681 cancer risk-is reasonably well established. Given this sequence, a public health approach would demand intervention at all stages: public education to prevent people starting to smoke; pharmacological or behavioural treatment to help tobacco addicts to stop smoking; and surgical excision of lung carcinoma for those who become afflicted. Interventions at each stage require assessment as to efficacy, safety, and
ing, addiction,
cost.
These criticisms should not overshadow the importance of Brown’s work to the attention of physicians; depressions are the most prevalent of adult psychiatric disorders and are usually treated to non-psychiatrists.
bringing
Harvard Medical School, Boston, Massachusetts, U.S.A.
GERALD L. KLERMAN
Depression Research Unit, Connecticut Mental Health Center, New Haven, Connecticut,
06519
that the suspended crystals cannot easily pass through the narrow constriction between the needle bevel and the subcutaneous tissue. The probability of blockage appears to increase if the injection is given slowly but it is not clear what the injection-rate has to be to avoid blockage. Since most insulin syringes used in North America are disposable the problem is not due to inadequate cleaning of reusable needles. It has been reported that spontaneous blockage cannot be induced by storing filled syringes with the needle downward. In view of these findings, the reason for plugging during adjustment of the dosage as reported by Dr O’Mullane and Dr Robinson (July 15, p. 165) is difficult to explain.. Clinical Devices Division, Bureau of Medical Devices, Health and Welfare Canada, Tunney’s Pasture, Ottawa, Canada
PHILIP D. NEUFELD
MYRNA M. WEISSMAN
PHOTODEGRADATION OF DACARBAZINE NEEDLE PLUGGING AND INSULIN
INJECTION
SiR,—Needle plugging during injection of insulin has been reported to us on several occasions and has attracted notice in the United States and, lately, in your correspondence columns. In January, 1976, the U.S. Food and Drug Administration held a meeting with manufacturers, and the July, 1976 issue of Diabetes carried an F.D.A. appeal for information on this problem. Although the exact cause is not well understood, the reports share certain characteristics which suggest a possible mechanism. Most cases occur with crystalline insulin suspensions such as lente or ultralente, and in North America the problem reports seem to have begun with the widespread use of the U-100 (100 units/ml)concentration in 1973. We have simulated this plugging in glass micropipette tubing cemented to a needle hub attached to a 1 ml syringe filled with U-100 lente insulin. The bore of the tubing was roughly 0.38 mm, which corresponds to a 22 or 23 gauge needle, a fairly large size for insulin injection. The end of the tubing was held with moderate pressure against a wad of paper tissue or a. finger tip and the insulin was expressed slowly. Crystals rapidly accumulated at the tip of the tubing and the flow was sometimes blocked before 0-5ml had been ejected (see figure). This suggests that the plugging is caused simply by the fact
SiR,—There is evidence that the anti-tumour drug dacarba-
(D.T.I.C., dimethyltriazeno-imidazole carboxamide) is susceptible to photodegradation in solution’ and, as commonly administered, its breakdown products (including 5-diazoimidazole carboxamide and 2-azohypoxanthine) may be responsible for the troublesome local venous pain and other systemic sideeffects such as nausea, vomiting, and hepatic toxicity. Having regularly seen these side-effects we have lately tried reconstituting and rapidly injecting the drug at a concentration of 100 mg in 10 ml in a room lit by a red photographic lamp only. In a total of fourteen such injections in three patients pain was entirely eliminated or reduced to minor discomfort during the first few seconds. These patients had previously experienced moderate to severe pain along the vein throughout the injection. There also seemed to be less nausea and vomiting. The improved patient acceptability was striking. Evidence that the tumoricidal value of D.T.I.C. is enhanced by preventing photodegradation will be less easy to obtain. zine
Department of Hæmatology, Royal Hospital for Sick Children, Glasgow, G3 8SJ
GILLIAN M. BAIRD M. L. N. WILLOUGHBY
ABUSE OF BENZODIAZEPINES
Simulated needle plugging with U-100 lente insulin.
Upper. crvsta) blockade at end of microptpettc tubing. I.oBvcrr mat;mticaoun shwang plug of msutm crystals.
SIR,-It is worth reinforcing the hazards of prescribing psychotropic drugs to recovered alcoholics. A 42-year-old man was admitted to my alcohol treatment programme this year with a history of an alcohol-related divorce, two to three bottles of whisky per day from early morning onwards, black-outs, amnesias, and so on. He had been an inpatient at another hospital and had gone to Alcoholics Anonymous meetings in the hope of curing his addiction, but without success. His progress was satisfactory and he was discharged at the end of the six-week programme but things soon went badly. He had, before admission, been prescribed various tranquillisers, and he now became addicted to lorazepam, behaving with lorazepam precisely as he had with alcohol: he lied in order to obtain supplies, which he then hid surreptitiously around the house, and he took unknown quantities of the drug: "After the first three or four you don’t know how many you have taken". Calculations suggested that he took at least 80 2.5 mg capsules between 5 P.M. and 10 A.M. the next morning. Withdrawal symptoms of tremor, guilt, and remorse were precisely as they were with alcohol and his erratic behaviour was identicallying and illogical, hazardous conduct (e.g., putting an empty saucepan on the cooker). "You blank out the same as you do with alcohol." 1
Shealy, Y , Krauth,
C. A,
Montgomery, J. A. J.
org. Chem
1962, 27, 2150
682 What is
worrying
is that he found it
so
easy
to
sign
on as
temporary resident with any general practitioner and, in almost every case, to obtain 100 capsules aftera brief interview, and to get 100-capsule repeat prescriptions without seethe doctor. It was, he observed, "Far too easy to con them". The addictive-properties of benzodiazepines may have been underrated and there may well have to be a campaign on their use and restriction-a point underlined by my local underworld contacts telling me that diazepam 10 mg tablets currently sell at no less than L1 each.
ing
macrocytosis, megaloblastic haemopoiesis, and low serum and red cell folate in non-anxmlc treated epileptics,2 that the drugs also play a role in the occasional anxmia. of
University Department of Neurology, Institute of Psychiatry,
E. H. REYNOLDS M. LAUNDY
RICHARD Fox
HÆMATOLOGICAL EFFECTS OF ANTICONVULSANT TREATMENT be surprised at their failure to detect macrocytosis in all but 1 of 96 mentally retarded patients on anticonvulsant therapy. Their findings are apparently at variance with at least nine studies in which macrocytosis was detected, by various techniques, in from 8% to 53% of epileptic patients.2 In the one previous report of the absence of macrocytosis, Jensen and Olesen3also failed to find any fall in red-cell folate, although Rose and Johnson agree with others that this is common. We have also examined mean cell volume (M.c.v.) with the Coulter S counter in 118 outpatient epileptics, all on a combination of phenytoin and primidone and compared the result with those of 18 untreated epileptic patients. All the untreated patients had an mt.c.v. within the normal control range of 80-90 fLm3, whereas 42% of the drug-treated patients had macrocytosis (see figure).2 Our findings accord with those of Eastham et al. who investigated an institutionalised retarded population, similar to that of Rose and Johnson, who do not refer to Eastham’s work. Rose and Johnson provide no details of the M.c.v. data for their patients, nor do they mention any control group. We are unaware of any evidence that "anticonvulsant therapy is often associated with megaloblastic anxmia". Indeed it
SIR,-Rose and Johnson1
3. 4.
may pregnancy. However, we agree with Dr Hawkins (Aug. 5, p. 317) that in many patients nutritional deficiency is not present, and there can be little doubt, in view of the high mcidence
London SE5 9RS
Severalls Hospital, Colchester C04 5HG
1. 2.
appears to be very uncommon, being seen in well under 1% of patients.2 It has long been recognised that additional nutrinonal deficiency may sometimes precipitate the anaemia,25 as
are
right
to
Rose, M. S., Johnson, I. Lancet, 1978, i, 1349.
Reynolds, E. H. in Clinics in Hæmatology vol. v, (edited by A. V. Hoffbrand); p. 661. London, 1976. Jensen, O. N., Olesen, O. V. Archs Neurol. 1969, 21, 208. Eastham, R. D, Jancar, J., Cameron, J. D. Br. J. Psychiat 1975, 126, 263.
MULTISYSTEM TOXICITY AFTER CO-TRIMOXAZOLE
SIR,-A report of fatal multisystem toxicity after co-trimoxazole’ prompts us to report a similar case, though with a hap-
pier outcome. This 84-year-old woman had a history of arthritis, diabetes controlled by diet, hypertension, cholecystectomy (1955), and a reaction to gold therapy. Previous medications included hydrochlorothiazide, chlorthalidone, clonidine (not tolerated), oestrogens, and porassium supplements. A previous urinaryinfection had been treated with co-trimoxazole. In 1974 intravenous pyelography and kidney function were normal (blood-urea-nitrogen 19 mg/dl). On May 19, 1978, she complained of dysuria and her doctor prescribed co-trimoxazole, which she started taking on May 20. She was admitted to hospital May 22 with an erythematous maculopapular eruption over the entire body, weakness, fever, low-back pain, cough, and decreased air entry to her right lower lobe. Other findings included: blood-urea-nitrogen 33 mg/dl, Hb 17.1g/dl, white blood-cells 18 100/µl, bloodsugar 169 mg/dl, and chloride 85, sodium 127, and potassium tract
2.9
mmol/l.
The second day after admission the patient had purpura on her back and under the E.c.G. suction cup sites and perioral pallor with cedema of eyes, neck, uvula, and lips. Other findings included Hb 18.7g/dl, white blood-cells 24 100/µl, tachycardia (115/min), prothrombin-time 54.0 s, and consolidation of right lower lobe on chest X-ray. On the third day the patient’s condition deteriorated, with oliguria (
ing, addiction,
cost.
These criticisms should not overshadow the importance of Brown’s work to the attention of physicians; depressions are the most prevalent of adult psychiatric disorders and are usually treated to non-psychiatrists.
bringing
Harvard Medical School, Boston, Massachusetts, U.S.A.
GERALD L. KLERMAN
Depression Research Unit, Connecticut Mental Health Center, New Haven, Connecticut,
06519
that the suspended crystals cannot easily pass through the narrow constriction between the needle bevel and the subcutaneous tissue. The probability of blockage appears to increase if the injection is given slowly but it is not clear what the injection-rate has to be to avoid blockage. Since most insulin syringes used in North America are disposable the problem is not due to inadequate cleaning of reusable needles. It has been reported that spontaneous blockage cannot be induced by storing filled syringes with the needle downward. In view of these findings, the reason for plugging during adjustment of the dosage as reported by Dr O’Mullane and Dr Robinson (July 15, p. 165) is difficult to explain.. Clinical Devices Division, Bureau of Medical Devices, Health and Welfare Canada, Tunney’s Pasture, Ottawa, Canada
PHILIP D. NEUFELD
MYRNA M. WEISSMAN
PHOTODEGRADATION OF DACARBAZINE NEEDLE PLUGGING AND INSULIN
INJECTION
SiR,—Needle plugging during injection of insulin has been reported to us on several occasions and has attracted notice in the United States and, lately, in your correspondence columns. In January, 1976, the U.S. Food and Drug Administration held a meeting with manufacturers, and the July, 1976 issue of Diabetes carried an F.D.A. appeal for information on this problem. Although the exact cause is not well understood, the reports share certain characteristics which suggest a possible mechanism. Most cases occur with crystalline insulin suspensions such as lente or ultralente, and in North America the problem reports seem to have begun with the widespread use of the U-100 (100 units/ml)concentration in 1973. We have simulated this plugging in glass micropipette tubing cemented to a needle hub attached to a 1 ml syringe filled with U-100 lente insulin. The bore of the tubing was roughly 0.38 mm, which corresponds to a 22 or 23 gauge needle, a fairly large size for insulin injection. The end of the tubing was held with moderate pressure against a wad of paper tissue or a. finger tip and the insulin was expressed slowly. Crystals rapidly accumulated at the tip of the tubing and the flow was sometimes blocked before 0-5ml had been ejected (see figure). This suggests that the plugging is caused simply by the fact
SiR,—There is evidence that the anti-tumour drug dacarba-
(D.T.I.C., dimethyltriazeno-imidazole carboxamide) is susceptible to photodegradation in solution’ and, as commonly administered, its breakdown products (including 5-diazoimidazole carboxamide and 2-azohypoxanthine) may be responsible for the troublesome local venous pain and other systemic sideeffects such as nausea, vomiting, and hepatic toxicity. Having regularly seen these side-effects we have lately tried reconstituting and rapidly injecting the drug at a concentration of 100 mg in 10 ml in a room lit by a red photographic lamp only. In a total of fourteen such injections in three patients pain was entirely eliminated or reduced to minor discomfort during the first few seconds. These patients had previously experienced moderate to severe pain along the vein throughout the injection. There also seemed to be less nausea and vomiting. The improved patient acceptability was striking. Evidence that the tumoricidal value of D.T.I.C. is enhanced by preventing photodegradation will be less easy to obtain. zine
Department of Hæmatology, Royal Hospital for Sick Children, Glasgow, G3 8SJ
GILLIAN M. BAIRD M. L. N. WILLOUGHBY
ABUSE OF BENZODIAZEPINES
Simulated needle plugging with U-100 lente insulin.
Upper. crvsta) blockade at end of microptpettc tubing. I.oBvcrr mat;mticaoun shwang plug of msutm crystals.
SIR,-It is worth reinforcing the hazards of prescribing psychotropic drugs to recovered alcoholics. A 42-year-old man was admitted to my alcohol treatment programme this year with a history of an alcohol-related divorce, two to three bottles of whisky per day from early morning onwards, black-outs, amnesias, and so on. He had been an inpatient at another hospital and had gone to Alcoholics Anonymous meetings in the hope of curing his addiction, but without success. His progress was satisfactory and he was discharged at the end of the six-week programme but things soon went badly. He had, before admission, been prescribed various tranquillisers, and he now became addicted to lorazepam, behaving with lorazepam precisely as he had with alcohol: he lied in order to obtain supplies, which he then hid surreptitiously around the house, and he took unknown quantities of the drug: "After the first three or four you don’t know how many you have taken". Calculations suggested that he took at least 80 2.5 mg capsules between 5 P.M. and 10 A.M. the next morning. Withdrawal symptoms of tremor, guilt, and remorse were precisely as they were with alcohol and his erratic behaviour was identicallying and illogical, hazardous conduct (e.g., putting an empty saucepan on the cooker). "You blank out the same as you do with alcohol." 1
Shealy, Y , Krauth,
C. A,
Montgomery, J. A. J.
org. Chem
1962, 27, 2150
682 What is
worrying
is that he found it
so
easy
to
sign
on as
temporary resident with any general practitioner and, in almost every case, to obtain 100 capsules aftera brief interview, and to get 100-capsule repeat prescriptions without seethe doctor. It was, he observed, "Far too easy to con them". The addictive-properties of benzodiazepines may have been underrated and there may well have to be a campaign on their use and restriction-a point underlined by my local underworld contacts telling me that diazepam 10 mg tablets currently sell at no less than L1 each.
ing
macrocytosis, megaloblastic haemopoiesis, and low serum and red cell folate in non-anxmlc treated epileptics,2 that the drugs also play a role in the occasional anxmia. of
University Department of Neurology, Institute of Psychiatry,
E. H. REYNOLDS M. LAUNDY
RICHARD Fox
HÆMATOLOGICAL EFFECTS OF ANTICONVULSANT TREATMENT be surprised at their failure to detect macrocytosis in all but 1 of 96 mentally retarded patients on anticonvulsant therapy. Their findings are apparently at variance with at least nine studies in which macrocytosis was detected, by various techniques, in from 8% to 53% of epileptic patients.2 In the one previous report of the absence of macrocytosis, Jensen and Olesen3also failed to find any fall in red-cell folate, although Rose and Johnson agree with others that this is common. We have also examined mean cell volume (M.c.v.) with the Coulter S counter in 118 outpatient epileptics, all on a combination of phenytoin and primidone and compared the result with those of 18 untreated epileptic patients. All the untreated patients had an mt.c.v. within the normal control range of 80-90 fLm3, whereas 42% of the drug-treated patients had macrocytosis (see figure).2 Our findings accord with those of Eastham et al. who investigated an institutionalised retarded population, similar to that of Rose and Johnson, who do not refer to Eastham’s work. Rose and Johnson provide no details of the M.c.v. data for their patients, nor do they mention any control group. We are unaware of any evidence that "anticonvulsant therapy is often associated with megaloblastic anxmia". Indeed it
SIR,-Rose and Johnson1
3. 4.
may pregnancy. However, we agree with Dr Hawkins (Aug. 5, p. 317) that in many patients nutritional deficiency is not present, and there can be little doubt, in view of the high mcidence
London SE5 9RS
Severalls Hospital, Colchester C04 5HG
1. 2.
appears to be very uncommon, being seen in well under 1% of patients.2 It has long been recognised that additional nutrinonal deficiency may sometimes precipitate the anaemia,25 as
are
right
to
Rose, M. S., Johnson, I. Lancet, 1978, i, 1349.
Reynolds, E. H. in Clinics in Hæmatology vol. v, (edited by A. V. Hoffbrand); p. 661. London, 1976. Jensen, O. N., Olesen, O. V. Archs Neurol. 1969, 21, 208. Eastham, R. D, Jancar, J., Cameron, J. D. Br. J. Psychiat 1975, 126, 263.
MULTISYSTEM TOXICITY AFTER CO-TRIMOXAZOLE
SIR,-A report of fatal multisystem toxicity after co-trimoxazole’ prompts us to report a similar case, though with a hap-
pier outcome. This 84-year-old woman had a history of arthritis, diabetes controlled by diet, hypertension, cholecystectomy (1955), and a reaction to gold therapy. Previous medications included hydrochlorothiazide, chlorthalidone, clonidine (not tolerated), oestrogens, and porassium supplements. A previous urinaryinfection had been treated with co-trimoxazole. In 1974 intravenous pyelography and kidney function were normal (blood-urea-nitrogen 19 mg/dl). On May 19, 1978, she complained of dysuria and her doctor prescribed co-trimoxazole, which she started taking on May 20. She was admitted to hospital May 22 with an erythematous maculopapular eruption over the entire body, weakness, fever, low-back pain, cough, and decreased air entry to her right lower lobe. Other findings included: blood-urea-nitrogen 33 mg/dl, Hb 17.1g/dl, white blood-cells 18 100/µl, bloodsugar 169 mg/dl, and chloride 85, sodium 127, and potassium tract
2.9
mmol/l.
The second day after admission the patient had purpura on her back and under the E.c.G. suction cup sites and perioral pallor with cedema of eyes, neck, uvula, and lips. Other findings included Hb 18.7g/dl, white blood-cells 24 100/µl, tachycardia (115/min), prothrombin-time 54.0 s, and consolidation of right lower lobe on chest X-ray. On the third day the patient’s condition deteriorated, with oliguria (
