effects of fenfluramine may possibly develop more slowly than to other chemically related drugs in patients with refractory obesity. The mechanism of its anorectic action is probably by an effect on the appetite control centres in the hypothalamus, rather than by an effect on glucose and lipid metabolism. However, its effect in enhancing glucose uptake into skeletal muscle may be of advantage in diabetes mellitus, preliminary studies suggesting that it is of potential use in maturity-onset obese diabetics who cannot be adequately controlled by dietary measures alone. The starting dosage in obesity of 40mg daily should be increased gradually over 2 to 4 weeks to 60 to 120mg. In general, little extra benefit is gained by higher dosage. When a course of therapy is to be discontinued, fenfluramine dosage should be reduced gradually over a period of 2 to 4 weeks in order to avoid mood depression which has occurred in some patients on abrupt withdrawal of the drug. With these recommendations, the majority of patients tolerate fenfluramine satisfactorily, although some patients may have to discontinue the drug because of troublesome gastro-intestinal problems, diarrhoea, drowsiness or dizziness. Unlike other amphetamine-derived anorectics, fenfluramine is not a central stimulant in therapeutic doses, and it probably has little abuse potential.